WO2004076434A1 - Dipeptidyl peptidase inhibitors - Google Patents

Dipeptidyl peptidase inhibitors Download PDF

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Publication number
WO2004076434A1
WO2004076434A1 PCT/IB2004/000525 IB2004000525W WO2004076434A1 WO 2004076434 A1 WO2004076434 A1 WO 2004076434A1 IB 2004000525 W IB2004000525 W IB 2004000525W WO 2004076434 A1 WO2004076434 A1 WO 2004076434A1
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hef
het
piperidinyl
oxo
butanediamine
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PCT/IB2004/000525
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French (fr)
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Simon Scharpe
Koen Augustyns
Achiel Haemers
Anne-Marie Lambeir
Ingrid De Meester
Kristel Senten
Pieter Van Der Veken
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Aic
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Priority claimed from PCT/IB2003/000792 external-priority patent/WO2004076433A1/en
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Publication of WO2004076434A1 publication Critical patent/WO2004076434A1/en

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Definitions

  • the present invention relates to novel inhibitors of serine type peptidases in general and of serine type dipeptidyl peptidases in particular.
  • the present invention further relates to the use of the dipeptidyl peptidase inhibitors for selective inhibition of serine type peptidases.
  • the present invention also relates to pharmaceutical compositions comprising these novel dipeptidyl peptidase inhibitors.
  • the present invention further relates to the use of the novel inhibitors in therapy, diagnosis and research.
  • Serine type proteases serve an important role in human physiology by mediating the activation of vital functions. In addition to their normal physiological function, serine proteases have been implicated in a number of pathological conditions in humans. Serine proteases are characterized by a catalytic triad consisting of aspartic acid, histidine and serine at the active site.
  • Serine peptidases like granzymes, mast cell tryptase, elastases, trypsin-like enzymes, prolyl oligopeptidase, and serine type dipeptidyl peptidases such as DPPII, DPPIV, QPP, FAP ⁇ , DPP8 and DPP9 are involved in various processes that take place in the body, such as blood coagulation, inflammation, immune response, and control of peptide hormone metabolism in general.
  • DPPs Dipeptidyl peptidases
  • DPP II EC 3.4.14.2
  • DPP IV EC 3.4.14.5
  • Xaa-Pro- or Xaa-Ala- N-terminal dipeptide moieties
  • DPP IV and DPP II share substrate specificity, they can be functionally and biochemically distinguished.
  • Dipeptidyl peptidase IV is a highly specific exopeptidase with a serine type mechanism of peptidase activity, cleaving off dipeptides from the amino-terminus of peptides with proline or alanine at the penultimate position. In addition the slow release of dipeptides of the type X-Gly or X-Ser is reported for some naturally occurring peptides.
  • DPP IV is constitutively expressed on epithelial and endothelial cells of a variely of different tissues, and is also found in body fluids. In the hematopoietic system, DPP IV was identified as the leukocyte antigen CD26.
  • DPP II DPP II, first identified by McDonald at al. (S. J. Biol. Chem., 1968, 243, 4143-4150), is believed to be involved in the physiological breakdown of some proline-containing oligopeptides and neuropeptides and in the degradation of collagen (Andersen ei al. Renal Physiol. Biochem., 1989, 12, 32-40) together with tripeptidyl peptidase and in lysosomal degradation and protein turnover. DPP II is generally localized in lysosomes and is found in a number of mammalian tissues and body fluids..
  • Dipeptidyl peptidase II and quiescent cell proline dipeptidase QPP have recently been suggested to be identical proteases based on sequence comparison of human quiescent cell proline peptidase and rat DPPII. Additional biochemical evidence is provided by Kau, B. et al. (Biochem. J. 2003, 371 , 525-532).
  • the invention also aims to provide novel inhibitors that have a more specific and selective DPP inhibitory activity than currently available inhibitors.
  • the invention provides compounds according to claim 1 , which are able to inhibit the enzymatic activity of serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • Such compounds according to the present invention induce strong inh bition of dipeptidyl peptidase enzyme activity.
  • the present novel dipeptidyl peptidase nhibitors are therefore very suitable for use in all kinds of research, therapeutic and d agnostic applications as described below.
  • the present invention further relates in another aspect to the use of said compounds as a medicament.
  • the invention concerns the use of said compounds in the treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase, or in diagnostic and research methods.
  • the present invention further relates to the use of the compounds in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase and in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
  • the present invention also relates to the use of the compounds in diagnostic and research methods.
  • the present invention also relates to pharmaceutical compositions and kits comprising tie compounds according to the invention.
  • the present invention relates to methods for inhibiting the activity of a serine type dipeptidyl peptidase in vitro, ex vivo and in vivo.
  • the present invention also relates to method for purifying and synthesizing the present compounds.
  • Figure 1 illustrates the synthesis of compounds having formulas IV, IX, XI, XII, XIII, XIV, XV, XVI and XXI as illustrated in example 2, Table B.
  • Figure 2 illustrates the synthesis of compounds having formulas XVIII, XVII, XX as illustrated in example 2, Table B.
  • Figure 3 illustrates the synthesis of compounds having formulas V, VI, VII, VIII, X, XIX as illustrated in example 2, Table B.
  • Figure 4 illustrates the synthesis of compounds having formulas XXII, XXlll, XXIV, XXV,
  • Figure 5 illustrates the synthesis of compounds having formulas XXXV and XXXVI as illustrated in example 2, Table B.
  • Figure 6 illustrates the synthesis of compounds having formulas XXXVll to XXXXI as illustrated in example 2, Table B.
  • Figure 7 illustrates the synthesis of compounds having formulas XXXXI I to XXXXVII as illustrated in example 2, Table B.
  • Figure 8 illustrates the synthesis of compounds having formulas 1-18, 19, 23, 24 and 25- 26 as illustrated in example 6, Table C.
  • Figure 9 illustrates the synthesis of compounds having formulas 20 and 3 as illustrated in example 6, Table C.
  • Figure 10 illustrates the synthesis of compounds having formulas 21 , 22, and 27-36 as illustrated in example 6, Table C.
  • Figure 11 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the relative DPPII activity in plasma in rabbits after intravenous administration.
  • Figure 12 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the relative DPPII activity in plasma in rats after oral administration.
  • Figure 13 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the specific activity of DPPII, DPPIV in several organs in rats.
  • the present invention relates to novel inhibitors of serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • serine type dipeptidyl peptidases or "dipeptidyl peptidases” or “DPP” are used as synonyms and refer to serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FAB ⁇ and QPP.
  • modulator inhibitor
  • compound inhibiting compound
  • modulating compound refers to compounds according to the invention having an modulating activity on DPP, which may mostly comprise inhibiting properties in various degrees going from very inhibiting to weakly inhibiting. Although the compounds will mostly have inhibiting properties, it is also within the scope of the invention that the present compounds may have in some situations enhancing properties.
  • the present invention relates a compound having a modulating activity on a serine type dipeptidyl peptidase, having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, formula I wherein 1 is selected from the group comprising -CH 2 -, oxa, thia and imino, or wherein Ft 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R 3 , R 4 and R 6 are selected from the group comprising hydrogen, oxyalkyl alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl, alkoxycarbonyl alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyi, cycloalkyl cycloalkylalkylalkyl, cyclo
  • alkylaminocarbonylaminoakyl arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxy
  • Het aralkanoyl Het 1 aroyl, Het 1 arylcarbonyl, Het 1 aryloxycarbonyl, Het 1 arylthiocarbonyi
  • Het aralkylaminocarbonylarrinoalkyl Het 1 alkylaminoaryl, Hefarylaminoaryl
  • Het aralkylaminoaryl Het 1 alkanoylaminoaryl, Het 1 aroylaminoaryl
  • Het arylaminocarbonylarrinoaralkyl Het alkylaminocarbonylaminoaralkyl.Het 2 , Het 2 oxy Het 2 alkyl, Het ⁇ oxyalkyl, Hef ⁇ cycloalkyl, He alkoxycarbonyl, Het ⁇ sxycarbonyl Het 2 alkanoyl, He alkyloxyalkyi, Hel ⁇ oxyalkylcarbonyl, Het 2 alkyloxyalkylcarbonyl Het 2 aminocarbonyl, Hefcarbonyloxyalkyl, He alkylcarbonyloxyalkyl, Hef ⁇ ryl Het 2 arylaminoalkoxy, Het 2 arylamino, Het 2 arylaminoalkyl, Hefarylaminoalkylamino Het 2 aryloxy, Hefaryloxyalkoxy, Het 2 aryloxyalkyl, Het 2 aryloxyalkylamino, Hefaralkyl Het 2 a
  • Het 2 aralkylaminoaryl He ⁇ alkanoylaminoaryl, Hef ⁇ roylaminoaryl Het 2 aralkanoylaminoaryl, He alkyloxycarbonylaminoaryl, Hef ⁇ ryloxycarbonylam ' noaryl Het 2 aralkoxycarbonylaminoaryl, Het 2 alkylaminocarbonylarrinoaryl
  • the highly specific and potent inhibitors of serine type dipeptidyl peptidases can advantageously be used to unravel of the physiological functions of the serine type dipeptidyl peptidase enzyme and are also very useful to differentiate between different serine type dipeptidyl peptidases activity in biological systems.
  • alkyl alone or in combination, means straight and branched chained saturated hydrocarbon radicals containing from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms.
  • examples of such radicals include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2- methylbutyl, pentyl, iso-amyl, hexyl, 3-methylpentyl, octyl and the like.
  • cycloalkyl alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or polycyclic alkyl radical wherein each cyclic moiety contains from about 3 to about 8 carbon atoms, more preferably from about 3 to about 7 carbon atoms.
  • monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, and the like.
  • cycloalkylalkyl means an alkyl radical as defined herein, in which at least one hydrogen atom on the alkyl radical is replaced by a cycloalkyl radical as defined herein.
  • examples of such cycloalkylalkyl radicals include cyclopropylmethyi, cyclobutylmethyl, cyclopentylmethyl, cyclohexyl methyl, 1-cyclopentylett ⁇ yl, 1-cyclohexyielhyl, 2- cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl,3-cyclopentylbutyl, cyclohexylbuty! and the like.
  • alkoxy or "alkyloxy”, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, hexanoxy and the like.
  • alkanoyl or "alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
  • alkylamino alone or in combination, means an alkyl amine radical (i.e. RNH-), wherein the term “alkyl” is defined as above.
  • alkylamino radicals include methylamino (NHCH 3 ), ethylamino (NHCH 2 CH 3 ), n-propylamino, isopropylamino, n- butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-hexylamino, and the like.
  • aminoalkyl alone or in combination, means an amine alkyl radical (i.e. NH 2 R-), wherein the term “alkyl” is defined as above.
  • aminoalkanoyl means an acyl group derived from an amino-substituted alkylcarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • aminocarbonyl alone or in combination, means an amino-substituted carbonyl (carbamoyl) group wherein the amino group can be a primary, secondary ortertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • aryl alone or in combination, is meant to include phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, Het 1 , amido, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsultbnyl, and phenyl optionally substituted with one or more substituents selected from C
  • aryl includes phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3- methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3- acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl ⁇ 3- aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl, 2,4-dimethyl-3- aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, 3- amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6 ⁇ dimethoxy-2- naphthyl and the like.
  • halogen as a group or part of a group is generic for fluoro, chloro, bromo or iodo.
  • haloalkyl alone or in combination, means an alkyl radical having the meaning as defined above wherein one or more hydrogens are replacedwith a halogen, preferably, chloro or fluoro atoms, more preferably fluoro atoms.
  • haloalkyl radicals include chloromeihyl, 1-bromoethyl, fluoromethyl, difluoromettiyl, trifluoromethyl, 1 ,1 ,1- trifluoroethyi and the like.
  • Het 1 alone or in combination, is defined as a saturated or partially unsaturated monocyclic, bicyclic or polycyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino
  • Het 2 as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het 1 , Het 1 alkyl
  • arylamino alone or in combination means an aryl amine radical, wherein the term “aryl” is defined as above.
  • aralkyl alone or in combination, means an alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkyl radicals include benzyl, phenethyl, di benzyl methyl, methylphenylmethyl, 3- (2-naphthyl)-butyl, and the like.
  • aralkanoyl means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropfonyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4- methoxyhydrocinnamoyl.and the like.
  • aralkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkoxy radicals include 2- phenyletinoxy, 2-phenyM-propoxy, and the like.
  • aralkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkylamino radicals include 2-phenethylamino, 4-phenyl-n-butylamino, and the like.
  • aroyl means an acyl radical derived from an arylcarboxylic acid, ayl having the meaning given above.
  • arylcarboxylic acid radicals include substituted and unsubstituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4- carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2- naphthoyl, 3-(benzyloxyformamidol-2-naphthoyl, and the like.
  • arylaminoakoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • alkoxy radicals include 2- (phenylamino)-ethoxy, 2- (2- naphthylamino)-1-butoxy, and the like.
  • arylaminoalkyl means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • arylaminoakyl radicals include phenylaminoethyl, 4- (3-methoxyphenylarrino)- 1 -butyl, and the like.
  • arylaminoalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • Examples of (arylamino) alkylamino radicals include 3- (naphthylamino)-propylamino, 4- (phenylamino)-l- butylamino, and the like.
  • aryloxy means a radical of the formula aryl-O-in which the term aryl has the significance given above.
  • aryloxyalkanoyl means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.
  • aryloxyalkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkoxy radicals include 2-phenoxyethoxy, A- (3-aminophenoxy)-1- butoxy, and the like.
  • aryloxyalkyl means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • aryloxyalkyl radicals include phenoxyethyl, 4- (3-aminophenoxy)-l-butyl, and the like.
  • aryloxyalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • alkylamino radicals include 3-phenoxy-npropylamino, 4-ph ⁇ noxybutylamino, and the like.
  • arylthioalkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkoxy radicals include 2- (phenylthio)-ethoxy, and the like.
  • alkylthio means an alkyl thioether radical, wherein the term “alkyl” is defined as above.
  • alkylthio radicals include methylthio (SCH 3 ), ethylthio (SCH 2 CH 3 ), n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio, and the like.
  • aralkoxycarbonyl alone or in combination, means a radical of the formula aralkyl-O-C(O)- in which the term “aralkyl” has the significance given above.
  • aralkoxycarbonyl radical examples are benzyloxycarbonyl and 4- methoxyphenylmethoxycarbonyl.
  • aralkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein.
  • aralkylthio radicals include 3- phenyl-2-propylthio, 2- (2-naphthyl)-ethylthio, and the like.
  • arylaminoalkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein.
  • Examples of (arylamino) alkylthio radicals include 2- (phenylamino)- ethylthio, 3- (2-naphlhylamino)-n-propylthio, and the like.
  • aryloxyalkyithio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein.
  • Examples of (aryloxy) alkylthio radicals include 3-phenoxypropylthio, 4 (2-fluorophenoxy)-butylthio, and the like.
  • arylthioalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkylamino radicals include 2- (phenylthio)- ethylamino, and the like.
  • arylthioalkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein.
  • alkylthio radicals include 2- (naphthylthio)- ethylthio, 3- (phenyllhio)-propylthio, and the like.
  • cycloalkylalkoxycarbonyl means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl hasthe meaning given above.
  • cycloalkylcarbonyl means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino, amido, mono and dialkyl substituted amino, mono and dialkyl substituted amido and the like, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1 ,2,3,4-tetrahydro-2-naphthoyl.
  • He ⁇ alkoxy means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • He alkoxy radicals include 2- pyridylmethoxy, 4- (l-imidazolyl)-butoxy, and the like.
  • Het 2 alkyl means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • Het 2 alkyl radicals include 2- pyridylmethyl, 3- (4-thiazolyl)-propyl, and the like.
  • Hefalkylamino means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • Het 2 alkylamino radicals include 4-pyridylmethylamino, 3 (2-furanyl)-propylamino, and the like.
  • He ⁇ alkylthio means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by a Het 2 as defined herein.
  • Examples of Het 2 alkylthio radicals include 3-pyridylmethylthio, 3 (4-thiazolyl)-propylthio, and the like.
  • Hefamino means Het 2 as defined herein, wherein a hydrogen atom on the Het 2 ring is replaced by a nitrogen.
  • Het 2 amino radicals include, for example, 4- thiazolylamino, 2-pyridylamino, and the like.
  • Het 2 oxy means Het 2 as defined herein, wherein a hydrogen atom on the Het 2 ring is replaced by an oxygen.
  • Het 2 oxy radicals include, for example, 4-pyridyloxy, 5- quinolyloxy, and the like.
  • He oxycarbonyl means an acyl radical derived from a carbonic acid represented by Het 2 -O-COOH wherein Het 2 has the meaning given above.
  • Het 1 alkanoyl is an acyl radical derived from a Het 1 -substituted alkylcarboxylic acid wherein Het 1 has the meaning given above.
  • Het 1 alkoxycarbonyl means an acyl group derived from Het 1 -O-COOH wherein Het 1 is as defined above.
  • oxa refers to the group -O-.
  • thia refers to the group -S-.
  • amino refers to the group -NH-.
  • cyano refers to the group -CN.
  • nitro refers to the group -NO 2 .
  • substituted is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • the term “one or more” covers the possibility of all the available C- atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable, e.g. halogen or alkyl, occurs more than one time in any constituent, each definition is independent.
  • the term "compound(s) of the invention” or a similar term is meant to include the compounds of general formula I or formula II and any subgroup thereof. This term also refers to the compounds as depicted in Table A and B and their N- oxides, salts, stereoisomeric forms, racemic mixtures, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues.
  • the ⁇ /-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • the compounds according to the invention may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the compounds as described herein, are intended to be included within the scope of the present invention.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as purified enantiomers/diasteromers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds per se, as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • pro-drug means the pharmacological ⁇ acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug.
  • the reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated.
  • Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component.
  • pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference.
  • Pro-drugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • the “salts” of the compounds according to the invention are those wherein the counterion is pharmaceulically or physiologically acceptable.
  • the pharmaceutically acceptable salts of the analogues according to the invention i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate aspartate, benzoate, benzenesulfonafe, bisulfate, butyrate, citrate, camphorate camphorsulfonaie, cyclopentanepropiorate, digluconate, dodecylsulfete, ethanesulfonate fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate persulfate, 3-phenylpropbnate, picrate, pivalate, propionate, succinate, tartrate thiocyanate, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylarrine salts, N-methyl-D- glucamine, and salts with amino acids such a sarginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • esters refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred.
  • alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred.
  • other esters such as pheny alkyl may be employed if desired.
  • solvate refers to a complex of variable stoichiometry formed by a solute or a salt or pharmaceutical functional derivative thereof and a solvent.
  • solvents for the purpose of the invention should not interfere with the biological activity of the solute.
  • solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutical acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
  • pharmaceutically functional derivative refers to any pharmaceutical acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation.
  • the compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism. All polymorphic forms (“polymorphs”) are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure, or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics that are known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the invention relates to a compound having the general formula l, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, thia and imino, or wherein R 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyt alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylaminamino,
  • Hefalkyloxyalkylcarbonyl Het 1 aminocarbonyl, Het 1 carbonyloxyalkyl
  • Het 1 aralkylaminoalkyl Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
  • Het 1 alkylaminocarbonylaminoalkyl Het 1 arylaminocarbonyiaminoalkyl
  • Het 1 aralkylaminocarbonylarrinoalkyl Het 1 alkylaminoaryl, Hefarylaminoaryl
  • Het 1 aralkylaminoaryl Hefalkanoylaminoaryl, Het 1 aroylaminoaryl
  • Het 1 aralkanoylaminoaryl Het 1 alkyloxycarbonylaminoaryl, Het 1 aryloxycarbonylarrinoaryl Het 1 aralkoxycarbonylaminoaryl, Het 1 alkylaminocarbonylarrinoaryl
  • Het 2 aralkylaminoalkyl Hefalkanoylaminoalkyl, He ⁇ aroylaminoall Het 2 aralkanoylaminoalkyl, Het 2 alkyloxycarbonylarninoalkyl
  • Het 2 aralkylaminoaryl Hel ⁇ alkanoylaminoaryl, Hef ⁇ roylaminoaryl Het aralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, He ⁇ aryloxycarbonylarrinoaryl Het 2 aralkoxycarbonylaminoaryl, Het 2 alkylaminocarbonylarrinoaryl
  • the invention provides a compound having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, and thia, or wherein R 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyl alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aral
  • Hefaralkanoylaminoalkyl Het 1 alkyloxycarbonyiaminoalkyl
  • Hefaralkylaminocarbonylarrinoalkyl Hefalkylaminoaryl, Hefarylaminoaryl Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
  • Hefaralkanoylaminoaryl Hefalkyloxycarbonylaminoaryl, Hefaryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hefalkylaminocarbonylarrinoaryl
  • Hefalkyloxycarbonylaminoarakyl Hefaryloxycarbonylarrinoaralkyl Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
  • Hefarylaminocarbonylarrinoaralkyl Hefaralkylaminocarbonylaminoaralkyl.Het 2 , Het 2 oxy Het 2 alkyl, Het ⁇ oxyalkyl, He ⁇ cycloalkyl, Hefalkoxycarbonyl, He oxycarbonyl Het 2 alkanoyl, Hefalkyloxyalkyi, Het 2 oxyalkylcarbonyl, Het 2 alkyloxyalkylcarbonyJ Het 2 aminocarbonyl, Hefcarbonyloxyalkyl, He ⁇ alkylcarbonyloxyalkyl, Hefaryl Het 2 arylaminoalkoxy, He arylamino, Het 2 arylaminoalkyl, Hefarylaminoalkylamino Het 2 aryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Het 2 aryloxyalkoxy, Hefaryloxyalkyl, Het 2 aryloxyal
  • Het 2 aralkylaminoalkyl Het ⁇ alkanoylaminoalkyl, Hef ⁇ roylaminoalkyl
  • Het 2 aralkanoylaminoalkyl Het 2 alkyloxycarbonylaminoalkyl Het 2 aryloxycarbonylaminoakyl, Het 2 aralkoxycarbonylaminoalkyl
  • Het 2 aralkanoylaminoaryl He ⁇ alkyloxycarbonylaminoaryl, He ⁇ aryloxycarbonylaminoaryl Het 2 aralkoxycarbonylaminoaryl, Het 2 alkylaminocarbonyIarrinoaryl
  • a compound having the general formula I or pharmaceulically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, and thia or wherein R 1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R 2 is selected from the group comprising hydrogen, methyl and cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl, aryl cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl alkylaminocarbonyl, alkylaminoalkyl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl arylaminoalkyl, arylaminoalkylamino, aryloxyalkylamino, aralkylamino, aryla
  • a compound according to the invention is a compound having the general formula I or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, thia wherein R 2 is selected from the group comprising hydrogen, methyl and cyano, wherein R 3 and R 4 are selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl, amidinoalkyl
  • a compound according to the invention is a compound having the general formula I or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R 1 is selected from the group comprising -CH 2 -, oxa, thia wherein R 2 is selected from the group comprising hydrogen, methyl and cyano, wherein R 3 is hydrogen and R 4 is selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoakyl, amidinoalkyl,
  • the compounds of the invention have general formula II as represented below,
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 have the same meaning as indicated herein, wherein R 4' , R 8 , R 9 , R 10 are selected from the group comprising nitrogen hydrogen, oxyalkyl, alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl alkoxycarbonyl, alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyl cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyl cycloalkylalkoxycarbonyl, cycloalkylalkoxytiiocarbonyl, cycloalkyllhioalkyl alkylcarbonyloxyalkyl, cycloalkylcarbonyl
  • Hefarylaminocarbonylarrinoaralkyl Hefaralkylaminocarbonylaminoaralkyl.Het 2 , Het 2 oxy Het 2 alkyl, Hefoxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl, Het 2 oxycarbonyl Het 2 alkanoyl, Hefalkyloxyalkyl, Het 2 oxyalkylcarbonyl, Het 2 alkyloxyalkylcarbonyl Hefaminocarbonyl, Hefcarbonyloxyalkyl, Hefalkylcarbonyloxyalkyl, Hefaryl Hefarylaminoalkoxy, Hefarylamino, Hefarylaminoalkyl, Hefarylaminoalkylamino Hefaryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkoxy, Hefaryloxy
  • Hefarylalkylthiocarbonyl Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl
  • Hefaralkylaminoalkyl Hefalkanoylaminoalkyl, Hefaroylam noalkyl
  • Hefaralkylaminoaryl Hefalkanoylaminoaryl, Hefaroylaminoaryl Hefaralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl
  • Hefalkylaminoaralkyl He arylaminoarakyl, Hefaralkylaminoaralkyl Hefalkanoylaminoaralkyl, Het 2 aroylaminoaralkyl, Hefaralkanoylaminoaralkyl
  • substituents independently selected from the group comprising hydrogen, amino, hydroxy,
  • a compound is provided being N 1 -benzyl-4-oxo-4-(1- piperidinyl 1 ,3(S)-butanediamine as indicated with formula IV according to the specification given below.
  • This particular compound corresponding to formula IV as represented below is also referred to as KS IV.7.
  • the potency of the compounds to inhibit serine type dipeptidyl peptidases accordingto the present invention are expressed as IC 50 value.
  • the "IC 50 value” is defined as the concentration of a compound, which causes the enzyme activity to decrease with 50 % under assay conditions.
  • a compound selected from the group comprising N 1 -benzyl-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1 -piperidinyl)- 1 ,3(R)-butanediarnine, A-(A- morpholinyl)-4 -oxo-1 ,3(S)-butanediamine, 4-oxo-4-(1-piperazinyl)-1 ,3(S)-butanediamine, benzyl 3-amino-1(S)-(1-piperidinylearbonyl)propyJcarbamate, benzyl 3-atnino-4-o ⁇ o-4- (1 piperidinyl)butyicarbamate, N 1 -benzyl-2(S)-(1-piperidinylcarbonyl>
  • a compound is provided selected from the group comprising /V-(2-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -(3- chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -(4-chlorobenzyl)-4-oxo-4- (1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -[2-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)- 1 ,3(S)-butanediamine, ⁇ / 1 -[4-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, ⁇ / 1 -[4-(benzyloxy)benzy
  • the compounds according to the present invention all preferably inhibit DPP activity, exhibiting relatively high activity at relatively low concentrations, as indicated by low IC 50 values.
  • the IC 50 values of the compounds according to the present invention are lower than 100 ⁇ M, more preferred lower than 10 ⁇ M, even more preferred lower than 0.1 ⁇ M.
  • some of the presented compounds are very useful to differentiate between DPP II and DPP IV activity in biological systems, since some of these compounds are highly specific and selective for DPPII inhibitory activity than currently available inhibitors.
  • DPP II and DPP IV both preferentially release N- terminal dipeptide moieties (Xaa-Pro- or Xaa-Ala-) from some oligopeptides or proteins.
  • DPP IV and DPP II share substrate specificity, and differentiating between these acitivites is generally a challenging and difficult task.
  • the compound KS IV.7 as defined above is a particularly active and selective DPPII inhibitor.
  • This compound has an IC 50 value of 0.00203 ⁇ M for DPPII.
  • the IC 50 value of this compound towards DPP IV comprises 247 ⁇ M.
  • This compound thus has a particularly high selectivity of for DPPII, and is particularly suitable for in applications wherein a differentiation is required between DPP II and DPP IV activity.
  • the invention thus relates to compounds for use as a medicament.
  • the compounds according to the present invention can be used in the treatment of pathological states associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
  • said compounds according to the invention can be used in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPIV.
  • said compounds according to the invention can be used in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPII.
  • the invention also relates to the use of the compounds according to the invention in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for inhibiting the activity of DPPIV.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for inhibiting the activity of DPPII.
  • the invention also relates to the use of the compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPIV.
  • the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPII.
  • Such medicaments are then specifically intended for treatment and prophylaxis of the conditions listed below.
  • the compounds of the present invention are believed useful for the treatment of a variety of metabolic, neuroendocrine, gastrointestinal, viral, and inflammatory diseases, including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, (auto)immune disorders such as encephalomyelitis, complement mediated disorders such as glomerulonepritis, lipodyslrophy, and tissue damage, psychosomatic, depressive, and neuropsychiairic disease such as anxiety, depress on, insomnia, schizophrenia, epilepsy, spasm, and chronic pain, HIV infection, allerg es, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart fa lure, tumors, and stress-induced abortions.
  • metabolic, neuroendocrine, gastrointestinal, viral, and inflammatory diseases including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, (auto)imm
  • the invention also relates to the diagnostic use of the compounds.
  • the compounds according to the present invention can be used in diagnostic and research methods such as fluorescence, purification and radio-assays, imaging, in situ histochemical and cytochemical staining.
  • the present invention relates to the use of a compound according to the invention in purification procedures of serine type peptidases and preferably of dipeptidyl peptidases.
  • the said compounds can be immobilized to a suitable matrix or used as a competitor to elute bound enzyme from a matrix containing an immobilized compound.
  • the present invention also includes compounds, which have been modified without abolishing the reactivity with the active site.
  • modifications are the incorporation of radioactive labels such as Iodine 125 , or non-radioactive labels such as biotin or a fluorophore.
  • the incorporation of a (radioactive) label is useful in diagnostic methods using the modulating compounds.
  • Labelled compounds can be used essentially in the same type of appli cations as labelled monoclonal antibodies, e.g. fluorescence and radioassays, cytofluorimetry, fluorenscence activated cell sorting, etc ... The principles of such techniques are well known to the person skilled in the art.
  • DPP inhibitors described above which form complexes with dipeptidyl peptidases are therefore suitable for diagnostic applications such as imaging and histochemical staining of DPP.
  • Formulations of the compounds to be used in diagnostic applications are also part of this invention.
  • DPP activities can interfere with certain assays by cleaving the substrate used in the test and thereby giving either false positive (when a chromogenic substrate is cleaved) orfalse negative results (when a peptide is degraded).
  • the inhibitors of this invention can be used to inactivate a contaminating DPP activity before carrying on with the analysis.
  • DPP target protease
  • the label can be fluorescent for fluorescence microscopy, radioactive for autoradiography, or electron dense for electron microscopy.
  • the target structures can be whole cells, cells fixed onto slides or sections through solid tissue.
  • a useful modification of these techniques is to use an indirect (“sandwich") assay employing the specific high affinity interaction between biotin and avidin (reviewed in Methods in Enzymology, vol. 184, 1990).
  • inhibitors labeled with a suitable isotope e.g. I 125 or I 131
  • a suitable isotope e.g. I 125 or I 131
  • the compounds of the invention which form a stable adduct with DPP may be used as a tool for diagnosing of the above cited disease states.
  • compositions prepared for storage and subsequent administration which have a therapeutically effective amount of one or more compounds of the invention and a pharmaceutically acceptable excipient, carrier or diluent.
  • Such pharmaceutical preparations are intended for the treatment and prophylaxis of the above conditions.
  • terapéuticaally effective amount means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • Preservatives, stabilizers, dyes and flavoring agents may be provided in the pharmaceutical compositions.
  • Preservatives, stabilizers, dyes and flavoring agents may be provided in the pharmaceutical compositions.
  • sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • compositions of this invention may be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions or suspensions for injectable administration; aerosols; unguents for topical administration.
  • absorption enhancing preparations e.g. liposomes
  • the amount of the active substances(s) in a dosage unit may vary between 0.01 mg and 1 g.
  • Formulations of the present invention include those especially formulated for oral, buccal, parental, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • oral administration typically is preferred.
  • tablets, capsules, and caplets may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, and/or wetting agents.
  • binding agents include syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, or polyvinylpyrrolidone (PVP).
  • fillers include, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol.
  • lubricants include, for example, magnesium sterate, stearic acid, talc, polyethylene glycol or silica.
  • disintegrants include, for example, potato starch or sodium starch glycollate.
  • a non-limiting example of a wetting agent includes sodium lauryl sulfate.
  • the tablets additionally may be coated according to methods known in the art.
  • the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs.
  • formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Liquid preparations may contain conventional additives.
  • Non-limiting examples of such additives include suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum sterate gel or hydrogenated edible fats.
  • emulsifying agents such as lecithin, sorbitan mono-oleate or acacia
  • non-aqueous vehicles which may include edible oils
  • preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid, may be incorporated into the preparation.
  • Such preparations may also be formulated as suppositories, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
  • formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
  • the formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation, for example, subcutaneously or intramuscularly, or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials, such as an emulsion in an acceptable oil, ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt.
  • the compounds of the present invention may be used in combination with one or more other therapeutic or diagnostic agents in the treatment, prevention, suppression, amelioration, or diagnosing of diseases or conditions for which compounds of the invention or the other agents may have utility, where the combination of the drugs together are safer or more effective than either agent alone.
  • Such other agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition in unit dosage form containing such other agents and the compound of the invention is preferred.
  • the combination therapy may also include therapies in which the compound of the invention, and one or more other agents are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • Examples of other active ingredients that may be administered in combination with a compound of the present invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to other dipeptidyl peptidase inhibitors.
  • certain compounds of the invention can be combined with each other such that synergetic inhibiting effects are obtained.
  • combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other agents that are used in the treatment/prevention/suppression or amelioration of diseases or conditions for which compounds of the present invention are useful.
  • the weight ratio of a compound of the present invention to a second active ingredent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication.
  • the pharmaceutical compositions of this invention can be administered to humans in dosage ranges specific for each compound comprised in said compositions.
  • the dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain certain amounts of a compound of the present invention depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Examples of such amounts include the formulation containing about 0.1 to about 99.9% active ingredient.
  • Preferred unit dosage formulations are those containing a predetermined dose, such as a daily dose, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • the invention in another embodiment, relates to a method of treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention.
  • a pharmaceutical composition according to the invention.
  • the term "individual,” as used herein refers to an animal, preferably a mammal, and most preferably a human, who has been the object of treatment, observation or experiment
  • said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment.
  • the present invention relates to a method for inhibiting the activity of a serine type dipeptidyl peptidase by administering a compound according to the present invention.
  • the present invention relates to a method for in vitro inhibition of the activity of a serine type dipeptidyl peptidase by means of administering a suitable concentration of a compound of the invention.
  • Such method is in particular useful when a DPP enzyme inactivates a peptide prior to measurement thereof in a peptide assay.
  • the compounds of the invention can be used to inhibit the degradation of the peptide substrate by the enzyme in such assay.
  • the compounds of the invention are also useful in a method for ex vivo inhibition of the activity of a serine type dipeptidyl peptidase, such as the treatment outside the body of cells and organs for transplantation in order to avoid rejection thereof by the recipient body.
  • the method comprises administering a suitable concentration of a compound according to the invention.
  • the compounds of the invention can be used in a method for in vivo inhibiting of the activity of a serine type dipeptidyl peptidase by means of administering to a living organism a suitable amount of a compound of the invention.
  • the present invention relates to kits comprising a compound according to the invention.
  • the invention further provides for assay kits for assaying the inhibition of the activity of a serine type dipeptidyl peptidase comprising a compound according to the invention and means to detect said inhibition.
  • Example 1 Non-limiting examples of compounds according to the invention
  • Non-limiting examples of compounds according to the invention and having general formula II are listed in Table A, wherein reference is made to R 1 , R 2 , R 3 , R 4' , R 5 , R 6 , R 7 , R 8 ,
  • Example 2 Specific examples of compounds ac ⁇ rding to the invention
  • the present example illustrates some specific examples of compounds according to the invention (Table B). Also indicated are the IC 50 values of the indicated compounds for DPPII and DPPIV.
  • the compounds according to the invention strongly inhibit DPPII activity, as indicated by the low IC 50 values of the illustrated compounds for DPPII.
