WO2004089362A1 - 2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv) - Google Patents

2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv) Download PDF

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WO2004089362A1
WO2004089362A1 PCT/DK2004/000232 DK2004000232W WO2004089362A1 WO 2004089362 A1 WO2004089362 A1 WO 2004089362A1 DK 2004000232 W DK2004000232 W DK 2004000232W WO 2004089362 A1 WO2004089362 A1 WO 2004089362A1
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alkyl
compound according
aryl
independently selected
optionally substituted
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PCT/DK2004/000232
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English (en)
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Anders Bendtz Kanstrup
Jane Marie Lundbeck
Lise Brown Christiansen
Marit Kristiansen
Leif Christensen
Inge Thøger Christensen
Andrew Neil Bowler
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Novo Nordisk A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to new therapeutically active and selective inhibitors of the enzyme DPP-IV.
  • the invention furthermore relates to pharmaceutical compositions comprising the compounds and the use of such compounds for the manufacture of medicaments for treating diseases that are associated with proteins which are subject to inactivation by DPP- IV, such as type 2 diabetes and obesity, as well as methods for treating such diseases.
  • DPP-IV Dipeptidyl peptidase-IV
  • DPP-IV Dipeptidyl peptidase-IV
  • serine protease belonging to the group of post- proline/alanine cleaving amino-dipeptidases specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2.
  • DPP-IV DPP-IV
  • DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones Glucagon like peptide-1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N- terminal amino acids inactivates them. In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. Therefore, such inhibitors have been proposed for the treatment of patients with Type 2 diabetes, a disease characterised by decreased glucose tolerance. (Hoist, J. J.; Deacon, C. F.
  • Diabetic dyslipidemia is characterized by multiple lipoprotein defects, including moderately high serum levels of cholesterol and triglycerides, small LDL particles, and low levels of HDL cholesterol.
  • the results of recent clinical trials reveal beneficial effects of cholesterol-lowering therapy in diabetic and non-diabetic patients, thus supporting increased emphasis on treatment of diabetic dyslipidemia.
  • the National Cholesterol Education Program's Adult Treatment Panel II advocated this need for intensive treatment of diabetic dyslipidemia.
  • Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension and diabetes.
  • the incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world.
  • Even mild obesity increases the risk for premature death, dia- betes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer.
  • the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority.
  • initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients eventually regain their weight.
  • An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.
  • Inhibitors of DPP-IV have previously been disclosed in WO 95/15309 (Ferring B.V.), WO 98/19998, WO 00/34241, US 6124305 (Novartis AG), WO 03/00180 (Merck & Co.), and WO 02/38541 (Taisho Pharmaceutical Co.). However, there is still a need for compounds with improved pharmacological properties.
  • the present invention provides novel potent and selective inhibitors of DPP-IV of formula I, that are effective in treating conditions that may be regulated or normalised via inhibition of DPP-IV.
  • the invention also concerns methods for preparing the compounds, pharmaceutical compositions comprising the compounds, a method of inhibiting DPP-IV comprising administering to a patient in need of such treatment a therapeutically effective amount thereof, the compounds for use as a pharmaceutical, and their use in a process for the preparation of a medicament for treating a condition which may be regulated or normalised via inhibition of DPP-IV.
  • DPP-IV Dipeptidyl peptidase IV (EC 3.4.14.5; DPP-IV), also known as CD26. DPP-IV cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline or alanine residue in the penultimate position.
  • treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • beta cell degeneration is intended to mean loss of beta cell function, bets cell dysfunction, and death of beta cells, such as necrosis or apoptosis of beta cells.
  • C 1 . 15 alkyl refers to a straight or branched, saturated hydrocarbon chain having from 1-15 carbon atoms such as bu1 not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. Butyl, isobutyl, tert. Butyl, n- pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl and the like.
  • C 2 . ⁇ 5 -alkenyl used herein, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-15 carbon atoms and at least one double bond such as but not limited to vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n- pentenyl and n-hexenyl and the like.
  • C 2 . ⁇ 5 -alkenyl used herein, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-15 carbon atoms and at least one double bond such as but not limited to vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n- pentenyl and n-hexenyl and the like.
  • C 2 . ⁇ 5 -alkenyl used herein, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from
  • 15 alkynyl refers to an unsaturated hydrocarbon chain having from 2-15 carbon atoms and at least one triple bond such as but not limited to -C ⁇ CH, -C ⁇ CCH 3 , -CH 2 G ⁇ CH, -CH 2 -CH 2 -C ⁇ CH, -CH(CH 3 )C ⁇ CH and the like.
  • d.-io-alkoxy as used herein, alone or in combination is intended to include those C,- Cio-alkyl groups of the designated length in either a linear or branched or cyclic configuration linked through an ether oxygen having its free valence bond from the ether oxygen.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • C 3 The term "C 3 .
  • 15 -cycloalkyl refers to a radical of one or more saturated cyclic hydrocarbon having from 3-15 carbon atoms, including bi- or polycyclic hydrocarbon systems, non-limiting examples of C 3 -C 15 -cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.
  • spiro-C 3 . 10 -cycloalkyl refers to a C 3 . 10 -cycloalkyl radical as defined above having from 3 to 10 carbon atoms connected to the group to which it is attached through a common carbon atom.
  • the term as used herein refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-15 carbon atoms, including bi- or polycyclic hydrocarbon systems having at least one double bond, non-limiting examples of Cs- 15 -cycloalkenyl are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4- ⁇ yclo- octadienyl, bicyclo[2.2.1]hept-5-en-2-yl and the like.
  • halogen refers to fluoro, chloro, bromo, and iodo.
  • Cs-io-cycloheteroalkyl represents a non-aromatic 5 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpho>linyl, aziridinyl, tetrahydrofuranyl and the like.
  • the term as used herein represents a non-aromatic 5 to 10 membered ring having at least one double bond and containing one or more heteroatoms selected from nitrogen, oxygen and sulphur.
  • aryl as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems. Representative examples are phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, azulenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4- dihydronaphthyl and the like.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above.
  • aroyl as used herein denotes a group -C(0)-aryl, wherein aryl is as defined above.
  • heteroaryl as used herein is intended to include aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur.
  • Representative examples are furyl, thienyl, pyrrolyl, pyrazolyl, 3- oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4- triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non- limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • the term "ArG1" as used herein is intended to include an aryl radical, where aryl is as defined above but limited to phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, and azulenyl.
  • ArG2 as used herein is intended to include an aryl radical, where aryl is as defined above but limited to phenyl, biphenylyl, naphthyl, fluorenyl, and indenyl.
  • Het1 as used herein is intended to include a heteroaryl radical, where heteroaryl is as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1 ,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4- thiadiazoly
  • Het2 as used herein is intended to include a heteroaryl radical, where heteroaryl is as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4- thiadiazolyl,
  • Het3 is intended to include a heteroaryl radical, where heteroaryl is as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, tetrazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, quinoxalinyl, carbazolyl, thiazolidinyl, 2- thiooxothiazolidinyl.
  • Aryl-C ⁇ o-alkyl "heteroaryl-C ⁇ o-alkyl”, “aryl-C 2 . 10 -alkenyr, Aryl-C ⁇ o-alkoxy etc. is intended to mean C ⁇ . 10 -alkyl, C ⁇ o-alkoxy or C 2 . 10 -alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • the term "optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different. Furthermore, when the groups are made up of two distinct parts, e.g. aryl-C ⁇ o-alkyl, where the parts are aryl and C ⁇ o-alkyl respectively, either or both of the parts may be substituted with one or more of the substituents specified which may be the same or different.
  • the present invention provides compounds of formula I
  • B and D are independently selected from carbon, nitrogen, oxygen, or sulphur.
  • the bond between B and D may be a single bond, and when one or both of B and D is not carbon, the bond connecting B and D may be a double bond.
