WO2003040174A2 - Composes d'aminocetone substitues - Google Patents

Composes d'aminocetone substitues Download PDF

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WO2003040174A2
WO2003040174A2 PCT/EP2002/012288 EP0212288W WO03040174A2 WO 2003040174 A2 WO2003040174 A2 WO 2003040174A2 EP 0212288 W EP0212288 W EP 0212288W WO 03040174 A2 WO03040174 A2 WO 03040174A2
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chronic
optionally substituted
compounds
treatment
residues
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PCT/EP2002/012288
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WO2003040174A3 (fr
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Hans-Ulrich Demuth
Ulrich Heiser
André NIESTROJ
Torsten Hoffmann
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Probiodrug Ag
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Priority to JP2003542219A priority Critical patent/JP2005518350A/ja
Priority to EP02783071A priority patent/EP1442049A2/fr
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Publication of WO2003040174A3 publication Critical patent/WO2003040174A3/fr

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    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to substituted amino ketone compounds and salts thereof, hereinafter referred to as amino ketones, and to the use of the compounds for the preparation of a medicament for the in vivo inhibition of DP IV and/or DP IV- like enzymes.
  • the invention relates especially to the use of the compounds for the preparation of a medicament for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals, for the treatment of metabolism-related hypertension and of cardiovascular sequelae caused by hypertension in mammals, for the prophylaxis or treatment of skin diseases and diseases of the mucosae, autoimmune diseases and inflammatory conditions, and for the treatment of psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain.
  • psychosomatic, neuropsychiatric and depressive illnesses such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain.
  • Dipeptidyl peptidase IV is a post-proline (to a lesser extent post-alanine, post-serine or post-glycine) cleaving serine protease found in various tissues of the body including kidney, liver, and intestine, where it removes dipeptides from the N- terminus of biologically active peptides with a high specificity when proline or alanine form the residues that are adjacent to the N-terminal amino acid in their sequence.
  • DP IV Dipeptidyl peptidase IV
  • DP IV was originally believed to be the only membrane-bound enzyme specific for proline as the penultimate residue at the amino-terminus of the polypeptide chain.
  • DP IV-like enzymes which are identified so far, are e.g.
  • fibroblast activation protein ⁇ dipeptidyl peptidase IV ⁇ , dipeptidyl aminopeptidase-like protein, N-acetylated ⁇ -linked acidic dipeptidase, quiescent cell proline dipeptidase, dipeptidyl peptidase II, attractin and dipeptidyl peptidase IV related protein (DPP 8), DPL1 (DPX, DP6) and DPL2, and are described in the review articles by Sedo & Malik (Sedo & Malik, Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities?
  • DP IV-like enzymes are disclosed in WO 01/19866, WO 02/34900 and WO02/31134.
  • WO 01/19866 discloses novel human dipeptidyl aminopeptidase 8 (DPP8) with structural und functional similarities to DP IV and fibroblast activation protein (FAP).
  • WO 02/34900 discloses a novel dipeptidyl peptidase 9 (DPP9) with significant homology to the amino acid sequences of DP IV and DPP8.
  • WO 02/31134 discloses three DP IV-like enzymes, DPRP1 , DPRP2 and DPRP3. Sequence analysis revealed that DPRP1 is identical to DPP8 as disclosed in WO 01/19866, that DPRP2 is identical to DPP9 and that DPRP3 is identical to KIAA1492 as disclosed in WO 02/04610.
  • DP IV is responsible for inactivating glucagon-like peptide-1 (GLP-1 ) and glucose-dependent insulinotropic peptide also known as gastric-inhibitory peptide (GIP). Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal, in WO 97/40832 and US 6,303,661 inhibition of DP IV and DP IV-like enzyme activity was shown to represent an attractive approach for treating non-insulin-dependent diabetes mellitus (NIDDM).
  • NIDDM non-insulin-dependent diabetes mellitus
  • DP IV and DP IV-like enzyme activity for cleaving such substrates in vivo can serve to suppress undesirable enzyme activity effectively both under laboratory conditions and in pathological conditions of mammals.
  • Diabetes mellitus type II also diabetes of old age
  • hyperglycaemia and its associated causes and sequelae are treated according to the current state of the art by administering insulin (for example material isolated from bovine pancreas or also material obtained by genetic engineering) to those affected, in various forms of administration.
  • DPIV-inhibitors may be useful for the treatment of impaired glucose tolerance and diabetes mellitus (International Patent Application, Publication Number WO 99/61431 , Pederson RA et al, Diabetes. 1998 Aug; 47(8): 1253-8 and Pauiy RP et al, Metabolism 1999 Mar; 48(3):385-9).
  • DPIV-lnhibitors comprising an amino acid residue and a thiazoleidine or pyrrolidine group, and salts thereof, especially L-f/ireo-isoleucyl thiazoleidine, L-a//o-isoleucyl thiazoldine, L-f ?reo-isoleucyl pyrrolidine, L-a//o- isoleucyl thiazoldine, L-a//o-isoleucyl pyrrolidine, and salts thereof.
  • low molecular weight dipeptidyl peptidase IV inhibitors are agents such as tetrahydroisoquinolin-3-carboxamide derivatives, N-substituted 2-cyanopyrroles and -pyrrolidines, N-(N'-substituted glycyl)-2-cyanopyrrolidines, N- (substituted glycyl)-thiazoldines, N-(substituted glycyl)-4-cyanothiazoldines, amino- acyl-borono-prolyl-inhibitors and cyclopropyl-fused pyrrolidines.