  • most of the compounds in the following examples have an activity in inhibiting DPPII generally lower than 100 ⁇ M and in some cases lower than 10 ⁇ M and even lower than 1 ⁇ M. Such results are indicative of the intrinsic activity of the compounds in use as inhibitors of DPPII enzyme activity.
  • the compound with formula IV is a particularly active and selective DPPII inhibitor.
  • This compound has an IC 50 value of 0.00203 ⁇ M for DPPII.
  • the IC 50 value of this compound towards DPP IV comprises 247 ⁇ M.
  • This compound thus has a particularly high selectivity of for DPPII, and is particularly suitable for in applications wherein a differentiation is required between DPP II and DPP IV activity.
  • the present compounds may be active, i.e. have a strong inhibitory activity on DPP II.
  • the present compounds as claimed in claim 1 may show a high selectivity for DPPII.
  • the presented compounds are very useful to be applied in all kinds of research, therapeutic and diagnostic applications for inhibiting the activity of a serine type dipeptidyl peptidase.
  • the present example illustrates the synthesis of compounds as illustrated in Table B of example 2, according to different synthesis schemes.
  • Procedure E Deprotection of the benzyloxycarbonyl (Z) group was done by hydrogenolysis: to a mixture of compound obtained from previous step in methanol (50 ml) was added Pd/C (20%) and acetic acid (1 ml). A flow of nitrogen-gass was carried over the solution for 10 minutes, followed by a flow of H 2 -gas. The reaction was monitored by TLC. After completion, again a flow of nitrogen was carried over the solution for 10 minutes. The mixture was filtered over a celite and the methanol was removed in vacuo. The compound obtained was used as such in the next step.
  • N-Boc protected title compound was obtained by submitting N-Boc-N- cyclohexylglycine b procedure A (81%)
  • the title compound was obtained by sequentially applying procedures H, N, O, A and B to benzylamine.
  • the title compound was obtained by sequentially applying procedures M and B to N-Boc- ⁇ /-benzyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
  • the title compound was obtained by sequentially applying procedures M and B to /V-Boc- ⁇ /-piperonyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
  • Example 4 Use of a compound of the invention as affinity ligand during the purifica ⁇ on of DPPII
  • This example illustrates the use of a compound (formula XXII) according to the present invention as affinity ligand during the purification of DPPII.
  • NHS-activated Sepharose 4 fast flow gel (Amersham) was used as matrix.
  • An appropriate amount of the gel was washed on a sintered glass filter with 1 mM HCI.
  • An excess of Lys- Pip (formula XXII) was solubilized in isopropanol (1 column volume) and allowed to react with the matrix during 24 h at room temperature in an end over end mixer. Afterwards the gel was washed with an excess isopropanol, followed by water.
  • the low pH buffer consisted of 100 mM acetate pH 4.0 containing 500 mM NaCI.
  • the high pH buffer consisted of 50 mM Tris base with 500 mM NaCI.
  • the Lys-Pip affinity matrix was stored in 100 mM cacodylate at 4-8°C.
  • a biological sample containing DPPII was applied onto the Lys-Pip affinity matrix in Na- acetate buffer, 50 mM pH 5.5. Unbound protein was removed by washing with 100 mM cacodylate pH 5.5. Elution was performed with 100 mM cacodylate pH 5.5 containing 500 mM NaCI.
  • the present example is a further illustration of the present invention.
  • the invention relates to the development of highly specific and potent inhibitors of DPP II, which will contribute to the unravelling of the physiological fundions of this enzyme and will be helpfull to differentiate between DPP II and DPP IV in biological systems.
  • the resembling substrate specificity and catalytic mechanism can complicate this challenging task.
  • DPPs Dipeptidyl peptidases
  • DPP II is generally localized in lysosomes and is found in a number of mammalian tissues and body fluids. Recently it is reported to be identical to human quiescent cell proline dipeptidase (QPP), based on the significant sequence homology (79.4%) found between human QPP and rat DPP II (Araki et al. J.
  • DPP IV has been studied extensively over the last three decades and a broad array of diverse functional properties in the immune, nerve and endocrine system is suggested Augustyns et al. Curr. Med. Chem., 1999, 6, 311-327; Villhaueret al. Annual Reports in Medicinal Chemistry, Academic Press, 2001 , Vol 36, pp 191-200).
  • DPP IV is bound to the cell membrane and expressed quite ubiquitously in mammalian tissues. In the hematopoietic system it was identified as the leukocyte antigen CD26. Inhibition of DPP IV can be valuable in the treatment of type 2 diabetes and some important DPP IV inhibitors are currently under evaluation in this field (Villhaueret al.
  • DPP IV inhibitors resemble often the dipeptide cleavage product with a proline mimic at the Pi-site.
  • Amino acyl pyrrolidides (1) and thiazolidides (2) are known as potent, competitive inhibitors of DPP IV ( see below). Substituting the pyrrolidine ring with 6- or 7-membered rings or acyclic amines results in loss of potency (Auguslyns et al. Eur. J. Med. Chem., 1997, 32, 301-309).
  • Cha cyclohexylalanine
  • IC 50 3 ⁇ M
  • the expected increase of DPP IV inhibition that occurs in general with the replacement of pyrrolidine by thiazolidine is notseen for this compound.
  • Replacing the pyrrolidine ring by piperidine in 8.3 and 8.4 we can observe a 2 to 6-fold improvement of the DPP II inhibition.
  • this introduction of a 6-membered ring gives a serious decrease in potency for DPP IV inhibitors.
  • Lys-Pip (8.4) came out as the most potent DPP ll-inhibitor in this series exhibiting an IC 50 of 1.6 ⁇ M. This compound is also the most selective towards DPP IV with a selectivity index of 156.
  • b Cha cyclohexylalanine
  • c Dab 2,4-diaminobutyric acid
  • d Dap 2,3-diaminopropionic acid
  • Abu 2-aminobutyric acid
  • f Nva norvaline
  • b Dab 2,4-diaminobutyric acid
  • c Cha cyclohexylalanine
  • Selectivity is also declined although a selectivity index of more than 4000 can still be considered high.
  • b Cha cyclohexylalanine
  • Dab 2,4-diaminobutyric acid
  • Dab-Pip (10.7) As the most potent and selective inhibitor, some analogues were prepared by replacing the piperidine ring with respectively morfoline (12) and piperazine (13) (Table 8).
  • Aminoacylpyrrolidide-2-nitriles are slow-binding, reversible inhibitors of DPP IV with approximately a 1000-fold increase in potency compared to the parent amino acyl pyrrolidides (low nM Kj) and a more than 500-fold selectivity against DPP II (Li et al. Arch. Biochem. Biophys., 1995, 323, 1 , 148-154).
  • DPP II Low nM Kj
  • the formulas for synthesised dipeptide nitriles (14, 15, 16) are provided below.
  • the selectivity could be reversed by replacing the pyrrolidine ring with piperidine.
  • Lys-Pip-2-CN (16.1) only slightly affect the DPP II inhibition while inhibitory activity of DPP IV declined with a factor 160.
  • Compound 16.1 is therefore a more selective DPP II inhibitor compared to the cyanopyrrolidide analogue (15).
  • Lys-Pip (8.4) no improvement in DPP II inhibitory potency is observed and is toweried by a 4-fold decrease in selectivity. It must be noticed that for this compound a mixture of diastereomers was tested: the inactive L-Lys-Pip-2(R)-CN and biological active -Lys-Pip- 2(S)-CN isomer.
  • b The compound tested was -Lys-Pip-2(R,S)-CN.
  • Reverse phase HPLC was run on a Gilson instrument (Viliers-le-bel, France) equipped with an Ultrasphere ODS column (4.6 x 250 mm, 5 ⁇ m, Beckman, Fullerton, CA, USA) and a uv-detector (10-100% ACN, 35 min, 214 nm, 1 ml/min).
  • Preparative TLC was performed on Silicagel 60PF 254 containing gypsum.
  • DPP IV was purified from human seminal plasma as described previously (De Meester et al. J. Immunol. Methods 1996, 189, 99 105).
  • DPP II was isolated from the same source using techniques described previously for purification of the enzyme from porcine seminal plasma (Huang et al. Biochim. Biophys. Acta 1996, 1290, 149 156), supplemented with adenosine deaminase affinity chromatography to eliminate contaminating DPP IV(De Meester et al. J. Immunol. Methods 1996, 189, 99 105).
  • Enzyme activity was measured kinetically with the chromogenic substrates Gly-Pro-p-nitroanilide at pH 8.3 and Lys-Ala-p- nitroanilide at pH 5.5 for DPP IV and DPP II respectively.
  • Test compounds were dissolved and diluted in DMSO (final concentration DMSO during assay 5% v/v). Highest concentration of compounds tested is 1 mM.
  • IC 50 value was defined as the inhibitor concentration, which caused a 50% decrease of the activity under assay conditions.
  • the protected amino acids amides (respectively 2 and 10) were prepared by parallel synthesis using the PASP-protocol. Thioxylation of these compounds was performed according to the following procedure: To a solution of the Boc-protected amino acid amides (2 eq) in 5 ml of toluene was added 2,4-bis(p-methoxyphenyl)-1 ,3- dithiadiphosphatane 2,4-disulfide (Lawesson's reagent) (1 eq). The reaction mixture was stirred for 2 h at 80°C. The solvent was removed by evaporation and the crude compound was purified by preparative TLC (EtOAc/hexane, 40:60). Pure compounds were deprotected according to the general procedure. Lys ⁇ fCS-NJ-Thia (4.1).
  • 3-Substituted pyrrolidide analogues were synthesised from 1-rN-(tert-butyloxycarbonyl)-L- lysyll-3(R,S)-hydroxy-pyrrolidine.
  • Example 6 specific examples of compounds according to the invention
  • Table C illustrates some specific examples of compounds according to the invention (Table C). Also indicated are the IC 50 values of the indicated compounds for DPPII and DPPIV.
  • the compounds of formula 1 to 36 specifically relates to the structures as illustrated in Table C and are distinct and different from the compounds described in example 5, and are not to be confused therewith. Table C
  • the compounds according to the invention strongly inhibit DPPII activity, as indicated by the low IC 50 values of the illustrated compounds for DPPII, and are active in the nanomolar range.
  • the present invention encompasses all the compounds as described in Tables A, B and C.
  • Example 7 Synthesis of the compounds according to the invention The present example illustrates the synthesis of compounds as illustrated in Table C of example 6, according to different synthesis schemes illustrated in Figures 8, 9 and 10.
  • the procedures A to M described in this example and in Figures 8 to 10 for the synthesis of compounds listed in Table C are distinct and different from the procedures described in example 3, and are not to be confused therewith.
  • LC-MS were recorded on an Agilent 1100 Series HPLC system using a Discovery Cyano column (2.1 x 50 mm, 5 ⁇ m, Supelco, Sigma-Aldrich) coupled with a Bruker Esquire 3000 plus mass spectrometer (0-80% ACN, 22 min, 0.2 ml/min).
  • Reversed phase HPLC was run on a Gilson instrument (Viliers-le-bel, France) equipped with an Ultrasphere ODS column (4.6 x 250 mm, 5 ⁇ m, Beckman, Fullerton, CA, USA) and a uv-detection (10-100% ACN, 35 min, 214 nm, 1 ml/min).
  • Serum levels of DPPII were measured using the chromogenic substrate Lys-Ala-p- nitroanilide at pH 5.5 in an assay with a final % dilution of the serum.
  • the DPP II activity in tissues was determined after homogenizing parts of the organs using n-octylglycoside as a detergent using the same substrate and buffer. Final dilution of extract in the assay was 1/20.
  • Tissue DPPIV activity was measured using Gly-Pro-p-nitroanilide as the substrate in Tris-HCI buffer pH 8.3.
  • Figure 11 shows the influence of intravenous administration of Compound 3 on the DPPII activity in serum of rabbits. Blood samples were taken at different timepoints after the injection of compound or vehicle (control animal). The 3 panels show 3 separate experiments in the same animals. The relative activity of serum DPPPII is given with the pretest value of each animal considered as 100
  • Figure 12 gives the influence of oral administration (gavage) of Compound 3 on the DPPII activity in serum of rats. After the administration of compound or vehicle (control animals) blood samples were taken from the tail at the timepoints indicated. In a first experiment (upper panel), the same dose was given to the 2 experimental animals. Very comparable and significant inhibition of serum DPPII activity was seen 1 hour after oral administration of compound. In a second experiment (lower panel), 2 different doses were compared. From this preliminar experiment a dose-dependency of the effect is expected.
  • Figure 13 details the influence of compound 3 on the specific activity of DPPII and DPPIV in several organs. Euthanasia of the animals was carried out 2 hours after compound administration. The measurements were carried out in a final dilution of 1/20 so the results underestimate the in vivo inhibition level obtained after oral administration of compound 3.
  • the upper panel depicts the DPPII specific activity and the lower panel represents the DPPIV activity. The preliminar results predict a dose dependent inhibition of DPPII but not DPPIV in the peripheral organsof the rat.

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Abstract

The present invention relates to novel inhibitors of serine type peptidases in general and of serine type dipeptidyl peptidases in particular. The present invention further relates to the use of the dipeptidyl peptidase inhibitors for selective inhibition of dipeptidyl peptidases. The present invention also relates to pharmaceutical compositions comprising these novel dipeptidyl peptidase inhibitors. The present invention further relates to the use of the novel inhibitors in therapy, diagnosis and research.

Description

Dipeptidyl peptidase inhibitors
Field of the invention
The present invention relates to novel inhibitors of serine type peptidases in general and of serine type dipeptidyl peptidases in particular. The present invention further relates to the use of the dipeptidyl peptidase inhibitors for selective inhibition of serine type peptidases. The present invention also relates to pharmaceutical compositions comprising these novel dipeptidyl peptidase inhibitors. The present invention further relates to the use of the novel inhibitors in therapy, diagnosis and research.
Background of the invention
Serine type proteases serve an important role in human physiology by mediating the activation of vital functions. In addition to their normal physiological function, serine proteases have been implicated in a number of pathological conditions in humans. Serine proteases are characterized by a catalytic triad consisting of aspartic acid, histidine and serine at the active site.
Serine peptidases like granzymes, mast cell tryptase, elastases, trypsin-like enzymes, prolyl oligopeptidase, and serine type dipeptidyl peptidases such as DPPII, DPPIV, QPP, FAPα, DPP8 and DPP9 are involved in various processes that take place in the body, such as blood coagulation, inflammation, immune response, and control of peptide hormone metabolism in general.
Dipeptidyl peptidases (DPPs, EC 3.4.14) have been identified in various mammalian tissues and catalyze the sequential release of dipeptides from peptides. Among these enzymes, DPP II (EC 3.4.14.2) and DPP IV (EC 3.4.14.5) preferentially release N-terminal dipeptide moieties (Xaa-Pro- or Xaa-Ala-) from some oligopeptides or proteins. Although DPP IV and DPP II share substrate specificity, they can be functionally and biochemically distinguished.
Dipeptidyl peptidase IV is a highly specific exopeptidase with a serine type mechanism of peptidase activity, cleaving off dipeptides from the amino-terminus of peptides with proline or alanine at the penultimate position. In addition the slow release of dipeptides of the type X-Gly or X-Ser is reported for some naturally occurring peptides. DPP IV is constitutively expressed on epithelial and endothelial cells of a variely of different tissues, and is also found in body fluids. In the hematopoietic system, DPP IV was identified as the leukocyte antigen CD26.
DPP II, first identified by McDonald at al. (S. J. Biol. Chem., 1968, 243, 4143-4150), is believed to be involved in the physiological breakdown of some proline-containing oligopeptides and neuropeptides and in the degradation of collagen (Andersen ei al. Renal Physiol. Biochem., 1989, 12, 32-40) together with tripeptidyl peptidase and in lysosomal degradation and protein turnover. DPP II is generally localized in lysosomes and is found in a number of mammalian tissues and body fluids.. The order of expression of DPP-II is kidney > > testis > or = heart > brain > or = lung > spleen > skeletal muscle > or = liver (Araki H et al., J Biochem (Tokyo) 2001, 129:27988).
Dipeptidyl peptidase II and quiescent cell proline dipeptidase QPP have recently been suggested to be identical proteases based on sequence comparison of human quiescent cell proline peptidase and rat DPPII. Additional biochemical evidence is provided by Leitung, B. et al. (Biochem. J. 2003, 371 , 525-532).
It is a general object of the present invention to provide novel serine type peptidase inhibitors in general and dipeptidyl peptidase inhibitors in particular, with recognized utility and exhibiting relatively high activity at relatively low concentrations, which can be exploited in medical applications. The invention also aims to provide novel inhibitors that have a more specific and selective DPP inhibitory activity than currently available inhibitors. These and other objects and advantages of the present invention will be recognized by those skilled in the art from the following description and illustrative examples.
Summary
According to a first aspect, the invention provides compounds according to claim 1 , which are able to inhibit the enzymatic activity of serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FABα and QPP. Such compounds according to the present invention induce strong inh bition of dipeptidyl peptidase enzyme activity. The present novel dipeptidyl peptidase nhibitors are therefore very suitable for use in all kinds of research, therapeutic and d agnostic applications as described below.
The present invention further relates in another aspect to the use of said compounds as a medicament. In addition, the invention concerns the use of said compounds in the treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase, or in diagnostic and research methods. The present invention further relates to the use of the compounds in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase and in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase. The present invention also relates to the use of the compounds in diagnostic and research methods.
In addition, the present invention also relates to pharmaceutical compositions and kits comprising tie compounds according to the invention.
In a further aspect, the present invention relates to methods for inhibiting the activity of a serine type dipeptidyl peptidase in vitro, ex vivo and in vivo.
The present invention also relates to method for purifying and synthesizing the present compounds.
Detailed description of the figures
Figure 1 illustrates the synthesis of compounds having formulas IV, IX, XI, XII, XIII, XIV, XV, XVI and XXI as illustrated in example 2, Table B.
Figure 2 illustrates the synthesis of compounds having formulas XVIII, XVII, XX as illustrated in example 2, Table B.
Figure 3 illustrates the synthesis of compounds having formulas V, VI, VII, VIII, X, XIX as illustrated in example 2, Table B. Figure 4 illustrates the synthesis of compounds having formulas XXII, XXlll, XXIV, XXV,
XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV as illustrated in example 2,
Table B.
Figure 5 illustrates the synthesis of compounds having formulas XXXV and XXXVI as illustrated in example 2, Table B. Figure 6 illustrates the synthesis of compounds having formulas XXXVll to XXXXI as illustrated in example 2, Table B.
Figure 7 illustrates the synthesis of compounds having formulas XXXXI I to XXXXVII as illustrated in example 2, Table B.
Figure 8 illustrates the synthesis of compounds having formulas 1-18, 19, 23, 24 and 25- 26 as illustrated in example 6, Table C. Figure 9 illustrates the synthesis of compounds having formulas 20 and 3 as illustrated in example 6, Table C.
Figure 10 illustrates the synthesis of compounds having formulas 21 , 22, and 27-36 as illustrated in example 6, Table C. Figure 11 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the relative DPPII activity in plasma in rabbits after intravenous administration.
Figure 12 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the relative DPPII activity in plasma in rats after oral administration.
Figure 13 represents bar diagrams showing the effect of N1-(4-chlorobenzyl)-4-oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine (compound 3) on the specific activity of DPPII, DPPIV in several organs in rats.
Detailed description of the 'invention
The present invention relates to novel inhibitors of serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FABα and QPP.
As used herein the terms "serine type dipeptidyl peptidase" or "dipeptidyl peptidases" or "DPP" are used as synonyms and refer to serine type dipeptidyl peptidases such as DPPII, DPPIV, DPP8, DPP9, FABα and QPP.
In this application the terms "modulator", "inhibitor", "compound" and "modulating compound" are used interchangeably. These terms as used herein refer to compounds according to the invention having an modulating activity on DPP, which may mostly comprise inhibiting properties in various degrees going from very inhibiting to weakly inhibiting. Although the compounds will mostly have inhibiting properties, it is also within the scope of the invention that the present compounds may have in some situations enhancing properties.
In a first embodiment, the present invention relates a compound having a modulating activity on a serine type dipeptidyl peptidase, having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof,
Figure imgf000007_0001
formula I wherein 1 is selected from the group comprising -CH2-, oxa, thia and imino, or wherein Ft1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R3, R4 and R6 are selected from the group comprising hydrogen, oxyalkyl alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl, alkoxycarbonyl alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyi, cycloalkyl cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbony cycloalkylalkoxycarbonyl, cycloalkylalkoxy iiocarbonyl, cycloalkylthioalkyl alkylcarbonyloxyalkyl, cycloalkylcaibonyloxyalkyl, alkylaminocarbonyl, alkylaminoalkyl aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyt aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl. alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylarrinoaralkyl aralkoxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl arylaminocarbonylaminoaralkyl, aralkylaminocarbonylam'noaralkyl, carboxyl piperazinyl piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl amidinoalkyl, Het1, Hefoxy, Het1alkyl, Het1 oxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl Het1oxycarbonyl, Het1alkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyi
Het1alkyloxyalkyicarbonyl, Het1aminocarbonyl, Hefcarbonyloxyalkyi
Hefalkylcarbonyloxyalkyl, Het1aryl, Het1arylaminoalkoxy, Het1arylamino Het arylaminoalkyl, Het arylaminoalkylamino, Het1aryloxy, Het1aryloxyalkoxy
Het aryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl, Hefaralkoxy, Het1aralkylamino
Het aralkanoyl, Het1aroyl, Het1 arylcarbonyl, Het1aryloxycarbonyl, Het1 arylthiocarbonyi
Het aralkoxycarbonyl, Hefarylalkylthiocarbonyl, Het1 aryloxyalkyl, Het1arylthioalkyl
He haloalkyl, Het1aryloxycarbonylalkyl, Het1aryloxyalkanoyl, Het1aralkylcarbonyloxyalkyi
Het arylaminocarbonyl, Hefaralkylaminocarbonyl, Hβt1alkylam noaikyl
Het' aralkylaminoalkyl, Het1alkanoylaminoalkyl, Het1aroylam noalkyl
Het aralkanoylaminoalkyl, Hefalkyloxycarbonylam noaikyl
Het aryloxycarbonylaminoakyl, Hefaralkoxycarbonyiam noalkyl
Het alkylaminocarbonylaminoalkyl, Herarylaminocarbonyiam noaikyl
Het aralkylaminocarbonylarrinoalkyl, Het1alkylaminoaryl, Hefarylaminoaryl
Het aralkylaminoaryl, Het1alkanoylaminoaryl, Het1aroylaminoaryl
Het aralkanoylaminoaryl, Het1alkyloxycarbonylaminoaryl, Het1aryloxycarbonylam'noaryl
Het aralkoxycarbonylaminoaryl, Het1alkylaminocarbonylarrinoaryl
Het arylaminocarbonylarrinoaryl, Het1aralkylarninocarbonylarrinoaryl
Het alkylaminoaralkyl, Het1arylaminoarakyl, Hefaralkylaminoaralkyt
Het alkanoylaminoaralkyl, Hefaroylaminoaralkyl, Het1aralkanoylaminoaralkyl
Het alkyloxycarbonylaminoarakyl, Het1aryloxycarbonylarrinoaralkyl
Het aralkoxycarbonylaminoarakyl, Het1alkylaminocarbonylarrinoaralkyl
Het arylaminocarbonylarrinoaralkyl, Het alkylaminocarbonylaminoaralkyl.Het2, Het2oxy Het2alkyl, Het^oxyalkyl, Hef^cycloalkyl, He alkoxycarbonyl, HetΛsxycarbonyl Het2alkanoyl, He alkyloxyalkyi, Hel^oxyalkylcarbonyl, Het2alkyloxyalkylcarbonyl Het2aminocarbonyl, Hefcarbonyloxyalkyl, He alkylcarbonyloxyalkyl, Heføryl Het2arylaminoalkoxy, Het2arylamino, Het2arylaminoalkyl, Hefarylaminoalkylamino Het2aryloxy, Hefaryloxyalkoxy, Het2aryloxyalkyl, Het2aryloxyalkylamino, Hefaralkyl Het2aralkoxy, He aralkylamino, Het2aralkanoyl, He aroyl, Het^arylcarbonyl
Het2aryloxycarbonyl, Het2arylthiocarbonyl, Het2aralkoxycarbonyl
Het2arylalkylthioca onyl, Het2aryloxyalkyl, Het2arylthioalkyl, Het2haloalkyl
Het2aryloxycarbonylakyl, He aryloxyalkanoyl, Het2aralkylcarbonyloxyalkyl
Het2arylaminocarbonyl, Heføralkylaminocarbonyl, He alkylaminoalkyl
Het2aralkylaminoalkyl, He^alkanoylaminoalkyl, He aroylaminoalkyl
Het2aralkanoylaminoalkyl, He alkyloxycarbonyiaminoalkyl
Het2aryloxycarbonylaminoakyl, Het2aralkoxycarbonylaminoalkyl
Het2alkylaminocarbonylaminoalkyl, Het2arylaminocarbon aminoalkyl
Het2aralkylaminocarbonylarrinoalkyl, He^alkylaminoaryl, Hel^arylaminoaryl
Het2aralkylaminoaryl, He^alkanoylaminoaryl, Heføroylaminoaryl Het2aralkanoylaminoaryl, He alkyloxycarbonylaminoaryl, Heføryloxycarbonylam'noaryl Het2aralkoxycarbonylaminoaryl, Het2alkylaminocarbonylarrinoaryl
Het2arylaminocarbonylarrinoaryl, Het2aralkylaminocarbonylarrinoaryl
Het2alkylaminoaralkyl, Heførylaminoarakyl, He aralkylaminoaralkyl Het2alkanoylaminoaralkyl, Het2aroylaminoaralkyl, He^aralkanoylarπinoaralkyi
Het2alkyloxycarbonylaminoarakyl, He aryloxycarbonylarrinoaralkyl
Het2aralkoxycarbonylaminoarakyl, Het2alkylaminocarbonylam'noaralkyl
He arylaminocarbonylarrinoaralkyl, Het2aralkylaminocarbonylaminoaralkyl, wherein R3, R4 and R6 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyl, alkylamino, alkanoyl, alkyloxy, aralkoxy hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoa yl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Het1 and Het2; wherein R5 is oxo or thio, and wherein R7 is selected from the group comprising hydrogen, alkyl and halogen.
According to the present invention, it was then found that all of the compounds of formula I claimed in claim 1 and their corresponding pharmaceutically acceptable salts are useful in inhibiting serine type dipeptidyl peptidases and are potent modulators, in particular inhibitors, of DPPII in particular. Specific members of the cited R groups will be listed below.
The highly specific and potent inhibitors of serine type dipeptidyl peptidases, according to the present invention, can advantageously be used to unravel of the physiological functions of the serine type dipeptidyl peptidase enzyme and are also very useful to differentiate between different serine type dipeptidyl peptidases activity in biological systems.
The term "alkyl", alone or in combination, means straight and branched chained saturated hydrocarbon radicals containing from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of such radicals include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2- methylbutyl, pentyl, iso-amyl, hexyl, 3-methylpentyl, octyl and the like. The term "cycloalkyl" alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or polycyclic alkyl radical wherein each cyclic moiety contains from about 3 to about 8 carbon atoms, more preferably from about 3 to about 7 carbon atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, and the like.
The term "cycloalkylalkyl" means an alkyl radical as defined herein, in which at least one hydrogen atom on the alkyl radical is replaced by a cycloalkyl radical as defined herein. Examples of such cycloalkylalkyl radicals include cyclopropylmethyi, cyclobutylmethyl, cyclopentylmethyl, cyclohexyl methyl, 1-cyclopentylettιyl, 1-cyclohexyielhyl, 2- cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl,3-cyclopentylbutyl, cyclohexylbuty! and the like.
The term "alkoxy" or "alkyloxy", alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, hexanoxy and the like.
The term "alkanoyl" or "alkylcarbonyl", alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
The term "alkylamino", alone or in combination, means an alkyl amine radical (i.e. RNH-), wherein the term "alkyl" is defined as above. Examples of alkylamino radicals include methylamino (NHCH3), ethylamino (NHCH2CH3), n-propylamino, isopropylamino, n- butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-hexylamino, and the like.
The term "aminoalkyl", alone or in combination, means an amine alkyl radical (i.e. NH2R-), wherein the term "alkyl" is defined as above.
The term "aminoalkanoyl" means an acyl group derived from an amino-substituted alkylcarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. The term "aminocarbonyl" alone or in combination, means an amino-substituted carbonyl (carbamoyl) group wherein the amino group can be a primary, secondary ortertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
The term "aryl" alone or in combination, is meant to include phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, Het1, amido, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsultbnyl, and phenyl optionally substituted with one or more substituents selected from C|.6alkyl, Cι-6alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC1-6alkyl, carboxyl,
Figure imgf000011_0001
C3-7cycloalkyl, Het1, optionally mono- or disubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het1, Het1alkyl, Hefalkyl, Hefoxy, Het1 oxyalkyl, phenyl, phenyloxy, phenyloxyalkyl, phenylalkyl, alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the amino groups may optionally be mono- or where possible di-substituted with alkyl. Examples of aryl includes phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3- methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3- acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl~3- aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl, 2,4-dimethyl-3- aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, 3- amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6~dimethoxy-2- naphthyl and the like.
As used herein, the term "halogen" as a group or part of a group is generic for fluoro, chloro, bromo or iodo.
The term "haloalkyl" alone or in combination, means an alkyl radical having the meaning as defined above wherein one or more hydrogens are replacedwith a halogen, preferably, chloro or fluoro atoms, more preferably fluoro atoms. Examples of such haloalkyl radicals include chloromeihyl, 1-bromoethyl, fluoromethyl, difluoromettiyl, trifluoromethyl, 1 ,1 ,1- trifluoroethyi and the like.
The term "Het1" alone or in combination, is defined as a saturated or partially unsaturated monocyclic, bicyclic or polycyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het2, He^alkyl, Het2oxy, He oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the amino groups may optionally be mono- or where possible dl-substituted with alkyl.
The term "Het2" as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het1, Het1alkyl, Het1oxy, Het1oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the amino groups may optionally be mono- or where possible di-substituted with alkyl.
The term "arylamino" alone or in combination means an aryl amine radical, wherein the term "aryl" is defined as above.
The term "aralkyl" alone or in combination, means an alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkyl radicals include benzyl, phenethyl, di benzyl methyl, methylphenylmethyl, 3- (2-naphthyl)-butyl, and the like.
The term "aralkanoyl" means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropfonyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4- methoxyhydrocinnamoyl.and the like.
The term "aralkoxy" means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkoxy radicals include 2- phenyletinoxy, 2-phenyM-propoxy, and the like.
The term "aralkylamino" means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkylamino radicals include 2-phenethylamino, 4-phenyl-n-butylamino, and the like.
The term "aroyl" means an acyl radical derived from an arylcarboxylic acid, ayl having the meaning given above. Examples of such arylcarboxylic acid radicals include substituted and unsubstituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4- carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2- naphthoyl, 3-(benzyloxyformamidol-2-naphthoyl, and the like.
The term "arylaminoakoxy" means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of (arylamino) alkoxy radicals include 2- (phenylamino)-ethoxy, 2- (2- naphthylamino)-1-butoxy, and the like.
The term "arylaminoalkyl" means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of arylaminoakyl radicals include phenylaminoethyl, 4- (3-methoxyphenylarrino)- 1 -butyl, and the like.
The term "arylaminoalkylamino" means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of (arylamino) alkylamino radicals include 3- (naphthylamino)-propylamino, 4- (phenylamino)-l- butylamino, and the like.
The term "aryloxy" means a radical of the formula aryl-O-in which the term aryl has the significance given above.
The term "aryloxyalkanoyl" means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above. The term "aryloxyalkoxy" means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkoxy radicals include 2-phenoxyethoxy, A- (3-aminophenoxy)-1- butoxy, and the like.
The term "aryloxyalkyl" means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of aryloxyalkyl radicals include phenoxyethyl, 4- (3-aminophenoxy)-l-butyl, and the like.
The term "aryloxyalkylamino" means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkylamino radicals include 3-phenoxy-npropylamino, 4-phβnoxybutylamino, and the like.
The term "arylthioalkoxy" means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein. Examples of (arylthio) alkoxy radicals include 2- (phenylthio)-ethoxy, and the like.
The term "alkylthio" means an alkyl thioether radical, wherein the term "alkyl" is defined as above. Examples of alkylthio radicals include methylthio (SCH3), ethylthio (SCH2CH3), n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio, and the like.
The term "aralkoxycarbonyl", alone or in combination, means a radical of the formula aralkyl-O-C(O)- in which the term "aralkyl" has the significance given above. Examples of an aralkoxycarbonyl radical are benzyloxycarbonyl and 4- methoxyphenylmethoxycarbonyl.
The term "aralkylthio" means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkylthio radicals include 3- phenyl-2-propylthio, 2- (2-naphthyl)-ethylthio, and the like.
The term "arylaminoalkylthio" means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of (arylamino) alkylthio radicals include 2- (phenylamino)- ethylthio, 3- (2-naphlhylamino)-n-propylthio, and the like. The term "aryloxyalkyithio" means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkylthio radicals include 3-phenoxypropylthio, 4 (2-fluorophenoxy)-butylthio, and the like.
The term "arylthioalkylamino" means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein. Examples of (arylthio) alkylamino radicals include 2- (phenylthio)- ethylamino, and the like.
The term "arylthioalkylthio" means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein. Examples of (arylthio) alkylthio radicals include 2- (naphthylthio)- ethylthio, 3- (phenyllhio)-propylthio, and the like.
The term "cycloalkylalkoxycarbonyl" means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl hasthe meaning given above.
The term "cycloalkylcarbonyl" means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino, amido, mono and dialkyl substituted amino, mono and dialkyl substituted amido and the like, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1 ,2,3,4-tetrahydro-2-naphthoyl.
The term "He^alkoxy" means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by a Het2 as defined herein. Examples of He alkoxy radicals include 2- pyridylmethoxy, 4- (l-imidazolyl)-butoxy, and the like.
The term "Het2alkyl" means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by a Het2 as defined herein. Examples of Het2alkyl radicals include 2- pyridylmethyl, 3- (4-thiazolyl)-propyl, and the like.
The term "Hefalkylamino" means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by a Het2 as defined herein. Examples of Het2alkylamino radicals include 4-pyridylmethylamino, 3 (2-furanyl)-propylamino, and the like. The term "He^alkylthio" means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by a Het2 as defined herein. Examples of Het2alkylthio radicals include 3-pyridylmethylthio, 3 (4-thiazolyl)-propylthio, and the like.
The term "Hefamino" means Het2 as defined herein, wherein a hydrogen atom on the Het2 ring is replaced by a nitrogen. Het2amino radicals include, for example, 4- thiazolylamino, 2-pyridylamino, and the like.
The term "Het2oxy" means Het2 as defined herein, wherein a hydrogen atom on the Het2 ring is replaced by an oxygen. Het2oxy radicals include, for example, 4-pyridyloxy, 5- quinolyloxy, and the like.
The term "He oxycarbonyl" means an acyl radical derived from a carbonic acid represented by Het2-O-COOH wherein Het2 has the meaning given above.
The term "Het1alkanoyl" is an acyl radical derived from a Het1 -substituted alkylcarboxylic acid wherein Het1 has the meaning given above.
The term "Het1alkoxycarbonyl" means an acyl group derived from Het1-O-COOH wherein Het1 is as defined above.
As used herein the term "oxa" refers to the group -O-.
As used herein the term "thia" refers to the group -S-. As used herein the term "imino" refers to the group -NH-.
As used herein the term "cyano" refers to the group -CN.
As used herein the term "amidino" refers to the group -(HN=)C-NH2.
As used herein the term "acetyl" refers to the group -(O=)C-CH3.