  • R 1 is
  • R 1 may also be hydrogen
  • R 3 is hydrogen, hydroxy, halogen, d- 10 -alkoxy, C ⁇ . 10 -alkyl, aryl, aryloxy, aryl-d- 10 -alkoxy, heteroaryl, cyano, cyanoalkyl, and COOR 2 ;
  • R 4 is halogen, d- 5 -alkyl, nitro, hydroxy, OCF 3 , OCHF 2 , perhalomethyl, perhaloethyl, cyano, phenyl, COOR 5 , CONR 5 R 6 , 0(CO)R 5 , d. 10 -alkoxy, aryl-d- 10 -alkoxy, SR 5 , S0 3 R 5 , NR 5 R 6 ,
  • R 5 and R 6 are independently selected from hydrogen, d- 1 0-alkyl, aryl-d- 10 -alkyl, or aryl; R 5 and R 6 together may form a C 3 _ 7 -alkylene bridge that optionally may be substituted with one or more R 7 independently;
  • R 7 is independently selected from cyano, halogen, hydroxy, C ⁇ . 10 -alkyl, d-io-alkoxy, aryl, and heteroaryl;
  • R 8 is halogen, d- 5 -alkyl, nitro, hydroxy, OCF 3 , OCHF 2 , perhalomethyl, perhaloethyl, cyano, phenyl, COOR 9 , CONR 10 R 11 , O(C0)R 9 , d. 10 -alkoxy, -d. 10 -alkyl-C(O)-R 9 , -d. 10 -alkyl-C(O)-R 9 , aryl-d. 10 -alkoxy, SR 9 , S(0) 2 R 9 , S(O) 2 NR 10 R 11 , S0 3 R 9 , NR 10 R 11 , NHCOR 9 , or COR 9 ;
  • R 9 is d- 15 -alkyl, C 2 . 15 -alkenyl, C 2 . ⁇ 5 -alkynyl, Qj-io-cycloalkyl, Cs-nrcycloalkenyl, aryl, heteroaryl, Cs-io-cycloalkyl-Ci-io-alkyl, aryl-d- 10 -alkyl, aryl-C 2 . 10 -alkenyl, heteroaryl-d- 1 0-alkyl, C 5 - ⁇ o-cycloheteroalkyl, each optionally substituted with one or more substituents independently selected from R 2 ;
  • R 10 and R 11 are independently selected from hydrogen, d- 10 -alkyl, aryl-d- 10 -alkyl, or aryl;
  • R 12 is independently selected from halogen, C ⁇ -5-alkyl, nitro, hydroxy, OCF 3 , OCHF , perhalomethyl, perhaloethyl, cyano, phenyl, COOH, CONH 2 , d- 1 0-alkoxy, aryl-d- 10 -alkoxy, SH, or NH 2 ;
  • R 1 and R 2 together may form a C 3 - -alkylene or C3- -alkenylene bridge to which is fused a phenyl or a heteroaryl ring;
  • B is carbon, nitrogen or sulphur.
  • B is carbon or nitrogen.
  • B is carbon
  • D is carbon, nitrogen or sulphur. In one embodiment D is carbon or nitrogen.
  • D is carbon
  • R 1 is
  • R 1 is • d- 1 5-alkyl, C 3 . 10 -cycloalkyl, C 3 . 10 -cycloalkenyl, aryl, heteroaryl, or aryl-d- 10 -alkyl, each optionally substituted with one or more substituents independently selected from R 4
  • R 1 is • d- 1 5-alkyl, C 3 . 10 -cycloalkyl, C 3 . 10 -cycloalkenyl, ArG1 , heteroaryl, or ArGI-d- 10 -alkyl, each optionally substituted with one or more substituents independently selected from R 4
  • R 1 is
  • Ci o-cycloheteroalkyl or C5. 10 -cycloheteroalkenyl each optionally substituted with one or more substituents independently selected from R 8 .
  • R 1 is d- 15 -alkyl, C ⁇ o-cycloalkyl, C 3 . ⁇ 0 -cycloalkenyl, ArG1-d. 10 -alkyl, each optionally substituted with one or more substituents independently selected from R 4 , or
  • R 1 is cyclopentyl, cyclohexyl, cyclohexyl, bicyclo[2.2.1]heptyl, adamantyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-5-enyl, benzyl, each optionally substituted with one or more substituents independently selected from R 4 , or pyrrolyl, piperidinyl, or hexahydroazepinyl, each optionally substituted with one or more substituents independently selected from R 8 .
  • R 1 is 3-piperidinyl or 4-piperidinyl each optionally substituted by R 8 .
  • R 1 is 3-piperidinyl or 4-piperidinyl each optionally substituted at the nitrogen atom by R 8 .
  • heteroaryl is Het1.
  • heteroaryl is Het2. In one embodiment heteroaryl is Het3.
  • R 2 is hydrogen, d. 10 -alkyl, C 2 . 15 -alkenyl, C 3 . ⁇ 0 -cycloalkyl, C 3 _ 10 - cycloalkenyl, aryl, heteroaryl, aryl-d. 10 -alkyl, each optionally substituted with one or more substituents independently selected from R 4 .
  • R 2 is hydrogen, d. 10 -alkyl, Cs-io-cycloalkyl, phenyl-d- 1 0-alkyl, each optionally substituted with one or more substituents independently selected from R 4 .
  • R 2 is hydrogen
  • R 1 and R 2 together form a C 3 . 7 -alkylene or C 3 . 7 -alkenylene bridge to which is fused a phenyl ring.
  • R 3 is hydrogen, hydroxy, halogen, d. 10 -alkoxy, d. 10 -alkyl, aryl, aryloxy, or aryl-Ci.io-alkoxy.
  • R 3 is hydrogen, hydroxy, halogen, d- 10 -alkyl, or aryl-Ci.io-alkoxy.
  • R 3 is hydrogen or aryl-d. 10 -alkoxy.
  • R 3 is hydrogen
  • R 4 is halogen, d. 5 -alkyl, hydroxy, OCF 3 , OCHF 2 , phenyl, COOR 5 , CONR 5 R 6 , 0(CO)R 5 , d. 10 -alkoxy, aryl-d. 10 -alkoxy, NR 5 R 6 , or COR 5 .
  • R 4 is halogen, d-s-alkyl, hydroxy, phenyl, COOR 5 , CONR 5 R 6 , 0(CO)R 5 ,
  • R 4 is halogen, d-s-alkyl, COOR 5 , CONR 5 R 6 , NR 5 R 6 , or COR 5 .
  • R 4 is halogen, d-s-alkyl, COOR 5 , or CONR 5 R 6 .
  • R 5 is hydrogen or d- 10 -alkyl.
  • R 6 is hydrogen or d- 10 -alkyl.
  • R 5 and R 6 together form a C 3 . 7 -alkylene bridge optionally substituted with one or more R 7 .
  • R 7 is cyano, halogen, hydroxy, d. 10 -alkyl, or d. 10 -alkoxy. In one embodiment R 7 is cyano, halogen, hydroxy, or d. 10 -alkyl.
  • R 7 is cyano or halogen.
  • R 7 is cyano
  • R 8 is halogen, d. 5 -alkyl, nitro, hydroxy, OCF 3 , OCHF 2 , cyano, phenyl,
  • R 8 is halogen, d-s-alkyl, hydroxy, cyano, phenyl, COOR 9 , 0(CO)R 9 , d-
  • R 8 is halogen, d. 5 -alkyl, hydroxy, cyano, phenyl, COOR 9 , 0(CO)R 9 , d. 10 -alkoxy, S(0) 2 R 9 , S(O) 2 NR 10 R 11 , NR 10 R 11 , or COR 9 .
  • R 8 is halogen, d. 5 -alkyl, hydroxy, cyano, phenyl, NR 10 R 11 , or COR 9 .
  • R 9 is Ci-is-alkyl, C 2 . 15 -alkenyl, C 3 . ⁇ o-cycloalkyl, C 3 . 10 -cycloalkenyl, ArG1 ,
  • R 9 is C ⁇ - 1 5-alkyl, C 3 . 10 -cycloalkyl, Cs- ⁇ -cycloalkenyl, ArG1 , or C ⁇ o- cycloheteroalkyl, each optionally substituted with one or more substituents independently selected from R 12 .
  • R 9 is C ⁇ - 15 -alkyl, C 3 . 10 -cycloalkyl, C ⁇ o-cycloalkenyl, phenyl or C ⁇ o- cycloheteroalkyl, each optionally substituted with one or more substituents independently selected from R 12 .
  • R 10 and R 11 are independently selected from hydrogen, d. 10 -alkyl, or phenyl.
  • R 10 and R 11 are independently selected from hydrogen or methyl.
  • R 12 is halogen, d. 5 -alkyl, hydroxy, OCF 3 , OCHF 2 , cyano, phenyl, COOH, CONH 2 , d. 10 -alkoxy, SH, or NH 2 .
  • R 12 is halogen, d ⁇ -alkyl, hydroxy, cyano, phenyl, COOH, SH, or NH 2 .
  • the invention provides the use of any of the compounds of the invention as a pharmaceutical composition.
  • the invention provides a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.
  • the invention provides such a pharmaceutical composition in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound of the invention.