  • Inhibitors of dipeptidyl peptidase IV are described in US 6,011 ,155; US 6,107,317; US 6,110,949; US 6,124,305; US 6,172,081 ; WO 99/61431 , WO 99/67278, WO 99/67279, DE 198 34 591 , WO 97/40832, DE 196 16 486 C 2, WO 98/19998, WO 00/07617, WO 99/38501 , WO 99/46272, WO 99/38501 , WO 01/68603, WO 01/40180, WO 01/81337, WO 01/81304, WO 01/55105, WO 02/02560 and WO 02/14271, WO 02/076450, WO 02/051836, EP 02290755.4 and WO 02/38541, the teachings of which are herein incorporated by reference in their entirety concerning these inhibitors, their uses, definition and their production.
  • the problem of the invention is therefore to provide new compounds for the treatment of, for example, impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals, metabolism-related hypertension and cardiovascular sequelae caused by hypertension in mammals, for the prophylaxis or treatment of skin diseases and diseases of the mucosae, autoimmune diseases and inflammatory conditions, and for the treatment of psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain, and a simple method for the treatment of those diseases.
  • n 0 or 1
  • R 1 stands for H, C 1 -C 9 branched or straight chain alkyl, preferably H, n-butan-2- yl, n-prop-2-yl or isobutyl, C 2 -C 9 branched or straight chain alkenyl, C 3 -Cs cycloalkyl, preferably cyclohexyl, C 5 -C cycloalkenyl, aryl, heteroaryl or a side chain of a natural amino acid or mimetics thereof,
  • X 2 stands for O, NR 6 , N + (R 7 ) 2 , or S,
  • X 5 is H or an acyl or oxycarbonyl group including amino acids
  • R 5 is H, C 1 -C 9 branched or straight chain alkyl, preferably H, n-butan-2-yl, n- prop-2-yl or isobutyl, C 2 -C 9 branched or straight chain alkenyl, C 3 -C 8 cycloalkyl, preferably cyclohexyl, 3-hydroxyadamant-1-yl, Cs-C cycloalkenyl, aryl, heteroaryl or a side chain of a natural amino acid or derivatives thereof, or a group of the formula -(CH) m -NH-C 5 H 3 N-Y where m is an integer of 2-4, -
  • N-Y is a divalent pyridyl moiety and Y is a hydrogen atom, a halogen atom, a nitro group or a cyano group,
  • R 6 , R 7 R 8 and R 9 are independently selected from H, optionally substituted
  • C 5 branched or straight chain alkyl or optionally substituted C 2 -C 9 branched or straight chain alkenyl, preferably an C 2 -C 5 branched or straight chain alkenyl; or optionally substituted C 3 -C 8 cycloalkyl, preferably an optionally substituted C 4 -C 7 cycloalkyl; or an optionally substituted C 5 -C cycloalkenyl, or an optionally substituted aryl residue,
  • Z is selected from H, pyridyl or optionally substituted phenyl, optionally substituted alkyl groups, alkoxy groups, halogens, nitro, cyano and carboxy groups
  • W is selected from H, pyridyl or optionally substituted phenyl, optionally substituted alkyl groups, alkoxy groups, halogens, nitro, cyano and carboxy groups
  • W 1 is H or optionally substituted alkyl, alkoxy or optionally substituted phenyl
  • Z 1 is H, or optionally substituted alkyl
  • R 3 and R 4 are independently H, hydroxy, alkyl, alkoxy, aralkoxy, nitro, cyano or halogen,
  • D is an optionally substituted compound of the formula
  • X 8 to X 11 are independently CH, N, N + (R 7 ), or CR 8 , if unsaturated, or
  • X 8 to X 11 are independently CH 2 , NH, NH + (R 7 ), O or S if saturated,
  • X 12 is CHA, NA, CH 2 , NH, NH + (R 7 ), or CHR 8 , if saturated or
  • X 12 is CA, NA + , CH, N, N + (R 7 ), or CR 8 , if unsaturated and
  • A is H or an isoster of a carboxylic acid such as CN, SO 3 H, CONOH,
  • P0 3 R 5 R 6 a tetrazole, an amide, an ester or an acid anhydride.
  • D stands for optionally substituted C 4 -C cycloalkyl, preferably C 4 -C 6 cycloalkyl, optionally substituted C -C 7 cycloalkenyl, or optionally substituted (hetero)cycloalkyl of the formulae
  • B has the following formula:
  • B has the following formula:
  • Acyl can denote a C1-20 acyl residue, preferably a C1-8 acyl residue and especially preferred a C1-4 acyl residue;
  • cycloalkyl can denote a C3-12 cycloalkyl residue, preferably a C4, C5 or C6 cycloalkyl residue;
  • carbocyclic can denote a C3-12 carbocyclic residue, preferably a C4, C5 or C6 carbocyclic residue.
  • Heteroaryl is defined as an aryl residue, wherein 1 to 4, and more preferably 1 , 2 or 3 ring atoms are replaced by heteroatoms like N, S or O.
  • Heterocyclic is defined as a cycloalkyl residue, wherein 1 , 2 or 3 ring atoms are replaced by heteroatoms like N, S or O.
  • “Peptides” are selected from dipeptides to decapeptides, preferred are dipeptides, tripeptides, tetrapeptides and pentapeptides. The amino acids for the formation of the “peptides” can be selected from those listed below.
  • acyl groups are C1-C6-acyl groups.
  • alk(yl) groups are C1-C6-alk(yl) groups, which may be branched or unbranched.
  • alkoxy groups are C1-C6-alkoxy groups.
