WO2001055105A1 - 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv - Google Patents

2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv Download PDF

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WO2001055105A1
WO2001055105A1 PCT/DK2001/000045 DK0100045W WO0155105A1 WO 2001055105 A1 WO2001055105 A1 WO 2001055105A1 DK 0100045 W DK0100045 W DK 0100045W WO 0155105 A1 WO0155105 A1 WO 0155105A1
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optionally substituted
independently
alkyl
aryl
heteroaryl
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PCT/DK2001/000045
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English (en)
Inventor
Anders Kanstrup
Jane Marie Lundbeck
Lise Brown Christiansen
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Novo Nordisk A/S
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Priority to AU2001228309A priority Critical patent/AU2001228309A1/en
Priority to EP01946849A priority patent/EP1254113A1/fr
Priority to JP2001555047A priority patent/JP2003520849A/ja
Priority to AU2001233622A priority patent/AU2001233622A1/en
Priority to EP01905634A priority patent/EP1259246A2/fr
Priority to JP2001561331A priority patent/JP2003523396A/ja
Priority to PCT/DK2001/000115 priority patent/WO2001062266A2/fr
Priority to US09/790,002 priority patent/US7064145B2/en
Publication of WO2001055105A1 publication Critical patent/WO2001055105A1/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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, pharmaceutical compositions comprising the compounds and the use of such compounds for and the manufacture of medicaments for treating diseases that are associated with proteins which are subject to inactivation by DPP-IV, such as type II diabetes and obesity.
  • 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.
  • GLP-1 insulinotropic hormones Glucagon like peptide-1
  • GIP Gastric inhibitory peptide
  • 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 nondiabetic patients, thus supporting increased emphasis on treatment of diabetic dyslipidemia. This need for intensive treatment of diabetic dyslipidemia was advocated by the National Cholesterol Education Program's Adult Treatment Panel II.
  • 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, diabetes, 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.
  • compounds that are useful for inhibiting DPP-IV without suppressing the immune system are useful for inhibiting DPP-IV without suppressing the immune system.
  • the present invention provides novel 2-substituted unsaturated heterocyclic compounds, wherein a nitrogen atom in the heterocyclic ring is attached via an amide bond or a peptide bond to an amino acid or an amino acid derivative.
  • These compounds are potent and selective inhibitors of DPP-IV, and are effective in treating conditions that may be regulated or normalised via inhibition of DPP-IV.
  • the invention also concerns 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, beta cell dysfunction, and death of beta cells, such as necrosis or apoptosis of beta cells.
  • C 1 -C 1 0 alkyl refers to a straight or branched, saturated hydrocarbon chain having from 1-10 carbon atoms such as but not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. Butyi, isobutyl, tert. Butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, 2,2- dimethylpropyl and the like.
  • C 2 -C ⁇ o-alkenyl used herein, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-10 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.
  • Ci.io-alkoxy as used herein, alone or in combination is intended to include those C ⁇ - 1 0-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 isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • C3-C10 cycloalkyl refers to a radical of one or more saturated cyclic hydrocarbon having from 3-10 carbon atoms such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.
  • C3-C 1 0 cycloalkane refers to a saturated cyclic hydrocarbon having from 3-10 carbon atoms such as but not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane and the like.
  • C5-C 1 0 cycloalkenyl refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as but not limited to cyclopentenyl, cyclohexenyl and the like
  • aryl as used herein includes carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems.
  • heteroaryl as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
  • aryl and “heteroaryl” as used herein refers to an aryl which can be optionally substituted or a heteroaryl which can be optionally substituted and includes phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, , isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2
  • the present invention provides compounds of formula I
  • B is any alpha or beta amino acid connected to the ring with an amide or peptide bond; or a salt thereof with a pharmaceutically acceptable acid or base.
  • R 2 is H; C 1 -C 1 0 alkyl optionally substituted with one or more R 4 independently; C 2 - C 1 0 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ 0 -alkynyl optionally substituted with one or more R 4 independently; C 3 -C 10 -cycloalkyl optionally substituted with one or more R 4 ndependently; C5-C 1 Q cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently; or heteroaryl optionally substituted with one or more R 5 independently;
  • R 3 is H; C1-C10 alkyl optionally substituted with one or more R 4 independently; C 2 - C10 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ 0 -alkynyl optionally substituted with one or more R 4 independently; C3-C10 cycloalkyl optionally substituted with one or more R 4 independently; C5-C10 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently and/or fused to a C3-C 10 cycloalkane; or heteroaryl optionally substituted with one or more R 5 independently and/or fused to a C3-C10 cycloalkane;
  • R 2 may be connected to R 3 by a saturated or unsaturated bridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms or sulphur atoms independently, or a valence bond, thus forming a ring, said ring may be fused to an aryl or heteroaryl, optionally substituted by one or more R 5 independently;
  • R 4 is cycloalkyl, aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently; amino optionally substituted with one or more R 6 independently; -SO-R 6 ; -SO 2 -R 6 ; -CO-R 6 ; -COO-R 6 , - CONH-R 6 ; -CON(R 6 ) 2 ; -O-R 6 ; -S-R 6 ; carboxy; acetamido; cyano; nitro; halogen; hydroxy; trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;
  • R 5 is halogen, C1-C10 alkyl, C 1 -C 1 0 alkoxy, C1-C10 alkylamino, C.-C10 dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy; acetamido; hydroxy; sulfamoyl, carbamoyl;
  • R 6 is C1-C10 alkyl, C 2 -C10 alkenyl, C 2 -C ⁇ o-alkynyl, C 3 -C ⁇ 0 -cycloalkyl, C5-C10 cycloalkenyl where any one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally be substituted with aryl optionally substituted with one or more R 5 independently or heteroaryl optionally substituted with one or more R 5 independently; benzyl, phenethyl; aryl optionally substituted with one or more R 5 independently; or heteroaryl optionally substituted with one or more R 5 independently with the proviso that R 2 and R 3 cannot both be H; or a salt thereof with a pharmaceutically acceptable acid or base.