  • composition furthermore comprises an inhibitor of neutral endopeptidase (NEP).
  • NEP neutral endopeptidase
  • the invention provides the use of a compound of the general formula (I) or a diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of disorders and diseases in which an inhibition of DPP-IV has a beneficial effect.
  • the invention provides the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of IGT.
  • a compound of the invention for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • the invention provides the use of a compound of the invention for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the invention provides the use of a compound of the invention for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the invention provides a method for the treatment of disorders or diseases in which an inhibition of DPP-IV has a beneficial effect, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition as described above.
  • the invention provides the above method wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
  • the invention furthermore relates to treatment of a patient in which the compounds of the invention are combined with another form of treatment.
  • treatment of a patient with the compounds of the invention are combined with diet and/or exercise.
  • the compounds of the invention are administered in combination with one or more further active substances in any suitable ratios.
  • Such fu rther active substances may e.g. be selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.
  • the compounds of the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL- 316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita
  • the antiobesity agent is leptin. In another embodiment the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine. In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
  • the orally active hypoglycemic agents comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, insulin secretagogues such as glimepride, ⁇ -glucosidase inhibitors, agents acting on the ATP- dependent potassium channel of the ⁇ -cells e.g.
  • potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK
  • compounds of the invention are administered in combination with a sulphonylurea e.g. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • a sulphonylurea e.g. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • the compounds of the invention are administered in combination with a biguanide, e.g. metformin.
  • a meglitinide e.g. repaglinide or nateglinide.
  • a thiazolidinedione insulin sensitizer e.g.
  • troglitazone ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-01 1/CI- 1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41 120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
  • the pharmaceutical preparation of the invention may be administered in combination with an insulin sensitizer, e.g. such as Gl 262570, YM- 440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr.
  • an insulin sensitizer e.g. such as Gl 262570, YM- 440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00
  • the compounds of the invention are administered in combination with an ⁇ -glucosidase inhibitor, e.g. voglibose, emiglitate, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor e.g. voglibose, emiglitate, miglitol or acarbose.
  • the compounds of the invention are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells, e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • the pharmaceutical preparation of the invention may be administered in combination with nateglinide.
  • the compounds of the invention are administered in combination with an antilipidemic agent, e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antilipidemic agent e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the compounds of the invention are administered in combination with more than one of the above-mentioned compounds, e.g.
  • the compounds of the invention may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents examples include ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin.
  • the compounds of the invention may also be combined with NEP (neutral endopeptidase) inhibitors such as candoxatril.
  • antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference as well as orally active hypoglycemic agents.
  • the antidiabetic is insulin or an analogue thereof or a derivative thereof. More preferably the antidiabetic is human insulin or an analogue thereof or a derivative thereof.
  • porcine insulin is also an insulin species, which may be employed with the present invention. Preferably, porcine insulin is highly purified naturally produced porcine insulin.
  • Human insulin could be naturally produced insulin, or human insulin recombinantly produced.
  • Recombinant human insulin may be produced in any suitable host cell for example the host cells may be bacterial, fungal (including yeast), insect, animal or plant cells.
  • the host cells are yeast cells or bacterial cells such as for example E. coli.
  • the analogue of human insulin is a rapid-acting analogue.
  • the analogue may be selected from the group consisting of AspB28 human insulin and LysB28ProB29 human insulin.
  • the derivative is human insulin or an analogue thereof containing a C 6 to o lipophilic substituent in position B29.
  • the derivative may be selected from the group consisting of B29-N ⁇ -myristoyl-des(B30) human insulin, B29-N ⁇ -palmitoyl-des(B30) human insulin, B29-N ⁇ -myristoyl human insulin, B29-N ⁇ -palmitoyl human insulin, B28-N ⁇ -myristoyl ys B28 p r ⁇ B 2 9 numan j nsu
  • insulin compositions are antidiabetics which should also be considered to fall within the scope of the present invention.
  • this includes regular insulin, Semilente® insulin, isophane insulin, insulin zinc suspensions, protamine zinc insulin, and Ultralente® insulin.
  • Isophane insulin is an isophane mixture of protamine and insulin, wherein a ratio of protamine to insulin is mixed, which is equal to the ratio in a solution made by mixing equal parts of a solution of the two in which all the protamine precipitates and a solution of the two in which all the insulin precipitates.
  • the insulin compositions to be administered in combination with a compound of the invention are characterised by a fast onset of action, while in other embodiments the insulin compositions have a relatively slow onset but show a more or less prolonged action.
  • Fast acting insulin compositions are usually solutions of insulin, while retarded acting insulin compositions can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both.
  • some compositions have both a fast onset of action and a more prolonged action.
  • Such a composition may be an insulin solution wherein protamine insulin crystals are suspended.
  • compositions obtained by mixing an insulin solution with a suspension composition in the desired ratio are useful with the present invention.
  • the compounds of the present invention may be administered in combination with one or more compositions comprising analogues and/or derivatives of human insulin.
  • the compounds of the present invention may be administered in combination with one or more insulin compositions comprising one or more fast-acting analogues of human insulin, in particular analogues wherein the amino acid residue at position B28 is Asp, Lys, Leu, Val or Ala and the amino acid residue at position B29 is Lys or Pro; or des(B28-B30), des(B27) or des(B30) human insulin.
  • the insulin analogue may be selected from analogues of human insulin wherein the amino acid residue at position B28 is Asp or Lys, and the amino acid residue at position B29 is Lys or Pro, e.g. Asp B2 ⁇ human insulin and Lys B2 8 Pro B2 g human insulin.
  • the compounds of the present invention may be administered in combination with one or more insulin compositions comprising an insulin derivative having a protracted profile of action, such an insulin having one or more lipophilic substituents.
  • Lipophilic insulins may be acylated insulins, including those described in WO 95/07931 , e.g. human insulin derivatives wherein the ⁇ -amino group of LyS ⁇ 29 contains an acyl substituent which comprises at least 6 carbon atoms. It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable carrier or diluent.
  • Pharmaceutical compositions containing a compound of the invention of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed.. 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier that may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound of the invention which inhibits the enzymatic activity of DPP-IV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of the invention which inhibits the enzymatic activity of DPP-IV, dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg Modified cellulose gum (Ac-Di-Sol)® 7.5 mg Magnesium stearate Ad.
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g. type II diabetes, IGT, IFG, obesity, appetite regulation or as a blood glucose lowering agent, and especially type II diabetes.
  • a mammal especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g. type II diabetes, IGT, IFG, obesity, appetite regulation or as a blood glucose lowering agent, and especially type II diabetes.
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used.
  • a most preferable dosage is about 0.5 mg to about 250 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • the invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound of the invention that are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
  • the invention also encompasses active metabolites of a compound of the invention.
  • Step C1.1 Reacting a beta amino acid of formula C1 , Formula C1
  • N-protection group Pg 1 is a standard protecting group for use in peptide synthesis, such as the Boc-, Z-, Fmoc, or trityl- group, with a S-Proline amide, using standard conditions for amide bond formation, such as active ester formation (HOBt-esters, HOAt-esters, pentafluorophenyl-esters etc. ) via carbodiimide activation, symmetrical anhydride activation, unsymmetrical anhydride formation (e.g. reaction with chloroformate esters), or directly from the anhydrides, to form compounds of formula C7,
  • active ester formation HOAt-esters, HOAt-esters, pentafluorophenyl-esters etc.
  • unsymmetrical anhydride formation e.g. reaction with chloroformate esters
  • step C3.1 the beta amino acid is reacted with a S-2-Cyanopyrrolidine of formula C4 to give directly a compound of formula C8, wherein B, D, R 1 , R 2 , R 3 , and Pg 1 have the meaning described above, thus avoiding step C2.2.
  • Step C3.3 is identical to step C2.3 in method (C2)
  • beta amino acids of formula C6, wherein R ⁇ R 2 , and Pg 1 have the meaning described above, are either commercially available from general chemistry vendors such as Aldrich, Lancaster, Merck, or Maybridge, or from vendors specialised in amino acids and peptides, such as Bachem (Schwitzerland), Novabiochem (Germany), RSP (Ma, USA), Peptech (Ma, USA), Advanced Chemtech.
  • R 1 has the meaning described above.
  • a compound of formula D3 Reacting a compound of formula D3 with a suitable amine protecting agent, such as Boc- anhydride, Z-chloride, trityl chloride, or a polymer based protecting agent such as described in step C3.1. to give a compound of formula C6, wherein R 2 is H, and R 1 and Pg 1 have the meaning described above.