As used herein the term "nitro" refers to the group -NO2.
Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. As used herein before, the term "one or more" covers the possibility of all the available C- atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable, e.g. halogen or alkyl, occurs more than one time in any constituent, each definition is independent.
Whenever used hereinafter, the term "compound(s) of the invention" or a similar term is meant to include the compounds of general formula I or formula II and any subgroup thereof. This term also refers to the compounds as depicted in Table A and B and their N- oxides, salts, stereoisomeric forms, racemic mixtures, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues. The Λ/-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. The compounds according to the invention may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the compounds as described herein, are intended to be included within the scope of the present invention.
Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as purified enantiomers/diasteromers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds per se, as well as any wholly or partially equilibrated mixtures thereof. The present invention covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
The term "pro-drug" as used herein means the pharmacological^ acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated. Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
For therapeutic use, the "salts" of the compounds according to the invention, are those wherein the counterion is pharmaceulically or physiologically acceptable. The pharmaceutically acceptable salts of the analogues according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate aspartate, benzoate, benzenesulfonafe, bisulfate, butyrate, citrate, camphorate camphorsulfonaie, cyclopentanepropiorate, digluconate, dodecylsulfete, ethanesulfonate fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate persulfate, 3-phenylpropbnate, picrate, pivalate, propionate, succinate, tartrate thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylarrine salts, N-methyl-D- glucamine, and salts with amino acids such a sarginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
The "pharmaceutically acceptable esters" of the compounds according to the invention refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred. However, other esters such as pheny alkyl may be employed if desired.
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute or a salt or pharmaceutical functional derivative thereof and a solvent. Such solvents for the purpose of the invention should not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to water, methanol, ethanol, and acetic acid. Preferably the solvent used is a pharmaceutical acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
The term "pharmaceutically functional derivative" refers to any pharmaceutical acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation.
The compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism. All polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure, or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics that are known in the art such as x-ray diffraction patterns, solubility, and melting point.
In a preferred embodiment, the invention relates to a compound having the general formula l, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, thia and imino, or wherein R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyt alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoaikyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl Het1oxycarbonyl, Het1alkanoyl, Hefalkyloxyalkyl, Het1oxyalkylcarbonyI
Hefalkyloxyalkylcarbonyl, Het1aminocarbonyl, Het1carbonyloxyalkyl
Het1alkylcarbonyloxyalkyl, Het1aryl, Het1arylaminoalkoxy, Het1arylamino
Het1arylaminoalkyl, Het1arylaminoalkylamino, Het1aryloxy, Het1aryloxyalkoxy Het1aryloxyalkyl, Het aryloxyalkylamino, Het1aralkyl, Het1aralkoxy, Het1aralkylamino Het1aralkanoyl, Het1aroyl, Hefarylcarbonyl, Het1 aryloxycarbonyl, Hefarylthiocarbonyi Hefaralkoxycarbonyl, Het1arylalkylthiocarbonyl, Het1aryloxyalkyl, Het1arylthioalkyl Het1 haloalkyl, Het1aryloxycarbonylalkyl, Het1 aryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi Het1arylaminocarbonyl, Het1aralkylaminocarbonyl, Hefalkylaminoalkyl
Het1aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
Het1aralkanoylaminoalkyl, Hefalkyloxycarbonylaminoalkyl
Het1aryloxycarbonylaminoakyl, Hefaralkoxycarbonylaminoalkyl
Het1alkylaminocarbonylaminoalkyl, Het1arylaminocarbonyiaminoalkyl
Het1aralkylaminocarbonylarrinoalkyl, Het1alkylaminoaryl, Hefarylaminoaryl
Het1aralkylaminoaryl, Hefalkanoylaminoaryl, Het1aroylaminoaryl
Het1aralkanoylaminoaryl, Het1alkyloxycarbonylaminoaryl, Het1aryloxycarbonylarrinoaryl Het1aralkoxycarbonylaminoaryl, Het1alkylaminocarbonylarrinoaryl
Het1arylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylarrinoaryl
Het1alkylaminoaralkyl, Het1arylaminoarakyl, Het1aralkylaminoaralkyl
Het1alkanoylamincaralkyl, Hefaroylaminoaralkyl, Het1aralkanoylaminoaralkyl
Het1alkyloxycarbonylaminoarakyl, Hefaryloxycarbonylam'noaralkyl
Het1aralkoxycarbonylaminoarakyl, Het1alkylaminocarbonylarrinoaralkyl
Het1arylaminocarbonylanrinoaralkyl, Het1aralkylaminocarbony!arninoaralkyl, Het2, Het2oxy Het2alkyl, Hel^oxyalkyl, He^cycloalkyl, He^alkoxycarbonyl, He oxycarbonyi Het2alkanoyl, Hefalkyloxyalkyl, Het2oxyalkylcarbonyl, Het2alkyloxyalkylcarbonyJ Het2aminocarbonyl, Hefcarbonyloxyalkyl, He alkylcarbonyloxyalkyl, Hel^aryl Het2arylaminoalkoxy, Het2arylamino, Het2arylaminoalkyl, Heførylaminoalkylamino Het2aryloxy, Heføryloxyalkoxy, Het2aryloxyalkyl, Het2aryloxyalkylamino, Hefaralkyl Het2aralkoxy,
Figure imgf000020_0001
Het2aryloxycarbonyl, Het2arylthiocarbonyl, He aralkoxycarbonyl Het2arylalkylthiocarbonyl, Het2aryloxyalkyl, Het2arylthioalkyl, Het2haloalkyl
Het2aryloxycarbonylakyl, He aryloxyalkanoyl, Het2aralkylcarbonyloxyalkyl
Het2arylaminocarbonyl, Hel^aralkylaminocarbonyl, He alkylaminoalkyl
Het2aralkylaminoalkyl, Hefalkanoylaminoalkyl, He^aroylaminoall Het2aralkanoylaminoalkyl, Het2alkyloxycarbonylarninoalkyl
Het2aryloxycarbonylaminoakyl, Hefaralkoxycarbonylaminoalkyl
Het2alkylaminocarbonylaminoalkyJ Het2arylaminocarbonylaminoall
Het2aralkylaminocarbonylarrinoalkyl, He^alkylaminoaryl, Het^arylaminoaryl
Het2aralkylaminoaryl, Hel^alkanoylaminoaryl, Heføroylaminoaryl Het aralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, He^aryloxycarbonylarrinoaryl Het2aralkoxycarbonylaminoaryl, Het2alkylaminocarbonylarrinoaryl
Het2arylaminocarbonylarrinoaryl, Het2aralkylaminocarbonylarrinoaryl
Het2alkylaminoaralkyl, He^arylaminoarakyl, He^aralkylaminoaralkyl
Het2alkanoylaminoaralkyl, Het2aroylaminoaralkyl, Het^aralkanoylaminoaralkyl Het2alkyloxycarbonylaminoarakyl, Het^aryloxycarbonylarrinoaralkyl
Het2aralkoxycarbonylaminoarakyl, Het2alkylaminocarbonylarrinoaralkyl
Het2arylaminocarbonylarrinoaralkyl, Het2aralkylaminocarbonylaminoaralkyl, and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyl, alkylamino, alkanoyl, alkyloxy, aralkoxy, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Het1 and Het2; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is selected from the group comprising hydrogen, alkyl and halogen
In a more preferred embodiment, the invention provides a compound having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, and thia, or wherein R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyl alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyl aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoara yl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyi aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylaninoaralkyl aralkoxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl arylaminocarbonylaminoaralkyl, aralkylaminocarbonylarrinoaralkyl, carboxyl piperazinyl piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl amidinoalkyl, Het1, Hefoxy, Het1alkyl, Het1 oxyalkyl, Het1cycloalkyl, Het1alkoxycarbonyl Hefoxycarbonyl, Het1alkanoyl, Het1alkyloxyalkyl, HetOxyalkylcarbonyi
Het1alkyloxyalkyicarbonyl, Het1aminocarbonyl, Het1carbonyloxyalky!
Het1alkylcarbonyloxyalkyl, Het1aryl, Het1arylaminoalkoxy, Het1arylamino
Het1arylaminoalkyl, Het1arylaminoalkylamino, Hefaryloxy, Hefaryloxyalkoxy Hefaryloxyalkyl, Het1aryloxyalkylamino, Het1aralkyl, Het1aralkoxy, Het1aralkyIamino Hefaralkanoyl, Het1aroyl, Het1arylcarbonyl, Het1aryloxycarbonyl, Hefarylthiocarbonyi Het1aralkoxycarbonyl, Het1arylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl Het1 haloalkyl, Hefaryloxycarbonylalkyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyf He arylaminocarbonyl, Hefaralkylaminocarbonyl, Hefalkylaminoalkyl Hefaralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
Hefaralkanoylaminoalkyl, Het1 alkyloxycarbonyiaminoalkyl
Hefaryloxycarbonylaminoakyl, Hefaralkoxycarbonylaminoalkyl
Hefalkylaminocarbonylaminoalkyl, He arylaminocarbonylaminoalkyl
Hefaralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hefarylaminoaryl Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
Hefaralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, Hefaryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hefalkylaminocarbonylarrinoaryl
Hefarylaminocarbonylaninoaryl, Hefaralkylaminocarbonylarrinoaryl
He alkylaminoaralkyl, He arylaminoarakyl, Hefaralkylaminoaralkyl Hefalkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyt
Hefalkyloxycarbonylaminoarakyl, Hefaryloxycarbonylarrinoaralkyl Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
Hefarylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl.Het2, Het2oxy Het2alkyl, Het^oxyalkyl, He^cycloalkyl, Hefalkoxycarbonyl, He oxycarbonyl Het2alkanoyl, Hefalkyloxyalkyi, Het2oxyalkylcarbonyl, Het2alkyloxyalkylcarbonyJ Het2aminocarbonyl, Hefcarbonyloxyalkyl, He^alkylcarbonyloxyalkyl, Hefaryl Het2arylaminoalkoxy, He arylamino, Het2arylaminoalkyl, Hefarylaminoalkylamino Het2aryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Het2aryloxyalkylamino, Hef alkyl Het2aralkoxy, He aralkylamino, Het2aralkanoyl, Hefaroyl, Het^arylcarbonyl Het2aryloxycarbonyl, Hefarylthiocarbonyl, Het2aralkoxycarbonyl Het2arylalkylfhiocarbonyl, Hefaryloxyalkyl, Heførylthioalkyl, Het2haloalkyl
Het2aryloxycarbonylakyl, Heføryloxyalkanoyl, Het2aralkylcarbonyloxyalkyj
Het arylaminocarbonyl, He^aralkylaminocarbonyl, He^alkylaminoalkyl
Het2aralkylaminoalkyl, Het^alkanoylaminoalkyl, Heføroylaminoalkyl
Het2aralkanoylaminoalkyl, Het2alkyloxycarbonylaminoalkyl Het2aryloxycarbonylaminoakyl, Het2aralkoxycarbonylaminoalkyl
Het2alkylaminocarbonylaminoalkyl, Het2arylaminocarbonyIaminoalkyl
Het2aralkylaminocarbonylarrinoalkyl, Hef^alkylaminoaryl, Het^arylaminoaryl
Het2aralkylaminoaryl, He^alkanoylaminoaryl, He aroylaminoaryl
Het2aralkanoylaminoaryl, He^alkyloxycarbonylaminoaryl, He^aryloxycarbonylaminoaryl Het2aralkoxycarbonylaminoaryl, Het2alkylaminocarbonyIarrinoaryl
Het2arylaminocarbonylarrinoaryl, Het2aralkylaminocarbonylarrinoaryl
Het alkylaminoaralkyl, Hefarylaminoarakyl, He^aralkylaminoaralkyl
Het2alkanoylaminoaralkyl, Het2aroylaminoaralkyl, He aralkanoylaminoaralkyl
Het2alkyloxycarbonylaminoarakyl, Het^aryloxycarbonylarrinoaralkyl Het2aralkoxycarbonylaminoarakyl, Het2alkylaminocarbonylarrinoaralkyl
Het2arylaminocarbonylarrinoaralkyl, Het2aralkylaminocarbonylaminoaralkyl, and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoalkyl, arylaminoalkylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Het1 and Het2; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, fluor or methyl. In another more preferred embodiment a compound is provided having the general formula I or pharmaceulically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, and thia or wherein R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, methyl and cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl, aryl cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl alkylaminocarbonyl, alkylaminoalkyl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl arylaminoalkyl, arylaminoalkylamino, aryloxyalkylamino, aralkylamino, arylaminocarbonyl aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylaninoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylarrinoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylarrinoaralkyl aralkoxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl arylaminocarbonylaminoaralkyl, aralkylaminocarbonylaminoaralkyl, piperazinyl piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl amidinoalkyl and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyol, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Het1 and Het2; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, fluor or methyl.
In a particularly preferred embodiment, a compound according to the invention is a compound having the general formula I or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, thia wherein R2 is selected from the group comprising hydrogen, methyl and cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl, amidinoalkyl and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoalkylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Het1 and Het2; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, methyl or fluor.
In another particularly preferred embodiment, a compound according to the invention is a compound having the general formula I or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, thia wherein R2 is selected from the group comprising hydrogen, methyl and cyano, wherein R3 is hydrogen and R4 is selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoakyl, amidinoalkyl and wherein R4 is optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoalkylamino, aralkanoyl, aroyl, pperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Het1 and Het2; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, methyl or fluor.
In a more preferred embodiment, the compounds of the invention have general formula II as represented below,
Figure imgf000026_0001
formula II wherein R1, R2, R3, R5, R6, R7 have the same meaning as indicated herein, wherein R4', R8, R9, R10 are selected from the group comprising nitrogen hydrogen, oxyalkyl, alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl alkoxycarbonyl, alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyl cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyl cycloalkylalkoxycarbonyl, cycloalkylalkoxytiiocarbonyl, cycloalkyllhioalkyl alkylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, alkylaminocarbonyl, alkylaminoalkyl aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylaminoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylamnoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylarrinoaralkyl aralkoxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl arylaminocarbonylaminoaralkyl, aralkylaminocarbonylarrinoaralkyl, carboxyl piperazinyl piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl amidinoalkyl, Het1, Hefoxy, Hefalkyl, Het1 oxyalkyl, Het1 cycloalkyl, Hefalkoxycarbonyl Hefoxycarbonyl, Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyl
Hefalkyloxyalkyicarbonyl, Hefaminocarbonyl, Hefcarbonyloxyalkyi Hefalkylcarbonyloxyalkyl, Hefaryl, He arylaminoalkoxy, Hefarylamino Het ""arylaminoalkyl, Hefarylaminoalkylamino, Hefaryloxy, Hefaryloxyalkoxy Het :1aryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl, Hefaralkoxy, Hefaralkylamino Het :1aralkanoyl, Hefaroyl, Hefarylcarbonyl, Hefaryloxycarbonyl, He arylthiocarbonyi Het 1 aralkoxycarbonyl, Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl Het :1haloalkyl, Hefaryloxycarbonylalkyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi Hel ;1arylaminocarbonyl, Hefaralkylaminocarbonyl, Hef alkylaminoalkyl Het :1aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalky Het :1aralkanoylaminoalkyl, Hefalkyloxycarbonyiaminoalky Het :1aryloxycarbonylaminoakyl, Hef aralkoxycarbonylaminoalkyl Het ;1alkylaminocarbonylaminoalkyl, Hefarylaminocarbonylaminoalky Het :1aralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hefarylaminoary Het 1aralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl Het :1aralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, Hefaryloxycarbonylaminoary Het :1aralkoxycarbonylaminoaryl, Hefalkylaminocarbonylarrinoary Het :1arylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylarrinoaryl Het :1alkylaminoaralkyl, Hefarylaminoarakyl, Hefaralkylaminoaralkyl Het :1alkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl
Hefalkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
Hefarylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl.Het2, Het2oxy Het2alkyl, Hefoxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl, Het2oxycarbonyl Het2alkanoyl, Hefalkyloxyalkyl, Het2oxyalkylcarbonyl, Het2alkyloxyalkylcarbonyl Hefaminocarbonyl, Hefcarbonyloxyalkyl, Hefalkylcarbonyloxyalkyl, Hefaryl Hefarylaminoalkoxy, Hefarylamino, Hefarylaminoalkyl, Hefarylaminoalkylamino Hefaryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl Hefaralkoxy, He aralkylamino, Hefaralkanoyl, Hefaroyl, Hefarylcarbonyl Hefaryloxycarbonyl, Hefarylthiocarbonyl, Hefaralkoxycarboπyl
Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl
Hefaryloxycarbonylakyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi
Hefarylaminocarbonyl, Hefaralkylaminocarbonyl, Hefalkylami noalkyl
Hefaralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylam noalkyl
Hefaralkanoylaminoalkyl, Hefalkyloxycarbonylam noalkyl
He aryloxycarbonylaminoakyl Hefaralkoxycarbonylam noalkyl
Hefalkylaminocarbonylaminoalkyl, Hefarylaminocarbonyiam noalkyl
Hefaralkylaminocarbonylaninoalkyl, Hefalkylaminoaryl Hefarylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl Hefaralkanoylaminoaryl, Hefalkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl
Hefarylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylam'noaryl
Hefalkylaminoaralkyl, He arylaminoarakyl, Hefaralkylaminoaralkyl Hefalkanoylaminoaralkyl, Het2aroylaminoaralkyl, Hefaralkanoylaminoaralkyl
Hefalkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
Hefaralkoxycarbonylaminoarakyl, He alkylaminocarbonylarrinoaralkyl
Hefarylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl, and wherein R4', R8, R9, R10 are optionalfy substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoalkyl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef.
In a specific embodiment, a compound is provided being N1-benzyl-4-oxo-4-(1- piperidinyl 1 ,3(S)-butanediamine as indicated with formula IV according to the specification given below. This particular compound corresponding to formula IV as represented below is also referred to as KS IV.7.
Figure imgf000028_0001
formula IV
The potency of the compounds to inhibit serine type dipeptidyl peptidases accordingto the present invention are expressed as IC50 value. The "IC50 value" is defined as the concentration of a compound, which causes the enzyme activity to decrease with 50 % under assay conditions.
In another specific embodiment a compound is provided selected from the group comprising N1-benzyl-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1 -piperidinyl)- 1 ,3(R)-butanediarnine, A-(A- morpholinyl)-4 -oxo-1 ,3(S)-butanediamine, 4-oxo-4-(1-piperazinyl)-1 ,3(S)-butanediamine, benzyl 3-amino-1(S)-(1-piperidinylearbonyl)propyJcarbamate, benzyl 3-atnino-4-oκo-4- (1 piperidinyl)butyicarbamate, N1-benzyl-2(S)-(1-piperidinylcarbonyl>1 ,4-butanediamine, Λ/-[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl]acetamide, 4-Oxo-4-(1-piperidinyl>Λ/1-(4- piperidinyl)-1 ,3(S)-butanediamine, benzyl 4-{[4-amino-2(S)-(1- piperidinylcarbonyl)buty]amino}-1-piperidinecarboxylate, /-[3(S)-amino-4-oxo-4-(1- piperidinyl)butyβguanidine, Λ/-[3-amino-1(S)-(1-piperidinylcarbonyl)propy]guanidine, N-(2- oxo-2-piperidin-1 -ylethyl)piperidin-4-amine, benzyl 4{[2-oxo-2-(1 -piperidinyl)ethyl]amino}- 1-piperidinecarboxylafe, A/-[2-oxo-2-(1-piperidinyl)ethyl]cyclopentanamine, 1-Benzyl-/V-[2- oxo-2-(1-piperidinyl)ethyl]-4-piperidinamine, 4-oxo-4-(1-piperidinyl)-N3-(4-piperidinyl)-
1 ,3(S)-butanediamine, 6-oxo-6-(1-piperidinyl)-1 ,5(S)-hexanediamine, benzyl 5(S)-amino- 6-oxo-6-(1-piperidinyl)hexylcarbamate, 5-oxo-5-(1-piperidinyl}-1 ,4(S)-pentanediamine, 3- oxo-3-(1-piperidinyl)-1 ,2(S)-propanediamine, 3-(1H-imidazo 4-yl)-1-oxo-1-(1-piperidinyl)- 2(S)-propanamine, 3-cyclohexyM -oxo-1 -(1 -piperidinyl)-2(S)-propanamine, 3-methyI-1 - oxo-1 -(1 -piperidinyl)-2(S)-pentanamine, 2(S)-amino-3-oxo-3-( 1 -piperidinyl)-1 -propanol, 1 - oxo-1 -(1 -piperidinyl)-2(S)-butanamine, 1 -oxo-1 -(1 -piperidinyl)-2(S)-pentanamine, 1 -oxo-1 - (1-piperidinyl}-2(S)-hexanamine, 6-(3,6-dihydro-1(2H)-pyridinyl)-6-oxo-1 ,5(S)- hexanediamine, Λ/-[4(S)-amino-5-oxo-5-(1-piperidinyl)pentyl]guanidine, 1-(S-2,6- Diaminohexanoyl)-2(r:?,S)-piperidinecarbonitrile, 1-(S-2,4-diaminobutanoyl)-2(S)- piperidinecarbonitrile, 3-cyclohexyH-(1-piperidinyl)-1-thioxo-2(S)-propanamine, 2(S)- methyl-1-(1-piperidinylcarbo1hioyl)butylamine, 4-(1-piperidinyl)-4-thioxo-1 ,3(S)- butanediamine, 5-(1-piperidinyl)-5-thioxo-1 ,4(S)-pentanediamine, 6-(1-piperidinyI)-6- thioxo-1 ,5(S)-hexanediamine, Λ/-cyclohexyl-2-oxo-2-(1-piperidinyl)-ethaneamine, N- benzyl-2-oxo-2-(1-piperidinyl ethaneamine, Λ/-piperonyl-2-oxo-2-(1-piperidinyl)- ethaneamine, Λ/-cyclohexyl-2-thioxo-2-(1-piperidinyl)-ethaneamine, Λ/-benzyl-2-thioxo-2- (1-piperidinyl)-ethaneamine, Λ/-piperonyl-2-thioxo-2-(1-piperidinyl)-ethaneamine.
In yet another specific embodiment, a compound is provided selected from the group comprising /V-(2-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, Λ/1-(3- chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, Λ/1-(4-chlorobenzyl)-4-oxo-4- (1-piperidinyl)-1 ,3(S)-butanediamine, Λ/1-[2-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)- 1 ,3(S)-butanediamine, Λ/1-[4-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)-1 ,3(S)- butanediamine, 3-({[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl^mino}methyl)benzonitrile, Λ1- (2-methoxybenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, /V1-(3-methoxybenzyi)-4- oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, Λ/1-(4-methoxybenzyl)-4-oxo-4-(1-piperidinyl)- 1 ,3(S)-butanediamine, /V1-(2,4-dimethoxybenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)- butanediamine, 4-oxo-4-(1-piperidinyl)-A '-(2-thienylme1hyl)-1 ,3(S)-butanediamine, 4-oxo- 4-(1-piperidinyl)-W1-(4-pyridinylmethyl)-1 ,3(S)-butanediamine, Λ/1-(1-naphthylmethyl)-4- oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, Λ/1-(2-naphthylmethyl)-4-oχo-4-(1-piperidiπyl)- 1 ,3(S)-butanediamine, 4-oxo-Λ/1-(2-phenylethyl)-4-(1-piPeπdiny|)"1 -3(S)-butanediamine, 4- oxo-Λ/1-(3-phenylpropyl)-4-(1-piperidinyl)-1 ,3('S -butanediamine, /^-(cyclohexylmethyl)^- oxo-4-(1-piperidinyl)-1 ,3(S)-butanedia ine, Λ/1-cyclohexyl-4-oxo-4-(1-p perid nyl)-1 ,3(S)- butanediamine, /V1-(4-chlorobenzyl //1-methyl-4-oxo-4-(1-pi p| erid nyl)-1 ,3(S)- butanediamine, /V -(4-chlorobenzyl)-/¥3-methyl-4-oxo-4-(1-pi| rid nyl)-1 ,3(S)- butanediamine, /V/1,/v'1-dibenzyl-4-oxo-4-(1 -piperidinyl)- 1 ,3(S)-butanediamine, A/1,/V-di(4- chloroben∑yl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, 4-oxo- V1-phenyl-4-(1- piperidinyi)-1 ,3(S)-butanediamine, N-[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl]benzamide, Λ 1-(3-nitro-2-pyridinyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine, 6-{[3(S)-amino-4- oxo-4-(1-piperidinyl)butyl]amino}nicotinonitrile, A "-(4-chlorobenzyl>4-(2-methyI-1- piperidinylH-oxo-I .SfS -butanediamine, Λ/1-(4-chlorobenzyl)-4-(3-methyl-1-piperidinyl)-4- oxo-1 ,3(S -butanediamine, Λ/1-(4-chlorobenzyl)-4-(4-methyl-1 -piperidinyl)-4-oxo-1 ,3(S)- butanediamine, 1-{2 S -amino-4-[(4-chlorobenzyl)amino]butanoyl}-3-piperidinoI, 1-{2(S - amino-4-[(4-chlorobenzyl)amino]butanoyl}-4-pipsridinol, Λ/1-(4-chlorobenzyl)-4-(3-fluoro-1- piperidinyl^-oxo-I .SfSJ-butanediamine, Λ/1-(4-chlorobenzyl)-4-(4-fIuoro-1-piperidinyl)-4- oxo-1 ,3(S -butanediamine, Λ/1-(4-chlorobenzyl)-4-(3,6-dehydro-1 (2H)-pyridinyl)-4-oxo- 1.SfSj-butanediamine, 1 -[2(S)-amino-4-(benzylamino)butanoyl]-2(S)-piperidinecarboni1rile, 1-{2(S)-amino-4-[(4-chlorobenzyi)amino]butanoyl}-2(S)-piperidinecarbonitrile.
The compounds according to the present invention all preferably inhibit DPP activity, exhibiting relatively high activity at relatively low concentrations, as indicated by low IC50 values. Preferably, the IC50 values of the compounds according to the present invention are lower than 100 μM, more preferred lower than 10μM, even more preferred lower than 0.1 μM.
According to another preferred embodiment, some of the presented compounds are very useful to differentiate between DPP II and DPP IV activity in biological systems, since some of these compounds are highly specific and selective for DPPII inhibitory activity than currently available inhibitors. DPP II and DPP IV both preferentially release N- terminal dipeptide moieties (Xaa-Pro- or Xaa-Ala-) from some oligopeptides or proteins. DPP IV and DPP II share substrate specificity, and differentiating between these acitivites is generally a challenging and difficult task.
In an example, the compound KS IV.7 as defined above is a particularly active and selective DPPII inhibitor. This compound has an IC50 value of 0.00203 μM for DPPII. For comparison, the IC50 value of this compound towards DPP IV comprises 247 μM. This compound thus has a particularly high selectivity of for DPPII, and is particularly suitable for in applications wherein a differentiation is required between DPP II and DPP IV activity.
In a preferred embodiment, the invention thus relates to compounds for use as a medicament. The compounds according to the present invention can be used in the treatment of pathological states associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase. In a preferred embodiment, said compounds according to the invention can be used in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPIV. In another preferred embodiment, said compounds according to the invention can be used in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPII.
According to a further aspect the invention also relates to the use of the compounds according to the invention in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase. In a preferred embodiment the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for inhibiting the activity of DPPIV. In another preferred embodiment the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for inhibiting the activity of DPPII.
Preferably, the invention also relates to the use of the compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase. In a preferred embodiment, the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPIV. In another preferred embodiment, the invention also relates to the use of said compounds according to the invention in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPII. Such medicaments are then specifically intended for treatment and prophylaxis of the conditions listed below. Starting from the available information on the correlation between a particular serine type dbeptidyl peptidase activity and various disease states the skilled person will be able to define therapeutic utilities for the inhibitory compounds of the invention. While not being limited thereby, the compounds of the present invention are believed useful for the treatment of a variety of metabolic, neuroendocrine, gastrointestinal, viral, and inflammatory diseases, including, but not limited to, diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, (auto)immune disorders such as encephalomyelitis, complement mediated disorders such as glomerulonepritis, lipodyslrophy, and tissue damage, psychosomatic, depressive, and neuropsychiairic disease such as anxiety, depress on, insomnia, schizophrenia, epilepsy, spasm, and chronic pain, HIV infection, allerg es, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart fa lure, tumors, and stress-induced abortions.
The invention also relates to the diagnostic use of the compounds. In another preferred embodiment, the compounds according to the present invention can be used in diagnostic and research methods such as fluorescence, purification and radio-assays, imaging, in situ histochemical and cytochemical staining.
In particular, the present invention relates to the use of a compound according to the invention in purification procedures of serine type peptidases and preferably of dipeptidyl peptidases. The said compounds can be immobilized to a suitable matrix or used as a competitor to elute bound enzyme from a matrix containing an immobilized compound.
The present invention also includes compounds, which have been modified without abolishing the reactivity with the active site. Examples of such modifications are the incorporation of radioactive labels such as Iodine125, or non-radioactive labels such as biotin or a fluorophore. The incorporation of a (radioactive) label is useful in diagnostic methods using the modulating compounds. Labelled compounds can be used essentially in the same type of appli cations as labelled monoclonal antibodies, e.g. fluorescence and radioassays, cytofluorimetry, fluorenscence activated cell sorting, etc ... The principles of such techniques are well known to the person skilled in the art.
The DPP inhibitors described above which form complexes with dipeptidyl peptidases are therefore suitable for diagnostic applications such as imaging and histochemical staining of DPP. This requires the introduction of a radioisotope, e.g. iodine, or a fluorescent or other type of reporter group. Because of their small size they are expected to penetrate tissue more easily as, for example, antibodies. Formulations of the compounds to be used in diagnostic applications are also part of this invention. DPP activities can interfere with certain assays by cleaving the substrate used in the test and thereby giving either false positive (when a chromogenic substrate is cleaved) orfalse negative results (when a peptide is degraded). The inhibitors of this invention can be used to inactivate a contaminating DPP activity before carrying on with the analysis.
In cytochemistry and histochemistry labeled inhibitors can be used to directly visualize tie cellular distribution of the target protease (DPP). The label can be fluorescent for fluorescence microscopy, radioactive for autoradiography, or electron dense for electron microscopy. The target structures can be whole cells, cells fixed onto slides or sections through solid tissue. A useful modification of these techniques is to use an indirect ("sandwich") assay employing the specific high affinity interaction between biotin and avidin (reviewed in Methods in Enzymology, vol. 184, 1990).
For imaging of tumours expressing high amounts of the target protease (DPP), inhibitors labeled with a suitable isotope (e.g. I125 or I131) can be injected and after clearing of the excess inhibitor from the circulation, the tumour can be visualized byradio-scintigraphy.
The compounds of the invention which form a stable adduct with DPP may be used as a tool for diagnosing of the above cited disease states.
Furthermore, the present invention also encompasses pharmaceutical compositions prepared for storage and subsequent administration, which have a therapeutically effective amount of one or more compounds of the invention and a pharmaceutically acceptable excipient, carrier or diluent. Such pharmaceutical preparations are intended for the treatment and prophylaxis of the above conditions.
The term "therapeutically effective amount" as used herein means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
Acceptable carriers and diluents are well known and are described, for example, in
Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Preservatives, stabilizers, dyes and flavoring agents may be provided in the pharmaceutical compositions. For example, sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid may be added as preservatives. In addition antioxidants and suspending agents may be used.
The compositions of this invention may be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions or suspensions for injectable administration; aerosols; unguents for topical administration. If desired, absorption enhancing preparations (e.g. liposomes) or other appropriate delivery systems may be used. The amount of the active substances(s) in a dosage unit may vary between 0.01 mg and 1 g.
Formulations of the present invention include those especially formulated for oral, buccal, parental, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
Among the variety of administrations, oral administration typically is preferred. For oral administration tablets, capsules, and caplets may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, and/or wetting agents. Non-limiting examples of binding agents include syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, or polyvinylpyrrolidone (PVP). Non-limiting examples of fillers include, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol. Non-limiting examples of lubricants include, for example, magnesium sterate, stearic acid, talc, polyethylene glycol or silica. Non-limiting examples of disintegrants include, for example, potato starch or sodium starch glycollate. A non-limiting example of a wetting agent includes sodium lauryl sulfate. The tablets additionally may be coated according to methods known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives. Non-limiting examples of such additives include suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum sterate gel or hydrogenated edible fats. Additionally, emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol my be included. Further, preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid, may be incorporated into the preparation. Such preparations may also be formulated as suppositories, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
Additionally, formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
The formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation, for example, subcutaneously or intramuscularly, or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials, such as an emulsion in an acceptable oil, ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt.
The compounds of the present invention may be used in combination with one or more other therapeutic or diagnostic agents in the treatment, prevention, suppression, amelioration, or diagnosing of diseases or conditions for which compounds of the invention or the other agents may have utility, where the combination of the drugs together are safer or more effective than either agent alone.
Such other agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other agents, a pharmaceutical composition in unit dosage form containing such other agents and the compound of the invention, is preferred. However, the combination therapy may also include therapies in which the compound of the invention, and one or more other agents are administered on different overlapping schedules.
It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
Examples of other active ingredients that may be administered in combination with a compound of the present invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to other dipeptidyl peptidase inhibitors. In a preferred embodiment, certain compounds of the invention can be combined with each other such that synergetic inhibiting effects are obtained.
The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other agents that are used in the treatment/prevention/suppression or amelioration of diseases or conditions for which compounds of the present invention are useful.
The weight ratio of a compound of the present invention to a second active ingredent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 :1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication. The pharmaceutical compositions of this invention can be administered to humans in dosage ranges specific for each compound comprised in said compositions. The dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain certain amounts of a compound of the present invention depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Examples of such amounts include the formulation containing about 0.1 to about 99.9% active ingredient. Preferred unit dosage formulations are those containing a predetermined dose, such as a daily dose, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
In another embodiment, the invention relates to a method of treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention. The term "individual," as used herein refers to an animal, preferably a mammal, and most preferably a human, who has been the object of treatment, observation or experiment
In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment.
It will be understood, however, that specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific analogue employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
In another aspect, the present invention relates to a method for inhibiting the activity of a serine type dipeptidyl peptidase by administering a compound according to the present invention. The present invention relates to a method for in vitro inhibition of the activity of a serine type dipeptidyl peptidase by means of administering a suitable concentration of a compound of the invention. Such method is in particular useful when a DPP enzyme inactivates a peptide prior to measurement thereof in a peptide assay. The compounds of the invention can be used to inhibit the degradation of the peptide substrate by the enzyme in such assay. The compounds of the invention are also useful in a method for ex vivo inhibition of the activity of a serine type dipeptidyl peptidase, such as the treatment outside the body of cells and organs for transplantation in order to avoid rejection thereof by the recipient body. The method comprises administering a suitable concentration of a compound according to the invention. Furthermore, the compounds of the invention can be used in a method for in vivo inhibiting of the activity of a serine type dipeptidyl peptidase by means of administering to a living organism a suitable amount of a compound of the invention.
In a further embodiment the present invention relates to kits comprising a compound according to the invention. In a more preferred embodiment, the invention further provides for assay kits for assaying the inhibition of the activity of a serine type dipeptidyl peptidase comprising a compound according to the invention and means to detect said inhibition.
The present invention will be further elucidated with reference to the following examples which are only given for illustration purposes and are in no way intended to limit the invention.
Examples
Example 1 Non-limiting examples of compounds according to the invention Non-limiting examples of compounds according to the invention and having general formula II are listed in Table A, wherein reference is made to R1, R2, R3, R4', R5, R6, R7, R8,
R9, R10.