  • the aryl residues are C5-C12 aryl residues that have optionally one, two or three fused rings having, e.g. 3, 4 or 5 additional C-atoms each.
  • cycloalkyl residues are C3-C8-cycloalkyl residues.
  • heteroaryl residues are C4-C11 aryl residues that have optionally one, two or three fused rings having, e.g. 3, 4 or 5 additional C-atoms each and, in at least one ring, additionally from 1 to 4 preferably
  • hetero atoms such as O, N and/or S.
  • peptide residues are corresponding residues containing from 2 to 50 amino acids.
  • heterocyclic residues are C2-C7- cycloalkyl radicals that additionally have from 1 to 4, preferably 1 or 2 hetero atoms, such as O, N and/or S.
  • the carboxy groups are C1 - C6 carboxy groups, which may be branched or unbranched.
  • the oxycarbonyl groups are groups of the formula -O-(CH 2 ) 1-6 C00H.
  • the amino acids can be any natural or synthetic amino acid, preferably natural alpha amino acids.
  • L and D-amino acids N-methyl-amino-acids; allo- and f/ireo-forms of lie and Thr, which can, e.g. be ⁇ -, ⁇ - or ⁇ -amino acids, whereof -amino acids are preferred.
  • amino acids are: aspartic acid (Asp), glutamic acid (Glu), arginine (Arg), lysine (Lys), histidine (His), glycine (Gly), serine (Ser) and cysteine (Cys), threonine (Thr), asparagine (Asn), glutamine (Gin), tyrosine (Tyr), alanine (Ala), proline (Pro), valine (Val), isoleucine (lie), leucine (Leu), methionine (Met), phenylalanine (Phe), tryptophan (Trp), hydroxyproline (Hyp), beta-alanine (beta-Ala), 2-amino octanoic acid (Aoa), azetidine-(2)-carboxylic acid (Ace), pipecolic acid (Pip), 3-amino propionic, 4-amino butyric and so forth, alpha-aminoisobutyric acid
  • ⁇ -amino acids are e.g.: 5-Ara (aminoraleric acid), 6-Ahx (aminohexanoic acid), 8-Aoc (aminooctanoic aicd), 9-Anc (aminovanoic aicd), 10- Adc (aminodecanoic acid), 11-Aun (aminoundecanoic acid), 12-Ado (aminododecanoic acid).
  • amino acids are: indanylglycine (Igl), indoline-2-carboxylic acid (Idc), octahydroindole-2-carboxylic acid (Oic), diaminopropionic acid (Dpr), diaminobutyric acid (Dbu), naphtylalanine (1-Nal), (2-Nal), 4-aminophenylalanin (Phe(4 ⁇ NH 2 )), 4- benzoylphenylalanine (Bpa), diphenylalanine (Dip), 4-bromophenylalanine (Phe(4- Br)), 2-chlorophenylalanine (Phe(2-CI)), 3-chlorophenylalanine (Phe(3-CI)), 4- chlorophenylalanine (Phe(4-CI)), 3,4-chlorophenylalanine (Phe (3.4-CI 2 )), 3- fluorophenylalanine (Phe(3-F)), 4- flu
  • side chains of amino acids are known to people skilled in the art: an amino acid has a backbone containing an amino and a carboxy group. Substituents of the backbone are called side chains.
  • Such side chains are for instance, but not restricted to, homoserine addition, pyroglutamic acid addition, disulphide bond formation, deamidation of asparagine or glutamine residues, methylation, t-butylation, t-butyloxycarbonylation, 4- methylbenzylation, thioanysilation, thiocresylation, benzyloxymethylation, 4- nitrophenylation, benzyloxycarbonylation, 2-nitrobencoylation, 2-nitrosulphenylation, 4-toluenesulphonylation, pentafluorophenylation, diphenylmethylation, 2- chlorobenzyloxycarbonylation, 2,4,5-trichlorophenylation, 2- bromobenzyloxycarbonylation, 9-fluorenylmethyIoxycarbonylation, triphenylmethylation, 2,2,5,7,8,-pentamethylchroman-6-sulphonylation, hydroxylation, oxidation of methionine, for
  • Peptide mimetics per se are known to a person skilled in the art. They are preferably defined as compounds which have a secondary structure like a peptide and optionally further structural characteristics; their mode of action is largely similar or identical to the mode of action of the native peptide; however, their activity (e.g. as an antagonist or inhibitor) can be modified as compared with the native peptide, especially vis a vis receptors or enzymes. Moreover, they can imitate the effect of the native peptide (agonist).
  • Examples of peptide mimetics are scaffold mimetics, non-peptidic mimetics, peptoides, peptide nucleic acids, oligopyrrolinones, vinylogpeptides and oligocarbamates. For the definitions of these peptide mimetics see Lexikon der Chemie, Spektrum Akademischer Verlag Heidelberg, Berlin, 1999.
  • the aim for using these mimetic structurs is increasing the activity, increasing the selectivity to decrease side effects, protect the compound (drug) against enzymatical degradation for prolongation of the effect.
  • the endogenous (or additionally exogenously administered) insulinotropic peptides GIP ⁇ . 42 and GLP-1 -36 (or GLP-1 7-37 or analogues thereof), for example, are broken down to a lesser degree by DP IV or DP IV-like enzymes.
  • the compounds of the present invention lower or inhibit the activity of DP IV or DP IV-like enzymes at least by about 10, preferably about 50, more preferably about 75, 90 or 100% and prolong the half live of their substrates in a mammal by at least about 2fold, preferably about 3fold, more preferably about 4fold, 5fold or higher relative to the absence of the compound and hence the reduction in the concentration of those peptide hormones and their analogues is reduced or delayed.