  • a suitable amine protecting agent such as Boc- anhydride, Z-chloride, trityl chloride, or a polymer based protecting agent such as described in step C3.1.
  • the aldehyde (9.6 mmol), malonic acid (9.6 mmol), and ammonium acetate (19.5 mmol) are allowed to react in 96 % ethanol (2 ml) at 100 °C for 1-6 h or in a micro wave oven for 1-5 min at 150 °C. Upon cooling to room temperature the precipitate is filtered of and washed with ethanol/acetone (1 :1) (2 x 1 ml) to give the product.
  • step A The isolated product from step A (9.6 mmol) is mixed with water (15 ml). A solution of (Boc) 2 0 (1.1 eq.) in THF (10 ml) and 1 N NaOH (10 ml) are added, and the reaction is stirred for 16 hours. The acidity is adjusted to pH 1-2 with 1 N HCl. The mixture is extracted with ethyl acetate (3 x 10 ml), dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo to give the product, which can be further purified by preparative HPLC (method A). Step C:
  • step B The product from step B (1.13 mmol) is dissolved in DCM (6 ml). HOBt (0.19; 1.4 mmol) and EDAC, HCl (0.27 g; 1.4 mmol) are added, followed by (S)-pyrrolidine-2-carbonitrile (0.213 g; 0.10 mmol). The mixture stirred at room temperature for 16 hours and poured into potassium hydrogen sulphate (15 ml 0.5 M in water). After stirring for one hour the organic phase was isolated and washed with 10 % NaHC0 3 (2 x 5 ml).
  • step D The product from step D (44 mg, 0.13 mmol) is dissolved in acetonitrile (0.3 ml). Water (0.3 ml) and TFA (0.111 ml) is added, and the reaction mixture is stirred at room temperature for 4 days. The reaction mixture is evaporated in vacuo to give the product, which can be further purified by preparative HPLC (method A).
  • a shaking vessel was charged with the Rink amide resin (NovaBiochem - loading 0.61 mmol/g - 83 mg, 50 mmol).
  • the resin was briefly swelled in DCM with gentle agitation for 2 h.
  • the Fmoc group was then removed by treatment with 20 % piperidine/NMP (1ml) and shaken for 30 min.
  • the resin was then washed with NMP (6 x 1 ml).
  • To the Rink amine was added a solution of the Fmoc-protected amino acid (400 ⁇ mol) in NMP/DCP/DIEA (4.5:4.5:1 , 1 ml) followed by a solution of PyBroP (400 ⁇ mol) in DCP (0.5 ml).
  • the reaction was shaken for 4 h, filtered and washed with NMP (1 x 1 ml), DCM (1 x 1 ml), and NMP (1 x 1 ml).
  • the Fmoc group was then removed by treatment with 20 % piperidine/NMP (1 ml) and shaken for 30 min.
  • the resin was then washed with NMP (6 x 1 ml).
  • step B To the product from step B was dissolved in a mixture of TFAA (70 ⁇ l) and DCM (430 ⁇ l). Pyridine (0.5 ml) was added; the mixture was shaken for 1 h and evaporated in vacuo to give the N-substituted trifluoroacetylated pyrrolidinecarbonitrile.
  • step C The product from step C was dissolved in a saturated ammonia-methanol solution (1 ml) and shaken for 20 h. The solvent was removed in vacuo to give the product, which was further purified by preparative HPLC (method A).
  • the resin starting material is commercially available from Novabiochem or it can be produced by reacting 4-(hydroxymethyl)phenoxymethyl polystyrene resin with p-nitrophenyl chloroformate in DCM and DIEA. (Dressman, B. A.; Spangle, L. A.: Tetrahedron. Lett. 37 (1996) 937-40).
  • the amino acid (100 ⁇ mol) and DMAP (50 ⁇ mol) is dissolved in a mixture of NMP, DCP,
  • Activation of the above resin bound amino acid is carried out by adding a mixture of N- methyl-2-pyrrolidone and pyridine (9:1 , 1 ml) and pentafluorophenoltrifluoromethylacetate (80 ⁇ l). The mixture is allowed to react at 25 °C for 4h. Then the resin is washed with N-methyl-2- pyrrolidone (2x1 ml).
  • step A The isolated product from step A is dissolved in 1N NaOH:EtOH (15:50 ml), and stirred at room temperature for 16 hours. (Boc) 2 0 (1.3 eq.) is added, and the reaction is further stirred for 16 hours.
  • the EtOH is stripped from the reaction mixture in vacuo, further water is added, and the acidity is adjusted to pH 1-2 with 1 N HCl.
  • the mixture is extracted with DCM (3x100 ml), dried (MgS0 4 ), filtered, and evaporated in vacuo to give the product, which is further purified by preparative HPLC (method A).
  • Step C The product from step B is dissolved in DMF (30 ml). HOBt (0.15; 0.44 mmol), and EDAC (0.126g; 0.66mmol), is added, followed by L-prolinamide (0.050g; 0.44mmol). The mixture stirred at room temperature for 2.5 hours, and evaporated in vacuo. The residue is dissolved in DCM (75 ml), and washed with 1 N NaOH (50 ml). The NaOH phase is back extracted with DCM (75 ml), and the combined DCM phase is was washed with 5% aqueous acetic acid, dried (MgS0 4 ), filtered and evaporated in vacuo to give the product, which is further purified by preparative HPLC (method A).
  • step C The product from step C is dissolved in DCM (3 ml) and cooled to 0° on ice. Pyridine (0.379 g; 4.79 mmol) is added, and then phosphorous oxychloride (0.196 g; 1.28 mmol) is added slowly. The reaction mixture is stirred at 0° C for 4 hours. The reaction is poured onto ice, and extracted with DCM (2 x 6 ml). The combined DCM phase is washed with saturated NaHS0 4 (2 ml), NaHC0 3 (2 ml), and brine (2ml), dried with MgS0 4 , filtered, and evaporated in vacuo to give the product, which is further purified by preparative HPLC (method A).
  • Step E The product from step D is dissolved in acetonitrile (10 ml). TFA (1 ml) is added, and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is evaporated in vacuo to give the product, which is further purified by preparative HPLC (method A).
  • Step C f3-(2-Cvano-pyrrolidin-1-v ⁇ -3-oxo-1-pyridin-3-yl-propyll-carbamic acid tert-butyl ester (1C)
  • Step D 1-(3-Amino-3-pyridin-3-yl-propionyl)-pyrrolidine-2-carbonitrile (1) [3-(2-Cyano-pyrrolidin-1-yl)-3-oxo-1-pyridin-3-yl-propyl]-carbamic acid tert-butyl ester was reacted as described in general procedure (A), step D, to afford the title compound as an oil in 93 % yield.
  • Step C f3-(2-Cvano-pyrrolidin-1-yl)-3-oxo-1-thiophen-3-yl-propyl1-carbamic acid tert-butyl ester (2C)
  • Step D 1-(3-Amino-3-thiophen-3-yl-propionyl)-pyrrolidine-2-(R)-carbonitrile (2) [3-(2-Cyano-pyrrolidin-1-yl)-3-oxo-1-thiophen-3-yl-propyl]-carbamic acid tert-butyl ester was reacted as described in general procedure (A), step D, to afford the title compound as an oil.
  • Step C (1-r2-(2-Cvano-pyrrolidin-1-yl)-2-oxo-ethvn-2-methyl-propyl ⁇ -carbamic acid tert-butyl ester (3C)
  • Step D 1-(3-Amino-4-methyl-pentanoyl)-pyrrolidine-2-carbonitrile (3)
  • Step C f1-r2-(2-Cvano-pyrrolidin-1-yl)-2-oxo-ethyll-2-ethyl-butyl>-carbamic acid tert-butyl ester
  • Step D 1-(3-Amino-4-ethyl-hexanoyl)-pyrrolidine-2-carbonitrile (4)
  • Step B 3-tert-Butoxycarbonylamino-3-cvclohex-3-enyl-propionic acid
  • Step C r3-(2-Cvano-pyrrolidin-1-yl)-1-cvclohex-3-enyl-3-oxo-propyll-carbamic acid tert-butyl ester
  • Step D 1 -(3-Amino-3-cvclohex-3-enyl-propionyl)-pyrrolidine-2-carbonitrile
  • Step A 3-Amino-3-bicyclor2.2.1lhept-5-en-2-yl-propionic acid
  • Step B 3-Bicvclor2.2.nhept-5-en-2-yl-3-tert-butoxycarbonylamino-propionic acid
  • Step C f 1 -Bicyclof2.2.1 lhept-5-en-2-yl-3-(2-cvano-pyrrolidin-1 -yl)-3-oxo-propyll-carbamic acid tert-butyl
  • Step D 1-(3-Amino-3-bicvclor2.2.1lhept-5-en-2-yl-propionyl)-pyrrolidine-2-carbonitrile
  • 1 H-NMR (CD 3 OD) ⁇ 6.32 (m), 6.15 (m), 6.10 (m), 5.69 (m), 4.77 (m, 1 H), 3.65 (m, 1 1 / 2 H), 3.48 (m, 1 1 / 2 H), 3.1 - 2.8 (m, 3H), 2.78 (m, 1 H), 2.62 (m, 1 H), 2.34 (m, 1 H), 2.25 (m, 2H), 2.16 (m, 2H), 1.96 (m, 1 H), 1.6 - 1.35 (m, 2H).