Figure imgf000038_0001
formula
Table A
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Table A (continued)
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Table A (continued)
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Table A (continued)
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Table A (continued)
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Table A (continued)
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Table A (continued)
Figure imgf000061_0001
Figure imgf000062_0001
61
Figure imgf000063_0001
Figure imgf000064_0001
Table A (continued)
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Table A (continued)
Figure imgf000068_0002
Figure imgf000069_0001
Example 2 Specific examples of compounds ac∞rding to the invention The present example illustrates some specific examples of compounds according to the invention (Table B). Also indicated are the IC50 values of the indicated compounds for DPPII and DPPIV.
Table B
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
As illustrated in this example, the compounds according to the invention strongly inhibit DPPII activity, as indicated by the low IC50 values of the illustrated compounds for DPPII. In particular, most of the compounds in the following examples have an activity in inhibiting DPPII generally lower than 100 μM and in some cases lower than 10μM and even lower than 1 μM. Such results are indicative of the intrinsic activity of the compounds in use as inhibitors of DPPII enzyme activity.
In particular, the compound with formula IV is a particularly active and selective DPPII inhibitor. This compound has an IC50 value of 0.00203 μM for DPPII. For comparison, the IC50 value of this compound towards DPP IV comprises 247 μM. This compound thus has a particularly high selectivity of for DPPII, and is particularly suitable for in applications wherein a differentiation is required between DPP II and DPP IV activity. In a preferred embodiment of the present invention, the present compounds may be active, i.e. have a strong inhibitory activity on DPP II. In addition, in another preferred embodiment, the present compounds as claimed in claim 1 may show a high selectivity for DPPII.
Due to their inhibiting activity, the presented compounds are very useful to be applied in all kinds of research, therapeutic and diagnostic applications for inhibiting the activity of a serine type dipeptidyl peptidase.
In another preferred embodiment a compound according to the invention is represented with following formula 111:
Figure imgf000077_0001
Formula III
Example 3 Synthesis of the compounds according to the invention
The present example illustrates the synthesis of compounds as illustrated in Table B of example 2, according to different synthesis schemes.
The compounds having formulas IV, IX, XI, XII, XIII, XIV, XV, XVI and XXI as illustrated in example 2, Table B, are synthetised as follows. The synthesis of compounds having formulas IV, IX, XI, XII, XIII, XIV, XV, XVI and XXI is illustrated in Figure 1.
N1-benzyl-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (IV) Procedure A To a mixture of Λ/-α-benzyloxycarbonyl-Λ/-ε-terf-butyloxycarbonyl-/--diaminobutyric acid (19.4 mmol), triethylamine (53.8 mmol) and TBTU (19.4 mmol) in DMF (40 ml) was added piperidine (17.6mmol). After stirring at room temperature overnight, water was added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with 1 N HCI (2 x 25 ml), 5% NaHC03 (2 x 25 ml) and brine (25 ml). The organic layer was dried over Na2S04, evaporated and purified by column chromatography (94 %). Procedure B
Deprotection of fe/Y-butyloxycarbonyl (Boc) was done by dissolving in 15 ml of a TFA/dichloromethane (1 :1) mixture. The solution was stirred for 3 h and the volatile part was removed under reduced pressure. After coevaporating several times with ether, the oily residue was used as such for the next step (95%). Procedure C
To a mixture of compound obtained in previous step (2.3 mmol) and the appropiate aldehyde/keton (IV: benzaldehyde) (2.3 mmol) in dry methanol (15 ml) was added NaCNBH3 (1.65 mmol). The mixture was stirred overnight at room temperature. Concentrated HCI was added until pH < 2, and the methanol was removed in vacuo. The residue was taken up in 20 ml of water and extracted with diethylether (2 x 20 ml). The aqueous solution was brought to pH > 11 with 2N NaOH and extracted several times with diethylether. The combined extracts were dried over Na2S04 and evaporated in vacuo. The residue was purified by preparative TLC using EtOAc/MeOH (95:5) as eluent (50%). Procedure D
Deprotection of the benzyloxycarbonyl (Z) group was done by acidolysis: the compound resulted from previous step was dissolved in 30% HBr in acetic acid. After completion of the deprotection which was monitored by TLC, the volatile part was removed in vacuo. The residue was coevaporated several times with diethylether and was finally precipitated in diethylether (90%).
1H-NMR (D20, 400 MHz) 1.58-1.74 (m, 6H, CH2), 2.29-2.48 (m, 2H, β-C 2), 3.15-3.24 (m, 2H, ^CH2), 3.48-3.60 (m, 4H, CH2), 4.36 (s, 2H, CH2), 4.65-4.74 (m, 1H, α-CH), 7.58 (s, 5H, Haram); MS (ES+) m/z 276 (M + H)+; HPLC (214 nm): rt 9.92 min, 94%.
Benzyl 3-amino-1(S)-(1-piperidinylcarbonyl)propylcarbamate (IX)
The title compound was obtained according to procedure A, followed by procedure B. 1H-NMR (D20, 400 MHz) £ 1.41-1.71 (m, 6H, CH2), 1.98-2.17 (m, 2H, y CH2), 3.02-3.76 (m, 6H, rCH2, CH2), 4.70-4.85 (m, 1H, α-CH), 5.17 (s, 2H, CH2), 7.46 (s, 5H, Harom); MS (ES+) m/z 320 (M + H)+; LC-MS: rt 17.3 min, 100%, m/z 320 (M + H)+; UV-HPLC: rt 14.48 min, 96%.
N1-ben∑yl-2(S)-(1-piperidinylcarbonyl)-1,4-butanediamine (XI) The synthesis of this compound started by carrying out procedure A.
Procedure E Deprotection of the benzyloxycarbonyl (Z) group was done by hydrogenolysis: to a mixture of compound obtained from previous step in methanol (50 ml) was added Pd/C (20%) and acetic acid (1 ml). A flow of nitrogen-gass was carried over the solution for 10 minutes, followed by a flow of H2-gas. The reaction was monitored by TLC. After completion, again a flow of nitrogen was carried over the solution for 10 minutes. The mixture was filtered over a celite and the methanol was removed in vacuo. The compound obtained was used as such in the next step.
Reductive amination was carried out with benzaldehyde according to procedure C. The title compound was finally obtained by deprotection of the tert-butyloxycarbonyl group using procedure B. The final product could be precipitated in diethylether. MS (ES+) m/z 276 (M + H)+; HPLC (214 nm): rt 10.63 min, 98%.
N-[3(S)-amino-4-oxo-4-(1-piperidinyl)but l]acet:amide (XII)
The synthesis of this compound started following procedure A and B.
Procedure F
The compound (1.57 mmol) obtained from previous step was dissolved in pyridine (5 ml) and acetic acid anhydride (2.35 mmol) was added. The solution was stirred overnight and pyridine was evaporated in vacuo. The residue was extracted with 2N HCI and diethylether. The combined organic layers were dried over Na2S04 and evaporated.
Purification was carried out by preparative TLC using EtOAc/MeOH (95:5) as eluent
(50%). The title compound was finally obtained by deprotection of the benzyloxycarbonyl group according to procedure D.
1H-NMR (D20, 400 MHz) £ 1.55-1.76 (m, 6H, CH2), 2.03-2.18 (m, 5H, CH3, yδ-CH2), 3.30- 3.64 (m, 6H, rCH2, CH2), 4.41-4.67 (m, 1H, α-CH); MS (ES+) m/z 228 (M + H)+; HPLC
(214 nm): rt 6.50 min, 96%.
4-Oxo-4-(1 -piperidinyl)-N1-(4-piperidinyl)-1 ,3(S)-butanediamine (XIII)
This compound was synthesised according to procedure A and B, followed by procedure
C using benzyl 4-oxo-1-piperidinecarboxylate for reductive amination. The title compound was finally obtained by deprotection of the benzyloxycarbonyl group according to procedure D.
MS (ES+) m/z 269 (M + H)+; HPLC (214 nm): rt 5.46 min, 90%.
Benzyl-4-{[4-amino-2(S)-(1-piperidinylcarbonyl)butyl]amino}-1- piperidinecart∞jylate (!0V) This compound was synthesised according to procedure A and E, followed by procedure C using 4-oxo-Z-piperidine for reductive amination. The title compound was finally obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. The final product could be precipitated in diethylether.
MS (ES+) m/z 403 (M + H)+; HPLC (214 nm): rt 14.25 min, 96%.
M-[3(S)-sιmino- -θ2jo- -(1-piperidinj l)bi!iϊyl]guanidin© p )
The synthesis of this compound started according to procedure A and B.
Procedure G
To a stirred solution of 1-H-pyrazole-1-[Af, tV-bis(tert-butyloxycarbonyl)]carboxamide (1.2 mmol) in ACN/H20 (95:5, 20 ml) was added the appropiate amine (1.2 mmol) and DIEA (3.6 mmol). The mixture was refluxed for 2h. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by preparative TLC using DCM/MeOH (95:5) as eluent.
Deprotection of the tert-butyloxycarbonyl groups was done according to procedure B.
Finally the title compound was obtained by deprotection of the benzyloxycarbonyl group according to procedure E.
MS (ES+) m/z 228 (M + H)+; HPLC (214 nm): rt 5.61 min, 95%.
N-[3-amino-1(S)-(1-piperidinylcarbonyl)propyl]guanidine (XVI)
This compound was synthesised according to procedure A and E, followed by procedure G. The title compound was finally obtained by deprotection of the tert-butyloxycarbonyl groups according to procedure B. The final product could be precipitated in diethylether. MS (ES+) m/z 228 (M + H)+.
4-oxo-4-(1-piperidinylrN3-(4-piperidinyl)-1,3(S)-butanediamine (XXI) This compound was synthesised according to procedure A and E, followed by procedure C benzyl 4-oxo-1-piperidinecarboxy!ate for reductive amination. The title compound was finally obtained by deprotection of the tert-butyloxycarbonyl group and benzyloxycarbonyl group according to procedure D. The final product could be precipitated in diethylether. MS (ES+) m/z 269 (M + H)+.
The compounds having formulas XVIII, XVII and XX as illustrated in example 2, Table B, are synthetised as follows. The synthesis of these compounds illustrated in Figure 2.
Benzyl 4{[2-oxo-2-(1-piperidinyl)efhyl]amino}-1-piperidinecarbo^late (XVIII) The synthesis of this compound started from N-α-tert.-butyloxycarbonyl-L-glycine and was carried out according to procedure A, followed by procedure B. Reductive amination with benzyl 4-oxo-1-piperidinecarboxylate was done using procedure C to obtain the title compound.
MS (ES+) m/z 360 (M + H)+; HPLC (214 nm): rt 16.03 min, 92%.
M-(2-θ2Jo-2-piperidin-1-ylsthyl)piperidin-4-sιmin© (XVII)
The synthesis of this compound started from compound XVIII. The title compound was obtained by deprotection of the benzyloxycarbonyl group according to procedure D. 1H-NMR (D20, 400 MHz) δ 1.51-1.68 (m, 6H, CH2), 1.89-1.99 (m, 2H, CH2), 2.39-2.43 (m, 2H, CH2), 3.10-3.16 (m, 2H, CH2), 3.35-3.38 (m, 2H, CH2), 3.49-3.51 (m, 2H, CH2), 3.57- 3.62 (m, 3H, CH, CH2), 4.21 (s, 2H, CH2); MS (ES+) m/z 226 (M + H)+; HPLC (214 nm): rt 6.21 min, 94%.
1-Benzyl-N-[2-oxo-2-(1-piperidinyl)ethyl]-4-piperidinamine (XX)
The synthesis of this compound started from compound XVIII. Procedure H
To a solution of compound XVIII (5.7 mmol) in dioxane/H20 (1 :1 , 20 ml) was added TEA (17.2 mmol) and B0C2O (6.3 mmol). The mixture was stirred at room temperature for 5 hours. The dioxane was evaporated under reduced pressure, the aqueous solution was acidified and extracted with EtOAc (2 x 50 ml). The combined organic layers were dried over Na2S04 and evaporated.
Deprotection of the benzyloxycarbonylgroupwas done according to procedure E, followed by reductive amination with benzylaldehyde according to procedure C. The title compound was obtained by final deprotection of the ferf-butyloxycarbonyl group using procedure B. The final product could be precipitated in diethylether. MS (ES+) m/z 316 (M + H)+.
The compounds having formulas V, VI, VII, VIII, X and XIX as illustrated in example 2,
Table B, are synthetised as follows. The synthesis of these compounds is illustrated in
Figure 3.
4-Oxo-4-(1-piperidinyl)-1,3(S)-butanediarnine (V)
The synthesis of this compound started from Λ/-α,^di-ferf;.-butyloxycarbonyl-Z-- diaminobutyric acid.
Procedure I Compounds were prepared by parallel synthesis using a PASP-protocol: protected amino acid (0.375 mmol), HOBt (0.425 mmol) and PS-Carbodiimide (0.75 mmol) were added to a dry reaction vessel. Dichloromethane (4 ml) was added and the mixture was stirred for 10 min prior to the addition of the appropriate amine. After stirring at room temperature overnight the polymer-bound polyamine (1.5 mmol) was added and stirring was continued for 5 h. The reaction mixture was filtered and the amide product was collected in the filtrate. The resins are washed two times with A ml of dichloromethane and the combined fractions were evaporated under reduced pressure. The purity of the compounds was checked by TLC and reverse phase HPLC. Compounds were purified by preparative TLC using a mixture of EtOAc and hexane (usually 40/60) as eluent.
The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £ 1.59-1.73 (m, 6H, CH2), 2.27-2.34 (m, 2H, /?-CH2), 3.12-3.23 (m, 2H, ^CH2), 3.50-3.71 (m, 4H, CH2), 4.72 (t, 1H, α-CH); LC-MS: rt 0.8 min, 100%, m/z 186 (M + H)+; HPLC (214 nm): rt 3.62 min, 100%.
4-Oxo-4-(1-piperidinyl)-1,3(R)-butanediamine (VI)
The synthesis of this compound started from /V-a^di-tert.-butyloxycarbonyl-D- diaminobutyric acid according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.50-1.62 (m, 6H, CH2), 2.15-2.21 (m, 2H, 0-CH2), 3.02-3.11 (m, 2H, rCH2), 3.41-3.59 (m, 4H, CH2), 4.61 (t, 1 H, α-CH); LC-MS: rt 0.7 min, 100%, m/z 186 (M + H)+; HPLC (214 nm): rt 4.66 min, 100%.
4-(4-morpholinyl)-4-oxo-1 ,3(S)-butanediamine (VII)
The synthesis of this compound started from Λ/-c-,^di-tert.-butyloxycarbonyl- - diaminobutyric acid according to procedure I using morfoline as amine compound. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £2.27-2.38 (m, 2H, y#-CH2), 3.12-3.28 (m, 2H, -CH2), 3.61-3.85
(m, 8H, CH2), 4.71 (t, 1H, α-CH); LC-MS: rt 0.6 min, 100%, m/z 188 (M + H)+; HPLC (214 nm): rt 3.41 min, 100%.
4-oxo-4-(1-piperazinyl)-1,3(S)-butanediamine (VIII)
The synthesis of this compound started from Λ/-α,γ-di-tert.-butyloxycarbonyl-L- diaminobutyric acid according to procedure I using Boc-piperazine as amine compound. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £2.25-2.40 (m, 2H, CH2), 3.12-3.28 (m, 2H, f-CH2), 3.33-3.50 (m, 4H, CH2),), 3.75-4,15 (m, 4H, CH2) 4.76 (t, 1H, α-CH); LC-MS: rt 0.5 min, 94%, m/z 187 (M + H)+; HPLC (214 nm): rt 3.40 min, 100%.
Bensyl 3-amino-4-OJCO-4-(1pip ridinyl)butylcarbamate (X)
The synthesis of this compound started from A/-α-fert.-butyloxycarbonyl-/V-^ benzyloxycarbonyl- - diaminobutyric acid according to procedure I using piperidine as amine compound. The title compound was obtained by deprotection of the tert- butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £ 1.20-1.71 (m, 6H, CH2), 1.85-2.05 (m, 2H, y?-CH2), 3.29-3.55 (m, 6H, CH2, ^CH2), 4.44 (m, 1 H, α-CH), 5.13 (s, 2H, CH2), 7.43 (s, 5H, Harom); LC-MS: rt 17.2 min, 99%, m/z 320 (M + H)+; UV-HPLC: rt 14.85 min, 97%.
Λ/-[2-oxo-2-(1-piperidinyl)ethyl]cyclopentanamine (XIX)
Procedure J
To a stirred and cooled solution of the appropiate amine (50 mmol) in diethylether (10 ml) was added dropwise over 30 minutes a solution of bromoacetic acid (10 mmol) in diethylether (2 ml). The mixture was stirred several hours at 0 °C and was then allowed to warm up and stirred overnight. The pH was raised to 12 with 2N NaOH and extracted with ether to remove unreacted amine. The aqueous layer was acidified (pH = 1) and evaporated in vacuo. The residue was taken up in a small volume of methanol, filtrated and evaporated under reduced pressure. The residue was used as such in the next step. Introduction of tert-butyloxycarbonyl (Boc) was done according to procedure H. The title compound was finally obtained according to procedure I using piperidine as amine compound, followed by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.49-1.72 (m, 12H, CH2) , 2.02-2.07 (m, 2H, CH2), 3.31 (t, 2H, CH2), 3.45 (t, 2H, CH2), 3.51-3.59 (m, 1H, CH), 4.03 s, 2H, CH2); MS (ES+) m/z 211 (M + H)+; HPLC (214 nm): rt 9.52, 98%.
The compounds having formulas XXII, XXlll, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV as illustrated in example 2, Table B, are synthetised as follows. The synthesis of these compounds is illustrated in Figure 4. 6-oxo-6-(1-piperidinyl)-1,5(S)-hexanediamine (XXII).
The synthesis of this compound started from Λ/-α,£-di-tert.-butyloxycarbonyl-L-lysine according to procedure I. The title compound was obtained by deprotection of the tert- butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £1.34-1.87 (m, 12H, CH2), 2.95 (t, 2H, ε-C 2), 3.43-3.53 (m, 4H, CH2), 4.50 (t, 1H, α-CH); LC-MS rt 1.0 min, 93%, m/z 214 (M + H)+; HPLC (214 nm): rt 2.59 min, 86%.
bensj l 5(S)-amino-6-o∑-θ-6-(1-piperidinyl)he2.ylcarbamate (XXlll). The synthesis of this compound started from Λ/-α-fert.-butyloxycarbonyl-/V-£-- benzyloxycarbonyl-L-lysine according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.37-1.76 (m, 10H, CH2), 1.84-1.98 (m, 2H, CH2), 3.14-3.28 (m, 2H, ff-CHz), 3.41-3.68 (m, 4H, CH2), 4.47-4.57 (m, 1H, α-CH), 5.11-5.26 (m, 2H, CH2- Z), 7.49 (s, 5H, Harom); LC-MS rt 18.7 min, 100%, m/z 348 (M + H)+; HPLC (214 nm): rt 14.59 min, 100%.
5-oxo-5-(1-piperidinyl)-1,4(S)-pentanediamine (XXIV).
The synthesis of this compound started from Λ/-α-benzyloxycarbonyl-/V-£-tert.- butyloxycarbonyl-L-ornithine according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure D.
1H-NMR (D20, 400 MHz) £1.59-1.91 (m, 8H, CH2), 1.97-2.03 (m, 2H, CH2), 3.11 (t, 2H, £-
CH2), 3.53-3.66 (m, 4H, CH2), 4.66 (t, 1 H, α-CH); LC-MS rt 0.8 min, 100%, m/z 200 (M +
H)+; HPLC (214 nm): rt 3.74 min, 100%.
3-oxo-3-(1-piperidinyl)-1,2(S)-propanediamine (XXV).
The synthesis of this compound started from Λ/-α, ?-di-fert.-butyloxycarbonyl-L-2/3- diaminopropanoic acid according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.57-1.81 (m, 6H, CH2), 3.42-3.85 (m, 6H, CH2, y#-CH2), 4.97
(m, 1 H, α-CH); LC-MS rt 0.7 min, 100%, m/z 172 (M + H)+; HPLC (214 nm): rt 3.60 min,
100%. 3-(1H-imidazol-4-yl)-1-oxo-1-(1-piperidinyl)-2(S)-propanamine (XXVI).
The synthesis of this compound started from Λ/-α-fert.-butyloxycarbonyl-/V-im-trityl-/_- histidine according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.52-1.79 (m, 6H, 3-CH2, 4-CH2, 5-CH2), 3.31-3.72 (m, 6H, β- CH2, 2-CH2, 6-CH2), 4.81-4.93 (m, 1 H, α-CH), 7.54 (s, 1 H, 4-CH-His), 8.81 (s, 1 H, 2-CH- His); LC-MS rt 1.0 min, 100%, m/z 223 (M + H)+; HPLC (214 nm): rt 4.04 min, 88%.
3-cyclohexyl-1-o o-1-(1-piperidinyl)-2(S)-propanamine POCVII) The synthesis of this compound started from N-α-fert.-butyloxycarbonyl-/.- cyclohexylalanire according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 0.91-1.79 (m, 19H, CH2), 3.40-3.53 (m, 4H, 2-CH2, 6-CH2), 4.49 (t, 1H, α-CH); MS (ES+) m/z 239 (M + H)+; LC-MS rt 1.0-1.4 min, m/z 239 (M + H)+; UV-HPLC rt 23.49 min, 100%.
3-methyl-1-oxo-1-(1-piperidinyl)-2(S)-pentanamine (XXVIII).
The synthesis of this compound started from Λ/-α-tert.-butyloxycarbonyl-/--isoleucine acid according to procedure I. The title compound was obtained by deprotection of the tert- butyloxycarbonyl group according to procedure B.
1H-NMR (DMSO-de, 400 MHz) £ 0.85 (t, 3H, £-CH3), 0.94 (d, 3H, ^CH3), 1.00-1.25 (m, 1H, jf€ ), 1.35-1.70 (m, 7H, ^CH, 3-CH2, 4-CH2, 5-CH2 ), 1.70-1.85 (m, 1H, ^CH), 3.20- 3.65 (m, 4H, 2-CH2, 6-CH2), 4.25 (d, 1 H, α-CH), 8.07 (br s, 3 H, NH3+); MS (ES+) m/z 199 (M + H)+; LC-MS rt 0.6-0.7 min, m/z 199 (M + H)+; UV-HPLC rt 11.30 min, 100%.
2(S)-amino-3-oxo-3-(1-piperidϊnyl)-1-propanol (XXIX).
The synthesis of this compound started from /V-a-tert.-butyloxycarbonyl-O-tert.-butyl-L- serine according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £1.59-1.73 (m, 6H, CH2), 3.50-3.64 (m, 4H, CH2), 3.90-3.95 (m, 1H, β-CH2), 4.02-4.06 (m, 1H, β-CH2), 4.62-4.68 (m, 1H, α-CH); MS (ES+) m/z 173 (M + H)+; LC-MS rt 0.5-0.6 min, m/z 173 (M + H)+; UV-HPLC rt 4.91 min, 93%. 1 -oxo-1 -(1-piperidinyl)-2(S)-butanamine (XXX).
The synthesis of this compound started from Λ/-α-tert.-butyloxycarbonyl- -2-aminobutyric acid according to procedure I. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £1.05 (t, 3H, CH3), 1.63-1.77 (m, 6H, CH2), 1.89-2.00 (m, 2H, β- CH2), 3.50-3.68 (m, 4H, CH2), 4.52 (t, 1 H, α-CH); MS (ES+) m/z 171 (M + H)+; LC-MS rt 0.5-0.6 min, m/z 171 (M + H)+; UV-HPLC rt 7.92 min, 96%.
1-θ2Jθ-1-(1-piperidinyl>-2(S)-pentanamine (XXXI). The synthesis of this compound started from N-α-fert.-butyloxycarbonyl-L-norvaline according to procedure I. The title compound was obtained by deprotection of the tert- butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £ 1.01 (t, 3H, CH3), 1.41-1.51 (m, 2H, ^CH2), 1.59-1.78 (m, 6H, CH2), 1.85-1.89 (m, 2H, β-Oά2 3.50-3.68 (m, 4H, CH2), 4.55 (t, 1H, α-CH); MS (ES+) m/z 185 (M + H)+; LC-MS rt 0.7-0.8 min, m/z 185 (M + H)+; UV-HPLC rt 9.91 min, 100%.
1-oxo-1-(1-piperidinyl)-2(S)-hexanamine (XXXII).
The synthesis of this compound started from Λ/-α-tert.-butyloxycarbonyl-/.-norleucine according to procedure I. The title compound was obtained by deprotection of the tert- butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £0.95 (t, 3H, CH3), 1.30-1.42 (m, 4H, CH2), 1.59-1.76 (m, 6H, CH2), 1.87-1.90 (m, 2H, >3-CH2), 3.49-3.69 (m, 4H, CH2), 4.54 (t, 1H, α-CH); MS (ES+) m/z 199 (M + H)+; LC-MS rt 0.5-0.7 min, m/z 199 (M + H)+; UV-HPLC rt 11.96 min, 96%.
6-(3,6-dihydro-1 (2H)-pyridinyl)-6-oxo-1 ,5(S)-hexanediamine (XXXIII).
The synthesis of this compound started from Λ/-α, ?-di-tert.-butyloxycarbonyl-/.-lysine according to procedure I using 1,2,3,6-tetrahydropyridine as amine compound. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.45-1.55 (m, 2H, CH2), 1.69-1.81 (m, 2H, CH2), 1.91-2.00 (m, 2H, CH2), 2.23-2.36 (m, 2H, 5-CH2), 3.05 (b, 2H, ε-CH2), 3.62-3.81 (m, 2H, 6-CH2), 4.03- 4.17 (m, 2H, 2-CH2), 4.55 (t, 0.5H, α-CH), 4.62 (t, 0.5H, α-CH), 5.75-5.82 (m, 1 H, 4-CH), 5.96-6.06 (m, 1H, 3-CH); MS (ES+) m/z 212 (M + H)+. V-[4(S)-amino-5-oxo-5-(1-piperidinyl)pentyl]guanidine (XXXIV).
The synthesis of this compound started from Λ/-α-fert.-butyIoxycarbonyi-/v>;/ >bis- benzyloxycarbonyl-L-arginine according to procedure I. Deprotection of the benzyloxycarbonyl groups was done according to procedure E. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £ 1.50-1.80 (m, 8H, CH2), 1.92-2.00 (m, 2H, CH2), 3.25-3.38 (m, 2H, £-CH2), 3.44-3.77 (m, 4H, CH2), 4.60-4.70 (m, 1 H, α-CH); LC-MS rt 1.0 min, 98%, m/z 242 (M + H)+; HPLC (214 nm): rt 4.58 min, 91%.
The compounds having formulas XXXV and XXXVI as illustrated in example 2, Table B, are synthetised as follows. The synthesis of these compounds is illustrated in Figure 5.
1-(S-2,6-Diaminohexanoyl)-2(/?,S)-piperidinecarbonitrile (XXXV). Procedure K L-HomoProNH2 was prepared from L-pipecolinic acid (1 eq) by reaction with N- hydroxysuccinimide (1.05 eq) and dicyclohexylcarbodiimide (DCC, 1.05 eq) in DCM (yield: 90%), followed by treatment of a solution of the obtained compound in dioxane with ammonium gas (yield: 99%). The synthesis of the title compound started by coupling Λ/-α,^-di-tert.-butyIoxycarbonyl-L- lysine 2-D,L-piperidinecarboxamide according to procedure A. Procedure L
Dehydratation of the amide function to the nitrile was done according the following procedure: To a solution of Boc-Xaa-YaaNH2 (1 eq) and imidazol (2 eq) in pyridine at -30 °C was slowly added phosphorusoxychloride (4 eq). The solution was allowed to attain room temperature and the reaction was monitored by TLC. After completion of the reaction the solvent was evaporated and the residue was extracted with 1 N HCI and diethylether. The organic layer was dried, evaporated and the residue was purified by prepartive TLC to yield the Boc protected dipeptide nitrile (60%). The title compound was obtained by deprotection of the tert-butyloxycarbonyl groups according to procedure B.
1H-NMR (D20, 400 MHz) £ 1.42-1.63 (m, 3H, CH2), 1.71-2.02 (m, 8H, CH2), 2.18-2.29 (m, 1H, CH2), 3.00-3.41 (m, 2H, 6-CH2), 3.46-3.50 (m, 1H, -CH2), 3.88-4.00 (m, 1H, ε-CH2), 4,53-4.67 ( , 1 H, α-CH), 5.69-5.88 (m, 1H, 2-CH); LC-MS rt 1.0 min, 100%, m/z 239 (M + H)+; HPLC (214 nm): rt 5.78 min, 99%. 1 -(S-2,4-diaminobutanoyl)-2(S)-piperidinecarbonitrile (XXXVI).
The synthesis of the title compound started by coupling N-a, y-di-tert.-butyloxycarbonyl-L- diaminobutyric acid and 2-L-piperidinecarboxamide according to procedure A. Dehydratation of the amide function to the nitrile was done according to procedure L. Finally, the title compound was obtained by deprotection of the tert-butyloxycarbonyl groups according to procedure B.
1H-NMR (D20, 400 MHz) £ 1.50-1.68 (m, 1H, CH2), 1.72-2.00 (m, 4H, CH2), 2.08-2.19 (m, 1 H, CH2), 2.35-2.49 (m, 2H, CH2), 3.10-3.29 (m, 2H, 6-CH2), 3.48-3.53 (m, 1H, rCH2), 3.85-3.98 ( , 1 H, ^CH2), 4.70-4.82 (m, 1H, α-CH), 5.69-5.89 (m, 1H, 2-CH2); LC-MS rt 0.8 min, 100%, m/z 211 (M + H)+; HPLC (214 nm): rt 6.56 min, 100%.
The compounds having formulas XXXVll to XXXXI as illustrated in example 2, Table B, are synthetised as follows. The synthesis of these compounds is illustrated in Figure 6.
3-cyclohexyl-1-(1-piperidinyl)-1-thioxo-2(S)-propanamine (XXXVll) procedure M
The protected amino acids amides were procuced according to procedure I. To a solution of these compounds (2 eq) in 5 ml of toluene was added 2,4-bis(p-methoxyphenyl)-1 ,3- dithiadiphosphatane 2,4-disulfide (Lawesson's reagent) (1 eq). The reaction mixture was stirred for 2 h at 80°C. The solvent was removed by evaporation and the crude compound was purified by preparative TLC (EtOAc/hexane, 40:60).
Finally, the title compound was obtained by deprotection of the tert-butyloxycarbonyl groups according to procedure B.
1H-NMR (D20, 400 MHz) £0.95-2.1 (m, 19H, CH2, CH), 3.71-3.90 (m, 2H, CH2), 4.15-4.39 (m, 2H, CH2), 4.62-4.75 (m, 1 H, α-CH); MS (ES+) m/z 255 (M + H)+.
2-(S)-methyl-1-(1-piperidinylcarbothioyl)butylamine (XXXVIII)
The synthesis of this compound was started according to procedure M. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £0.95-1.08 (m, 6H, CH3), 1.10-2.12 (m, 9H, CH2, CH), 3.10-3.26 (m, 1 H, CH2), 3.71-3.95 (m, 2H, CH2), 4.1-4.21 (m, 1 H, CH2), 4.42-4.50 (m, 0.5H, α- CH),4.6-4.76 (m, 0.5H, α-CH); MS (ES+) m/z 215 (M + H)+. 4-(1-piperidinyl)-4-thioxo-1 ,3(S)-butanediamine (XXXIX)
The synthesis of this compound was started according to procedure M. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B. 1H-NMR (D20, 400 MHz) £1.61- 1.63 (m, 6H, 3-CH2, 4-CH2, 5-CH2), 2.30-2.35 (m, 2H, β- CH2), 3.10-3.26 (m, 2H, f-CH2), 3.82-3.98 (m, 2H) and 4.12-4.20 (m, 1 H) and 4.36-4.44 (m, 1H) (2-CH2, 6-CH2), 4.91 (t, 1H, α-CH); MS (ES+) m/z 202 (M + H)+.
5-(1-piperidinyl)-5-thioxo-1 ,4($)-p@ntan@diamin@ (JOQϋC) The synthesis of this compound was started according to procedure M. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £1.82-1.99 (m, 8H, CH2), 2.03-2.09 (m, 2H, ?-CH2), 3.12 (t, 2H,
£-CH2), 3.89-4.03 (m, 2H, CH2), 4.20-4.27 (m, 1H, CH2), 4.42-4.48 (m, 1 H, CH2), 4.90 (t, 1 H, α-CH); MS (ES+) m/z 216 (M + H)+.
6-(1-piperidinyl)-6-thioxo-1,5(S)-hexanediamine (XXXXI)
The synthesis of this compound was started according to procedure M. The title compound was obtained by deprotection of the tert-butyloxycarbonyl group according to procedure B.
1H-NMR (D20, 400 MHz) £1.43-1.62 (m, 2H) and 1.71-1.83 (m, 8H) (rCH2, £-CH2, 3-CH2, 4-CH2, 5-CH2), 1.93-2.00 (m, 2H, β-QW2), 3.04 (t, 2H, £-CH2), 3.80-3.96 (m, 2H) and 4.07- 4.22 (m, 1 H), 4.34-4.41 (m, 1H) (2-CH2, 6-CH2), 4.74- 4.79 (m, 1H, α-CH); MS (ES+) m/z 230 (M + H)+.
The compounds having formulas XXXXII to XXXXVII as illustrated in example 2, Table B, are synthetised as follows. The synthesis of these compounds is illustrated in Figure 7.
/V-cyclohexyl-2-oxo-2-(1-piperidϊnyl)-ethaneamine (XXXXII) Cyclohexylamine was protected with a tert-butyloxycarbonyl(Boc)-group carrying out procedure H.
Procedure N.
For the synthesis of /V-Boc-/V-cyclohexylglycine ethyl ester, /V-Boc-Cyclohehexylam'ne (10 mmol) dissolved in freshly dried THF (50ml) was cooled to -78°C under nitrogen. To this solution was dropped n-BuLi (11 mmol) over a period of 2 minutes. After Stirring for 5 minutes, ethyl bromoacetate (11 mmol), dissolved in dry ether (5ml) was added in one portion via a syringe and the cooling bath was removed. The solution was allowed to reach room temperature and stirred for another 2 hours. Then, all volatile components were evaporated. In this way, the crude product was obtained. Procedure ©
For the synthesis of /V-Boc-Λ/-cyclohexylglycine, the crude product obtained by carrying out procedure N., was mixed with a 1M solution of KOH in aqueous 70% MeOH (12ml). After stirring for 4 hours at rt, the solvent was evaporated under reduced pressure and the residue redissolved in water (140 ml). The aqueous layer was washed with diethylether (2x50 ml), acidified to pH=1 and extracted with EtOAc (2x50ml). The combined organic layers were dried over MgS04 and evaporated under reduced pressure yielding N-Boc-N- cyclohexylglycine, which was recrystallised from EtOAc/Hexanes (1 :4). (72% over three steps).
The N-Boc protected title compound was obtained by submitting N-Boc-N- cyclohexylglycine b procedure A (81%)
The title compound was obtained by deprotection with a TFA/DCM mixture (1 :1) acoording to procedure B and precipitation from dry ether.(84%).