  • the invention is based, therefore, on the finding that a reduction of the DP IV or DP IV-like enzyme activity in the bloodstream results in influencing of the blood sugar level.
  • the compounds of the present invention are therefore useful for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals.
  • the compounds of the present invention lower or inhibit the degradation of other substrates of DP IV or DP IV-like enzymes and are therefore useful for the treatment of metabolism-related hypertension and of cardiovascular sequelae caused by hypertension in mammals, for the prophylaxis or treatment of skin diseases and diseases of the mucosae, autoimmune diseases and inflammatory conditions, and for the treatment of psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain.
  • psychosomatic, neuropsychiatric and depressive illnesses such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain.
  • the oral administration of the high-affinity, low-molecular-weight enzyme inhibitors of the invention is a more cost-effective alternative, for example, to invasive surgical techniques in the treatment of pathological symptoms.
  • chemical design of stability, transport and clearance properties their mode of action can be modified and matched to individual characteristics.
  • the salts of the compounds of the invention may, if they have basic properties, be in the form of inorganic or organic salts.
  • the compounds of the present invention can be converted into and used as acid addition salts, especially pharmaceutically acceptable acid addition salts.
  • the pharmaceutically acceptable salt generally takes a form in which a basic side chain is protonated with an inorganic or organic acid.
  • Representative organic or inorganic acids include hydrochloric, hydrobromic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toulenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the invention accordingly relates to inhibitors of dipeptidyl peptidase IV (DPIV) and DP IV-like enzyme activity and to their use for lowering the blood sugar level below the glucose concentration characteristic of hyperglycaemia in the serum of a mammal.
  • the invention relates especially to the use of the compounds of the invention for modulating DP IV and DP IV-like enzyme activity in order to prevent or alleviate pathological metabolic abnormalities of mammals, such as, for example, impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy, and sequelae caused by diabetes mellitus in mammals.
  • the invention further relates to the use of the compounds of the invention for modulating DP IV and DP IV-like enzyme activity in order to prevent or alleviate neurodegenerative diseases and high blood pressure.
  • the invention relates to the improvement of signal action at the cells of the islets of Langerhans and of insulin sensitivity in the peripheral tissue in the postprandial phase.
  • the invention further relates to the use of the compounds of the invention for the chronic treatment of chronic metabolic diseases in humans; for the chronic treatment of chronically impaired glucose tolerance, chronic glucosuria, chronic hyperlipidaemia, chronic metabolic acidosis, chronic diabetes mellitus, chronic diabetic neuropathy and nephropathy and of chronic sequelae caused by diabetes mellitus, chronic neurodegenerative diseases and chronic disturbance of signal action at the cells of the islets of Langerhans and chronic insulin sensitivity in the peripheral tissue in the postprandial phase of mammals; for the chronic treatment of chronic metabolism-related hypertension and of chronic cardiovascular sequelae caused by hypertension in mammals; for the chronic treatment of chronic psychosomatic, chronic neuropsychiatric and depressive illnesses, such as chronic anxiety, chronic depression, chronic sleep disorders, chronic fatigue, chronic schizophrenia, chronic epilepsy, chronic nutritional disorders, spasm and chronic pain.
  • the compounds of the present invention may be used in the form prodrugs.
  • these prodrugs can be used as inhibitors of DP IV and DP IV-like enzymes and it is possible to define the site of their action, the time of onset of their action and the duration of action precisely.
  • Upon administration such prodrugs are cleaved, for example by suitable enzymes, and the active inhibitors are released.
  • the active inhibitors can be released both by chemical and enzymatic mechanisms.
  • esterases, proteases and peptidases serve to release the active inhibitors from the prodrugs according to the invention.
  • esterases, proteases, etc. are disclosed, for example, in WO 97/45117, US 5433955, US 5614379 and US 5624894.
  • Preferred proteases are aminopeptidases, dipeptidyl aminopeptidases, endoproteases, and endopeptidases.
  • Especially preferred proteases for the release of the active inhibitors from the prodrugs of the present invention are aminopeptidase N, aminopeptidase P, pyroglutaminyl aminopeptidase, dipeptidyl peptidase IV and dipeptidyl peptidase IV- like enzymes.
  • the released active inhibitors can interact with the DP IV and DP IV-like enzymes.
  • the above-mentioned insulinotropic peptides are broken down to a lesser degree and the effectiveness of insulin is thereby increased.
  • the present invention uses the concept to stabilize unstable inhibitors by masking them in prodrug form.
  • the properties of the active inhibitors according to the invention can be designed in such a way that the deactivation time of the DP IV-inhibitors e.g. by intramolecular cyclisation after their release from the prodrugs, is definable. ln particular, the prodrugs of the compounds of the invention are advantageous in that the active inhibitors of DP IV and DP IV-like enzymes are released according to individual patients' needs.
  • a prodrug of a compound of the invention interacts with a DP IV molecule or a aminopeptidase N molecule, it is cleaved by these enzymes and the active inhibitor is released.
  • the active inhibitor will inhibit DP IV and/or DP IV-like enzymes so that DP IV itself cannot cleave any further compounds for a defined time.
  • the remaining prodrugs are not degraded during this defined time and thus, constitute an inhibitor reservoir until the concentration of DP IV molecules or aminopeptidase N molecules rises again or active inhibitor molecules are eliminated or inactivated.