  • Step C f1-f2-(2-Cvano-pyrrolidin-1-yl)-2-oxo-ethvn-2-phenyl-propyl)-carbamic acid tert-butyl ester
  • Step D 1 -(3-Amino-4-phenyl-pentanoyl)-pyrrolidine-2-carbonitrile
  • Step C f1- r 2-(2-Cvano-pyrrolidin-1-yl)-2-oxo-ethyll-2-methyl-pentyl)-carbamic acid tert-butyl ester
  • Step D 1 -(3-Amino-4-methyl-heptanoyl)-pyrrolidine-2-carbonitrile
  • Step B 3-tert-Butoxycarbonylamino-4-methyl-tridecanoic acid
  • Step C f1-r2-(2-Cvano-pyrrolidin-1-v ⁇ -2-oxo-ethvn-2-methyl-undecyl ⁇ -carbamic acid tert- butyl ester
  • Step A 2-(1-Amino-2-carboxy-ethyl)-cvclopropanecarboxylic acid ethyl ester
  • Step B 2-(1-tert-Butoxycarbonylamino-2-carboxy-ethv ⁇ -cvclopropanecarboxylic acid ethyl ester
  • Step C 2-f1-tert-Butoxycarbonylamino-3-(2-cyano-pyrrolidin-1-yl)-3-oxo-propyll- cvclopropanecarboxylic acid ethyl ester
  • Step D 2-ri-Amino-3-(2-cyano-pyrrolidin-1-yl)-3-oxo-propyn-cyclopropanecarboxylic acid ethyl ester
  • Step B 3-tert-Butoxycarbonylamino-3-cvclopropyl-propionic acid
  • Step C f3-(2-Cvano-pyrrolidin-1-yl)-1-cvclopropyl-3-oxo-propyll-carbamic acid tert-butyl ester
  • Step C r3-(2-Cvano-pyrrolidin-1-yl)-3-oxo-1-thiophen-2-yl-propyll-carbamic acid tert-butyl ester
  • Step B 3-tert-Butoxycarbonylamino-3-thiophen-2-yl-propionic acid
  • Step C r3-(2-Cvano-pyrrolidin-1-yl)-3-oxo-1-thiophen-2-yl-propyn-carbamic acid tert-butyl ester
  • Step D 1-(3-Amino-3-thiophen-2-yl-propionyl)-pyrrolidine-2-carbonitrile (CD3OD): ⁇ 7.52 (d, 1H), 7.28 (d, 1H), 7.09(dd, 1H), 5.07 (t, 1H) 4.78 (t, 1H), 3.67 (m, 1H), 3.50 (m, 1H), 3.15 (d, 2H)), 2.3-2.1 (m, 4H).
  • Step B 3-Adamantan-1-yl-3-tert-butoxycarbonylamino-propionic acid
  • Step C ri-Adamantan-1-yl-3-(2-cvano-Pyrrolidin-1-yl)-3-oxo-propyll-carbamic acid tert-butyl ester
  • Step D 1-(3-Adamantan-1-yl-3-amino-propionyl)-pyrrolidine-2-carbonitrile (DMSO-d 6 ): ⁇ 4.80-4.73 (m, 1H), 3.75-3.39 (m, 3H), 2.85-2.74 (m, 1 H), 2.46-2.35 (m, 1 H), 2.16 (m, 2H), 2.08-1.97 (m), 1.69-1.54 (m)
  • Example 15 General procedure (A) 1-(3-Amino-3-cvcloheptylpropionyl)-pyrrolidine-2-carbonitrile
  • Step B 3-tert-Butoxycarbonylamino-3-cvcloheptyl-propionic acid
  • Step C r3-(2-Cvano-pyrrolidin-1-yl)-1-cvcloheptyl-3-oxo-propyll-carbamic acid tert-butyl ester
  • Step B 3-tert-Butoxycarbonylamino-3-cyclopentylpropionic acid
  • Step C r3-(2-Cyano-pyrrolidin-1-vD-1-cyclopentyl-3-oxo-propyH-carbamic acid tert-butyl ester
  • Step D 1-(3-Amino-3-cvclopentyl-propionyl)-pyrrolidine-2-carbonitrile
  • Step B 3-Bicvclo r 2.2.Hhept-2-yl-3-tert-butoxycarbonylamino-propionic acid.
  • Step D 1-(3-Amino-3-bicvclof2.2.1lhept-2-yl-propionyl)-pyrrolidine-2-carbonitrile
  • Step B 3-Benzofuran-2-yl-3-tert-butoxycarbonylamino-propionic acid.
  • Step C ri-Benzofuran-2-yl-3-(2-cvano-pyrrolidin-1-yl)-3-oxo-propyll-carbamic acid tert-butyl ester.
  • Step D 1-(3-Amino-3-benzofuran-2-yl-propionyl)-pyrrolidine-2-carbonitrile
  • Step A 4-(1-Amino-2-carboxy-ethv ⁇ -piperidine-1-carboxylic acid tert-butyl ester
  • Step B 4-(1-tert!-Butoxycarbonylamino-2-carboxy-ethyl)-piperidine-1-carboxylic acid tert- butyl ester
  • Step C 4-f1-tert-Butoxycarbonylamino-3-(2-cvano-pyrrolidin-1-yl)-3-oxo-propyll-piperidine-1- carboxylic acid tert-butyl ester
  • Step D 1-(3-Amino-3-piperidin-4-yl-propionyl)-pyrrolidine-2-carbonitrile (DMSO-de): ⁇ 4.80-4.74 (m, 1 H), 3.69-3.57 (m, 1 H), 3.50-3.30 (m, 4H), 2.90-2.70 (m, 3H), 2.55-2.52 (m, 1 H), 2.20-1.77 (m, 8H), 1.49-1.37 (m, 2H).
  • Step B 3-tert-Butoxycarbonylamino-3-cvclohexyl-propionic acid
  • Step C r3-(2-Cvano-pyrrolidin-1-yl)-1-cvclohexyl-3-oxo-propyll-carbamic acid tert-butyl ester
  • Step D 1-(3-Amino-3-cvclohexyl-propionyl)-pyrrolidine-2-(S)-carbonitrile (CD 3 OD): ⁇ 4.78 (t, 1 H), 3.74-3.62 (m, 1H). 3.57-3.40 m, 2H), D2.89-2.76 (m, 1 H), 2.65-2.56 (m, 1H), 2.28-2.15 (m, 4H), 1.88-1.65 (m, 6H), 1.38-1.07 (m, 5H).
  • Example 21 General procedure (B))
  • Step A 4-Benzo[b1thiophen-2-yl-azetidin-2-one (25A)
  • step A from phenylsulfonyl-2-azetidinone (1.0g; 0.47mmol) and 4-benzo[b]thiophene-2- magnesium bromide (0.01 mol).
  • the Grignard analogue was generated from the 2-lithium-4- benzo[b]thiophene by exchange with MgBr 2 at RT. 25A was isolated as white crystals. Yield
  • Step C ri-Benzorblthiophen-2-yl-3-(2-S-carbamoyl-pyrrolidin-1-yl)-3-oxo-propyll-carbamic acid tert-butyl ester (25C)
  • Step D f1-Benzorb1thiophen-2-yl-3-(2-S-cvano-pyrrolidin-1-yl)-3-oxo-propy ⁇ -carbamic acid tert-butyl ester (25D)
  • Step E 1-(3-Amino-3-benzorblthiophen-2-yl-propionyl)-pyrrolidine-2-S-carbonitrile.
  • TFA (25) [1 -Benzo[b]thiophen-2-yl-3-(2-S-cyano-pyrrolidin-1 -yl)-3-oxo-propyl]-carbamic acid tert-butyl ester was reacted in exactly the same manner as described in general procedure (D) step E giving the title compound.