1H-NMR (D20, 400MHz) £1.15-1.31 (m, 2H, CH2(Cy)) 1.34-1.49(m, 4H, CH2(Cy)) 1.51- 1.78(m, 6H, CH2) 1.81-1.98(m, 2H, CH2(Cy)) 2.01-2.11(m, 1H, CH2(Cy)) 2.13-2.25(m, 1H,
CH2(Cy)) 3.01-3.21 (m, 1H, CH(Cy)) 3.38-3.47(m, 2H, CH2) 3.52-3.68(m, 2H, CH2) 4.06-
4.11(s, 2H, CH2)
MS(ES+): m/z 225.3 (M+H)+
/V-benzyl-2-oxo-2-(1-piperidinyl)-ethaneamine (XXXXIII)
The title compound was obtained by sequentially applying procedures H, N, O, A and B to benzylamine.
1H-NMR (D20, 400MHz) £1.43-1.52(m, 4H, CH2) 1.54-1.68(m, 2H, CH2) 3.24-3.33(m, 2H, CH2) 3.37-3.53(m, 2H, CH2) 3.97-4.09(s, 2H, CH2) 4.21-4.33(s, 2H, ArCH2) 7.38-7.59(brs, 5H, Ar).
MS(ES+): m/z 233.1 (M+H)+ m/z 255.2 (m+Na)+
Λ^piperonyl-2-orø-2-(1-piperidinyl)-efchaneamirιe (XXJϋCIV)
The title compound was obtained by sequentially applying procedures H, M, O, A and B to piperonylamine. 1H-NMR (D20, 400MHz) £1.46-1.55(m, 4H, CH2) 1.58-1.69(m, 2H, CH2) 3.18-3.27(m, 2H, CH2) 3.33-3.46(m, 2H, CH2) 3.74-3.92(s, 2H, ArCH2) 3.99-4.12(s, 2H, CH2) 4.21-4.33(s, 2H, ArCH2) 6.51-6.82 (m, 1H, Ar) 6.86-7.14(br m, 2H, Ar). MS(ES+): m/z 277.2 (M+H)+ m/z 289.3 (M+Na)+
f"Cyclohe-.yl-2-thio- o-2-(1 -pi ®ridinyl)-ethaneamin© PCXXXV) The title compound was obtained by sequentially applying procedures M and B to N-Boc- Λ/-cyclohexyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
1H-NMR (D20, 400MHz) £1.15-1.31(m, 2H, CH2(Cy)) 1.34-1.49(m, 4H, CH2(Cy)) 1.58- 1.73(m, 6H, CH2) 1.83-1.98(m, 2H, CH2(Cy)) 2.0-2.12(m, 1H, CH2(Cy)) 2.12-2.23(m, 1H, CH2(Cy)) 2.98-3.17(m, 1H, CH(Cy)) 3.42-3.51 (m, 2H, CH2) 3.62-3.73(m, 2H, CH2) 4.34- 4.42(s, 2H, CH2) MS(ES+): m/z 241.(M+H)+
Λ/-benzyl-2-thioxo-2-(1-piperidinyl)-ethaneamine (XXXXVI)
The title compound was obtained by sequentially applying procedures M and B to N-Boc- Λ/-benzyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
1H-NMR (D20, 400MHz) £1.46-1.55(m, 4H, CH2) 1.54-1.68(m, 2H, CH2) 3.28-3.36(m, 2H, CH2) 3.39-3.51 (m, 2H, CH2) 4.14-4.28(s, 2H, CH2) 4.24-4.37(s, 2H, ArCH2) 7.38-7.59(brs, 5H, Ar).
MS(ES+): m/z 249.3 (M+H)+; m/z 271.2 (M+Na)+
Λ/-piperonyl-2-thioxo-2-(1-piperidinyl)-ethaneamine (XXXXVII)
The title compound was obtained by sequentially applying procedures M and B to /V-Boc- Λ/-piperonyl-2-oxo-2-(1-piperidinyl)-ethaneamine.
1H-NMR (D20, 400MHz) £1.44-1.569(br m, 6H, CH2) 3.17-3.27(m, 2H, CH2) 3.32-3.41(m, 2H, CH2) 3.76-3.90(s, 2H, ArCH2) 4.26-4.34(s, 2H, CH2) 4.20-4.33(s, 2H, ArCH2) 6.52- 6.80 (m, 1 H, Ar) 6.86-7.14(br m, 2H, Ar). MS(ES+):m/z 293.4(M+H)+
Example 4 Use of a compound of the invention as affinity ligand during the purificaϋon of DPPII
This example illustrates the use of a compound (formula XXII) according to the present invention as affinity ligand during the purification of DPPII. NHS-activated Sepharose 4 fast flow gel (Amersham) was used as matrix. An appropriate amount of the gel was washed on a sintered glass filter with 1 mM HCI. An excess of Lys- Pip (formula XXII) was solubilized in isopropanol (1 column volume) and allowed to react with the matrix during 24 h at room temperature in an end over end mixer. Afterwards the gel was washed with an excess isopropanol, followed by water. Remaining active groups were blocked with 2 column volumes of 200 mM Tris-HCI pH 8.0 during 2 hours at room temperature. The additional washing procedure included 3 cycles of alternating pH wash steps. The low pH buffer consisted of 100 mM acetate pH 4.0 containing 500 mM NaCI. The high pH buffer consisted of 50 mM Tris base with 500 mM NaCI. The Lys-Pip affinity matrix was stored in 100 mM cacodylate at 4-8°C.
A biological sample containing DPPII was applied onto the Lys-Pip affinity matrix in Na- acetate buffer, 50 mM pH 5.5. Unbound protein was removed by washing with 100 mM cacodylate pH 5.5. Elution was performed with 100 mM cacodylate pH 5.5 containing 500 mM NaCI.
Example 5
The present example is a further illustration of the present invention.
In a further aspect, the invention relates to the development of highly specific and potent inhibitors of DPP II, which will contribute to the unravelling of the physiological fundions of this enzyme and will be helpfull to differentiate between DPP II and DPP IV in biological systems. The resembling substrate specificity and catalytic mechanism can complicate this challenging task.
Dipeptidyl peptidases (DPPs, EC 3.4.14.-) have been identified in various mammalian tissues and catalyze the sequential release of dipeptides from polypeptides. Among these enzymes, DPP II (EC 3.4.14.2) and DPP IV (EC 3.4.14.5) preferentially release N- terminal dipeptide moieties (Xaa-Pro- or Xaa-Ala-) at acidic (DPP II) or weak basic (DPP IV) pH from some oligopeptides or proteins. Although DPP IV and DPP II share substrate specificity, they can be functionally and biochemically distinguished. DPP II, first identified by McDonald at al. (J. Biol. Chem. 1968, 243, 4143-4150), is believed to be involved in the physiological breakdown of some proline-containing neuropeptides and in the degradation of collagen (Andersen, et al. Renal Physiol. Biochem, 1989, 12, 32-40) together with tripeptidyl peptidase. However, its physiological functions remain elusive and potential therapeutic targets of DPP II inhibitors are still unclear. DPP II is generally localized in lysosomes and is found in a number of mammalian tissues and body fluids. Recently it is reported to be identical to human quiescent cell proline dipeptidase (QPP), based on the significant sequence homology (79.4%) found between human QPP and rat DPP II (Araki et al. J. Biochem., 2001, 129, 279-288). Human QPP, which was recently isolated and cloned from human T cells (Chiravuri et al. J. Immunol. 1999, 163, 3092-3099; Underwood et al. J. Biol. Chem. 1999, 274, 48, 34053-34058), is a 58-kDa glycoprotein functionally active as a homodimer formed with a leucine zipper motif (Chiravuri et al. J. Biol. Chem. 2000, 275, 35, 26994- 26999). It has been shown that QPP inhibitors cause apoptosis in quiescent lymphocytes, but not in activated or transformed lymphocytes. This process is believed to be independent of DPP IV, because both DPP IV* and DPP IV T cells undergo apoptosis (Chiravuri et al. J. Immunol. 1999, 163, 3092-3099). No sequence homology has been found between DPP ll/QPP and DPP IV.
DPP IV has been studied extensively over the last three decades and a broad array of diverse functional properties in the immune, nerve and endocrine system is suggested Augustyns et al. Curr. Med. Chem., 1999, 6, 311-327; Villhaueret al. Annual Reports in Medicinal Chemistry, Academic Press, 2001 , Vol 36, pp 191-200). DPP IV is bound to the cell membrane and expressed quite ubiquitously in mammalian tissues. In the hematopoietic system it was identified as the leukocyte antigen CD26. Inhibition of DPP IV can be valuable in the treatment of type 2 diabetes and some important DPP IV inhibitors are currently under evaluation in this field (Villhaueret al. Annual Reports in Medicinal Chemistry, Academic Press, 2001 , Vol 36, pp 191-200; Villhauer et al. J. Med. Chem. Lett., 2002). DPP IV inhibitors resemble often the dipeptide cleavage product with a proline mimic at the Pi-site. Amino acyl pyrrolidides (1) and thiazolidides (2) are known as potent, competitive inhibitors of DPP IV ( see below). Substituting the pyrrolidine ring with 6- or 7-membered rings or acyclic amines results in loss of potency (Auguslyns et al. Eur. J. Med. Chem., 1997, 32, 301-309). Substitution with a nitrile group in 1 or 2 at position 2 and 4 also affords competitive inhibitors with approximately a 1000-fold increase in potency compared to the parent compounds (Ashworth et al. Bioorg. Med. Chem. Lett.,
1996, 6, 10, 1163-1166; (1) Li et al. Arch. Biochem. Biophys., 1995, 323, 1 , 148-154;
Ashworth et al. Bioorg. Med. Chem. Lett., 1996, 6, 22, 2745-2748). Introduction of a thio-amide bond, as a peptide bond surrogate, results in thioxo amino acid pyrrolidides (3) and thiazolidides (4), which are also reported to inhibit DPP IV as well as DPP II Stδckel-Maschek et al. Biochim. Biophys. Acta, 2000, 1479, 15-31). The inhibitory potential of all these compounds for DPP IV is well described and recently reviewed (Villhaueret al. Annual Reports in Medicinal Chemistry, Academic Press, 2001 , Vol 36, pp 191-200; Augustyns et al. Eur. J. Med. Chem., 1997, 32, 301-309). Hereunder Reported DPP II and DPP IV inhibitors are shown.
Figure imgf000094_0001
Among these classes of inhibitors, some compounds have been reported to have some DPP II inhibitory activity, although with no selectivity with respect to DPP IV (Senten et al. Biol. Med. Chem. Lett., 2002). The boronic acid dipeptide analogue Val-boroPro (5), used to inhibit QPP in the apoptosis studies (Chiravuri et al. J. Immunol. 1999, 163, 3092- 3099) is in fact a more effective inhibitor for DPP IV (Table 1). Ala-pyrr-2-CN (6) was reported (Li et al. Arch. Biochem. Biophys., 1995, 323, 1 , 148-154) as a weak inhibitor for DPP II, but also with higher potency toward DPP IV. Thiazolidides (2) are more effective DPP II inhibitors than the corresponding pyrrolidides (1) (Stδckel-Maschek et al. Biochim. Biophys. Acta, 2000, 1479, 15-31). The same argument, however, also serves for DPP IV inhibition. From a series with Ala, Phe, Val, lie at P , lle-Thia (2, Xaa = lie) was the most potent DPP IV inhibitor, while lle-Pyrr (1 , Xaa = lie) is the most selective DPP IV inhibitor with respect to DPP II. Thioxylation of the amide bond (3 and 4) gave different results for DPP II and DPP IV. Thioxylation increased DPP II inhibition up to 10 times, whereas thioamides are 20 times less efficient inhibitors for DPP IV than the corresponding amides (Stδckel-Maschek et al. Biochim. Biophys. Acta, 2000, 1479, 15-31). Thioamide analogues such as Ala ψ[CS-N]-Pyrr (3, Xaa = Ala) and Ala ψ[CS-N]-Thia (4, Xaa = Ala) are the only DPP ll-DPP IV inhibitors described on this series to have some selectivity towards DPP II (Stόckel-Maschek et al. Biochim. Biophys. Acta, 2000, 1479, 15-31 ).
Incorporation of an electrophilic phosphonate group on the proline mimic at P-, affords dipeptide proline diphenyl phosphonates, that are well known irreversible inhibitors of DPP IV. Recently, our laboratory reported a series of dipeptide α-aminoalkyl diphenyl phosphonates in which various P diphenyl phosphonate building blocks were combined with commercially available or easily accessible amino acids. These compounds were used for the rapid profiling of DPP II. Most of these dipeptide diphenyl phosphonates gave DPP II inhibition to a moderate or high extent. Λ/-cyclopentyl-NH(C6H5)PO(OPh)2 (7) came out as the most selective and potent DPP II inhibitor (Senten et al. J. Comb. Chem., 2003).
Table 1 Inhibitory activity of DPP II inhibitors reported in literature
Figure imgf000095_0001
SI = selectivity index = value for DPP IV divided by value for DPP II.
Values taken from Stόckel-Maschek et al. Biochim. Biophys. Acta, 2000, 1479, 15-31. °Values taken from Underwood et al. J. Biol. Chem. 1999, 274, 48, 34053-34058
Values taken from Li et al. Arch. Biochem. Biophys., 1995, 323, 1, 148-154.
Values taken from Senten et al. J. Comb. Chem., 2003.
In this aspect of the invention the systematic search for a potent and selective DPP II inhibitor is reported, the structrure-activity relationship of several classes of inhibitors is reported. This aspect aims to identify lead compounds for the further development of highly selective and potent DPP II inhibitors.
Chemistry
Most compounds reported in this example were rapidly prepared by parallel synthesis.
Commercially available amino acids with tert-butyloxycarbonyl as α-amino protection and acid-labile side-chain protecting groups were coupled with the appropriate amine using a polymer-assisted solution-phase procedure as reported earlier (Senten et al. Tetrahedron Lett., 2001 , 42, 9135-9138). In this two step synthesis we were able to produce a large number of compounds without difficult purification steps. Some compounds, however, were purified before final deprotection by preparative TLC in order to assure the 95% purity needed for biological evaluation. Compounds A and 11 were prepared by thioxylation using Lawesson's reagent after the parallel synthesis of the corresponding protected amides (Stόckel-Maschek et al. Biochim. Biophys. Acta, 2000, 1479, 15-31). Inhibitory activities for DPP IV of pyrrolidide analogues with different ring sizes, open ring structures and other homologues have been reported earlier (Augustyns et al. Eur. J. Med. Chem., 1997, 32, 301-309) These compounds (8) were now also evaluated for their DPP II inhibitory capacity (see formulas below). As standard P2 amino acid L-lle was used, although also several analogues were synthesised containing Lys as P2 amino acid. The substituted pyrrolidides (9) were obtained by coupling of Boc protected amino acid (lie or Lys) to 3-hydroxyproline. Various reactions at the hydroxyl function and cleavage of the protecting group resulted in the 3-substituted pyrrolidides (9, Table 4) (Augustyns et al. Eur. J. Med. Chem., 1997, 32, 301-309). An azide (9.3, 9.4) was obtained from a tosylate intermediate, prepared with tosylsulphonyl chloride and sodium azide. Treatment with benzoyl chloride afforded the benzoate (9.5, 9.6). Fluorine was introduced with diethylaminosulphur trifluoride (DAST. The synthesis of dipeptide nitriles (14, 15, 16, see formulas below) started by coupling Yaa-NH2 and the required Boc protected amino acid, followed by dehydratation of the amide function to the nitrile using phosphorusoxychloride and subsequent acid catalysed deprotection.
Biochemical evaluation
To establish the most optimal N-terminal amino acid (P2) for DPP II inhibition, we prepared a series of pyrrolidides (1). IC50 values for DPP II and DPP IV inhibition of compounds 1 are summarized in Table 2. A selectivity index is given as a means to evaluate the selectivity towards DPP IV. Lys-Pyrr (1.8) with an IC50 = 9.9 μM and His-Pyrr (1.6) exhibiting an IC50 = 1.16 μM came out as the most active DPP II inhibitors. These two compounds were also the most selective with respect to DPP IV. From this set of pyrrolidides (1) we can conclude that basic (Lys, 1.8) and neutral amino acids at P2 are preferable over acidic amino acids. An acidic amino acid at this position seems not to be tolerated (Asp, 1.3), which is in agreement with the reported substrate specificity (Mentlein et al. J. Nβurocherα, 1989, 52, 1284-1293). Xaa-N (1)
Table 2 Inhibitory activities and selectivity index of pyrrolidides (1)
Figure imgf000097_0001
SI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II.
Cha = cyclohexylalanine.
In a quest for the optimal C-terminal residue s-position), we replaced the pyrrolidine ring by several analogues such as pyrroline, thiazolidine, tetrahydropyridine, 4-, 6-, or 7- membered ring structures and acyclic amines, as indicated below.
Ile- H -O »e- Xaa—
8.1 8.2 2.1 Xaa = lie
2.2 Xaa = Lys
Xaa— N Xaa-N J Xaa— N J
8.3 Xaa = lie 8.5 Xaa = lie 8.7 Xaa = lie
8.4 Xaa = Lys 8.6 Xaa = Lys 8.8 Xaa = Lys
/ /
Lys-N^ lle-N lle-N \
8.9 8.10 8.11
/ lle-N lle-N
8.12 8.13
Results are summarized in Table 3. lie was used as a standard P2 amino acid. Lys identified as a good P2 amino acid for more potent and selective DPP II inhibition, was also used in combination with the P-i building blocks that revealed the most interesting results. The results of these series 7 must be compared to lle-Pyr (1.7) (IC50 for DPP II = 110 μM) and Lys-Pyrr (1.8) (IC50 for DPP II = 9.9 μM).
Table 3 Inhibitory activities and selectivity index for the above described compounds in series 8
Figure imgf000098_0001
Figure imgf000099_0001
aSI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II.
Taken the nitrogen out of the ring (8.1) or introducing a pyrroline ring (8.2), results in loss of DPP II as well as of DPP IV inhibition. This decrease in potency is also seen for the open structure pyrrolidides (8.10-8.13) and with introduction of 4- (8.9) or 7-membered (8.7, 8.8) rings. As already pointed out in the introduction thiazolidides have been reported to give an increase of both DPP II and DPP IV inhibition compared to the corresponding pyrrolidides. For the thiazolidides 2.1 and 2.2 the DPP II inhibition is increased with a factor 3 to 4, whereas inhibition of DPP IV increases slightly for lie (2.1) in P2, but decreases 8 times for Lys as P2 amino acid. Lys-Thia (2.2) is 3 times more active DPP II inhibitor (IC50 = 3 μM) and far more selective towards DPP IV (SI = 106) than Lys-Pyrr (1.7). The expected increase of DPP IV inhibition that occurs in general with the replacement of pyrrolidine by thiazolidine is notseen for this compound. Replacing the pyrrolidine ring by piperidine in 8.3 and 8.4, we can observe a 2 to 6-fold improvement of the DPP II inhibition. As reported earlier (Augustyns et al. Eur. J. Med. Chem., 1997, 32, 301-309), this introduction of a 6-membered ring gives a serious decrease in potency for DPP IV inhibitors. For DPP II inhibition, however, piperidine seems to be tolerated. Introducing a tetrahydropyridine in the P-i-position decreases as reported (Augustyns et al. Eur. J. Med. Chem., 1997, 32, 301-309) the DPP IV inhibition , but results only in an improvement of DPP II inhibition for lie (8.5) as P2-amino acid, while with Lys (8.6) the DPP II inhibition is only slightly affected.
Lys-Pip (8.4) came out as the most potent DPP ll-inhibitor in this series exhibiting an IC50 of 1.6 μM. This compound is also the most selective towards DPP IV with a selectivity index of 156.
To further explore the role of the P position, some 3-substituted pyrrolidides (9.1-9.6- see table 4) were evaluated for their DPP II inhibitory potency. A two-fold increase of DPP II inhibition is seen for the azide substitent (9.3 and 9.4). Lys-Pyrr-3-N3 has an IC50 of 4.9 μM and shows good selectivity towards DPP IV. With other substituents, the DPP II as well as the DPP IV inhibition decreases with exception of the fluorine. With this fluorine substituent (9.7), which is considered to be isosteric to a hydrogen, the inhibition of both enzymes is not affected.
,,R Xaa— N J
(9)
Table < Inhibitory activities and selectivity index of 3-substituted pyrrolidides (9)
Figure imgf000100_0001
aSI = selectiv ty index= IC50 value or IV d v e y 50 va ue or DPP II.
From these series 8 and 9, it appears that for DPP II inhibition a broader variation in the P-i position seems to be allowed, while for the inhibition of DPP IV the P-i-building block is restricted to pyrrolidine or thiazolidine. This conclusion can also be drawn from the earlier reported dipeptide α-aminoalkyl diphenyl phosphonates, where a broad set of various of P-, phosphonate building blocks was introduced (Senten et al. J. Comb. Chem, 2003). Most of these compounds inhibited DPP II to a moderate or high extent, whereas little or no inhibition of DPP IV was observed.
Recognizing the importance of the piperidine ring, a broad series of Xaa-piperidides (10) was synthesised. Results are sumarized in Table 5. The significance of this piperidine ring is again confirmed: compared to the pyrrolidide series (1), an increase in DPP II inhibition up to 6 times is observed, whereas inhibition of DPP IV decreased simultanously with a factor between 6 and 17. Therefore, changing pyrrolidine to piperidine results in a considerable increase in potency and selectivity for DPP II. With basic amino acids (Arg (10.1), His (10.3), and Lys (8.4)), high DPP II inhibitory activities are observed.
Xaa— > (10)
Table 5 Inhibitory activities and selectivity index of piperidides (10)
Figure imgf000101_0001
SI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II. bCha = cyclohexylalanine cDab = 2,4-diaminobutyric acid dDap = 2,3-diaminopropionic acid eAbu = 2-aminobutyric acid f Nva = norvaline
9Nle = norleucine
The side chain length ((CH2)nNH2) in Lys-Pip is investigated by replacing the P2 amino acid lysine (n = 4) (8.4) with respectively omithine (n = 3) (10.6), 2,4-diaminobutyric acid (n = 2) (10.7) and 2,3-diaminopropionb acid (n = 1 ) (10.11). Decreasing the side chain length to n = 2 enhanced the DPP II inhibitory potency. Further decrease of theside chain revealed a reduction in potency (10.11 , n = 1 ). Also selectivity was significantly improved since inhibition of DPP IV declined tremendously with decreasing side chain length. Dab- Pip (10.7) with an IC50 = 0.13 μM and a selectivity index of more than 7000 is the most active and most selective DPP II inhibitor in this series.
Blocking the side chain amino function in Lys-Pip and Dab-Pip with benzyloxycarbonyl (10.5, 10.9 respectively) afforded for Dab(Z)-Pip (10.9) a decrease in potency up to 9 times, whereas selectivity was reduced here by a factor 17. The significance of this side chain amino function is also revealed in compounds 10.12 to 10.14 where this amino function is omitted: the DPP II inhibition is decreased tremendously and these compounds show no selectivity at all towards DPP IV. The highest potency here is observed with 10.14 (n = 3, IC50 = 32.4 μM) and decreases slightly with decreasing chain length ((CH2)nCH3). From compounds 10.5, 10.9 and 10.12 to 10.14 we can assume that basic amino acids in P2 are preferable for DPP II inhibition, but moreover might benecessary to introduce selectivity. With D-Dab-PiP (10.8) the importance of the L-conflguration of the P2-amino acid for DPP II inhibition is confirmed, like is seen for DPP IV inhibition: a 1000- fold decrease in DPP II inhibitory activity is noticed.
The series of thiazolidides (2) (Table 6) was completed by combining thiazolidine with some interesting P2 amino acids from the previous series 10. In general, we observe for this Xaa-Thiazolidides compared to the pyrrolidide series (1)an enhancement in DPP II as well as in DPP IV inhibition with the exception of Lys-Thia (2.2) where DPP IV inhibition declined 8 times. Compared to the corresponding piperidides (10), these Xaa-thiazolidides (2) are no better DPP II inhibitors: depending on the P2 amino acid only a slight decrease or increase of the DPP II inhibition is observed. Selectivity, however, is significantly affected: for all these compounds the selectivity index decreased 2 to 22 times. Thiazolidides (2) are therefore less selective DPP II inhibitors compared to the corresponding piperiddes (10).
Xaa-N /--s
(2)
Table 6 Inhibitory activities and selectivity index of thiazolidides (2)
Figure imgf000102_0001
Figure imgf000103_0001
aSI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II. bDab = 2,4-diaminobutyric acid cCha = cyclohexylalanine
Thioxylation of the amide bond in Lys-thiazolidide leading to 4.1 (Table 6) afforded as expected a higher inhibition of DPP II. However, inhibition of DPP IV increased, which is in contrast with previous reports. Thioamides of some Xaa-piperidides are summarized in Table 7. In this series of Xaa Ψ[CS-N]-piperidides (11) dubious results are seen. Lys Ψ[CS-N]-piperidide (11.5) with an IC50 = 0.49 μM and a selectivity index of more than 2000 is an important progress compared to the corresponding amide Lys-Pip (8.4). We see a 3-fold increase in DPP II inhibitory potency while selectivity is greatly enhanced by a factor 13. Unfortunately, this increase in DPP II inhibition and selectivity as a result of thioxylation, is not seen with thioxylation of the more potent Dab-PiP (10.7). Dab Ψ[CS-N]-piperidide (11.3) exhibited an IC50 = 0.22 μM and is therefore a less active DPP II inhibitor compared to Dab-Pip (10.7). Selectivity is also declined although a selectivity index of more than 4000 can still be considered high.
Xaa -Ψ(CS-N) f Xaa-Ψ(CS-N);
11
Table 7 Thioxylated amides (4, 11)
Figure imgf000103_0002
aSI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II. bCha = cyclohexylalanine cDab = 2,4-diaminobutyric acid
Having identified Dab-Pip (10.7) as the most potent and selective inhibitor, some analogues were prepared by replacing the piperidine ring with respectively morfoline (12) and piperazine (13) (Table 8). The DPP II inhibitory activity is declined tremendously for Dab-piperazide (13), whereas for Dab-morfolide (12) the DPP II inhibition is decreased with a factor 4 and can still be considered as a potent DPP II inhibitor with a IC50 = 0.51 μM.
Dab-N O Dab-N NH
(12) (13)
Table 8 Inhibitory activities and selectivity index of Dab-Pip analogues
Figure imgf000104_0001
aSI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II.
Aminoacylpyrrolidide-2-nitriles are slow-binding, reversible inhibitors of DPP IV with approximately a 1000-fold increase in potency compared to the parent amino acyl pyrrolidides (low nM Kj) and a more than 500-fold selectivity against DPP II (Li et al. Arch. Biochem. Biophys., 1995, 323, 1 , 148-154). However, we investigated some dipeptide nitriles (14,15,16) for their DPP II inhibitory activity. The formulas for synthesised dipeptide nitriles (14, 15, 16) are provided below. Based on the frequently used Lys-Ala chromogenic substrate for measurement of DPP II activity, Lys-Ala-CN (14) was prepared. This compound (14) inhibits DPP II to a certain magnitude (IC50 = 84 μM) while a minimal DPP IV inhibition is observed. The cyanopyrrolidide analogue, Lys-Pyrr-2-CN (15) inhibited DPP II to a greater extent (IC50 = 1.0 μM), but appeared indeed to be a better inhibitor for DPP IV (IC50 = 0.30 μM). The selectivity could be reversed by replacing the pyrrolidine ring with piperidine. Compared to 15, Lys-Pip-2-CN (16.1) only slightly affect the DPP II inhibition while inhibitory activity of DPP IV declined with a factor 160. Compound 16.1 is therefore a more selective DPP II inhibitor compared to the cyanopyrrolidide analogue (15). However in comparison with Lys-Pip (8.4), no improvement in DPP II inhibitory potency is observed and is accompagnied by a 4-fold decrease in selectivity. It must be noticed that for this compound a mixture of diastereomers was tested: the inactive L-Lys-Pip-2(R)-CN and biological active -Lys-Pip- 2(S)-CN isomer.
Incorporation of a nitrile in Dab-Pip (10.7) enhanced the inhibition of DPP II with a factor 5. Dab-Pip-2-CN (16.2) exhibited an IC50 = 46 nM and can be regarded as the most active DPP II inhibitor in our investigation. However, for this compound (16.2) the selectivity index declined as well and is therefore less selective with respect to DPP IV compared to Dab-Pip (10.7).
Figure imgf000105_0001
14 15 16.1 Xaa = Lys
16.2 Xaa = Dab
Table 9 Inhibitory activities and selectivity index of dipeptide nitriles (14, 15 and 16).
Figure imgf000105_0002
aSI = selectivity index= IC50 value for DPP IV divided by IC50 value for DPP II. bThe compound tested was -Lys-Pip-2(R,S)-CN.
In conclusion, for DPP IV inhibition a significant increase in potency is seen for the 2- cyanopyrrolidices compared to the corresponding pyrrolidides. However, the increase in DPP II inhibition is not as distinct when going from piperidides to 2-cyanopiperHides. These investigated 2-cyanopiperidides (16.1 , 16.2) turned out to be less selective regarding to DPP IV than the parent piperidides.
In this example we were able to identify the most optimal N-terminal and C-terminal residue for potent and selective DPP II inhibition. Dab was selected as the most promising N-terminal amino acid with regard to DPP II inhibition and selectivity. The basic side chain amino function was proved to be essential for selective DPP II inhibition. Omitting this function or making it less basic by blocking it, decreased DPP II inhibitory potency and more important, the selectivity was negatively affected. In the quest for the most optimal Pi building block; piperidine was recognised as being superior over pyrrolidine and thiazolidine. Amino acyl thiazolidides (2) were more or less equipotentas DPP II inhibitors compared to the corresponding piperidides (10), but are regarded as less selective with respect to DPP IV. In this example, we observed that the nature of the Pi residue is less stringent for DPP II inhibition than it is for DPP IV inhibition. For DPP IV inhibition only pyrrolidide or thiazolidide is tolerated, while a large variety of P-i building blocks was allowed for DPP II inhibition, blocking this enzyme to a moderate or high extent.
Dab-Pip (10.7) has an IC50 = 130 nM and a selectivity index of more than 7000. Incorporation of a nitrile, leading to Dab-Pip-2-CN (16.2), increased potency with a factor 5. However, the selectivity index of this nitrile compound (16.2) declined to 3000 and is therefore less selective than compound 10.7. Both compounds are the most active and selective DPP II inhibitors reported to date. The high selectivity of these two compounds (10.7 and 16.2) must be emphasised. Val-Pyrr (1), identified as the most selective DPP IV inhibitor, is recently used in animal studies to evaluate the effects of DPP IV inhibitors in the treatment of type II diabetes. However, the IC50 value for DPP IV is only 56-fold lower than for DPP II and the selectivity towards DPP II can therefore be regarded as limited. One can argue if its selectivity is sufficient to study the role of DPP IV in biological systems. In this respect the Pro-Pro diaryl phosphonates reported (Belyaev et al. J. Med. Chem., 1999, 42, 1041-1052) by our group, with very low DPP II inhibitory activity, seems a better choice to selectively inhibit DPP IV.
These two compounds (10.7 and 16.2) may offer the opportunity to study the physiological role of DPP II and possible therapeutic benefits of DPP II inhibition. Their high selectivity will enable to differentiate between DPP II and DPP IV in biological systems. Both compounds can also serve as lead compounds for further development of DPP II inhibitors in our laboratory. According to this example, the structures of the most potent and selective DPP II inhibitors are the following:
Figure imgf000107_0001
10.7 R = H
16.2 R = CN
Experimentally, for preparing the compounds represented in this example, parallel synthesis was performed using the Quest 210 Organic Synthesizer (Argonaut Technologies). Boc-protected amino acids, N-cyclohexycarbodiimide, N'- methylpolystyrene resin (PS-carbodiimide) and tris-(2-aminoethyl)-amine polystyrene resin were purchased from Novabiochem. Other reagents were obtained from Sigma- Aldrich or Acros. Compounds 8.1 , 8.2, 8.5, 8.7, 8.10-8.13, 9.1, 9.3, 9.5, 9.7 were synthesised as reported earlier (Augustyns et al. Eur. J. Med. Chem., 1997, 32, 301-309).
Analysis
Characterisation of all compounds was done with 1H-NMR and mass spectrometry. 1H-
NMR were recorded on a Bruker Avance DRX-400 spectrometer (400 MHz). Fast Atom Bombardement (FAB+) mass spectra were obtained on a VG 70-SEQ hybrid mass spectrometer (Micromass, Manchester, UK), equipped with a cesium ion gun. Electrospray (ES+) mass spectra were acquired on a Autospec-ao-TOF mass spectrometer (Micromass, Manchester, UK) or a tripple quadruple mass spectrometer (Quattro II, Micromass, Manchester, UK) or a Bruker Esquire 3000 plus mass spectrometer. Purity was verified using two diverse HPLC systems using respectively mass and uv-detection. LC-MS were recorded on a Agilent 1100 Series HPLC system using a Discovery Cyano column (2.1 x 50 mm, 5μm, Supelco, Sigma-Aldrich) coupled with a Bruker Esquire 3000 plus mass spectrometer (0-80% ACN, 22 min, 0.2 ml/min). Reverse phase HPLC was run on a Gilson instrument (Viliers-le-bel, France) equipped with an Ultrasphere ODS column (4.6 x 250 mm, 5 μm, Beckman, Fullerton, CA, USA) and a uv-detector (10-100% ACN, 35 min, 214 nm, 1 ml/min). Preparative TLC was performed on Silicagel 60PF254 containing gypsum.
Biochemical Evaluation DPP IV was purified from human seminal plasma as described previously (De Meester et al. J. Immunol. Methods 1996, 189, 99 105). DPP II was isolated from the same source using techniques described previously for purification of the enzyme from porcine seminal plasma (Huang et al. Biochim. Biophys. Acta 1996, 1290, 149 156), supplemented with adenosine deaminase affinity chromatography to eliminate contaminating DPP IV(De Meester et al. J. Immunol. Methods 1996, 189, 99 105). Enzyme activity was measured kinetically with the chromogenic substrates Gly-Pro-p-nitroanilide at pH 8.3 and Lys-Ala-p- nitroanilide at pH 5.5 for DPP IV and DPP II respectively. Test compounds were dissolved and diluted in DMSO (final concentration DMSO during assay 5% v/v). Highest concentration of compounds tested is 1 mM. IC50 value was defined as the inhibitor concentration, which caused a 50% decrease of the activity under assay conditions.
General procedure for synthesis of compounds 1, 2, 4, 8.3-8.9, 10, 11 , 12 and 13 These series were prepared by parallel synthesis using a PASP-protocol Senten et al. Tetrahedron Lett.., 2001 , 42, 9135-9138): protected amino acids (0.375 mmol), HOBt (0.425 mmol) and PS-Carbodiimide (0.75 mmol) were added to a dry reaction vessel. Dichloromethane (4 ml) was added and the mixture was stirred for 10 min prior to the addition of the appropriate amine (respectively pyrrolidine (1), thiazolidine (2, 4), 1,2,5,6- tetrahydropyridine (8.5, 8.6), hexamethyleneimine (8.7, 8.8), azetidine (8.9), piperidine (10, 11), morfoline (12) and Boc-piperazine (13)). After stirring at room temperature overnight the polymer-bound polyamine (1.5 mmol) was added and stirring was continued for 5 h. The reaction mixture was filtered and the amide product was collected in the filtrate. The resins are washed two times with 4 ml of dichloromethane and the combined fractions were evaporated under reduced pressure. The purity of the compounds was checked by TLC and reverse phase HPLC. Compounds were purified by preparative TLC using a mixture of EtOAc and hexane (usually 40/60) as eluent.
General procedure for fert-bytyloxycarbonyl (Boc) -deprotection
Deprotection was done by dissolving in 4 ml of a TFA/dichloromethane (1:1) mixture. The solution was stirred for 3 h and the volatile part was removed under reduced pressure. After coevaporating several times with ether, the residues were lyophilised from tert- butanol/water (4:1).