  • prodrugs has the further advantage that each organism will release exactly that amount of active inhibitor that is necessary to inhibit that amount of DP IV molecules, which is present in the body of the respective organism.
  • the present invention accordingly relates to novel compounds of inhibitors of the serine protease dipeptidyl peptidase IV or DP IV-like enzymes and their prodrugs, which can be used in the treatment of various disorders, especially of metabolic disorders associated with diabetes mellitus.
  • masked inhibitors are additionally considerably more effective than non-masked inhibitors: if identical amounts of non-masked DP IV-inhibitors and of compounds according to the invention are used, the compounds according to the invention produce a marked improvement in glucose tolerance in Diabetic Zucker rats.
  • the compounds according to the present invention are transported through the mucosa of the small intenstine without delay, for example simultaneously with nutrient intake. Moreover, the site of action, at which the active DP IV-inhibitors are released can also be controlled by the structure of the prodrugs.
  • the compounds of the present invention are useful in lowering or inhibiting DP IV and DP IV- like enzyme activity at least by about 10, preferably about 50, more preferably about 75, 90 or 100% and prolong the half live of their substrates in a mammal by at least about 2fold, preferably about 3fold, more preferably about 4fold, 5fold or higher relative to the absence of the compound and hence the reduction in the concentration of those peptide hormones and their analogues is reduced or delayed.
  • DP IV is present in a wide variety of mammalian organs and tissues e.g. the intestinal brush-border (Gutschmidt S. et al., "In situ" - measurements of protein contents in the brush border region along rat jejunal villi and their correlations with four enzyme activities.
  • DPP Dipeptidyl peptidase
  • reproductive organs e.g. cauda epididymis and ampulla, seminal vesicles and their secretions (Agrawal & Vanha-Perttula, Dipeptidyl peptidases in bovine reproductive organs and secretions. Int. J. Androl. 1986, 9 (6): 435-52).
  • human serum two molecular forms of dipeptidyl peptidase are present (Krepela E.
  • the compounds of the present invention, and their corresponding pharmaceutically acceptable acid addition salt forms are able to inhibit DP IV in vivo.
  • all molecular forms, homologues and epitopes of DP IV from all mammalian tissues and organs, also of those, which are undiscovered yet, are intended to be embraced by the scope of this invention.
  • the compounds of the present invention, and their corresponding pharmaceutically acceptable acid addition salt forms have only low, if no inhibitory activity against non-DP IV and non-DP IV- like proline specific enzymes. See example 11.
  • the compounds of the present invention are useful in treating conditions mediated by said enzyme activities.
  • the compounds disclosed herein are useful in the treatment of conditions such as immune, autoimmune disorders or central nervous system disorders, selected from the group consisting of strokes, tumors, ischemia, Parkinson's disease, and migraines.
  • the compounds of the present invention and their corresponding pharmaceutically acceptable acid addition salt forms improve glucose tolerance by lowering elevated blood glucose levels in response to an oral glucose challenge and, therefore, are useful in treating non- insulin-dependent diabetes mellitus.
  • the ability of the compounds of the present invention, and their corresponding pharmaceutically acceptable acid addition salt forms, to improve glucose tolerance in response to an oral glucose challenge may be measured in diabetic Zucker rats. The method is described in example 13.
  • the present invention therefore provides a method of preventing or treating a condition mediated by modulation of the DP IV or DP IV-like enzyme activity in a subject in need thereof which comprises administering any of the compounds of the present invention or pharmaceutical compositions thereof in a quantity and dosing regimen therapeutically effective to treat the condition.
  • the present invention includes the use of the compounds of this invention, and their corresponding pharmaceutically acceptable acid addition salt forms, for the preparation of a medicament for the prevention or treatment of a condition mediated by modulation of the DP IV activity in a subject.
  • the compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal, parenteral and combinations thereof.
  • the invention relates to pharmaceutical compositions, that is to say, medicaments, that contain at least one compound of the invention or salts thereof, optionally in combination with one or more pharmaceutically acceptable carriers and/or solvents.
  • compositions may, for example, be in the form of parenteral or enteral formulations and contain appropriate carriers, or they may be in the form of oral formulations that may contain appropriate carriers suitable for oral administration. Preferably, they are in the form of oral formulations.
  • the pharmaceutical compositions may additionally contain one or more hypoglycaemically active ingredients which may be active ingredients that are known per se.
  • the inhibitors or prodrugs of DP IV and DP IV-like enzymes administered according to the invention may be employed in pharmaceutically administrable formulations or formulation complexes alone or in combination with DP IV-inhibitors, substrates or pseudosubstrates of DP IV or DP IV-like enzymes, inhibitors of DP IV or DP IV-like enzyme expression, binding proteins of or antibodies against DP IV and DP IV-like enzymes in mammals.
  • the compounds of the invention make it possible to adjust treatment individually to patients and diseases, it being possible, in particular, to avoid individual intolerances, allergies and side-effects.
  • the compounds also exhibit differing degrees of activity as a function of time.
  • the method according to the invention represents especially a new approach to the reduction of raised blood glucose concentration in the serum of mammals. It is simple, susceptible of commercial application and suitable for use in the treatment of especially diseases that are based on above-average blood glucose values, on neurodegenerative diseases or on high blood pressure, in mammals and especially in human medicine.
  • the compounds are administered, for example, in the form of pharmaceutical preparations that contain the active ingredient in combination with customary additives like diluents, excipients and/or carriers known from the prior art.
  • customary additives like diluents, excipients and/or carriers known from the prior art.