  • Step A 4-lodomethylazetidin-2-one
  • Step A 3-tert-Butoxycarbonylaminopentanedioic acid HO OH
  • Step B ( ⁇ ) 3-(1,5-di-(2-(S)-Cvanopyrrolidin-1-yl)pentane)-1 ,5-dione carbamic acid tert-butyl ester
  • Step C ( ⁇ ) 3-Amino-1 ,5-(di-2-(S)-cvanopyrrolidin-1-yl)pentane-1.5-dione.
  • Step A (+ or -) and (- or +)-Trans r2-(2-(S)-cvanopyrrolidine-1-carbonyl)indan-1-yllcarbamic acid tert-butyl ester
  • the aqueous layer was extracted with 3 x 40 ml of DCM and the combined organic layers were washed with sodium hydrogen carbonate (40 ml), water (40 ml) and brine (40 ml), and then dried over sodium sulphate, filtered and evaporated to afford 691 mg of a yellow oil.
  • the diastereomers were separated and purified by flash 12 chromatography (Quad 1 , Biotage UK) using ethylacetate:1/heptan:1 as the eluent.
  • Step B (+ or -) Trans-1-(1-aminoindane-2-carbonyl)pyrrolidine-2-(S)-carbonitrile.
  • Step A r3-(2-(S)-Carbamoyl-pyrrolidin-1-yl)-3-oxo-1-(R)-phenethyl-propyn-carbamic acid tert butyl ester (48A)
  • N-Boc-3-(R)-amino-5-phenylpentanoic acid (Aldrich) (10 g, 34 mmol) was dissolved in DCM (300 ml) at 0°. HOAt (4.64 g, 34 mmol) was added, and the solution stirred for 3O min at 0°. EDAC (6.53 g, 34 mmol) was added, and stirring continued for 2 1 / 2 hours at 0° .
  • L- Prolinamide (3.89 g, 34 mmol) was added, followed by DIEA (5.84 ml, 34 mmol), and the stirring continued while the reaction was allowed to warm to room temperature.
  • Step B r3-(2-(S)-Cvano-pyrrolidin-1-yl)-3-oxo-1-(R)-phenethyl-propyn-carbamic acid tert butyl ester
  • [3-(2-(S)-Carbamoyl-pyrrolidin-1-yl)-3-oxo-1-(R)-phenethyl-propyl]-carbamic acid tert butyl ester (12 g, 30.8 mmol) was dissolved in dry pyridine (120 ml) and cooled to 0°, with stirring.
  • Step C 1-(3-(R)-Amino-5-phenyl-pentanoyl)-pyrrolidine-2-(S)-carbonitrile.
  • TFA (48) [3-(2-(S)-Cyano-pyrrolidin-1 -yl)-3-oxo-1 -(R)-phenethyl-propyl]-carbamic acid tert butyl ester (3.54 g, 9.53 mmol) was dissolved in MeCN (75 ml) and water (75 ml), and TFA was added (36.6 ml, 476 mmol). The reaction was stirred for 2 days, and evaporated to a yellow oil.
  • Step A r3-(2-(S)-Carbamoyl-pyrrolidin-1-yl)-3-oxo-1-(S)-phenethyl-propyll-carbamic acid tert butyl ester (49A)
  • N-Boc-3-(S)-amino-5-phenylpentanoic acid was reacted with L-prolinamide as described in Example 48, step A to afford 915 mg of compound 49A as white crystals in 79 % yield. Mp. 54 - 60°C.
  • Step B f3-(2-(S)-Cvano-pyrrolidin-1-yl)-3-oxo-1-(S)-phenethyl-propyll-carbamic acid tert butyl ester (49B)
  • Step A 3-(R)-tert-Butoxycarbonylamino-5-(2-(S)-carbamoylpyrrolidin-1 -yl)-5-oxo-pentanoic acid benzyl ester (50A)
  • Step B 3-(R)-tert-Butoxycarbonylamino-5-(2-(S)-cvanopyrrolidin-1-yl)-5-oxo-pentanoic acid benzyl ester (50B)
  • Step A 4-(2-Naphthalen-1-yl-ethyl)-azetidin-2-one (51A)
  • Step B 3-tert-Butoxycarbonylamino-5-naphthalen-1-yl-pentanoic acid (51 B)
  • Step C r3-(2-S-Carbamoyl-pyrrolidin-1 -yl)-1 -(2-naphthalen-1 -yl-ethyl)-3-oxo-propyll-carbamic acid tert-butyl ester (51 C)
  • Step D r3-(2-S-Cvano-pyrrolidin-1-yl)-1-(2-naphthalen-1-yl-ethyl)-3-oxo-propyll-carbamic acid tert-butyl ester (51 D) [3-(2-S-Carbamoyl-pyrrolidin-1-yl)-1-(2-naphthalen-1-yl-ethyl)-3-oxo-propyl]- carbamic acid tert-butyl ester (0.140 g; 0.319 mmol) was dissolved in DCM (3 ml) and cooled to 0° on ice.
  • Step E 1-(3-Amino-5-naphthalen-1-yl-pentanoyl)-pyrrolidine-2-(S)-carbonitrile.
  • Step A 4-(2-Methyl-2-phenyl-propyl)-azetidin-2-one (52A)
  • Step B 3-tert-Butoxycarbonylamino-5-methyl-5-phenyl-hexanoic acid (52B)
  • Step C (1 -r2-(2-(S)-Carbamoylpyrrolidin-1 -yl)-2-oxoethyll-3-methyl-3-phenylbutyl carbamic acid tert-butyl ester (52C) 3-tert-Butoxycarbonylamino-5-methyl-5-phenyl-hexanoic acid and L-prolineamide was reacted and purified as described in step C, example 51 , giving 82 mg (70 %) of compound 52C as an oil.
  • Step D f1-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethvn-3-methyl-3-phenylbutyl)carbamic acid tert-butyl ester (52D)
  • Step E 1 -(3-Amino-5-methyl-5-phenylhexanoyl)pyrrolidine-2-(S)-carbonitrile.
  • Step A 4-Phenylethvnyl-azetidin-2-one (53A)
  • Phenylacetylen (3.87 g; 37.9 mmol) was dissolved in dry THF (20 ml). Ethylmagnesiumbromide (3 M) in tert-butylmethyl ether (37.9 ml) was added under N2 at -40 °C. The Grignard salt of phenylacetylene precipitated. THF (30 ml) was added and the reaction was stirred at RT for 30 min. The reaction mixture was cooled to -40 °C and a solution of phenylsulfonyl-2-azetidinone (2.0 g; 0.95 mmol) in THF (30 ml) was added. The mixture was allowed to warm up to RT and stirred for 1.5 hour.
  • Step B 3-tert-Butoxycarbonylamino-5-phenyl-pent-4-vnoic acid (53B)
  • Step C (S)-(1-f2-(2-Cvanopyrrolidin-1-yl)-2-oxoethyll-3-phenylprop-2-vnyl)carbamic acid tert- butyl ester (53C)
  • Step D (S)-1-(3-Amino-5-phenylpent-4-vnoyl)pyrrolidine-2-carbonitrile.
  • Step A 4-Vinyl-azetidin-2-one (54A)
  • Phenylsulfonylazetidin-2-one (6 g; 28 mmol) was dissolved in dry THF (100 ml). The reaction mixture was cooled to -78°C under N2. Vinylmagnesium bromide (1 M; 70 ml; 70 mmol) was added keeping the temperature below -60°C. The reaction mixture was stirred an additional 30 minutes at -78°C, then allowed to warm up slowly to 0°C. Stirring was continued for an additional 10 min. at 0°C, then for 30 min at room temperature. Saturated NH 4 CI(aq.) was added resulting in a white precipitate. The slurry was evaporated in vacuo to remove the THF.