1-(L-Alanyl)pyrrolidine trifluoroacetate (1.1)
1H-NMR (D20, 400 MHz) δ 1.44 (d, 3H, CH3), 1.84-1.97 (m, 4H, CH2), 3.34-3.56 (m, AH,
CH2), 4.26 (m, 1H, α-CH); MS (ES+) m/z 143 (M + H)+.
1-(L-Asparaginyl)pyrtOlidine tifluoroaceiaie (1.2). 1H-NMR (D20, 400 MHz) δ 1.78-1.95 (m, 4H, CH2), 2.71 (dd, 1 H, CH2), 2.84 (dd, 1 H, CH2), 3.28-3.56 (m, H, CH2), 4.47 (t, 1H, α-CH); MS (FAB+) m/z 186 (M + H)+. 1-(L-Aspartyl)pyrrolidine trifluoroacetate (1.3).
1H-NMR (D20, 400 MHz) δ 1.84-1.97 (m, 4H, CH2), 2.86 (dd, 1H, CH2), 3.02 (dd, 1H,
CH2), 3.36-3.59 (m, 4H, CH2), 4.54 (t, 1H, α-CH); MS (FAB+) m/z 186 (M + Na)+.
1-(S-Cyclohexylalanyl)pyrrolidine trifluoroacetate (1.4). 1H-NMR (DMSO-dβ), 400 MHz) δ 0.70-2.00 (m, 17H, CH2, CH), 3.20-3.70 (m, 4H, CH2),
3.95-4.10 (m, 1H, α-CH), 8.30 (brs, 3H, NH3 +); MS (FAB+) m/z 224 (M + Na)+.
1-(L-Glycyl)pyrrolidine trifluoroacetate (1.5).
1H-NMR (D20, 400 MHz) δ 1.82-1.98 (m, 4H, CH2), 3.36-3.42 (m, 4H, CH2), 3.86 (s, 2H,
CH2); MS (ES+) m/z 129 (M + H)+. 1-(L-Histidyl)pyrrolidine ditrifluoroacetate (1.6).
1H-NMR (D20, 400 MHz) 1.90-2.01 (m, 4H, CH2), 3.22-3.28 (m, 1H, ^CH2), 3.44-3.57
(m, 4H, CH2), 3.64-3.69 (m, 1 H, ^CH2), 4.65 (t, 1 H, α-CH), 7.52 (s, 1H, 4H-His), 8.78 (s,
1H, 2H-His); MS (ES+) m/z 209 (M + H)+. l-(L-lsoleucyl) pyrrolidine ditrifluoroacetate (1.7). 1H-NMR (DMSO-d6, 250 MHz) £0.85 (t, 3H, δ-CH3), 0.93 (d, 3H, ^CH3), 1.05-1.20 (m, 1H, γ-CH2), 1.40-1.60 (m, 1 H, ^CH2), 1.70-2.00 (m, 5H, >3-CH, CH2), 3.25-3.70 (m, 4H, CH2),
3.93 (m, 1 H, α-CH), 8.14 (s, 3H, NH3 +); MS (FAB+) m/z 185 (M + Na)+.
1-(L-Lysyl)pyrrolidine ditrifluoroacetate (1.8).
1H-NMR (D20, 400 MHz) £ 1.42-1.48 (m, 2H, CH2), 1.63-1.71 (m, 2H, CH2), 1.83-2.00 (m, 6H, β-CH2, CH2), 2.96 (t, 2H, ε-CH2), 3.35-3.60 (m, 4H, CH2), 4.26 (t, 1 H, α-CH); MS (ES+) m/z 200 (M + H)+.
1-(L-Seryl)pyrrolidine trifluoroacetate (1.9).
1H-NMR (D20, 400 MHz) £ 1.78-1.95 (m, 4H, CH2), 3.32-3.56 (m, 4H, CH2), 3.81 (dd, 1H,
CH2), 3.90 (dd, 1H, CH2), 4.29 (t, 1H, α-CH); MS (FAB+) m/z 159 (M + H)+. 1-(L-Phenylalanyl)pyrrolidhe trifluoroacetate (1.10).
1H-NMR (D20, 400 MHz) £1.50-1.78 (m, 4H, CH2), 2.56-2.62 (m, 1H, CH2), 3.06-3.19 (m,
2H, CH2), 3.24-3.39 (m, 3H, CH2), 4.42 (t, 1 H, α-CH), 7.21 (m, 2H, o-Harom), 7.31-7.38 (m,
3H, m-, p-Harom); MS (ES+) m/z 219 (M + H)+.
1-(L-Prolyl)pyrnolidine Irifluoroacetate (1.11). 1H-NMR (D20, 400 MHz) £ 1.86-2.07 (m, 7H, ?-CH2-, ^CH2, CH2), 2.45-2.54 (m, 1 H, β-
CH2), 3.31-3.56 (m, 6H, £-CH2, CH2), 4.51 (t, 1H, α-CH); MS (ES+) m/z 169 (M + H)+.
1-(S-Thiaprolyl) pyrrolidine trifluoroacetate (1.12).
1H-NMR (D20, 400 MHz) £ 1.86-2.01 (m, 4H, CH2), 3.17 (dd, 1H, ^CH2), 3.37-3.59 (m,
4H, CH2), 3.63 (m, 1H, ^-CH2), 4.39 (d, 1H, £-CH2), 4,48 (d, 1H, £-CH2), 4.75-4.84 (m, 1 H, α-CH); MS (ES+) m/z 187 (M + H)+. '\-(L-Tyrosyl)pyrrolidine trifluoroacetate (1.13).
1H-NMR (D20, 400 MHz) £ 1.51-1.80 (m, 4H, CH2), 2.56-2.62 (m, 1H, CH2), 2.98-3.14 (m,
2H, CH2), 3.24-3.40 (m, 3H, CH2), 4.37 (t, 1 H, α-CH), 6.84 (d, 2H, 3-,5-Harom), 7.12 (d, 2H,
2-,6-Harom); MS (ES+) m/z 235 (M + H)+. 1-(L-Valyl)pyrrolidine Mluoroaceiaie (1.14).
1H-NMR (D20, 400 MHz) £ 0.97 (d, 3H, CH3), 1.02 (d, 3H, CH3), 1.82-1.98 (m, 4H, CH2),
2.18-2.26 (m, 1H, ^-CH2), 3.38-3.60 (m, 4H, CH2), 4.06 (d, 1 H, α-CH); MS (ES+) m/z 171
(M + H)+.
1-(L-lsoleucyl)thiazolidine trifluoroacetate (2.1). H-NMR (CDCI3, 400 MHz) £ 0.9-1.38 (m, 7H, CH3, CH2), 1.52-1.67 (m, 1H, CH2), 1.90-
2.02 (m, 1H, CH), 2.98-3.15 (m, 2H, 5-CH2), 3.69-3.80 (m, 1 H, 4-CH2), 3.88-4.02 (m, 1H,
4-CH2), 4.12-4.23 (m, 1H, α-CH), 4.41-4.68 (m, 2H, 2-CH2); MS (ES+) m/z 203 (M + H)+.
1-(L-Lysyl)thiazolidine trifluoroacetate (2.2).
1H-NMR (D20, 400 MHz) £1.81-2.11 (m, 6H, CH2), 3.15-3.29 (m, 4H, ε-CH2, 5-CH2), 3.82- 4.04 (m, 2H, 4-CH2), 4.60-4.82 (m, 3H, 2-CH2, α-CH); MS (ES+) m/z 218 (M + H)+.
1-(S-Ornithyl)thiazolidine trifluoroacetate (2.3).
1H-NMR (D20, 400 MHz) £ 1.83-1.91 (m, 2H, ^CH2), 2.05-2.10 (m, 2H, β-CH2), 3.12 (t,
2H, 5-CH2), 3.20 (t, 1H, £-CH2), 3.27 (t, 1H, £-CH2), 3.83-4.08 (m, 2H, 4-CH2), 4.52 (t,
0.5H, α-CH), 4.57 (t, 0.5H, α-CH), 4.59-4.84 (m, 2H, 2-CH2); MS (ES+) m/z 203 (M + H)+. 1-(S-2,4-Diaminobutanoyl)thiazolidhe trifluoroacetate (2.4).
1H-NMR (D20, 400 MHz) £ 2.34-2.40 (m, 2H, ^CH2), 3.18-3.28 (m, 4H, rCH2, 5-CH2),
3.84-4.07 (m, 2H, 4-CH2), 4.55-4.84 (m, 3H, 2-CH2, α-CH); MS (ES+) m/z 190 (M + H)+.
1-(S-Cyclohexylalanyl)thiazolidine trifluoroacetate (2.5).
1H-NMR (D20, 400 MHz) £0.84-2.05 (m, 13H, CH2, CH), 3.02-3.16 (m, 2H, 5-CH2), 3.84- 4.07 (m, 2H, 4-CH2), 4.20-4.25 (m, 1 H, α-CH), 4.41-4.68 (m, 2H, 2-CH2); MS (ES+) m/z
243 (M + H)+.
1-(L-Lysyl)-1,2,5,6-tetrahydropyridine tifluoroacetate (8.6).
1H-NMR (D20, 400 MHz) £ 1.45-1.55 (m, 2H, CH2), 1.69-1.81 (m, 2H, CH2), 1.91-2.00 (m,
2H, CH2), 2.23-2.36 (m, 2H, 5-CH2), 3.05 (b, 2H, £-CH2), 3.62-3.81 (m, 2H, 6-CH2), 4.03- 4.17 (m, 2H, 2-CH2), 4.55 (t, 0.5H, α-CH), 4.62 (t, 0.5H, α-CH), 5.75-5.82 (m, 1H, 4-CH),
5.96-6.06 (m, 1H, 3-CH); MS (ES+) m/z 212 (M + H)+.
1-(L-Lysyl)hexamelhyleneimine tifluoroacetate (8.8).
1H-NMR (D20, 400 MHz) £1.51-1.66 (m, 6H, CH2), 1.72-1.86 (m, 6H, CH2), 1.94-2.00 (m,
2H, CH2), 3.06 (t, 2H, £-CH2), 3.39-3.56 (m, 2H, CH2), 3.62-3.74 (m, 2H, CH2), 4.53 (t, 1 H, α-CH); MS (ES+) m/z 228 (M + H) . 1-(L-Lysyl)azetidine trifluoroacetate (8.9).
1H-NMR (D20, 400 MHz) £ 1.43-1.57 (m, 2H, CH2), 1.70-1.80 (m, 2H, CH2), 1.85-1.96 (m,
2H, CH2), 2.35-2.48 (m, 2H, 3-CH2), 3.05 (br s, 2H, ≤-CH2), 4.06-4.29 (m, 3H, CH2, α-CH),
4.39-4.44 (m, 1H, 3-CH); MS (ES+) m/z 186 (M + H)+. 1-(L-Arginyl)piperidhe ditrifluoroacetate (10.1).
1H-NMR (D20, 400 MHz) £1.50-1.80 (m, 8H, CH2), 1.92-2.00 (m, 2H, CH2), 3.25-3.38 (m,
2H, £-CH2), 3.44-3.77 (m, 4H, CH2), 4.60-4.70 (m, 1H, α-CH); MS (ES+) m/z 242 (M + H)+;
LC-MS rt 0.4-0.5 min, m/z 242 (M + H)+; UV-HPLC rt 4.58 min, 91%.
1-(S-Cyclohexylalanyl)pipe dine Mluoroacelaie (10.2). 1H-NMR (D20, 400 MHz) £ 0.91-1.79 (m, 19H, CH2), 3.40-3.53 (m, 4H, 2-CH2, 6-CH2),
4.49 (t, 1H, α-CH); MS (ES+) m/z 239 (M + H)+; LC-MS rt 1.0-1.4 min, m/z 239 (M + H)+;
UV-HPLC rt 23.49 min, 100%.
1-(L-Histidyl)piperidire ditrifluoroacetate (10.3).
1H-NMR (D20, 400 MHz) £ 1.52-1.79 (m, 6H, 3-CH2, 4-CH2, 5-CH2), 3.31-3.72 (m, 6H, β- CH2, 2-CH2, 6-CH2), 4.81-4.93 (m, 1H, α-CH), 7.54 (s, 1 H, 4-CH-His), 8.81 (s, 1H, 2-CH-
His); MS (ES+) m/z 223 (M + H)+; LC-MS rt 0.3-0.5 min, m/z 223 (M + H)+; UV-HPLC rt
4.04 min, 88%.
1-(L-lsoleucyl)piperidine tifluoroacetate (8.3).
1H-NMR (DMSO-de, 400 MHz) £ 0.85 (t, 3H, £-CH3), 0.94 (d, 3H, rCH3), 1.00-1.25 (m, 1 H, CH), 1.35-1.70 (m, 7H,
Figure imgf000111_0001
3.20-
3.65 (m, 4H, 2-CH2, 6-CH2), 4.25 (d, 1H, α-CH), 8.07 (br s, 3 H, NH3+); MS (ES+) m/z 199
(M + H)+; LC-MS rt 0.6-0.7 min, m/z 199 (M + H)+; UV-HPLC rt 11.30 min, 100%.
1-(L-Seryl)piperidine trifluoroacetate (10.4).
1H-NMR (D20, 400 MHz) £1.59-1.73 (m, 6H, CH2), 3.50-3.64 (m, 4H, CH2), 3.90-3.95 (m, 1H, ^-CH2), 4.02-4.06 (m, 1H, ^-CH2), 4.62-4.68 (m, 1 H, α-CH); MS (ES+) m/z 173 (M +
H)+; LC-MS rt 0.5-0.6 min, m/z 173 (M + H)+; UV-HPLC rt 4.91 min, 93%.
I-(L-Lysyl) piperidine ditrifuoroacetate (8.4).
1H-NMR (D20, 400 MHz) £1.34-1.87 (m, 12H, CH2), 2.95 (t, 2H, ε-CH2), 3.43-3.53 (m, 4H,
CH2), 4.50 (t, 1H, α-CH), MS (ES+) m/z 214 (M + H)+; LC-MS rt 0.3-0.5 min, m/z 214 (M + H)+; UV-HPLC rt 2.59 min, 86%.
1-(N-ε-(Benzyloxycarbonyl)-L-Lysyl )piperidine ditrifluoroacetate (10.5).
1H-NMR (D20, 400 MHz) £ 1.37-1.76 (m, 10H, CH2), 1.84-1.98 (m, 2H, CH2), 3.14-3.28
(m, 2H, £-CH2), 3.41-3.68 (m, 4H, CH2), 4.47-4.57 (m, 1H, α-CH), 5.11-5.26 (m, 2H, CH2-
Z), 7.49 (s, 5H, Harom); MS (ES+) m/z 348 (M + H)+; LC-MS rt 1.6-1.9 min, m/z 348 (M + H)+; UV-HPLC rt 14.59 min, 100%. l-(S-Ornithyl) piperidine ditrifuoroacetate (10.6).
1H-NMR (D20, 400 MHz) £1.59-1.91 (m, 8H, CH2), 1.97-2.03 (m, 2H, CH2), 3.11 (t, 2H, £-
CH2), 3.53-3.66 (m, 4H, CH2), 4.66 (t, 1H, α-CH); MS (ES") m/z 200 (M + H)+; LC-MS rt
0.4-0.6 min, m/z 200 (M + H)"; UV-HPLC rt 3.74 min, 100%. 1-(S-2.4-Diaminobuianoyl)piρe dine ditifluoroaceiate ( 10.7)).
1H-NMR (D20, 400 MHz) £ 1.59-1.73 (m, 6H, CH2), 2.27-2.34 (m, 2H, ^-CH2), 3.12-3.23
(m, 2H, ^CH2), 3.50-3.71 (m, 4H, CH2), 4.72 (t, 1 H, α-CH); MS (ES+) m/z 186 (M + H)";
LC-MS rt 0.5-0.6 min, m/z 186 (M + H)+; UV-HPLC rt 3.62 min, 100%.
1-(D-2.4-diaminobuianoyl)pipe dine diiήfuoroacelate (10.8). 1H-NMR (D20, 400 MHz) £ 1.50-1.62 (m, 6H, CH2), 2.15-2.21 (m, 2H, ^-CH2), 3.02-3.11
(m, 2H, rCH2), 3.41-3.59 (m, 4H, CH2), 4.61 (t, 1 H, α-CH); MS (ES") m/z 186 (M + H)";
LC-MS rt 0.4-0.5 min, m/z 186 (M + H)"; UV-HPLC rt 4.66 min, 100%.
1~(S-2,4-benzyloxycarbonyl-diaminobutanoyi)piperidine tifluoroacetate (10.9).
1H-NMR (D20, 400 MHz) £ 1.20-1.71 (m, 6H, CH2), 1.85-2.05 (m, 2H, ^-CH2), 3.29-3.55 (m, 6H, CH2, rCH2), 4.44 (m, 1 H, α-CH), 5.13 (s, 2H, CH2), 7.43 (s, 5H, Harom); MS (ES") m/z 320 (M + H)+; LC-MS rt 1.1-1.2 min, m/z 320 (M + H)"; UV-HPLC rt 14.85 min, 97%.
1-(S-2-benzyloxycarbonyl,4-diaminobutano i)piperidine tifluoroacetate (10.10).
1H-NMR (D20, 400 MHz) £ 1.41-1.71 (m, 6H, CH2), 1.98-2.17 (m, 2H, ^-CH2), 3.02-3.76
(m, 6H, rCH2, CH2), 4.70-4.85 (m, 1H, α-CH), 5.17 (s, 2H, CH2), 7.46 (s, 5H, Harom); MS (ES") m/z 320 (M + H)+; LC-MS rt 0.4-0.6 min, m/z 320 (M + H)"; UV-HPLC rt 14.48 min,
96%.
1-(S-2.3-diaminopropanoyl)piperidineditrifluoroacetate (10.11).
1H-NMR (D20, 400 MHz) £ 1.57-1.81 (m, 6H, CH2), 3.42-3.85 (m, 6H, CH2, y#-CH2), 4.97
(m, 1H, α-CH); MS (ES+) m/z 172 (M + H)"; LC-MS rt 0.4-0.5 min, m/z 172 (M + H)"; UV- HPLC rt 3.60 min, 100%.
1-(S-2-Aminobutanoyl)piperidine trifluoroacetate (10.12).
1H-NMR (D20, 400 MHz) £1.05 (t, 3H, CH3), 1.63-1.77 (m, 6H, CH2), 1.89-2.00 (m, 2H, β-
CH2), 3.50-3.68 (m, 4H, CH2), 4.52 (t, 1H, α-CH); MS (ES") m/z 171 (M + H)+; LC-MS rt
0.5-0.6 min, m/z 171 (M + H)"; UV-HPLC rt 7.92 min, 96%. 1-(S-Norvalyl)piperidine trifluoroacetate (10.13).
1H-NMR (D20, 400 MHz) £ 1.01 (t, 3H, CH3), 1.41-1.51 (m, 2H, ^CH2), 1.59-1.78 (m, 6H,
CH2), 1.85-1.89 (m, 2H, ^-CH2), 3.50-3.68 (m, 4H, CH2), 4.55 (t, 1 H, α-CH); MS (ES+) m/z
185 (M + H)"; LC-MS rt 0.7-0.8 min, m/z 185 (M + H)"; UV-HPLC rt 9.91 min, 100%.
1-(S-Norleucyl)piperidine trifluoroacetate (10.14). 1H-NMR (D20, 400 MHz) £ 0.95 (t, 3H, CH3), 1.30-1.42 (m, 4H, CH2), 1.59-1.76 (m, 6H,
CH2), 1.87-1.90 (m, 2H, ^-CH2), 3.49-3.69 (m, 4H, CH2), 4.54 (t, 1 H, α-CH); MS (ES") m/z
199 (M + H)"; LC-MS rt 0.5-0.7 min, m/z 199 (M + H)+; UV-HPLC rt 11.96 min, 96%.
4-(L-2.4-diaminobuianoyl)iTDrfoline ditrifluoroacetate (12).
1H-NMR (D20, 400 MHz) £2.27-2.38 (m, 2H, ^-CH2), 3.12-3.28 (m, 2H, rCH2), 3.61-3.85
(m, 8H, CH2), 4.71 (t, 1 H, α-CH); MS (ES") m/z 188 (M + H)+.
1-(L-2.4-diaminobutanoyl)piperazine tilrifluoroacetate (13).
1H-NMR (D20, 400 MHz) £2.25-2.40 (m, 2H, ^-CH2), 3.12-3.28 (m, 2H, rCH2), 3.33-3.50
(m, 4H, CH2),), 3.75-4.15 (m, 4H, CH2) 4,76 (t, 1H, α-CH); MS (ES") m/z 187 (M + H)".
General procedure for synthesis of thioamides (4, 11 )
The protected amino acids amides (respectively 2 and 10) were prepared by paralel synthesis using the PASP-protocol. Thioxylation of these compounds was performed according to the following procedure: To a solution of the Boc-protected amino acid amides (2 eq) in 5 ml of toluene was added 2,4-bis(p-methoxyphenyl)-1 ,3- dithiadiphosphatane 2,4-disulfide (Lawesson's reagent) (1 eq). The reaction mixture was stirred for 2 h at 80°C. The solvent was removed by evaporation and the crude compound was purified by preparative TLC (EtOAc/hexane, 40:60). Pure compounds were deprotected according to the general procedure. Lys ΨfCS-NJ-Thia (4.1).
1H-NMR (D20, 400 MHz) £1.43-1.80 (m, 4H, CH2), 1.95-2.07 (m, 2H, CH2), 3.04-3.34 (m, 4H, £-CH2, 5-CH2), 4.00-4.28 (m, 2H, CH2), 4.57-4.68 (m, 1H, α-CH), 4.80-5.09 (m, 2H, 2- CH2); MS (ES+) m/z 234 (M + H)". Cha Ψ[CS-N]-Pip (11.1). 1H-NMR (D20, 400 MHz) δ 0.95-2.1 (m, 19H, CH2, CH), 3.71-3.90 (m, 2H, CH2), 4.15-4.39 (m, 2H, CH2), 4.62-4.75 (m, 1H, α-CH); MS (ES+) m/z 255 (M + H)". lie Ψ[CS-N]-Pip (11.2).
1H-NMR (D20, 400 MHz) £0.95-1.08 (m, 6H, CH3), 1.10-2.12 (m, 9H, CH2, CH), 3.10-3.26 (m, 1H, CH2), 3.71-3.95 (m, 2H, CH2), 4.1-4.21 (m, 1H, CH2), 4.42-4.50 (m, 0.5H, α- CH),4.6-4.76 (m, 0.5H, α-CH); MS (ES") m/z 215 (M + H)". Dab Ψ[CS-N]-Pip (11.3).
1H-NMR (D20, 400 MHz) £ 1.61- 1.63 (m, 6H, 3-CH2, 4-CH2, 5-CH2), 2.30-2.35 (m, 2H, β- CH2), 3.10-3.26 (m, 2H, rCH2), 3.82-3.98 (m, 2H) and 4,12-4.20 (m, 1 H) and 4.36-4.44 (m, 1H) (2-CH2, 6-CH2), 4.91 (t, 1H, α-CH); MS (ES+) m/z 202 (M + H)". Orn ΨfCS-Nj-Pip (11.4). 1H-NMR (D20, 400 MHz) £ 1.82-1.99 (m, 8H, CH2), 2.03-2.09 (m, 2H, ^-CH2), 3.12 (t, 2H, £-CH2), 3.89-4.03 (m, 2H, CH2), 4.20-4.27 (m, 1H, CH2), 4.42-4.48 (m, 1H, CH2), 4.90 (t, 1 H, α-CH); MS (ES") m/z 216 (M + H)". Lys [CS-NJ-Pip (11.5). 1H-NMR (D20, 400 MHz) £1.43-1.62 (m, 2H) and 1.71-1.83 (m, 8H) (rCH2, £-CH2, 3-CH2, 4-CH2, 5-CH2), 1.93-2.00 (m, 2H, ^-CH2), 3.04 (t, 2H, f-CH2), 3.80-3.96 (m, 2H) and 4.07- 4.22 (m, 1H), 4.34-4.41 (m, 1 H) (2-CH2, 6-CH2), 4.74- 4.79 (m, 1H, α-CH); MS (ES") m/z 230 (M + H)".
3-Substituted pyrrolidide analogues were synthesised from 1-rN-(tert-butyloxycarbonyl)-L- lysyll-3(R,S)-hydroxy-pyrrolidine.
1-(L-Lysyl)-3(R,S)-hydroxypyrrolidine trifluoroacetate (9.2).
To a mixture of N-(tert-butyloxycarbonyl)-L-lysine (1.1 eq, 2.28 g), triethylamine (3 eq, 2.53 ml) and TBTU (1.1 eq, 2.12 g) in DMF (40 ml) was added (R,S)-3-hydroxypyrrolidine (1 eq, 522 mg). After stirring at room temperature overnight, water was added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with 1N HCI (2 x 25 ml), 5% NaHC03 (2 x 25 ml) and brine (25 ml). The organic layer was dried over NaS0 , evaporated and purified by column chromatography yielding 1-[N-(tert- butyloxycarbonyl)-L-lysyl]-3(R,S)-hydroxy-pyrrolidine (87%). This Boc-protected compound was treated with a mixture of TFA/DCM (1/1 , 10 ml) at room temperature. The title compound was obtained after evaporation and coevaporation with diethylether. 1H-NMR (D20, 400 MHz) δ 1.48-1.68 (m, 2H, CH2), 1.71-1.80 (m, 2H, CH2), 1.93-2.25 (m, 4H, CH2), 3.06 (br s, 2H, ε-CH2), 3.54-3.88 (m, 4H, CH2), 4.27-4.42 (m, 1H, α-CH), 4.57- 4.66 (m, 1H, 3-CH); MS (ES") m/z 216 (M + H)". 1-(L-Lysyl)-3(R,S)-azidopyrrolidine trifluoroacetate (9.4).
To a solution of 1-[N-(tert-butyloxycarbonyl}-L-lysyl]-3(R,S)-hydroxypyrrolidine (1.5 mmol, 620 mg) in dry 1.2-dichloroethane (20 ml) was added triethylamine (4.5 mmol, 574 μl) and p-toluenesulphonyl chloride (2.5 mmol, 457 mg) at 0°C. The mixture was stirred at room temperature for 48 h (after 24 h an second addition of p-toluenesulphonyl chloride (1.5 mmol) occured). Water (30 ml) was added and the mixture was extracted with CH2CI2 (2 x 80 ml). The organic layer was washed with 5% NaHC03 (2 x 50 ml), dried, evaporated and purified by column chromatography (CHCI3) yielding 1-[N-(terl-butyloxycarbonyl)-L- lysyl]-3(R,S)-azidoyrrolidine (70%). A solution of this compound (0.95 mmol, 540 mg) in DMF (15 ml) was treated with NaN3 (4.75 mmol, 390 mg) and stirred at 80 °C for 5 h. EtOAc (50 ml) was added and the resulting mixture was washed with 5% NaC03 (2 x 30 ml). The organic layer was dried, evaporated and purified by column chromatography yielding a pale yellow oil. Deprotection was done according to the general procedure to yield the title compound. 1H-NMR (D20, 400 MHz) δ 1.49-1.60 (m, 2H, CH2), 1.72-1.82 (m, 2H, CH2), 1.94-2.03 (m, 2H, CH2), 2.17-2.38 (m, 2H, 4-CH2), 3.07 (br s, 2H, ε-CH2), 3.56- 3.99 (m, 4H, CH2), 4.30-4.42 (m, 1H, α-CH), 4.46-4,55 (m, 1H, 3-CH); MS (ES") m/∑ 241 (M + H)+.
1-(L-Lysyl)-3(R,S)-benzoyloxypyrrolidine tifluoroacetate (9.6).
A solution of 1-[N-(tert-butyloxycarbonyl)-L-lysyl]-3(R,S)-hydroxypyrrolidine (1.16 mmol, 480 mg) in dry pyridine (15 ml) was treated with benzoyl chloride (1.28 mol, 148 μl) at 0 °C and stirred for 3 h at room temperature. After cooling the reaction mixture to 0 °C, water was added to the residue and solvents were evaporated. Dichloromethane was added to the redidue and the mixture was washed with 5% NaHC03. The organic layer was dried, evaporated and purified by preparative TLC using EtOAc as eluent to yield the pure 1-[N-(tert-butyloxycarbonyl)-L-lysyl]-3(R,S)-benzoyloxypyrrolidine as an oil (53%). Deprotection was done according to the general procedure to yield the title compound.
1H-NMR (D20, 400 MHz) δ 1.44-1.60 (m, 2H, CH2, 4H, CH2), 2.31-2.52 (m, 2H, CH2), 2.55-2.70 (m, 0.5H, ε-CH2), 2.90 (br s, 0.5H, ε-CH2), 3.08 (br s, 1 H, ε-CH2), 3.72-4.05 (m, 4H, CH2), 4.34-4.46 (m, 1 H, α-CH), 5.62-5.73 (m, 1H, 3-CH), 7.56-7.64 (m, 2H, m-Harom), 7.72-7.81 (m, 1H, p-Harom), 8.05-8.12 (m, 2H, o-Harom); MS (ES") m/z 320 (M + H)".
General procedure for the synthesis of dipeptide nitriles(14, 15 and 16). To a mixture of Boc-Xaa-OH (1.1 eq), triethylamine (3 eq) and TBTU (1.1 eq) in DMF was added YaaNH2 (1 eq) (AlaNH2 and ProNH2 were commercially available; L-HomoProNH2 was prepared from L-pipecolinic acid (1 eq) by reaction with N-hydroxysuccinimide (1.05 eq) and dicyclohexylcarbodiimide (DCC, 1.05 eq) in DCM (yield: 90%), followed by treatment of a solution in dioxanewith ammonium gas (yield: 99%). After stirring overnight at room temperature, water was added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with 1 N HCI (2 x 25 ml), 5% NaHC03 (2 x 25 ml) and brine (25 ml). The organic layer was dried over NaS04, evaporated and purified by column chromatography yielding of Boc-Xaa-YaaNH2 (86%). Dehydratation of the amide function to the nitrile was done according the following procedure: To a solution of Boc-Xaa-YaaNH2 (1 eq) and imidazol (2 eq) in pyridine at -30 °C was slowly added phosphorusoxychloride (4 eq). The solution was allowed to attain room temperature and the reaction was monitored by TLC. After completion of the reaction the solvent was evaporated and the residue was extracted with 1 N HCI and diethylether. The organic layer was dried, evaporated and the residue was purified by prepartive TLC to yield the Boc protected dipeptide nitrile (60%). Boc deprotection was done according to the general procedure.
2-amino-2-(L-Lysyl)propaneniirile ditrifluoroacetate (14). 1H-NMR (D20, 400 MHz) δ 1.43-1.57 (m, 2H, CH2), 1.61 (d, 3H, CH3), 1.69-1.78 (m, 2H,
CH2), 1.91-2.01 (m, 2H, CH2), 3.03 (t, 2H, ε-CH2), 4.04 (t, 1H, α-CH), 4.79-4.89 (m, 1H, α-
CH); MS (FAB") m/z 199 (M + H)".
1-(L-Lysyl)-2(S)-cyanopyrrolidine ditrifluoroacetate (15).
1H-NMR (D20, 400 MHz) δ 1.50-1.53 (m, 2H, CH2), 1.72-1.77 (m, 2H, CH2), 1.98-2.12 (m, 2H, CH2), 2.14-2.26 (m, 2H, CH2), 2.32-2.43 (m, 2H, CH2), 3.02-3.06 (m, 2H, ε-CH2), 3.70-
3.74 (m, 2H, 5-CH2), 4.37 (t, 1H, α-CH), 4.83-4.88 (m, 1H, α-CH); MS (FAB") m/z 225 (M
+ H)+.
1-(L-Lysyl)-2(R,S)-cyanopiperidne ditrifluoroacetate (16.1).
1H-NMR (D20, 400 MHz) δ 1.42-1.63 (m, 3H, CH2), 1.71-2.02 (m, 8H, CH2), 2.18-2.29 (m, 1H, CH2), 3.00-3.41 (m, 2H, 6-CH2), 3.46-3.50 (m, 1H, ε-CH2), 3.88-4.00 (m, 1H, ε-CH2),
4.53-4.67 (m, 1 H, α-CH), 5.69-5.88 (m, 1H, 2-CH); MS (ES") m/z 239 (M + H)".
1-(L-2,4-Diaminobutanoyi)-2(S)-cyanopiperidine ditriHuoroacetate (16.2).
1H-NMR (D20, 400 MHz) δ 1.50-1.68 (m, 1H, CH2), 1.72-2.00 (m, 4H, CH2), 2.08-2.19 (m,
1H, CH2), 2.35-2.49 (m, 2H, CH2), 3.10-3.29 (m, 2H, 6-CH2), 3.48-3.53 (m, 1H, γ-CH2), 3.85-3.98 (m, 1H, γ-CH2), 4.70-4.82 (m, 1H, α-CH), 5.69-5.89 (m, 1H, 2-CH2); MS (ES") m/z 211 (M + H)".
Example 6 specific examples of compounds according to the invention The present example illustrates some specific examples of compounds according to the invention (Table C). Also indicated are the IC50 values of the indicated compounds for DPPII and DPPIV. In this example, the compounds of formula 1 to 36 specifically relates to the structures as illustrated in Table C and are distinct and different from the compounds described in example 5, and are not to be confused therewith. Table C
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
As illustrated in this example, the compounds according to the invention strongly inhibit DPPII activity, as indicated by the low IC50 values of the illustrated compounds for DPPII, and are active in the nanomolar range. The present invention encompasses all the compounds as described in Tables A, B and C. Example 7 Synthesis of the compounds according to the invention The present example illustrates the synthesis of compounds as illustrated in Table C of example 6, according to different synthesis schemes illustrated in Figures 8, 9 and 10. The procedures A to M described in this example and in Figures 8 to 10 for the synthesis of compounds listed in Table C, are distinct and different from the procedures described in example 3, and are not to be confused therewith.
The synthesis of the compounds having formulas 1-18, 19, 23, 24 and 25-26 is illustrated in Figure 8. The synthesis of the compounds having formulas 20 and 3 is illustrated in Figure 9. The synthesis of the compounds having formulas 21 , 22 and, 27-36 is illustrated in Figure 10.
Parallel synthesis was performed using the Quest 210 Organic Synthesizer (Argonaut Technologies). Boc-S-Dab-OH was purchased from Novabiochem. Other reagents were obtained from Sigma-Aldrich or Acros.