  • they are administered parenterally (for example i.v. in physiological saline solution) or enterally (for example orally, formulated with customary carriers, such as, for example, glucose).
  • one or more doses of the compounds can be given per day in order to achieve the desired normalisation of the blood glucose values.
  • a dosage range in humans may be in the range of from 0.01 mg to 250.0 mg of compound per kilogram body weight per day, preferably in the range of from 0.01 to 100 mg of compound per kilogram of body weight per day.
  • the blood sugar level decreases by about 10%, preferably by about 15%, more preferably by about 20 or 30 % in the serum of the hyperglycaemic subject treated, compared to the untreated subject.
  • the blood sugar level of a subject is reduced down to a level below 140, especially preferred between 60 and 100 mg glucose /dl in the postprandial phase or below 100, preferably down to a level between 60 and 80 mg glucose /dl in the fasting state.
  • metabolic abnormalities such as impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and sequelae caused by diabetes mellitus in mammals, metabolism-related hypertension and cardiovascular sequelae caused by hypertension in mammals, skin diseases and diseases of the mucosae, autoimmune diseases, high blood pressure and inflammatory conditions, and psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain.
  • metabolic abnormalities such as impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and sequelae caused by diabetes mellitus in mammals, metabolism-related hypertension and cardiovascular sequelae caused by hypertension in mammals, skin diseases and diseases of the mucosae, autoimmune diseases, high blood pressure and inflammatory conditions, and psychosomatic, neuropsychiatric and
  • the compounds used according to the invention can accordingly be converted in a manner known per se into conventional formulations, such as, for example, tablets, capsules, dragees, pills, suppositories, granules, aerosols, syrups, liquid, solid and cream-like emulsions and suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers and additives or solvents.
  • the therapeutically effective compounds are preferably present in a concentration of approximately from 0.1 to 80 % by weight, preferably from 1 to 50 % by weight, of the total mixture, that is to say, in amounts sufficient for the mentioned dosage latitude to be obtained.
  • the substances can be used as medicaments in the form of dragees, capsules, bitable capsules, tablets, drops, syrups or also as suppositories or as nasal sprays.
  • the formulations are prepared, for example, by extending the active ingredient with solvents and/or carriers, optionally with the use of emulsifiers and/or dispersants, it being possible, for example, in the case where water is used as diluent, for organic solvents to be optionally used as auxiliary solvents.
  • excipients water, non-toxic organic solvents, such as paraffins (for example natural oil fractions), vegetable oils (for example rapeseed oil, groundnut oil, sesame oil), alcohols (for example ethyl alcohol, glycerol), glycols (for example propylene glycol, polyethylene glycol); solid carriers, such as, for example, natural powdered minerals (for example highly disperse silica, silicates), sugars (for example raw sugar, lactose and dextrose); emulsifiers, such as non-ionic and anionic emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulphonates and arylsulphonates), dispersants (for example lignin, sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talcum, stearic oils (for example magnesium ste
  • Administration is carried out in the usual manner, preferably enterally or parenterally, especially orally.
  • tablets may contain in addition to the mentioned carriers further additives such as sodium citrate, calcium carbonate and calcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talcum, can be used con- comitantly for tabletting.
  • various taste correctives or colourings can be added to the active ingredients in addition to the above-mentioned excipients.
  • solutions of the active ingredients using suitable liquid carriers can be employed.
  • the solution is introduced into soft gelatin capsules in a manner known per se.
  • the capsules are suitable for chewing or swallowing.
  • the finished tablet mixture of 30.0 kg is processed to form convex tablets weighing 300 mg.
  • the tablets can be coated or sugar-coated in a manner known per se.
  • Oxalylchloride (714 ⁇ l, 8.28mmol) was dissolved 10ml of dry dichlormethane and brought to -78°C. Then DMSO (817 ⁇ l, 8.28mmol) was added dropwise. The solution was stirred for 20min at -78°C. Then 1 (1.00g, 4.6mmol) was added and the mixture was stirred for 20 min. After that TEA (2.58ml, 18.4mmol) was added and the mixture was allowed to reach r.t. The mixture was diluted with hexane/ethylacetate (2/1 v/v) and 10ml of HCI (10% in water) was added. The organic layer was separated and the aqueous phase was extracted with 20ml of methylenechloride. All organic layers where collected and whashed with brine, followed by water, then dried.
  • the product was purified by column chromatography using silica gel and heptane/chloroform.
  • Cyclopentancarboxylic acid chloride 5 (1.00g, 7.54mmol) was dissolved in 5ml of dry ethyl ether and the solution was brought to -20°C. Then diazomethane (37.7mmol in 50ml dry ether) was added dropwise. The mixture was allowed to stirr at -30°C for 1.5h followed by 1.5h at 0°C. After that HBr (33% in acetic acid) (2.01ml, 11.3mmol) was added and the solution stirred for 30min at r.t. The solution was diluted by adding 50ml of ether and extracted using brine. The organic layer was dried and evaporated and the product was used without further characterisation.