  • Step B 4-f2-(2-Methylphenyl)-vinyll-azetidin-2-one (54B)
  • Step C 2-Oxo-4-(2-o-tolylvinyl)azetidine-1-carboxylic acid tert-butyl ester (54C)
  • Step D (1-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethvn-3-o-tolylallyl)carbamic acid tert-butyl ester (54D)
  • Step E 1-(3-Amino-5-o-tolylpent-4-enoyl)pyrrolidine-2-(S)-carbonitrile (54)
  • Step A 4-r2-(3-Methylphenyl)-vinyll-azetidin-2-one (55A)
  • Step B 2-Oxo-4-(2-m-tolylvinyl)azetidine-1-carboxylic acid tert-butyl ester (55B)
  • Step C (1-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethyll-3-m-tolylallyl)carbamic acid tert-butyl ester (55C)
  • Step D 1-(3-Amino-5-m-tolyl-pent-4-enoyl)pyrrolidine-2-(S)-carbonitrile (55)
  • Step A 4-r2-(4-Methylphenyl)-vinyll-azetidin-2-one (56A))
  • Step B 2-Oxo-4-(2-p-tolylvinyl)azetidine-1-carboxylic acid tert-butyl ester (56B)
  • Step C f1-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethyl1-3-p-tolylallyl)carbamic acid tert-butyl ester (56C)
  • Step D 1-(3-Amino-5-p-tolyl-pent-4-enoyl)pyrrolidine-2-(S)-carbonitrile.
  • Step A 4-f2-(2-Methoxyphenyl)-vinyll-azetidin-2-one (57)
  • Bis(tri-t-butylphosphin)palladium (0.026 g; 0.05 mmol) was dissolved in dry DMF under N 2 at RT. 4-Vinyl-azetidin-2-one (0.107 ml; 1.1 mmol); 2-methoxyiodobenzene (0.234 ml; 1.0 mmol) and TEA (0.28 ml; 2.0 mmol) were added. The reaction mixture was shaken and heated for 2 hours at 80°C, filtered, and evaporated in vacuo to give an oil, which was purified on a silica gel column using ethyl acetate as eluent to give compound 57A as a yellow oil. Yield 0.150 g (74 %).
  • Step B 2-r2-(2-Methoxyphenyl)vinvn-4-oxoazetidine-1-carboxylic acid tert-butyl ester
  • 57B 4-[2-(2-Methoxyphenyl)-vinyl]-azetidin-2-one was reacted and purified as described in example 54 step C to give 0.128 g of compound 57B as a crude product.
  • Step C ri-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethvn-3-(2- methoxyphenvDallyllcarbamic acid tert-butyl ester (57C)
  • Step D 1-r3-Amino-5-(2-methoxyphenyl)pent-4-enoyllpyrrolidine-2-(S)-carbonitrile.
  • TFA (57) ⁇ 1 -[2-(2-(S)-Cyanopyrrolidin-1 -yl)-2-oxoethyl]-3-o-methoxyphenylallyl ⁇ carbamic acid tert-butyl ester was reacted and purified as described in example 54 step D to give the title compound as the TFA salt. Yield 0.077g (57 %).
  • Step A 4-r2-(3-Methoxyphenyl)-vinyll-azetidin-2-one (58A) Bis(tri-t-butylphosphin)palladium (0.026 g; 0.05 mmol) was dissolved in dry DMF under N 2 at RT. 4-Vinyl-azetidin-2-one (0.107 ml; 1.1 mmol), 3-methoxyiodobenzene (0.233 g; 1.0 mmol), and TEA (0.28 ml; 2.0 mmol) were added.
  • Step C ri-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethvn-3-(3-methoxyphenyl)allyllcarbamic acid tert-butyl ester (58C)
  • Step E 1-f3-Amino-5-(3-methoxyphenyl)pent-4-enoyllpyrrolidine-2-(S)-carbonitrile.
  • TFA (58) ⁇ 1-[2-(2-(S)-Cyanopyrrolidin-1-yl)-2-oxoethyl]-3-m-methoxyphenylallyl ⁇ carbamic acid tert-butyl ester was reacted and purified as described in example 54 step E to give the title compound as the TFA salt. Yield 0.028 g (38 %).
  • Step A 4-r2-(4-Methoxyphenyl)-vinyll-azetidin-2-one (59A) Bis(tri-t-butylphosphin)palladium (0.026 g; 0.05 mmol) was dissolved in dry DMF under N 2 at RT. 4-Vinyl-azetidin-2-one (0.107 ml; 1.1 mmol); 3-methoxyiodobenzene (0.233 g; 1.0 mmol) and TEA (0.28 ml; 2.0 mmol) were added.
  • Step B 2-r2-(4-Methoxyphenyl)vinyll-4-oxoazetidine-1-carboxylic acid tert-butyl ester (59B) 4-[2-(4-Methoxyphenyl)-vinyl]-azetidin-2-one was reacted and purified as described in example 54 step C to give 0.103 g of compound 59B as a crude product.
  • Step C ri-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethyll-3-(4-methoxyphenyl)allyllcarbamic acid tert-butyl ester (59C)
  • Step D 1-r3-Amino-5-(4-methoxyphenyl)pent-4-enoyllPyrrolidine-2-(S)-carbonitrile.
  • Step A 4-r2-(2-Nitrophenyl)-vinvn-azetidin-2-one (60A)
  • Step B 2-r2-(2-Nitrophenyl)vinyll-4-oxoazetidine-1-carboxylic acid tert-butyl ester (60B)
  • Step C ri-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethvn-3-(2-nitrophenyl)allyllcarbamic acid tert- butyl ester (60C)
  • Step D 1-r3-Amino-5-(2-nitrophenyl)pent-4-enovnpyrrolidine-2-(S)-carbonitrile.
  • Step A 4-r2-(3-Nitrophenyl)-vinvn-azetidin-2-one (61 A)
  • Step B 2-f2-(3-Nitrophenyl)vinvn-4-oxoazetidine-1-carboxylic acid tert-butyl ester (61 B)
  • Step C ri-r2-(2-(S)-Cvanopyrrolidin-1-yl)-2-oxoethvn-3-(3-nitrophenyl)allyl1carbamic acid tert- butyl ester (61 C)
  • Step D 1-[3-Amino-5-(3-nitrophenyl)pent-4-enoyllpyrrolidine-2-(S)-carbonitrile.
  • Step A 4-r2-(4-Nitrophenyl)-vinvn-azetidin-2-one (62A) Bis(tri-t-butylphosphin)palladium (0.026 g; 0.05 mmol) was dissolved in dry DMF under N 2 at RT. 4-Vinyl-azetidin-2-one (0.107 ml; 1.1 mmol), 4-iodonitrobenzene (0.249 g;
  • Step B 2-r2-(4-Nitrophenyl)vinyll-4-oxoazetidine-1-carboxylic acid tert-butyl ester (62B)
  • Step C r2-Cvano-1 -r2-(2-(S)-cvano-pyrrolidin-1 -yl)-2-oxo-ethyll-3-(4-nitrophenyl)-propy ⁇ - carbamic acid tert-butyl ester (62C)
  • Step A 4-r2-(3-Amino-phenyl)-vinyll-azetidin-2-one (63A)
  • Bis(tri-t-butylphosphin)palladium (0.026 g; 0.05 mmol) was dissolved in dry DMF under N 2 at RT. 4-Vinyl-azetidin-2-one (0.107 ml; 1.1 mmol), 3-iodoaniline (0.219 g; 1.0 mmol), and TEA (0.28 ml; 2.0 mmol) were added. The reaction mixture was shaken and heated for 0.5 hours at 80°C, filtered, and evaporated in vacuo. The remaining oil was purified on a silica gel column using ethyl acetate as eluent to give compound 63A as an oil.
  • Step C f3-r3-tert-Butoxycarbonylamino-5-(2-(S)-cvanopyrrolidin-1 -yl)-5-oxopent-1 - enyllphenyllcarbamic acid tert-butyl ester (63C)
  • Step D 1-r3-Amino-5-(3-amino-phenyl)-pent-4-enovn-pyrrolidine-2-carbonitrile.
  • TFA (63) (3-[3-tert-Butoxycarbonylamino-5-(2-(S)-cyanopyrrolidin-1-yl)-5-oxopent-1- enyl]phenyl ⁇ carbamic acid tert-butyl ester was reacted and purified as described in example 54 step E to give the title compound as the TFA salt. Yield 0.071 g (42 %).
  • Step A 4-r2-(4-Amino-phenyl)-vinyll-azetidin-2-one (64A) Bis(tri-t-butylphosphin)palladium (0.026 g; 0.05 mmol) was dissolved in dry DMF under N 2 at RT. 4-Vinyl-azetidin-2-one (0.107 ml, 1.1 mmol); 4-iodoaniline (0.219 g; 1.0 mmol), and TEA (0.28 ml; 2.0 mmol) were added.
  • Step B 2-r2-(4-tert-Butoxycarbonylaminophenyl)vinyll-4-oxoazetidine-1-carboxylic acid tert- butyl ester
  • 64B 4-[2-(4-Amino-phenyl)-vinyl]-azetidin-2-one was reacted and purified as described in example 54 step C. except for the use of 3 eq. of Boc 2 0, to give 0.051 g of compound 64B as a crude product.