Characterisation of all compounds was done with 1H-NMR and mass spectrometry. 1H- NMR were recorded on a Bruker Avance DRX-400 spectrometer (400 MHz). Electrospray (ES+) mass spectra were acquired on an ion trapp mass spectrometer ( Esquire 3000, Bruker Daltonics). Purity was verified using two diverse HPLC systems using respectively mass and uv-detector. LC-MS were recorded on an Agilent 1100 Series HPLC system using a Discovery Cyano column (2.1 x 50 mm, 5μm, Supelco, Sigma-Aldrich) coupled with a Bruker Esquire 3000 plus mass spectrometer (0-80% ACN, 22 min, 0.2 ml/min). Reversed phase HPLC was run on a Gilson instrument (Viliers-le-bel, France) equipped with an Ultrasphere ODS column (4.6 x 250 mm, 5 μm, Beckman, Fullerton, CA, USA) and a uv-detection (10-100% ACN, 35 min, 214 nm, 1 ml/min). Preparative TLC was performed on Silicagel 60PF25 containing gypsum. Procedure A To 4-amino-2-S-[(tert-butoxycarbonyl)amino]butanoic acid (Boc-S-Dab-OH) (1 eq) in dioxane and H20 (1 :1) was added triethylamine (3 eq). The solution was cooled at 0°C and a solution of benzylchloroformate (1.1 eq) in dioxane (3ml) was added dropwise. The solution was allowed to stirr for several hours. The dioxane was evaporated, the aequous layer was acidified to pH<2 and extracted with EtOAc (2 times). The organic layer was dried over Na2S0 and evaporated. The oily residue was used as such for next step. Procedure B
To a mixture of the carboxylic acid (1.1 eq), triethylamine (3 eq) and TBTU (1.1 eq) in DMF (40 ml) was added the proper amine compound (piperidine, 2-S- piperidinecarboxamide, 2- or 3- or 4-methylpiperidine, 3-or 4-piperidinol, 3- or 4- fluoropiperidine (synthesized by procedure L) and 1,2,3,6-tetrahydropyridine) (1 eq) al 0°C. After stirring at room temperature overnight, water was added and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with 1 N HCI (2 x 25 ml), 5% NaHC03 (2 x 25 ml) and brine (25 ml). The organic layer was dried over Na2S04, evaporated and purified by column chromatography. Procedure C
Deprotection of the benzyloxycarbonyl (Z) group was done by hydrogenolysis: to a solution of the compound in methanol (50 ml) was added Pd/C (20%). A flow of nitrogen- gass was carried over the solution for 10 minutes, followed by a flow of H2-gas. The reaction was monitored by TLC. After completion, again a flow of nitrogen was carried over the solution for 10 minutes. The mixture was carried over celite and methanol was removed in vacuo. The compound obtained was used as such in the next step. Procedure D1
General procedure for the reductive amination in parallel using PAPS-technique: Tert-butyl 3-amino-1-S-(1-piperidinylcarbonyl)propylcarbarrate (Boc-S-Dab-Pip) (1.8 eq) was dissolved in DCM/acetic acid (90/10) (5 ml). The required aldehyde/keton (1 eq) was added and the polymer-bound cyanoborohydride (2.5 eq). After agitation overnight, the polymer-bound benzaldehyde (2.5 eq) was added to scavenge the excess of starting amine compound. After agitation for 5h the polymer-bound reagents were filtered off and the solvent was evaporated. Purification was done by preparative TLC. Procedure D2
General procedure for the reduction amination in solution phase:
Boc-S-Dab-OH (1.5 eq mmol) was dissolved in methanol (15 ml) dried over molecular sieves. The appropiate aldehyde/keton (1eq), acetic acid (5 eq) and NaCNBH3 (0.8 eq) was added. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was used as such in the next step. Procedure E
After stirring a mixture of (o-biphenyl)P(£-Bu)2 (0.25 mmol) and Pd2(dba)3 (0.25 mmol; 20 mol % Pd) in toluene (4 ml) for 10 minutes under N2-atmosphere, it was added to a solution of Boc-L-Dab-Pip (3 mmol), bromobenzene (2.5 mmol) and NaO -Bu (3.5 mmol) in dry toluene (6 ml). The mixture was stirred overnight at 40 °C under N2 atmosphere, diluted with dichloromethane and H20. The organic phase was separated and washed several times with H20, dried over Na2S04 and evaporated. The residue was purified by preparative TLC using EtOAc/hexane (1 :1) as eluent. Procedure F
To a solution of Boc-S-Dab-Pip (1 eq) in pyridine (10 ml) was added benzoylchloride (5 eq). The mixture was stirred overnight and the solvent evaporated. The residue was taken up in diethylether and washed with 1 HCI. The organic layer was dried over Na2S04 and evaporated. The residue was purified on preparative TLC. Procedure G To solution of the Boc-S-Dab-Pip (1eq) in DMF was added KHC03 (1.2eq) and 2-chloro-3- nitropyridine (26) or 6-chloronicotinonitrile (27) (1 eq). The mixture was stirred at 90°C for 8 hours. EtOAC was added to the solution and washed with sat. NaHC03. The organic layer was dried over Na2S04 and evaporated and the residue was purified on preparative TLC. Procedure H Introduction of a Boc protecting group was done as follow: to a solution of the compound (1eq) in dioxane/H20 (1 :1) mixture (30 ml) was added triethylamine (3eq) and Boc^O (1.1 eq). After stirring for several hours, dioxane was evaporated and the aqueous phase was acidified to pH<2 and extracted 2 times with EtOAc. The combined layers were dried over Na2S0 and evaporated. Purification was done by filtration over silicagel using diethyl ether as eluent. Procedure I
To a suspension of sodium hydride (60% dispersion in mineral oil; 2.5 mmol, 2eq) in THF (4 ml) was added dropwise a solution of fert-butyl 3-S-(tert-bytyloxycarbonyl)arrino-4-oxo- 4-(1-piperidinyl)butyl(4-chlorobenzyl)carba ate (1.25 mmol, 1 eq) and a catalytic amount of H20 in THF (3 ml) while maintaining an internal temperature of 17-20 °C. The mixture was stirred at the same temperature for 10 min, and dimethyl sulfate (2.25mmol, 1.8 eq) was added dropwise. The stirring was continued at the same temperature for 20 min and the reaction was monitored by TLC. The reaction mixture was quenched with 30% ammonium hydroxide (2 ml) which was added dropwise and the stirring was continued for 1 h. The mixture was diluted with dichloromethane and H20. The organic phase was separated, washed with H20, dried over Na2S04 and evaporated. The residue was purified by preparative TLC using EtOAc/Hexane (40:60) as eluent.
To a solution of fert-butyl 3-S-(tert-butyloxycarbonyl)anino-4-[2-(aminocarbonyl)-1- piperidinyI3-4-OXODUty 4-chlorobenzyl)carbamate (1eq) and imidazol (2 eq) in pyridine at-
30 °C was slowly added phosphorusoxychloride (4 eq). The solution was allowed to attain room temperature and the reaction was monitored by TLC. After completion of the reaction the solvent was evaporated and the residue was extracted with 1 N HCI and diethylether. The organic layer was dried, evaporated and the residue was purified by prepartive TLC. Procedure EC
Deprotection of ferf-butyloxycarbonyl (Boc) was done by dissolving in 8 ml of a TFA/dichloromethane (1 :1) mixture. The solution was stirred for 1 h and the volatile part was removed under reduced pressure. After coevaporating several times with ether, the compound was either converted to the HCI salt, precipitated in ether and lyophil'rzed from HzO or the oily residue was as such lyophileed from H20. Procedure L
Synthesis of 3- or 4-fluoropiperidine and 1 ,2,3,6-tetrahydropyridine started from respectively 3-piperidinol and 4-piperidinol. A tert-butyloxycarbonyl (Boc) protecting group was introduced according to procedure H. The Boc-protected 3- or 4- piperidinol (1 eq, 2 mmol) was dissolved in dry dichloromethane (15 ml) and DAST (1.3 eq, 2.6 mmol) was added to the solution. The mixture was stirred for 90 min at 0 °C under N2 atmosphere. The solution was diluted with 15 ml of dichloromethane and the reaction was quenched by means of 20 ml saturated NaHC03 solution. The organic phase was separated and the aequous layer was extracted with EtOAc. The combined organic phases were dried over Na2S04 and evaporated. In the case where 4-piperidinol was used as starting material, the reaction resulted in a mixture of Boc-4-fluoropiperidine and Boc-1 ,2,3,6- tetrahydropyridine (side product) which could both be isolated by flash chromatography. With 3-piperidinol as starting material, the Boc-3-fluoropiperidhe could be obtained by flash chromatography. Deprotection of the Boc-protecting group was done according to procedure K. Procedure M
Synthesis of 2-S-piperidinecarboxamide started from Boc-L-pipecolinic acid (1 eq) by reaction with Λ/-hydroxysuccinimide (1.05 eq) and dicyclohexylcarbodiimide (DCC, 1.05 eq) in DCM. After reaction for 5 h, the solution was titrated and the filtrate was evaporated. The residue was dissolved in dioxane and treated ammonium gas. Again after 15 min the solution was filtrated and the filtrate was evaporated. Boc-deprotection was done according to procedure K.
Λ ,-(2-chloroben2yl)-4-oκo-4-(1-piperidinyl)-1,3(S)-butsιnediamine (1) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 2-chlorobenzaldehyde following procedure D1. Final deprotection of the terf-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.53-1.75 (m, 6H, CH2), 2.29-2.42 (m, 2H, β-CW2), 3.24-3.30 (m, 2H, rCH2), 3.49-3.63 (m ,4H, CH2), 4,53 (s, 2H, CH2Ph), 4.71-4,80 (m, 1H, α-CH), 7.49-7.67 (m, 4H, Harom); MS (ES") m/z 310 (M + H)"; LC-MS: rt 8.2 min, m/z 310, 91%; HPLC (214 nm): rt 14,48 min, 95%.
i ,-(3-chloroben2yl)-4-ojco-4-(1-piperidinyl)-1,3(S)-butanediamine (2) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 3-chlorobenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.46-1.76 (m, 6H, CH2), 2.28-2.38 (m, 2H, y0-CH2), 3.13-3.23 (m, 2H, rCH2), 3.46-3.59 (m, 4H, CH2), 4.35 (s, 2H, CH2Ph), 4.70-4.78 (m, 1H, α-CH), 7.42-7.63 (m, 4H, Harom); MS (ES+) m/z 310 (M + H)"; LC-MS: rt 8.8 min, m/z 310, 95%; HPLC (214 nm): rt 15.64 min, 96%.
Λ^-^-chlorobenzylH-oxo^-fl-piperidinylJ-l ,3(S)-butanediamine (3)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 4-chlorobenzaldehyde following procedure D1. Final deprotection of the terf-butyloxycarbonyl (Boc) group was done according to procedure K.
The synthesis of the title compound in large quantities started from Boc-Z-Dab-OH according to procedures D2, H, B and K.
1H-NMR (D20, 400 MHz) £ 1.46-1.75 (m, 6H, CH2), 2.28-2.40 (m, 2H, ^-CH2), 3.12-3.38 (m, 2H, rCH2), 3.45-3.62 (m, 4H, CH2), 4.27 (s, 2H, CH2Ph), 4.70-4.77 (m, 1H, α-CH), 7.42-7.61 (m, 4H, Harom); 13C-NMR (D20, 400 MHz) 23.48, 25.13, 26.04, 26.82 (3,4,5- C(pip), β-C), 41.97, 42.22, 47.11 , 47.97, 50.42 (α-C, γ-C, C-Ph, 2,6-C(pip)), 128.82, 129.49, 131.65, 135.39 (Carom), 165,77 (CO); MS (ES") m/z 310 (M + H)"; LC-MS: rt 9.0 min, m/z 310, 96%; HPLC (214 nm): rt 14,89 min, 95%. Λ/1-[2-(benzyloxy)benzyl]-4-oxo-4-(1-piperldinyl)-1,3(S)-butanediamine (4)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 2-benyloxybenzaldehyde following procedure D1. Final deprotection of the fe/f-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.38-1.73 (m, 6H, CH2), 2.15-2.29 (m, 2H, /?-CH2), 3.05-3.17 (m, 2H, rCH2), 3.28-3.58 (m, 4H, CH2), 4.28 (s, 2H, CH2Ph), 4.54-4.63 (m, 1 H, α-CH), 5.32 (s, 2H, OCH2Ph), 7.14-7.17 (m, 1H, Harom), 7.27-7.29 (m, 1H, Harom), 7.46-7.59 (m, 7H, Harom); MS (ES") m/z 382 (M + H)"; LC-MS: rt 11.7 min, m/z 382, 100%.
Λ/l-[4-(benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamϊne (5)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 4-benzyloxybenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £1.38-1.75 (m, 6H, CH2), 2.21-2.35 (m, 2H, ^-CH2), 3.11 (t, 2H, rCH2), 3.44-3.63 (m, 4H, CH2), 4.30 (s, 2H, CH2Ph), 4.54-4.63 (m, 1 H, α-CH), 5.27 (s, 2H, OCH2Ph), 7.19-7.21 (m, 2H, Harom), 7.47-7.57 (m, 7H, Haram); MS (ES") m/z 382 (M + H)"; LC-MS: rt 11.2 min, m/z 382, 88%; HPLC (214 nm): rt 18.50 min, 90%.
3-({[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl]amino}methyl)benzonitrile (6)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 3-cyanobenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.50-1.76 (m, 6H, CH2), 2.32-2.37 (m, 2H, >#-CH2), 3.20-3.27 (m, 2H, ^CH2), 3.48-3.61 (m, 4H, CH2), 4.41 (s, 2H, CH2Ph), 4.72 (t, 1H, α-CH), 7.70-7.74 (m, 1H, Haram), 7.85-7.87 (m, 1H, Harom), 7.94-7.95 (m, 2H, Harom); MS (ES") m/z (M + H)"; LC-MS: rt 3.6 min, m/z , 82%; HPLC (214 nm): rt 13.31 min, 79%.
i -(2-methoπybensyl)-4-∞so-4-(1-piperidinyl)-1,3(S)-butanediamirιe (7) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 2-methoxybenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (DzO, 400 MHz) £ 1.42-1.73 (m, 6H, CH2), 2.28-2.37 (m, 2H, ^CH2), 3.10-3.18 (m, 2H, rCH2), 3.45-3.58 (m, 4H, CH2), 3.97 (s, 3H, CH3), 4.36 (s, 2H, CH2Ph), 4.69 (1, 1H, α-CH), 7.12-7.22 (m, 2H, Harom), 7.43-7.45 (m, 1H, Harom), 7.57-7.61 (m, 1H, Harom); MS (ES") m/z 306 (M + H)"; LC-MS: rt 8.1 min, m/z 306, 100%; HPLC (214 nm): rt 21.75 min, 90%.
/^1-(3-methoxybenzyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (8)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 3-methoxybenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K.
1H-NMR (D20, 400 MHz) £ 1.40-1.73 (m, 6H, CH2), 2.28-2.36 (m, 2H, /?-CH2), 3.16 (t, 2H, rCH2), 3.49-3.62 (m, 4H, CH2), 3.92 (s, 3H, CH3), 4.33 (s, 2H, CH2Ph), 4.70 (t, 1 H, α- CH), 7.13-7.18 (m, 3H, Harom), 7.50-7.54 (m, 1H, Harom); MS (ES+) m/z 306 (M + H)"; LC- MS: rt 7.7 min, m/z 306, 97%; HPLC (214 nm): rt 22.24 min, 96%.
Figure imgf000128_0001
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 4-methoxybenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.44-1.76 (m, 6H, CH2), 2.23-2.38 (m, 2H, β-CH2), 3.10-3.23 (m, 2H, ^CH2), 3.49-3.72 (m, 4H, CH2), 3.92(s, 3H, CH3), 4.30 (s, 2H, CH2Ph), 4.64-4.72 (m, 1H, α-CH), 7.13-7.16 (m, 2H, Harom), 7.48-7.50 (m, 2H, Harom); MS (ES+) m/z 306 (M + H)"; LC-MS: rt 0.9 min, m/z 306, 100%; HPLC (214 nm): rt 14.18 min, 95%.
Λf1-(2,4-dimethoxyben2yl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (10)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 2,4-dimethoxybenzaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. H-NMR (D20, 400 MHz) £ 1.35-1.86 (m, 6H, CH2), 2.24-2.35 (m, 2H, /?-CH2), 3.02-3.62 (m, 6H, ^CH2, CH2), 3.93 (s, 3H, CH3), 3.95 (s, 3H, CH3), 4,30 (s, 2H, CH2Ph), 4.65-4.74 (m, 1H, α-CH), 6.71-6.77 (m, 2H, Harom), 7.27-7.29 (m, 1H, Harom); MS (ES") m/z 336 (M + H)"; HPLC (214 nm): rt 15.04 min, 91%.
4-θ2co-4-(1-piperidin l)-i 1-(2- hienylmethyl)-1,3(S)-butanediamine (11)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 2-thiophenecarbalde yde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.52-1.76 (m, 6H, CH2), 2.23-2.37 (m, 2H, j5-CH2), 3.19-3.26 (m, 2H, ^CH2), 3.49-3.63 (m, 4H, CH2), 4.59(s, 2H, CH2Ph), 4.71 (t, H, α-CH), 7.21-7.23 (m, 1H, Harom), 7.32-7.38 (m, 1H, Harom), 7.65-7.67 (m, 1H, Harom); MS (ES") m/z 282 (M + H)"; LC-MS: rt 2.6 min, m/z 282, 91%; HPLC (214 nm): rt 14.45 min, 99%.
4-oxo-4-(1-piperidinyl)-Λf1-(4-pyridinylmethyl>"1J3(S)-butanediamine (12) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 4-pyridinecarboxaldehydefollowing procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.59-1.77 (m, 6H, CH2), 2.38-2.47 (m, 2H, β-C 2), 3.37-3.73 (m, 6H, 7-CH2, CH2), 4.72 (s, 2H, CH2Ph), 4.75-4.82 (m, 1H, α-CH), 8.25 (m, 2H, Harom), 8.85 (m, 2H, Harom); MS (ES") m/z 277 (M + H)"; LC-MS: rt 1.0 min, m/z 277, 95%; HPLC (214 nm): rt 8.29 min, 74%.
Λ1-(1-naphthylmethyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (13)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 1-naphtaldehyde following procedure D1. Final deprotection of the tert- butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.26-1.74 (m, 6H, CH2), 2.27-2.37 (m, 2H, ^CH2), 3.13-3.60 (m, 6H, r-CH2, CH2), 4.60-4.80 (m, 1H, α-CH), 4.87 (s, 2H, CH2Ph), 7.43-7.80 (m, 4H, Harom), 8.12-8.19 (m, 3H, Harom); MS (ES") m/z 326 (M + H)"; LC-MS: rt 10.1 min, m/z 326, 98%; HPLC (214 nm): rt 16.35 min, 85%.
Af-(2-naphihylnn(£thyl -4-O O-4-(1-pip(sridinyl)-1,3(S)-bu anediamine (14) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 2-naphtaldehyde following procedure D1. Final deprotection of the tert- butyloxycarbonyl (Boc) group was done according to procedure K. H-NMR (D20, 400 MHz) £ 1.11-1.60 (m, 6H, CH2), 2.22-2.37 (m, 2H, ^CH2), 3.07-3.19 (m, 2H, rCH2) 3.30-3.61 (m, 4H, CH2), 4.54 (s, 2H, CH2Ph), 4.61-4.69 (m, 1 H, α-CH), 7.57-7.75 (m, 3H, Harom), 8.00-8.14 (m, 4H, Harom); MS (ES") m/z 326 (M + H)"; LC-MS: rt 10.3 min, m/z 326, 100%; HPLC (214 nm): rt 16.83 min, 91%.
4-oxo-Λf1-(2-phenylethyl)-4-(1-piperidinyl)-1,3(S)-butanediamine (15)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using phenylacetaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £1.66-1.78 (m, 6H, CH2), 2.06-2.34 (m, 3H, CH2), 3.02-3.31 (m, 2H, CH2), 3.42-3.66 (m, 7H, CH2), 4.61-4.69 (m, 1 H, α-CH), 7.30-7.55 (m, 5H, Harom); HPLC (214 nm): rt 20.75 min, 86%.
4-oxo-Λf1-(3-phenylpropyl)-4-(1-piperidinyl)-1,3 S)-butanediamine (16)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using 3-phenylpropionaldehyde following procedure D1. Final deprotection of the tert-butyloxycarbonyl (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.64-1.73 (m, 6H, CH2), 2.00-2.14 (m, 2H, CH2), 2.25-2.38 (m, 2H, ^CH2), 2.74-2.85 (m, 2H, CH2), 3.08-3.28 (m, 4H, rCH2, CH2), 3.47-3.61 (m, 4H, CH2), 4.71 (t, 1 H, α-CH), 7.31-7.51 (m, 5H, Harom); MS (ES") m/z 304 (M + H)"; LC-MS: rt 8.6 min, m/z 304, 98%; HPLC (214 nm): rt 26.30 min, 98%.
A/1-(cycloheπylmeihyl)-4-oπo-4-(1-piperidinyl)-1,3(S)-butanediamine (17) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using cyclohexanecarbalde yde following procedure D1. Final deprotection of the tert-butyloxycarbonyi (Boc) group was done according to procedure K. 1H-NMR (D20, 400 MHz) £0.92-1.72 (m, 16H, CH2), 2.05-2.27 (m, 3H, CH, /?-CH2), 2.79 (d, 2H, CH2), 3.04-3.18 (m, 2H, rCH2), 3.40-3.63 (m, 4H, CH2), 4.64 (t, 1H, α-CH); MS (ES") m/z 282 (M + H)"; LC-MS: rt 11.2 min, m/z 282, 88%; HPLC (214 nm): rt 14.35 min, 81%.
Λ/,-cyclohexyl-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (18)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A reductive amination was carried out using cyclohexanon following procedure D1. Final deprotection of the tert- butyloxycarbonyl (Boc) group was done according to procedure K.
1H-NMR (D20, 400 MHz) £1.17-1.45 (m, 5H, CH2), 1.60-1.93 (m, 9H, CH2), 2.06-2.17 (m, 2H, ^-CH2), 2.25-2.35 (m, 2H, CH2), 3.13-3.69 (m, 7H, CH, CH2, ^CH2); MS (ES") m/z 268(M + H)"; LC-MS: rt 4.5 min, m/z 268, 97%; HPLC (214 nm): rt 12.91 min, 93 %.
Figure imgf000131_0001
Synthesis of the title compound started from Boc-S-Dab-OH according to procedures A, B, C. Reductive amination using 4-chlorobenzaldehydewas done according to procedure D2. After completion of the reaction the solvent was evaporated and extracted with dichloromethane and 1 N NaOH. The organic layer was separated, dried over Na2S0 and used again in the reductive amination reaction with an excess of paraformaldehyde according to procedure D2. Final deprotection was done according to procedure K. 1H-NMR (D20, 400 MHz) £1.29-1.74 (m, 6H, CH2), 2.23-2.52 (m, 2H, ^-CH2), 2.97 (s, 3H, CH3), 3.19-3.30 (m, 2H, r-CH2), 3.41-3.58 (m, 4H, CH2), 4.47 (s, 2H, CH2Ph), 4,67-4,73 (m, 1 H, α-CH), 7.43 (d, 2H, Harom), 7.53 (d, 2H, Haram); MS (ES") m/z 324 (M + H)"; LC-MS: rt 8.6 min, m/z 32 , 99%; HPLC (214 nm): rt 16.04 min, 98%. Λf1-(4-chlorobenzyl)-Λr-methyl-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (20)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by tert- butyloxycarbonyl (Boc) introduction according to procedure H. Coupling with piperidine was done following B. Methylation of the 3-aminofuntion was done according to procedure I. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) £1.44-1.74 (m, 6H, CH2), 2.31-2.40 (m, 2H, ^CH2), 2.75 (s, 3H, CH3), 3.08-3.16 (m, 2H, rCH2), 3.49-3.60 (m, 4H, CH2), 4.33 (s, 2H, CH2Ph), 4.64 (t, 1H, α-CH), 7.49-7.51 (m, 2H, Harom), 7.56-7.58 (m, 2H, Harom); MS (ES") m/z 324 (M + H)"; LC- MS: rt 8.3 min, m/z 324, 99%; HPLC (214 nm): rt 22.64 min, 100 %.
Λ(1, -dϊbenzyl-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (21)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using an excess (5 eq) of benzaldehyde was carried out according to procedure D2. Coupling with piperidine was done following B. Final deprotection was done according to procedure
K.
1H-NMR (D20, 400 MHz) £ 1.23-1.63 (m, 6H, CH2), 2.27-2.32 (m, 2H, ^CH2), 3.02-3.24
(m, 4H, CH2), 3.30-3.34 (m, 1H, CH2), 3.42-3.47 (m, 1 H, CH2), 4.38 (s, 2H, CH2Ph), 4.54 (t, 1H, α-CH), 7.38-7.53 (m, 10H, Harom); MS (ES") m/z 366 (M + H)"; LC-MS: rt 19.8 min, m/z 366, 97%; HPLC (214 nm): rt 16.94 min, 98%.
Λ ,Λ/1-di(4-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine (22)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using an excess (5 eq) of 4-chlorobenzaldehyde was carried out according to procedure D2.
Coupling with piperidine was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) £ 1.30-1.44 (m, 2H, CH2), 1.55-1.75 (m, 4H, CH2), 2.32-2.43 (m,
2H, /?-CH2), 3.13-3.65 (m, 6H, ^CH2, CH2), 4.48 (s, 2H, CH2Ph), 4.50 (s, 2H, CH2Ph), 4.65 (t, 1H, α-CH), 7.48-7.53 (m, 4H, Harom), 7.59-7.63 (m, 4H, Harom); MS (ES") m/z 434 (M +
H)"; LC-MS: rt 14.5 min, m/z 434, 78%; HPLC (214 nm): rt 25.56 min, 100%.
4-θ2Jθ-Af-phenyl-4-(1-piperidinyl)-1,3(S)-bu anediamine (23)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. A palladium catalysed reaction was carried out according to procedure E. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) £1.21-1.24 (m, 1 H, CH2), 1.43-1.68 (m, 5H, CH2), 2.26-2.39 (m, 2H, y^CH2), 3.37-3.76 (m, 6H, ^CH2, CH2), 4.70 (t, 1H, α-CH), 7.52-7.54 (m, 2H, Haram), 7.63-7.69 (m, 3H, Harom); MS (ES") m/z (M + H)"; LC-MS: rt 10.9 min, m/z 262, 82%; HPLC (214 nm): rt 22.66 min, 98%.
Af-[3(S)-amino-4-oxo-4-(1-piperidirιyl)butyl]berEaιnide (24) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. The synthesis continued by procedure F and final deprotection was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.44-1.73 (m, 6H, CH2), 2.25-2.30 (m, 2H, ?-CH2), 3.48-3.70 (m, 6H, CH2, ^CH2), 4.61 (t, 1H, α-CH), 7.58-7.84 (m, 5H, Hamm); MS (ES") m/z 290 (M + H)"; LC-MS: rt 10.1 min, m/z 290, 98%; HPLC (214 nm): rt 15.71 min, 99%.
^-(S-nitro^-pyridinylH-oxo^l-piperidinylJ-I.SfSJ-butanediamine (25)
Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. The synthesis continued by procedure G using 2-chloro-3-nitropyridine and final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) £ 1.40-1.68 (m, 6H, CH2), 2.22-2.40 (m, 2H, / )H2), 3.29-3.93 (m, 6H, ^CH2, CH2), 4.50-4.61 (m, 1 H, α-CH), 6.87-6.96 (m, 1 H, Harom), 8.41-8.50 (m, 1 H,
Haram), 8.56-8.65 (m, 1H, Harom); MS (ES") m/z 308 (M + H)"; LC-MS: rt 9.3 min, m/z 308,
96%; HPLC (214 nm): rt 17.10 min, 100%.
6-{[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl]amino}nicotinonitrile (26) Synthesis of the title compound started from Boc-S-Dab-OH according to procedure A, followed by a coupling reaction with piperidine according to procedure B. Deprotection of the benzyloxycarbonyl (Z) group was done according to C. The synthesis continued by procedure E using 6-chloronicotinanitrile and final deprotection was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.45-1.74 (m, 6H, CH2), 2.22-2.33 (m, 2H, β-C 2), 3.46-3.65 (m, 6H, rCH2, CH2), 4.58-4.66 (m, 1 H, α-CH), 6.97 (d, 1 H, Harom), 7.96 (d, 1H, Harom), 8.49 (s, 1 H, Haram); MS (ES") m/z 288 (M + H)"; LC-MS: rt 4.9 min, m/z 288, 99%; HPLC (214 nm): rt 14.77 min, 99%.
A 1-(4-chloroben2yl)-4-(2-methyl-1-piperidinyl)-4-o^o-1,3fSj-bu'!:an(edisimine (27) Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 2-methylpiperidine was done following B. Final deprotection was done according to procedure K.
1H-NMR (02O, 400 MHz) δ 1.04-1.27 (dd, 3H, CH3), 1.31-1.78 (m, 6H, CH2), 2.18-2.31 (m, 2H, ^CH2), 2.84-3.31 (m, 3H, CH, ^CH2), 3.49-3.59 (m, 1 H), 3.99-4.23 (m, 1 H), 4.25 (d, 2H, CH2Ph), 4.54-4.68 (m, 1H, α-CH), 7.41-7.52 (m, 4H, Harom); LC-MS : rt 9.4 min, m/z 324 (M+H)", 99%; HPLC (214 nm) : rt 16.86 min, 98%.
Λ1-(4-chlorobenzyl)-4-(3-methyl-1-piperidinyl)-4-oxo-1,3(5 -butanediamine (28) Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 3-methylpiperid e was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) δ 0.96-0.98 (m, 3H, CH3), 1.19-1.96 (m, 5H, CH, CH2), 2.26-2.37 (m, 2H,
Figure imgf000134_0001
3.65-3.73 (m, 1 H, CH2), 4.08-4.21 (m, 1H, CH2), 4.33 (d, 2H, CH2Ph), 4.67-4.77 (m, 1H, α-CH), 7.50-7.60 (m, 4H, Harom); LC-MS: rt 8.6 min, m/z 324 (M+H)", 100%; HPLC (214 nm) : rt 15.81 min, 100%.
Λ^-(4-chlorobenzyl)-4-(4-methyl-1-piperidinyl)-4-oxo-1,3(S -butanediamine (29) Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 4-methylpiperidhe was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) δ 0.90-1.05 (m, 4H, CH3, CH), 1.10-1.29 (m, 1 H, CH2), 1.66-1.90 (m, 3H, CH2), 2.23-2.38 (m, 2H, ^CH2), 2.69-2.90 (t, 1H, CH2), 3.09-3.30 (m, 3H, CH2, γ- CH2), 3.74-3.86 (m, 1 H), 4.27-4.41 (m, 3H, CH2Ph, CH), 4.63-4.75 (m, 1H, α-CH), 7.46- 7.62 (m, 4H, Harom); LC-MS: rt 8.4 min, m/z 324 (M+H)", 100% ; HPLC (214 nm): rt 16.33 min, 99.1% 1-{2(S -amino-4-[(4-chlorobenzyl)amino]butanoyl}-3-piperidinol (30)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 3-piperidinol was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) £1H-NMR (D20, 400 MHz) δ 1.36-1.94 (m, 4H, CH2), 2.17-2.36 (m, 2H, /2-CH2), 3.04-3.21 (m, 2H, f-CH2), 3.35-3.94 (m, 5H, CH2, CH), 4.20-4.26 (m, 2H, CH2Ph), 4.55-4.65 (m, 1 H, α-CH), 7.39-7.53 (m, 4H, Harom); LC-MS: rt 2.7 min, m/z 326 (M+H)", 100 % ; HPLC (214 nm): rt 13.52 min, 96%.
1-{2(5J-amino-4-[(4-chlorobenzyl)amino]butanoyl}-4-piperidinol (31)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 4-piperidinol was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) δ 1.35-1.55 (m, 2H, CH2), 1.83-1.99 (m, 2H, CH2), 2.18-2.29 (m, 2H, ^-CH2), 3.05-3.37 (m, 4H, rCH2, CH2), 3.65-3.77 (m, 1 H), 3.89-4.09 (m, 2H), 4.24 (d, 2H, CH2Ph), 4.60-4.66 (m, 1H, α-CH), 7.38-7.52 (m, 4H, Haram); LC-MS: rt 1.7 min, m/z 326 (M+H)", 96% ; HPLC (214 nm): rt 12.75 min, 99%.
Λ/1-(4-chlorobenzyl)-4-(3-fluoro-1-piperidϊnyI)-4-oxo-1,3 S -butanediamine (32)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using
4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 3-fluoropiperidne - which was prepared according to L - was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) δ 1.51-2.13 (m, 4H, CH2), 2.16-2.39 (m, 2H, β-C 2), 2.81-3.59
(m, 4H, rCH2, CH2), 3.69-4.04 (m, 1H), 4.16-4.45 (m, 1H), 4.25 (d, 2H, CH2Ph), 4.58-4.70 (m, 1H, α-CH), 4.83-5.00 (m, 1 H, 3-CH), 7.38-7.51 (m, 4H, Haram); LC-MS: rt 6.4 min, m/z
328 (M+H)", 49.6 % and rt 7.3 min, m/z 328 (M+H)", 50.4 % ; HPLC (214 nm): rt 15.05 min, 96% Λ^-(4-chlorobenzyl)-4-(4-fluoro-1-piperidinylH-oxo-1'3 SJ-butanediamine (33)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 4-fluoropiperidine - which was prepared according to L - was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) δ 1.72-1.98 (m, 4H, CH2), 2.19-2.29 (m, 2H, ^-CH2), 3.04-3.19 (m, 2H, ^CH2), 3.36-3.87 (m, 4H, CH2), 4.24 (s, 2H, CH2Ph), 4.61-4.68 (m, 1H, α-CH), 4.87-5.08 (m, 1H, 4-CH), 7.39-7.52 (m, 4H, Harom); LC-MS: rt 6.7 min, m/z 328 (M+H)", 100 % ; HPLC (214 nm): rt 15.24 min, 99%
/V-fi-chlorobenzylH^Sjβ-dehydro-l (2W)-pyridinyl)-4-oxo-1 ,3(S)-butanediarnine (34)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using
4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 1,2,3,6-tetrahydropyridine - which was prepared according to L (or commercialy available) - was done following B. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) δ 2.05-2.31 (m, 4H, β-CH2, CH2), 3.05-3.16 (m, 2H, rCH2), 3.49-
3.80 (m, 2H, CH2), 3.90-4.07 (m, 2H, CH2), 4.23-4.27 (d, 2H, CH2Ph), 4.59-4.70 (m, 1H, α- CH), 4.65-4.76 (m, 1H, CH), 4.84-4.96 (m, 1H, CH), 7.40-7.52 (m, 4H, Harom); LC-MS: rt
7.8 min, m/z 308 (M+H)", 99% ; HPLC (214 nm): rt 15.79 min, 100%
1-[2(S)-amino-4-(benzylamino)butanoyl]-2(S)-piperidinecarbonitrile (35)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using benzaldehyde was carried out according to procedure D2, followed by Boc-introduction according to procedure H. Coupling with 2-L-piperidinecarboxamide - which was prepared according to M- was done following B. Deshydratation of the amide function to the nitrile was done according to procedure J. Final deprotection was done according to procedure K. 1H-NMR (D20, 400 MHz) £ 1.52-2.12 (m, 6H, CH2), 2.28-2.41 (m, 2H, y#-CH2), 3.11-3.29 (m, 2H, rCH2), 3.34-3.45 (m, 1H, 5-CH2), 3.81-3.95 (m, 1H, 5-CH2), 4.34 (s, 2H, CH2Ph), 4.67-4,83 (m, 1H, α-CH), 5.65 (s, 0.5H, 2-CH), 5.81 (s, 0.5H, 2-CH), 7.56 (s, 5H, Harom); MS (ES") m/z 301 (M + H)+; LC-MS: rt 4.9 min, m/z 301, 93%; HPLC (214 nm): rt 14.04 min, 89%. 1-{2(S)-amino-4-[(4-chlorobenzyl)amino]butanoyl}-2(S)-piperidinecarbonitrile (36)
Synthesis of the title compound started from Boc-S-Dab-OH. A reductive amination using 4-chlorobenzaldehyde was carried out according to procedure D2, followed by Boc- introduction according to procedure H. Coupling with 2- -piperidinecarboxamide -which was prepared according to M - was done following B. Deshydratation of the amide function to the nitrile was done according to procedure J. Final deprotection was done according to procedure K.