  • Especially synthesized compounds of the invention are: example 2 1 -cyclopentyl-3-methyl-1 -oxo-2-pentanaminium chloride example 3 1 -cyclopentyl-3-methyl-1 -oxo-2-butanaminium chloride example 4 1 -cyclopentyl-3,3-dimethyl-1 -oxo-2-butanaminium chloride example 5 1 -cyclohexyl-3,3-dimethyl-1 -oxo-2-butanaminium chloride example 6 3-(cyclopentylcarbonyl)-1,2,3,4-tetrahydroisoquinolinium chloride example 7 A/-(2-cyclopentyl-2-oxoethyl)cyclohexanaminium chloride EINBETTENEINBETTEN
  • Example 9 Determination of ICso-Values 100 ⁇ l inhibitor stock solution were mixed with 100 ⁇ l buffer (HEPES pH7.6) and 20 ⁇ l diluted porcine DP IV and preincubated at 30°C. Reaction was started by addition of a mixture of 50 ⁇ l substrate (Gly-Pro-pNA, final concentration 0.4 mM) and 2 ⁇ l APN stock solution. Formation of the product pNA was measured at 405 nm and 30°C over 10 min using the HTS 7000Plus plate reader (Perkin Elmer) and slopes were calculated. The final inhibitor concentrations ranged between 1 mM and 30 nM. For calculation of IC50 GraFit 4.0.13 (Erithacus Software) was used.
  • DP II (3.4.14.2) releases N-terminal dipeptides from oligopeptides if the N- terminus is not protonated (McDonald, J.K., Ellis, S. & Reilly, T.J., 1966, J. Biol. Chem., 241 , 1494-1501). Pro and Ala in Pi-position are preferred residues.
  • the enzyme activity is described as DP IV-like activity, but DP II has an acidic pH- optimum. The enzyme used was purified from porcine kidney.
  • 100 ⁇ l inhibitor stock solution were mixed with 100 ⁇ l buffer (HEPES pH7.6) and 20 ⁇ l diluted attractin and preincubated at 30°C. Reaction was started by addition of a mixture of 50 ⁇ l substrate (Gly-Pro-pNA, final concentration 0.4 mM) and 2 ⁇ l APN stock solution. Formation of the product pNA was measured at 405 nm and 30°C over 10 min using the HTS 7000Plus plate reader (Perkin Elmer) and slopes were calculated. The final inhibitor concentrations ranged between 1 mM and 30 nM. For calculation of IC 50 values, GraFit 4.0.13 (Erithacus Software) was used.
  • the inhibitors were tested for their cross reacting potency against dipeptidyl peptidase I, prolyl oligopeptidase and Prolidase.
  • DP I or cathepsin C is a lysosomal cysteine protease which cleaves off dipeptides from the N-terminus of their substrates (Gutman, H.R. & Fruton, J.S., 1948, J. Biol: Chem., 174, 851-858) . It is classified as a cysteine protease.
  • the enzyme used was purchased from Qiagen (Qiagen GmbH, Hilden, Germany).
  • the enzyme was diluted 1000fold in MES buffer pH5,6 (40 mM MES, 4 mM DTT, 4 mM KCI, 2 mM EDTA, 0.015% Brij) and preincubated for 30 min at 30°C.
  • the IC ⁇ o-values were calculated using Graphit 4.0.15 (Erithacus Software, Ltd., UK).
  • Prolidase (X-Pro dipeptidase) Prolidase (EC 3.4.13.9) was first described by Bergmann & Fruton (Bergmann, M. & Fruton, JS, 1937, J. Biol. Chem. 189-202). Prolidase releases the J ⁇ -terminal amino acid from Xaa-Pro dipeptides and has a pH optimum between 6 and 9.
  • Prolidase from porcine kidney was solved (1 mg/ml) in assay buffer (20mM NH (CH 3 COO) 2 , 3mM MnCI 2 , pH 7.6). In order to get a fully active enzyme the solution was incubated for 60 min at room temperature.
  • 450 ⁇ l solution with the test compounds in an concentration range of 5*10 "3 M - 5*10 "7 M were admixed with 500 ⁇ l buffer solution (20mM NH 4 (CH 3 COO) 2 , pH 7.6) and 250 ⁇ l lle-Pro-OH (0.5mM in the assay mixture).
  • the assay mixture was preincubated at 30 °C for 5 min.
  • the IC ⁇ o-values were calculated using Graphit 4.0.15 (Erithacus Software, Ltd., UK).
  • Angiotensin-I converting enzyme (ACE)
  • Angiotensin l-converting enzyme (ACE; peptidyl-dipeptidase A) is a zinc metallopeptidase which cleaves the C-terminal dipeptide from angiotensin I to produce the potent vasopressor octapeptide angiotensin II (SkeggsL.T., Kahn, J.R. & Shumway, N.P. (1956) The preparation and function of the hypertensin-converting enzyme. J. Exp. Med. 103, 295-299.) and inactivates bradykinin by the sequential removal of two C-terminal dipeptides (YangH.Y.T., Erdos, E.G. & Levin, Y.
  • ACE cleaves C-terminal dipeptides from various oligopeptides with a free C-terminus. ACE is also able to cleave a C-terminal dipeptide amide.
  • IC50 determination of ACE an enzyme produced by Sigma was used (Prod. No. A-6778). The assay procedure and calculation of activity described by the manufacturer was adapted to half of the described volumes.
  • the IC 50-values were calculated using Graphit 4.0.15 (Erithacus Software, Ltd., UK).
  • AARE Acylamino acid-releasing enzyme
  • Acylaminoacyl-peptidase (EC 3.4.19.1) has also been referred to by the names acylpeptide hydrolase (GadeW. & Brown, J.L. (1978) Purification and partial characterization of a-N-acylpeptide hydrolase from bovine liver. J. Biol. Chem. 253, 5012-5018.; JonesW.M. & Manning, J.M. (1985) Acylpeptide hydrolase activity from erythrocytes. Biochem. Biophys. Res. Commun. 126, 933-940.; KobayashiK., Lin, L.-W., Yeadon, J.E., Vogelstein, L.B. & Smith, J.A.