  • Step C ⁇ 4-r3-tert-Butoxycarbonylamino-5-(2-(S)-cvanopyrrolidin-1-yl)-5-oxopent-1- enyllphenvDcarbamic acid tert-butyl ester (64C)
  • TFA (65) 1-(3-Amino-5-o-tolylpent-4-enoyl)-pyrrolidine-2-(S)-carbonitrile.
  • TFA (54) (0.040g; 0.101 mmol) was dissolved in methanol (5 ml). Pd/C (5mg) was added and the reaction mixture was stirred vigorously under a hydrogen atmosphere for 30 min. The reaction mixture was filtered, evaporated, and purified by preparative HPLC (Method A) to give the title compound as the TFA salt. Yield 22mg (XX %) oil.
  • CD26/DPP-IV Chemical compounds are tested for their ability to inhibit the enzyme activity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro- pNA by DPP-IV liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of generation of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate.
  • Ki The inhibition constant, Ki, for each compound
  • Porcine CD26/DPP-IV (Sigma D-7052), Gly-Pro-pNA (Sigma G0513).
  • Assay buffer 50 mM Tris pH 7.4, 150 mM NaCI, 0,1% Triton X-100.
  • Reactions containing identical amounts of enzyme, but varying concentrations of inhibitor and substrate, or buffer as control, are set up in parallel in individual wells of a 96- well ELISA plate.
  • the plate is incubated at 25 °C and absorbance is read at 405 nm after 60 min incubation.
  • the inhibitor constants are calculated by non-linear regression hyperbolic fit and the result is expressed as inhibition constant (Ki) in nM.
  • the Zucker Diabetic Fatty (ZDF) rat model can be used to investigate the effects of the compounds of the invention on both the treatment and prevention of diabetes as rats of this sub-strain are initially pre-diabetic although develop severe type 2 diabetes characterised by increased HbA1 c levels over a period of 6 weeks.
  • the same strain can be used to predict the clinical efficacy of other anti-diabetic drug types.
  • the model predicts the potency and limited clinical efficacy of thiazolidinedione insulin sensitizers compounds.

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Abstract

La présente invention a trait à des inhibiteurs à activité thérapeutique sélective de l'enzyme DPP-IV de formule (I). L'invention a également trait à des compositions pharmaceutiques comprenant les composés et l'utilisation de tels composés pour la fabrication de médicaments pour le traitement de maladies qui sont associées à des protéines qui sont sujettes à l'inactivation par la DPP-IV, telles que le diabète de type 2 et l'obésité.
PCT/DK2004/000232 2003-04-11 2004-04-02 2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv) WO2004089362A1 (fr)

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1702916A1 (fr) * 2005-03-18 2006-09-20 Santhera Pharmaceuticals (Schweiz) GmbH Inhibiteurs de DPP-IV
EP1729774A1 (fr) * 2004-03-09 2006-12-13 National Health Research Institutes Composes de pyrrolidine
WO2007053819A2 (fr) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Inhibiteurs à base d'amide et de bêta-amino de pyrrolidinyle de la dipeptidyl peptidase iv et procédés
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
JP2011507832A (ja) * 2007-12-21 2011-03-10 エルジー ライフ サイエンス リミテッド ジペプチジルペプチダーゼ−ｉｖ阻害化合物、同化合物を製造する方法、及び活性剤として同化合物を含む医薬組成物
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2011101861A1 (fr) * 2010-01-29 2011-08-25 Msn Laboratories Limited Procédé de préparation d'inhibiteurs de la dpp-iv
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
CN104059068A (zh) * 2013-03-20 2014-09-24 中国科学院上海药物研究所 β-氨基羰基类化合物、其制备方法、药物组合物及其用途
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
CN105272905A (zh) * 2015-10-29 2016-01-27 天津市斯芬克司药物研发有限公司 一种哌啶化合物及其制备方法
WO2018098269A2 (fr) 2016-11-23 2018-05-31 Mersana Therapeutics, Inc. Lieurs contenant des peptides pour des conjugués anticorps-médicament
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
WO2021165927A1 (fr) * 2020-02-21 2021-08-26 Wockhardt Bio Ag 2-cyano-pyrrolidines, -pipéridines ou -diazépines utilisées comme agents hyperglycémiques
CN115322129A (zh) * 2022-08-29 2022-11-11 湖北科技学院 双氰基吡咯烷类衍生物及其制备方法和应用

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WO2001055105A1 (fr) * 2000-01-24 2001-08-02 Novo Nordisk A/S 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
WO2001081337A1 (fr) * 2000-04-26 2001-11-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv
WO2003000180A2 (fr) * 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete

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Publication number Priority date Publication date Assignee Title
WO1998019998A2 (fr) * 1996-11-07 1998-05-14 Novartis Ag 2-cyanopyrrolidines a substitution n
WO2001055105A1 (fr) * 2000-01-24 2001-08-02 Novo Nordisk A/S 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
WO2001081337A1 (fr) * 2000-04-26 2001-11-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv
WO2003000180A2 (fr) * 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1729774A1 (fr) * 2004-03-09 2006-12-13 National Health Research Institutes Composes de pyrrolidine
EP1729774A4 (fr) * 2004-03-09 2009-05-06 Nat Health Research Institutes Composes de pyrrolidine
US7687504B2 (en) 2004-03-09 2010-03-30 National Health Research Institutes Pyrrolidine compounds
WO2006097175A1 (fr) * 2005-03-18 2006-09-21 Santhera Pharmaceuticals (Schweiz) Ag Inhibiteurs de la dpp-iv
EP1702916A1 (fr) * 2005-03-18 2006-09-20 Santhera Pharmaceuticals (Schweiz) GmbH Inhibiteurs de DPP-IV
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2007053819A2 (fr) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Inhibiteurs à base d'amide et de bêta-amino de pyrrolidinyle de la dipeptidyl peptidase iv et procédés
WO2007053819A3 (fr) * 2005-10-31 2008-03-13 Bristol Myers Squibb Co Inhibiteurs à base d'amide et de bêta-amino de pyrrolidinyle de la dipeptidyl peptidase iv et procédés
US7488725B2 (en) 2005-10-31 2009-02-10 Bristol-Myers Squibb Co. Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7728146B2 (en) 2006-04-12 2010-06-01 Probiodrug Ag Enzyme inhibitors
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
JP2011507832A (ja) * 2007-12-21 2011-03-10 エルジー ライフ サイエンス リミテッド ジペプチジルペプチダーゼ−ｉｖ阻害化合物、同化合物を製造する方法、及び活性剤として同化合物を含む医薬組成物
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011101861A1 (fr) * 2010-01-29 2011-08-25 Msn Laboratories Limited Procédé de préparation d'inhibiteurs de la dpp-iv
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2013186326A1 (fr) 2012-06-14 2013-12-19 Lek Pharmaceuticals D.D. Nouvelle voie de synthèse pour la préparation de composés de 5,6,7,8-tétrahydro[1,4]diazolo [4,3-alpha]pyrazin-7-yle substitués par ss-aminobutyryle
US9388188B2 (en) 2012-06-14 2016-07-12 Lek Pharmaceuticals D.D. Synthetic route for the preparation of β-aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha ]pyrazin-7-yl compounds
EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
CN105051046A (zh) * 2013-03-20 2015-11-11 中国科学院上海药物研究所 β-氨基羰基类化合物、其制备方法、药物组合物及其用途
WO2014146494A1 (fr) * 2013-03-20 2014-09-25 中国科学院上海药物研究所 Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants
CN104059068A (zh) * 2013-03-20 2014-09-24 中国科学院上海药物研究所 β-氨基羰基类化合物、其制备方法、药物组合物及其用途
CN105272905A (zh) * 2015-10-29 2016-01-27 天津市斯芬克司药物研发有限公司 一种哌啶化合物及其制备方法
WO2018098269A2 (fr) 2016-11-23 2018-05-31 Mersana Therapeutics, Inc. Lieurs contenant des peptides pour des conjugués anticorps-médicament
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
WO2021165927A1 (fr) * 2020-02-21 2021-08-26 Wockhardt Bio Ag 2-cyano-pyrrolidines, -pipéridines ou -diazépines utilisées comme agents hyperglycémiques
CN115322129A (zh) * 2022-08-29 2022-11-11 湖北科技学院 双氰基吡咯烷类衍生物及其制备方法和应用

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