1H-NMR (D20, 400 MHz) £ 1.55-2.12 (m, 6H, CH2), 2.31-2.36 (m, 2H, ^CH2), 3.16-3.24 (m, 2H, rCH2), 3.30-3.43 (m, 1 H, 5-CH2), 3.83-3.90 (m, 1H, 5-CH2), 4.32 (s, 2H, CH2Ph), 4.68-4.80 (m, 1H, α-CH), 5.64 (s, 0.5H, 2-CH), 5.80 (s, 0.5H, 2-CH), 7.49 (d, 2H, Harom), 7.55 (d, 2H, Harom); MS (ES") m/z 335 (M + H)"; LC-MS: rt 8.7 min, m/z 335, 92%; HPLC (214 nm): rt 16.31 min, 88%.
Example 8 In vivo administration of a DPP II inhibitor
In vivo applicability and oral availably are important issues in the development of protease inhibitors.
N1-(4-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine (Compound 3) (MW 382.5 ; in vitro IC50 DPPII 0.48 + 0.04 nM) was administered intravenously to New Zealand White rabbits (n=2) and orally to Wistar rats (n=4) and ICR mice (n=3). Control animals received an equal volume vehicle alone.
a) Acute toxicity upon administration of compound 3
Doses administered were as follows : Rabbits IV 0.2 and 1 μmol/kg
Rats PO 1 and 5 μmol/kg
Mice PO 5 μmol/kg
Upon administration of the compound, the animals were observed for the presence of acute toxic symptoms (mortality, convulsions, tremors, muscle relaxation, sedation etc.) during the first hours. Mortality was noted until 72 hours after treatment. No signs of toxicity were observed and no mortality occurred in the treated animals. b) DPPII activity in plasma and tissues upon administration of compound 3
Serum levels of DPPII were measured using the chromogenic substrate Lys-Ala-p- nitroanilide at pH 5.5 in an assay with a final % dilution of the serum. The DPP II activity in tissues was determined after homogenizing parts of the organs using n-octylglycoside as a detergent using the same substrate and buffer. Final dilution of extract in the assay was 1/20. Tissue DPPIV activity was measured using Gly-Pro-p-nitroanilide as the substrate in Tris-HCI buffer pH 8.3.
Rabbits
Upon IV administration of compound 3 to rabbits, the serum DPPII levels fell to less than 5% of the initial value in both animals. After 24 hours the plasma activity measured was 40 % of the pretest value. A second and third injection of the compound after 5 and 40 days respectively resulted in the same profound DPPII inhibition and comparable recovery kinetics. Reducing the dose to 0.2 μmol/kg resulted in a slightly less potent inhibition suggesting that dose dependency can be expected. Euthanasia of the animals was performed 2 hours after the last dose of compound using 100 mg/kg pentobarbital.
The results are summarized in Figure 11. Figure 11 shows the influence of intravenous administration of Compound 3 on the DPPII activity in serum of rabbits. Blood samples were taken at different timepoints after the injection of compound or vehicle (control animal). The 3 panels show 3 separate experiments in the same animals. The relative activity of serum DPPPII is given with the pretest value of each animal considered as 100
%.
Rats
Upon oral administration to rats at doses of 1 and 5 μmol/kg the serum levels fell within 1 hour to less than 30 % of the initial value after the administration of 1 μmol/kg .
Euthanasia of the animals was performed by carbon dioxide asphyxation 2 hours after the last dose of compound. Specific activities of DPPII and DPPIV were determined in a number of organs including liver, heart, kidney, brain. The results are summarized in
Figures 12 and 13.
Figure 12 gives the influence of oral administration (gavage) of Compound 3 on the DPPII activity in serum of rats. After the administration of compound or vehicle (control animals) blood samples were taken from the tail at the timepoints indicated. In a first experiment (upper panel), the same dose was given to the 2 experimental animals. Very comparable and significant inhibition of serum DPPII activity was seen 1 hour after oral administration of compound. In a second experiment (lower panel), 2 different doses were compared. From this preliminar experiment a dose-dependency of the effect is expected.
Figure 13 details the influence of compound 3 on the specific activity of DPPII and DPPIV in several organs. Euthanasia of the animals was carried out 2 hours after compound administration. The measurements were carried out in a final dilution of 1/20 so the results underestimate the in vivo inhibition level obtained after oral administration of compound 3. The upper panel depicts the DPPII specific activity and the lower panel represents the DPPIV activity. The preliminar results predict a dose dependent inhibition of DPPII but not DPPIV in the peripheral organsof the rat.

Claims

Claims
1. A compound having a modulating activity on a serine type dipeptidyl peptidase and having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof,
Figure imgf000140_0001
formula I wherein R1 is selected from the group comprising -CH2-, oxa, thia and imino, or wherein R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R3, R4 and R6 are selected from the group comprising hydrogen, oxyalkyl alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl, alkoxycarbonyl alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyl, cycloalkyl cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyi cycloalkylalkoxycarbonyl, cycloalkylalkoxytiiocarbonyl, cycloalkylthioalkyl alkylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, alkylaminocarbonyl, alkylaminoalkyl aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoalkylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoanj', alkylaminoaralkyl arylaminoaraϊkyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylarrinoaralkyl Hefoxycarbonyl, Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbony]
Het1alkyloxyalkyicarbonyl, Het1aminocarbonyl, Hefcarbonyloxyalkyi
Het1alkylcarbonyloxyalkyl, Hel1aryl, Het arylaminoalkoxy, Hefarylamino
Het1arylaminoalkyl, Het1arylaminoalkylarrino, Het1aryloxy, Hefaryloxyalkoxy Hefaryloxyalkyl, Het1aryloxyalkylamino, Het1aralkyl, Het1aralkoxy, Het1aralkylamino Hefaralkanoyl, Hefaroyl, Hefarylcarbonyl, Het1 aryloxycarbonyl, Hefarylthiocarbonyi Het1aralkoxycarbonyl, Hefarylalkylthiocarbor l, Hefaryloxyalkyl, Hefarylthioalkyl He haloalkyl, Hef aryloxycarbonylalkyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi He arylaminocarbonyl, Hefaralkylaminocarbonyl, Hef alkylaminoalkyl
He aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
He aralkanoylaminoalkyl, Hef alkyloxycarbonyiaminoalkyl
He aryloxycarbonylaminoakyl, Hef aralkoxycarbonylaminoalkyl
He alkylaminocarbonylaminoalkyl, Hefarylaminocarbonylaminoalkyl
He aralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hefarylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
He aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hef aralkoxycarbonylaminoaryl, Hef alkylaminocarbonylamnoaryl
He arylaminocarborylaminoaryl, Hefaralkylaminocarbonylarrinoaryl
Hefalkylaminoaralkyl, Hef arylaminoarakyl, Hefaralkylaminoaralkyl
Hefalkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl
He alkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
He aralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
He arylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl,Hef, Het2oxy Het2alkyl, Hefoxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl, Hefoxycarbonyl Het2alkanoyl, Hefalkyloxyalkyl, Het2oxyalkylcarbonyl, Hefalkyloxyalkylcarbonyi Het2aminocarbonyl, Hefcarbonyloxyalkyi, Hefalkylcarbonyloxyalkyl, Hefaryl Het2arylaminoalkoxy, Het2arylamino, Het2arylaminoalkyl, Hefarylaminoalkylamino
Hefaryl oxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl Hefara koxy, Hefaralkylamino, Hefaralkanoyl, Hefaroyl, Hefarylcarbonyl Hefaryl oxycarbonyl, Hefarylthiocarbonyl, Hefaralkoxycarbonyl Hefaryl alkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl Hefaryl alkyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi Hefarylaminocarbonyl, Hefaralkylaminocarbonyl, Hef alkylaminoalkyl
Hefaralkylaminoalkyl, Hefalkanoylaminoalkyl, He aroylaminoalkyl
Hefaralkanoylamincalkyl, Hef alkyloxycarbonyiaminoalkyl
Hefaryloxycarbonylaminoakyl, Hef aralkoxycarbonylaminoalkyl Hefalkylaminocarbonylaminoalkyl, Hefarylaminocarbonyiaminoalkyl
He aralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hefarylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
Hef aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl Hefarylaminocarbonylarrinoaryl, Hefaralkylaminocatbonylaminoaryl
Hefalkylaminoaralkyl, Hefarylaminoarakyl, Hefaralkylaminoaralkyl
Hefalkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl
Hefalkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
Hefaralkoxycarbonylaminoaralkyl, Hefalkylaminocarbonylarrinoaralkyl Hefarylaminocarbonylarrinoaralkyl, Hef aralkylaminocarbonylaminoaralkyl, wherein R3, R4 and R6 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoalkyl, arylaminoalkylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef; wherein R5 is oxo or thio, and wherein R7 is selected from the group comprising hydrogen, alkyl and halogen.
2. Compound according to claim 1 , having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, thia and imino, or wherein R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyi alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoaO<ylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylfriiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi arai kylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl ara kanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl ara koxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl ara kylaminocarbonylaminoakyl, alkylarninoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl oxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl aryl aminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl aminoaralkyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl ara kanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylarrinoaralkyl ara koxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl ary aminocarbonylaminoaralkyl, aralkylaminocarbonylarrinoaralkyl, carboxyl piperazinyl piperid inyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl am dinoalkyl, Hef, Hefoxy, Hef alkyl, Hef oxyalkyl, Hefcycloalkyl, Hef alkoxycarbonyl
Het oxycarbonyl, Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyl
Het alkyloxyalkylcarbonyl, Hefaminocarbonyl, Hefcarbonyloxyalkyi
Het alkylcarbonyloxyalkyl, Hefaryl, Hefarylaminoalkoxy, Hefarylamino
Het arylaminoalkyl, Hefarylaminoalkylamino, Hefaryloxy, Hefaryloxyalkoxy
Het aryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl, Hefaralkoxy, Hefaralkylamino
Het aralkanoyl, Hefaroyl, Hefarylcarbonyl, Hef aryloxycarbonyl, Hef arylthiocarbonyi
Het aralkoxycarbonyl, Hef arylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl
Het haloalkyl, Hef aryloxycarbonylalkyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi
Het arylaminocarbonyl, Hefaralkylaminocarbonyl, Hefalkylaminoalkyl
Het aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
Het aralkanoylaminoalkyl, Hef alkyloxycarbonyiaminoalkyl
Het aryloxycarbonylaminoalkyl, Hef aralkoxycarbonylaminoalkyl
Hef alkylaminocarbonylaminoalkyl, Hefarylaminocarbonyiaminoalkyl
Het aralkylaminocarbonylam'noalkyl, Hefalkylaminoaryl, Hef arylaminoaryl
Het aralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
Het aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl
Het aralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl
Hef arylaminocarbonylaninoaryl, Hefaralkylaminocarbonylarrinoaryl
Hef alkylaminoaralkyl, Hefarylaminoaral yl, Hefaralkylaminoaralkyl
Hef alkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylarrinoaralkyl
Het alkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
Hef aralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylaninoaralkyl
Hef arylaminocarbonylaminoaralkyl, He aralkylaminocarbonylaminoaralkyl,Hef, Hefoxy : Hefalkyl, Hefoxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl, Hefoxycarbonyl Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyl, Hefalkyloxyalkylcarbonyi Hefaminocarbonyl, Hefcarbonyloxyalkyi, Hefalkyicarbonyloxyalkyl, Hefaryl Hefarylaminoalkoxy, Hefarylamino, Hefarylaminoalkyl, Hefarylaminoalkylamino Hefaryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl Hefaralkoxy, Hefaralkylamino, Hefaralkanoyl, Hefaroyl, Hefarylcarbonyl Hefaryloxycarbonyl, Hefarylthiocarbonyl, Hefaralkoxycarbonyl
Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl
HefaryloxycarbonylaS^yl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi Hefarylaminocarbonyl, Hefaralkylaminocarbonyl, Hef alkylaminoalkyl
Hefaralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
Hefaralkanoylaminoalkyl, Hefalkyloxycarbonyiaminoalkyl
Hefaryloxycarbonylaminoakyl, Hef aralkoxycarbonylaminoalkyl
Hefalkylaminocarbonylaminoalkyl, Hefarylaminocarbonyiaminoalkyl Hefaralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hef arylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
Hef aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hefalkylaminocarbonylarrinoaryl
Hefarylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylarrinoaryl Hefalkylaminoaralkyl, Hefarylaminoarakyl, Hefaralkylaminoaralkyl
Hefalkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl
Hefalkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
Hefarylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl, and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoalkyl, arylaminoalkylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is selected from the group comprising hydrogen, alkyl and halogen
3. Compound according to claim 1 or 2 having the general formula I, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, and thia, or wherein R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2 is selected from the group comprising hydrogen, alkyl or cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, cycloalkyl, alkylaminocarbonyl alkylaminoalkyl, aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoaikylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkyllhiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonyiaminoalkyl aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylaminoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonylaminoaralkyl, aryloxycarbonylarrinoaralkyl aralkoxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl arylaminocarbonylaminoaralkyl, aralkylaminocarbonylarrinoaralkyl, carboxyl piperazinyl piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl amidinoalkyl, Hef, Hefoxy, Hefalkyl, Hefoxyalkyl, Hef cycloalkyl, Hefalkoxycarbonyl Hefoxycarbonyl, Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbony! Hefalkyloxyalkylcarbonyl, Hef aminocarbonyl, Hefcarbonyloxyalkyi
Hefalkylcarbonybxyalkyl, Hefaryl, Hefarylaminoalkoxy, Hefarylamino
Hefarylaminoalkyl, Hefarylaminoalkylamino, Hefaryloxy, Hefaryloxyalkoxy Hefaryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl, Hefaralkoxy, Hefaralkylamino Hefaralkanoyl, Hefaroyl, Hefarylcarbonyl, Hefaryloxycarbonyl, Hef arylthiocarbonyi Hefaralkoxycarbonyl, Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl He haloalkyl, Hef aryloxycarbonylalkyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi
Het arylaminocarbonyi, Hefaralkylaminocarbonyl, Hefalkylam noalkyl Het aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylam noalkyl Het aralkanoylaminoalkyl, Hefalkyloxycarbonylam noalkyl Hef aryloxycarbonylaminoakyl, Hefaralkoxycarbonyiam noalkyl Het alkylaminocarbonylamhoalkyl, He arylaminocarbonylami noalkyl Hefaralkylaminocarbonylaninoalkyl, Hefalkylaminoaryl, Hef arylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
Hef aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hefaryloxycarboπylaminoaryl Hefaralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl
He arylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylam'noaryl
Hef alkylaminoaralkyl, Hefarylaminoara&cyl, Hefaralkylaminoaralkyl
He alkanoylaminoaralkyl, He aroylaminoaralkyl, Hefaralkanoylaminoaralkyl
He alkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
He aralkoxycarbonylaminoarakyl, He alkylaminocarbonylam'noaralkyl
He arylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl.Hef, Hefoxy Hef alkyl, Hefoxyalkyl, Hefcycloalkyl, Hefalkoxycarbonyl, Hefoxycarbonyl Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyl, Hefalkyloxyalkylcarbonyi Hefaminocarbonyl, Hefcarbonyloxyalkyi, Hefalkylcarbonyloxyalkyl, Hefaryl Hefarylaminoalkoxy, Hefarylamino, Hefarylaminoalkyl, Hefarylaminoalkylamino Hefaryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl Hefaralkoxy, Hefaralkylamino, Hefaralkanoyl, Hefaroyl, Hefarylcarbonyl
Hef aryloxycarbonyl, Hef arylthiocarbonyi, Hefaralkoxycarbonyl
Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl
Hefaryloxycarbonyla yl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi
Hef arylaminocarbonyi, Hefaralkylaminocarbonyl, Hef alkylaminoalkyl
Hef aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoalkyl
Hefaralkanoylaminoalkyl, Hefalkyloxycarbonylaminoalkyl
Hefaryloxycarbonylaminoakyl, Hef aralkoxycarbonylaminoalkyl
Hefalkylaminocarbonylaminoalkyl, Hefarylaminocarbonyiaminoalkyl
Hefaralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hef arylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl
Hefaralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hefalkylaminocarbonylarrinoaryl
Hefarylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylarrinoaryl
Hef alkylaminoaralkyl, Hefarylaminoarakyl, Hefaralkylaminoaralkyl
Hefalkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl
Hefalkyloxycarbonylaminoarakyl, Hef aryloxycarbonylarrinoaralkyl
Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
Hefarylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl, and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoalkyl, arylaminoalkylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef; wherein R5 is oxo or thio, wherein Rδ is hydrogen, and wherein R7 is hydrogen, fluor or methyl.
4. Compound according to any of claims 1 to 3, or pharmaceutically acceptable salts, solvates or functional derivatives thereof, wherein R1 is selected from the group comprising -CH2-, oxa, and thia or wherein
R1 participates to a double bond between the carbon atoms in position 1 and 2, wherein R2is selected from the group comprising hydrogen, methyl and cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, aminoalkanoyl, aminocarbonyl, alkylaminocarbonyl, alkylaminoalkyl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoa yl, arylaminoalkylamino, aryloxyalkylamino, aralkylamino, arylaminocarbonyi, aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoalkyl, aroylaminoalkyl, aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl, aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl, aralkylaminocarbonylaminoakyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl, alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylaminoaryl, aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl, arylaminocarbonylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl, arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl, aralkanoylaminoaralkyl, alkyloxycarbonyiaminoaralkyl, aryloxycarbonylarrinoaralkyl, aralkoxycarbonylaminoaralkyl, alkylaminocarbonylarrinoaralkyl, arylaminocarbonylaminoardkyl, aralkylaminocarbonylarrinoaralkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl, amidinoalkyl and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyol, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, fluor or methyl.
5. Compound according to any of claims 1 to 4, or pharmaceutically acceptable salts, solvates or functional derivatives thereof. wherein R1 is selected from the group comprising -CH2-, oxa, thia wherein R2 is selected from the group comprising hydrogen, methyl and cyano, wherein R3 and R4 are selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl, amidinoalkyl and wherein R3 and R4 are optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl,
Het1 and Hef; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, methyl or fluor.
6. Compound according to any of claims 1 to 5, or pharmaceutically acceptable salts, solvates or functional derivatives thereof. wherein R1 is selected from the group comprising -CH2-, oxa, thia wherein R2 is selected from the group comprising hydrogen, methyl and cyano, wherein R3 is hydrogen and R4 is selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl, aralkyl, cycloalkylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl, aralkylamino, aralkylaminoalkyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoakyl, amidinoalkyl and wherein R4 is optionally substituted by one or more substituents independently selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoalkyl, arylaminoalkylamino, aralkanoyl, aroyl, Rterazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef; wherein R5 is oxo or thio, wherein R6 is hydrogen, and wherein R7 is hydrogen, methyl or fluor.
7. Compound according to claim 1 , wherein said compound is selected from the group comprising N1-benzyl-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, 4-Qxo-4-(1- piperidinyl)-1 ,3(S)-butanediamine, 4-Oxo-4-(1 -piperidinyl)- 1 ,3(R)-butanediamine, 4-(4- morpholinyl)-4-oxo-1 ,3(S)-butanediamine, 4-oxo-4-(1 -piperazinyl)-1 ,3(S)-butanediamine, benzyl 3-amino-1(S)-(1-piperidinylcarbonyl)propyicarbamate, benzyl 3-amino-4-oxo-4- (1 piperidinyl)butyicarbamate, N1-benzyl-2(S)-(1-piperidinylcarbonyl}1 ,4-butanediamine, Λ/-[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl]acetamide, 4-Oxo-4-(1-piperidinyl Λ/1-(4- piperidinyl)-1,3(S)-butanediamine, benzyl 4-{[4-amino-2(S)-(1- piperidinylcarbonyl)but ]amino -1-piperidinecarboxylate, Λ/-[3(S)-amino-4-oxo-4-(1- piperidinyl)butyj]guanidine, Λ/-[3-amino-1(S)-(1-piperidinylcarbonyl)propyi]guanidine, Λ/-(2- oxo-2-piperidin-1-ylethyl)piperidin-4-amine, benzyl 4{[2-oxo-2-(1-piperidinyl)ethyl]amino}- 1-piperidinecarboxylafe, Λ/-[2-oxo-2-(1-piperidinyl)ethyl]cyclopentanamine, 1-Benzyl-Λ/-[2- oxo-2-(1-piperidinyl)ethyl]-4-piperidinamine, 4-oxo-4-(1-piperidinyl)-N3-(4-piperidinyl)-
1 ,3(S)-butanediamine, 6-oxo-6-(1-piperidinyl)-1,5(S)-hexanediamine, benzyl 5(S)-amino- 6-oxo-6-(1-piperidinyl)hexylcarbamate, 5-oxo-5-(1-piperidinyl)-1 ,4(S)-pentanediamine, 3- oxo-3-(1-piperidinyl)-1 ,2(S)-propanediamine, 3-(1H-imidazol-4-yl)-1-oxo-1-(1~piperidiπyl)- 2(S)-propanamine, 3-cyclohexyH -oxo-1 -(1-piperidinyl)-2(S)-propanamine, 3-methyl-1- oxo-1-(1-piperidinyl)-2(S)-pentanamine, 2(S)-amino-3-oxo-3-(1-piperidinyl)-1-propanol, 1- oxo-1 -(1 -piperidinyl)-2(S)-butanamine, 1 -oxo-1 -(1 -piperidinyl)-2(S)-pentanamine, 1 -oxo-1 - (1-piperidinyl)-2(S)-hexanamine, 6-(3,6-dihydro-1 (2/- )-pyridinyl)-6-oxo-1 ,5(S)- hexanediamine, Λ/-[4(S)-amino-5-oxo-5-(1-piperidinyl)pentyl]guanidine, 1-(S-2,6- Diaminohexanoyl)-2(f?,S)-piperidinecarbonitrile, 1-(S-2,4-diaminobutanoyl)-2(S)- piperidinecarbonitrile, 3-cyclohexyH-(1-piperidinyl)-1-thioxo-2(S)-propanamine, 2(S)- methyl-1-(1-piperidinylcarbothioyl)butylamine, 4-(1-piperidinyl)-4-thioxo-1 ,3(S)- butanediamine, 5-(1-piperidinyl>-5-thioxo-1 ,4(S)-pentanediamine, 6-(1-piperidinyl)-6- thioxo-1 ,5(S)-hexanediamine, Λ/-cyclohexyr-2-oxo-2-(1-piperidinyl)-ethaneamine, N- benzyl-2-oxo-2-(1-piperidinyl)-ethaneamine, Λ-piperonyl-2-oxo-2-(1-piperidinyl)- ethaneamine, Λ/-cyclohexyl-2-thioxo-2-(1-piperidinyl)-ethaneamine, Λ/-benzyl-2-thioxo-2- (1-piperidinyl)-ethaneamine, Λ/-piperonyl-2-thioxo-2-(1-piperidinyl)-ethaneamine.
8. Compound according to claim 1 , wherein said compound is selected from the group comprising tV-(2-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine, Λ1-(3- chlorobenzyl)-4-oxo-4-(1-piperidinyI)-1 ,3(S)-butanediamine, Λ/1-(4-chlorobenzyl)-4-oxo-4- (1 -piperidinyl)-1 ,3(S)-butanediamine, Λ/1-[2-(benzyloxy)benzyl]-4-oxo-4-(1 -piperidinyl)- 1 ,3(S)-butanediamine, Λ/1-[4-(benzyloxy)benzyl 4-oxo-4-(1 -piperidiπyl)-1 ,3(S)- butanediamine, 3-({[3(S)-amino-4-oxo-4-(1 -piperidinyl)butyl^mino}methyl)benzonrιrile, A1- (2-methoxybenzyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine, A/1-(3-methoxyben∑yl)-4- oxo-4-(1-piperidinyl)-1 ,3(S)-butanedisrnine, W1-(4-rnethoxyben∑yl)-4-oxo-4-(1-piperidinyl)- 1 ,3(S)-butanediamine, /V1-(2,4-dimethoxybenzylH-∞∞-4-(1-piperidinyl)-1 ,3(S)- butanediamine, 4-oxo-4-(1-piperidinyl)-Λ/1-(2-thienylrnefrιyl)-1 ,3(S)-butanediamine, 4-oxo- 4-(1-piperidinyl)-/V1-(4-pyridinylmelhyi)-1 ,3(S)-butanediamine, W-(1-naphthylmethyl)-4- oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, tV1-(2-naphthylmethyl)-4-oxo-4-(1-piperidinvl)- 1 ,3(S)-butanediamine, 4-oxo-Λ/1-(2-phenylethyl>4-(1 -piperidinyl)-1 ,3(S)-butanediamine, 4- oxo-Λ/1-(3-phenylpropyl)-4-(1-piPeridiny^1.3('S)-butanediamine, A1-(cyclohexylmethyl)-4- oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, Λ/1-cyclohexyl-4-oxo-4-(1-piperidiηyl)-1 ,3(S)- butanediamine, Λ/1-(4-chlorobenzyl)-Λ/1-methyl-4-oxo-4-(1-piperidinyl)-1 ,3(S)- butanediamine, Λ/1-(4-chlorobenzyl)-tV3-methyl-4-oxo-4-(1 -piperidinyl)-1 ,3(S)- butanediamine, /V,A/1-dibenzyl-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, Λ^Λ^-dif chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1 ,3(S)-butanediamine, 4-oxo-/V-phenyl-4-(1- piperidinyl)-1 ,3(S)-butanediamine, Λ/-[3(S)-amino-4-oxo-4-(1-piperidinyl)butyl]benzamide, Λ/1-(3-nitro-2-pyridinyl)-4-oxo-4-(1-piperidinyl)-1,3(S)-butanediamine, 6-{[3(S)-amino-4- oxo-4-(1-piperidinyl)butyl]amino}nicotinonitrile, Λ/1-(4-chlorobenzyl 4-(2-methyl-1- piperidinyl)-4-oxo-1 ,3(S,)-butanediamine, Λ/l-(4-chlorobenzyl)-4-(3-methyl-1-piperidinyl)-4- oxo-1 ,3 SJ-butanediamine, Λ/1-(4-chlorobenzyl)-4-(4-methyl-1 -piperidinylr4-oxo'1 -3(S)- butanediamine, 1-{2CS -amino-4-t(4-chlorobenzyl)amino]butanoyl}-3-piperidinol, /\-{2(S)- amino-4-[(4-chlorobenzyl)amino]butanoyl}-4-piperidinol, Λ/ -(4-chlorobenzyl)-4-(3-fluoro-1- piperidinyl)-4-oxo-1,3CSJ-butanediamine, Λ/1-(4-chlorobenzyl)-4-(4-fluoro-1-piperidinyl)-4- oxo-1 ,3 S)-butanediamine, Λ/1-(4-chlorobenzyl)-4-(3,6-dehydro-1(2ry)-pyridinyl)-4-oxo- 1 ,3(S)-butanediamine, 1-[2(S)-amino-4-(benzylamino)butanoyl]-2(S)-piperidinecarbonitr.e, 1-{2(S)-amino-4-[(4-chlorobenzyl)amino]butanoyl}-2(S)-piperidinecarbonitrile.
9. Compound having general formula II, or pharmaceutically acceptable salts, solvates or functional deriva ves thereof,
Figure imgf000151_0001
formula II wherein R1, R2, R3, R5, R6, R7 have the same meaning as indicated claim 1 , wherein R R8, R9, R 0 are selected from the group comprising nitrogen, hydrogen oxyalkyl, alkyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkylamino, aminoalkyl alkoxycarbonyl, alkylthiocarbonyl, alkanoyl, aminoalkanoyl, aminocarbonyl, hydroxyalkyl cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyi cycloalkylalkoxycarbonyl, cycloalkylalkoxytiiocarbonyl, cycloalkylthioalkyl alkylcarbonyloxyalkyl, cycloalkylcarbonyioxyalkyl, alkylaminocarbonyl, alkylaminoalkyl aryl, arylaminoalkoxy, arylamino, aminoaryl, aminoaralkyl, arylaminoalkyl arylaminoakylamino, aryloxy, aryloxyalkoxy, aryloxyalkyl, aryloxyalkylamino, aralkyl aralkoxy, aralkylamino, aralkanoyl, aroyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyi aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl aryloxycarbonylalkyl, aryloxyalkanoyl, aralkylcarbonyloxyalkyl, arylaminocarbonyi aralkylaminocarbonyl, aralkylaminoalkyl, alkanoylaminoakyl, aroylaminoalkyl aralkanoylaminoalkyl, alkyloxycarbonyiaminoalkyl, aryloxycarbonylarrinoalkyl aralkoxycarbonylaminoalkyl, alkylaminocarbonylaminoakyl, arylaminocarbonylarrinoalkyl aralkylaminocarbonylaminoalkyl, alkylaminoaryl, arylaminoaryl, aralkylaminoaryl alkanoylaminoaryl, aroylaminoaryl, aralkanoylaminoaryl, alkyloxycarbonylarrinoaryl aryloxycarbonylarrinoaryl, aralkoxycarbonylaminoaryl, alkylaminocarbonylarrinoaryl arylaminocarborylaminoaryl, aralkylaminocarbonylaminoaryl, alkylaminoaralkyl arylaminoarakyl, aralkylaminoaralkyl, alkanoylaminoarakyl, aroylaminoaralkyl aralkanoylaminoaralkyl, alkyloxycarbonyiaminoaralkyl, aryloxycarbonylarrinoaralkyl aralkoxycarbonylaminoaralkyl, alkylaminocarbonylam'noaralkyl arylaminocarbonylaminoaralkyl, aralkylaminocarbonylarrinoaralkyl, carboxyl piperazinyl piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, guanidinoalkyl amidinoalkyl, Hef, Hefoxy, Hef alkyl, Hefoxyalkyl, Hef cycloalkyl, Hef alkoxycarbonyl Hefoxycarbonyl, Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyl
Hefalkyloxyalkylcarbonyl, Hef aminocarbonyl, Hefcarbonyloxyalkyi: Hefalkylcarbonyloxyalkyl, Hefaryl, Hefarylaminoalkoxy, Hefarylamino Het arylaminoalkyl, Hefarylaminoalkylamino, Hefaryloxy, Hefaryloxyalkoxy Hef aryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl, Hefaralkoxy, Hefaralkylamino Het aralkanoyl, Hefaroyl, Hefarylcarbonyl, Hefaryloxycarbonyl, Hefarylthiocarbonyi Het aralkoxycarbonyl, Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl Hef haloalkyl, Hef aryloxycarbonylalkyl, Hefaryloxyalkanoyl, Hef aralkylcarbonyloxya He arylaminocarbonyi, Hefaralkylaminocarbonyl, Hefalkylaminoa Het aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylaminoal Het aralkanoylaminoalkyl, Hefalkyloxycarbonyiarninoa Het aryloxycarbonylaminoakyl, Hefaralkoxycarbonylaminoa Het alkylaminocarbonylaminoalkyl, Hefarylaminocarbonyiaminoa Het aralkylaminocarbonylaminoalkyl, Hefalkylaminoaryl, Hef arylaminoaryl Hef aralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl Het aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hefaryloxycarbonylarrinoaryl Het aralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl Het arylaminocarbonylarrinoaryl, Hefaralkylaminocarbonylarrinoaryl Het alkylaminoaralkyl, Hefarylaminoarakyl, Hefaralkylaminoaralkyl Het alkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl Het alkyloxycarbonylaminoaralkyl, Hef aryloxycarbonylarrinoaralkyl Het aralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl Hef arylaminocarbonylam'noaralkyl, Hefaralkylaminocarbonylaminoaralkyl,Hef, Hefoxy Hefalkyl, Hefoxyalkyl, Hefcycloalkyl, Hef alkoxycarbonyl, Hefoxycarbonyl Hefalkanoyl, Hefalkyloxyalkyl, Hefoxyalkylcarbonyl, Hefalkyloxyalkylcarbonyi Hef aminocarbonyl, Hefcarbonyloxyalkyi, Hefalkylcarbonyloxyalkyl, Hefaryl Hefarylaminoalkoxy, Hefarylamino, Hefarylaminoalkyl, Hefarylaminoalkylamino Hefaryloxy, Hefaryloxyalkoxy, Hefaryloxyalkyl, Hefaryloxyalkylamino, Hefaralkyl Hefaralkoxy, Hefaralkylamino, Hef aralkanoyl, Hefaroyl, Hefarylcarbonyl
Hefaryloxycarbonyl, Hefarylthiocarbonyi, Hefaralkoxycarbonyl
Hefarylalkylthiocarbonyl, Hefaryloxyalkyl, Hefarylthioalkyl, Hefhaloalkyl
Hefaryloxycarbonylakyl, Hefaryloxyalkanoyl, Hefaralkylcarbonyloxyalkyi
Hefarylaminocarbonyl, Hefaralkylaminocarbonyl, Hefalkylam noalkyl
Hef aralkylaminoalkyl, Hefalkanoylaminoalkyl, Hefaroylam noalkyl
Hefaralkanoylaminoalkyl, Hefalkyloxycarbonyiam1 noalkyl
Hef aryloxycarbonylaminoakyl He aralkoxycarbonylami noalkyl
Hef alkylaminocarbonylaminoalkyl, Hefarylaminocarbon^aml noalkyl Hefaralkylaminocarbonylarrinoalkyl, Hefalkylaminoaryl, Hefarylaminoaryl
Hefaralkylaminoaryl, Hefalkanoylaminoaryl, Hefaroylaminoaryl Hef aralkanoylaminoaryl, Hef alkyloxycarbonylaminoaryl, Hef aryloxycarbonylarrinoaryl Hefaralkoxycarbonylaminoaryl, Hef alkylaminocarbonylarrinoaryl
Hefarylaminocarbonylarrinoaryl, Hef ralkylaminocarbonylam'noaryl
Hef alkylaminoaralkyl, Hefarylaminoarakyl, Hefaralkylaminoaralkyl Hefalkanoylaminoaralkyl, Hefaroylaminoaralkyl, Hefaralkanoylaminoaralkyl
Hefalkyloxycarbonylaminoarakyl, Hefaryloxycarborrylarninoaralkyf
Hefaralkoxycarbonylaminoarakyl, Hefalkylaminocarbonylarrinoaralkyl
Hefarylaminocarbonylarrinoaralkyl, Hefaralkylaminocarbonylaminoaralkyl, and wherein R4, R8, R8, R10 are optionally substituted by one or more substituents independentV selected from the group comprising hydrogen, amino, hydroxy, halogen, cyano, nitro, alkyloxy, aralkoxy, alkyl, alkylamino, alkanoyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aminoaryl, arylaminoakyl, arylaminoakylamino, aralkanoyl, aroyl, piperazinyl, piperidinyl, pyrrolidinyl, immidazolidinyl, morpholinyl, amidino, acetyl, Hef and Hef.
10. Compounds of the invention having general formula II as represented in Table A.
11. Compound according to any of claims 1 to 10 for use as a medicament.
12. Compound according to any of claims 1 to 10 for use in the treatment of diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
13. Compound according to any of claims 1 to 10 for use in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPIV.
14. Compound according to any of claims 1 to 10 for use in the treatment of diseases associated with excessive, impaired or unbalanced activity of DPPII.
15. Compound according to any of claims 1 to 10 for use in diagnostic and research methods such as fluorescence, purification and radio-assays, imaging, in situ histochemical and cytochemical staining.
16. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for inhibiting the activity of a serine type dipeptidyl peptidase.
17. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for inhibiting the activity of DPPIV.
18. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for inhibiting the activity of DPPII.
19. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of a serine type dipeptidyl peptidase.
20. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPIV.
21. Use of a compound according to any of claims 1 to 10 in the preparation of a medicament for treating diseases associated with excessive, impaired or unbalanced activity of DPPII.
22. Pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to any of claims 1 to 10, and a pharmaceutically acceptable excipient.
PCT/IB2004/000525 2003-02-28 2004-03-01 Dipeptidyl peptidase inhibitors WO2004076434A1 (en)

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