  • the products of the reaction are the free acyl amino acid and a peptide with a free N-terminus shortened by one amino acid.
  • the enzyme acts on a variety of peptides with different N-terminal acyl groups, including acetyl, chloroacetyl, formyl and carbamyl (JonesW.M., Scaloni, A., Bossa, F., Popowicz, A.M., Schneewind, O. & Manning, J.M. (1991) Genetic relationship between acylpeptide hydrolase and acylase, two hydrolytic enzymes with similar binding but different catalytic specificities. Proc. Natl Acad. Sci. USA 88, 2194- 2198.).
  • 100 ⁇ l solution with the inhibitors in an concentration range of 1*10 "4 M - 5*10 "8 M were admixed with 100 ⁇ l ⁇ l buffer solution (200 mM Natriumphosphat, pH 7.2) and 20 ⁇ l AARE solution.
  • the assay mixture was pre-incubated at 30 °C for 15 min. After pre-incubation, 50 ⁇ l Acetyl-Met-AMC solution (0.54 mM) was added. Release of the AMC was measured at 30°C using a Novovostar flourescence microplate reader (BMG) and excitation/emission wavelengths of 380/460 nm.
  • BMG Novovostar flourescence microplate reader
  • the IC 5 o-values were calculated from the slopes of the progress curves using Graphit 4.0.15 (Erithacus Software, Ltd., UK).
  • Example 12 Determination Of DP IV Inhibiting Activity After Intravasal And
  • Catheter insertion into carotid artery After ⁇ one week of adaptation at the housing conditions, catheters were implanted into the carotid artery of Wistar rats under general anaesthesia (i.p. injection of 0.25 ml/kg b.w. Rompun ® [2 %], BayerVital, Germany and 0.5 ml/kg b.w. Ketamin 10, Atarost GmbH & Co., Twistringen, Germany). The animals were allowed to recover for one week. The catheters were flushed with heparin-saline (100 lU/ml) three times per week. In case of catheter dysfunction, a second catheter was inserted into the contra-lateral carotid artery of the respective rat. After one week of recovery from surgery, this animal was reintegrated into the study. In case of dysfunction of the second catheter, the animal was withdrawn from the study. A new animal was recruited and the experiments were continued in the planned sequence, beginning at least 7 days after catheter implantation.
  • Rats with intact catheter function were administered placebo (1 ml saline, 0.154 mol/l) or test compound via the oral and the intra-vasal (intra-arterial) route. After overnight fasting, 100 ⁇ l samples of heparinised arterial blood were collected at -30, -5, and 0 min. The test substance was dissolved freshly in 1.0 ml saline (0.154 mol/l) and was administered at 0 min either orally via a feeding tube (75 mm; Fine Science Tools, Heidelberg, Germany) or via the intra-vasal route. In the case of oral administration, an additional volume of 1 ml saline was injected into the arterial catheter. In the case of intra-arterial administration, the catheter was immediately flushed with 30 ⁇ l saline and an additional 1 ml of saline was given orally via the feeding tube.
  • the assay mixture for determination of plasma DP IV activity consisted of 80 ⁇ l reagent and 20 ⁇ l plasma sample. Kinetic measurement of the formation of the yellow product 4-nitroaniline from the substrate glycylprolyl-4-nitroaniline was performed at 390 nm for 1 min at 30 °C after 2 min pre-incubation at the same temperature. The DP IV activity was expressed in mU/ml.
  • Example 13 The effect of substituted amino ketones on glucose tolerance in diabetic Zucker rats
  • N 30 male Zucker rats (fa/fa), mean age 11 weeks (5-12 weeks), mean body weight 350 g (150-400 g), were purchased from Charles River (Sulzfeld, Germany). They were kept for >12 weeks until all the fatty Zucker rats had the characteristics of manifest Diabetes mellitus.
  • Eppendorf tubes Eppendorf-Netheler-Hinz, Hamburg, Germany
  • 10 ⁇ l sodium citrate buffer pH 3.0
  • Eppendorf tubes were centrifuged immediately (12000 rpm for 2 min, Hettich Zentrifuge EBA 12, Tuttlingen; Germany): The plasma fractions were stored on ice until analysis.
  • Glucose levels were measured using the glucose oxidase procedure (Super G Glukoseme ⁇ gerat; Dr. M ⁇ ller Geratebau, Freital, Germany).
  • the compounds of the present invention tested in the in vivo assay, improved significantly the glucose tolerance after oral administration during an OGTT in Zucker rats (see 7.1 ).

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Abstract

L'invention a trait à des composés représentés par la formule générale (I) B (CH--R1)n--C(=X2) D, et à des sels pharmaceutiquement acceptables de ceux-ci, y compris les stéréo-isomères, à l'utilisation de ces composés pour traiter l'intolérance au glucose, la glycosurie, l'hyperlipidémie, l'acidose métabolique, le diabète sucré, la neuropathie diabétique et la néphropathie ainsi que les séquelles du diabète sucré chez des mammifères.
PCT/EP2002/012288 2001-11-09 2002-11-04 Composes d'aminocetone substitues WO2003040174A2 (fr)

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DE10154689A DE10154689A1 (de) 2001-11-09 2001-11-09 Substituierte Aminoketonverbindungen
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Cited By (59)

* Cited by examiner, † Cited by third party
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WO2004075815A2 (fr) 2003-02-27 2004-09-10 Aventis Pharma Deutschland Gmbh Derives de diarylcycloalkyle, procede de preparation associe et utilisation de ces derives comme medicaments
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
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