  • the invention provides compounds of formula III
  • R 2 is H; C 1 -C 1 0 alkyl optionally substituted with one or more R 4 independently; C 2 - C 1 0 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ 0 -alkynyl optionally substituted with one or more R 4 independently; C 3 -C ⁇ 0 -cycloalkyl optionally substituted with one or more R 4 independently; C5-C 1 0 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently; or heteroaryl optionally substituted with one or more R 5 independently;
  • R 3 is H; C 1 -C 1 0 alkyl optionally substituted with one or more R 4 independently; C 2 - C 1 0 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ 0 -alkynyl optionally substituted with one or more R 4 independently; C3-C10 cycloalkyl optionally substituted with one or more R 4 independently; C5-C 1 0 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently and/or fused to a C3-C 1 0 cycloalkane; or heteroaryl optionally substituted with one or more R 5 independently and/or fused to a C3-C 1 0 cycloalkane; R 2 may be connected to R 3 by a saturated or unsaturated bridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms, or sulphur atoms independently, or a valence bond
  • R 4 is cycloalkyl, aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently; amino optionally substituted with one or more R 6 independently; -SO-R 6 ; -S0 2 -R 6 ; -CO-R 6 ; -COO-R 6 , - CONH-R 6 ; -CON(R 6 ) 2 ; -O-R 6 ; -S-R 6 ; carboxy; acetamido; cyano; nitro; halogen; hydroxy; trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl; R is halogen, CrC 10 alkyl, C1-C10 alkoxy, C1-C10 alkylamino, C1-C10 dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl, trifluorometh
  • the invention provides compounds of formula IV
  • R 2 is H; C 1 -C 1 0 alkyl optionally substituted with one or more R 4 independently; C 2 - C10 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ 0 -alkynyl optionally substituted with one or more R 4 independently; C 3 -C ⁇ 0 -cycloalkyl optionally substituted with one or more R 4 independently; C5-C10 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently; or heteroaryl optionally substituted with one or more R 5 independently;
  • R 3 is H; C 1 -C 10 alkyl optionally substituted with one or more R 4 independently; C 2 - C10 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ o-alkynyl optionally substituted with one or more R 4 independently; C 3 -C ⁇ 0 cycloalkyl optionally substituted with one or more R 4 independently; C5-C 1 0 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently and/or fused to a C3-C10 cycloalkane; or heteroaryl optionally substituted with one or more R 5 independently and/or fused to a C3-C10 cycloalkane;
  • R 2 may be connected to R 3 or R 7 by a saturated or unsaturated bridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms, sulphur atoms independently, or a valence bond, thus forming a ring, said ring may be fused to an aryl or heteroaryl, optionally substituted by one or more R 5 independently;
  • R 4 is cycloalkyl; aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently; amino optionally substituted with one or more R 6 independently; -SO-R 6 ; -SO 2 -R 6 ; -CO-R 6 ; -COO-R 6 , - CONH-R 6 ; -CON(R 6 ) 2 ; -O-R 6 ; -S-R 6 ; carboxy; acetamido; cyano; nitro; halogen; hydroxy; trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;
  • R 5 is halogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylamino, C1-C10 dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy; acetamido; hydroxy; sulfamoyl, carbamoyl; R 6 is C ⁇ -C 10 alkyl, C 2 -C10 alkenyl, C 2 -C ⁇ 0 -alkynyl, C 3 -C ⁇ o-cycloalkyl, C5-C10 cycloalkenyl where any one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally be substituted with aryl optionally substituted with one or more R 5 independently or heteroaryl optional
  • R 7 is H; C1-C10 alkyl optionally substituted with one or more R 4 independently; C 2 - C10 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ 0 -alkynyl optionally substituted with one or more R 4 independently; C 3 -C ⁇ o-cycloalkyl optionally substituted with one or more R 4 independently; C5-C10 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently, halogen, C1-C10 alkoxy, C1-C10 alkylthio, C1-C10 alkylamino, C1-C10 dialkylamino, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N- hydroxyimino, cyano; carboxy; acetamido; hydroxy; s
  • the invention provides compounds of formula V
  • R 2 is H; C 1 -C 1 0 alkyl optionally substituted with one or more R 4 independently; C 2 -
  • R 3 is H; C1-C10 alkyl optionally substituted with one or more R 4 independently; C 2 - C10 alkenyl optionally substituted with one or more R 4 independently; C 2 -C ⁇ o-alkynyl optionally substituted with one or more R 4 independently; C3-C10 cycloalkyl optionally substituted with one or more R 4 independently; C5-C 1 0 cycloalkenyl optionally substituted with one or more R 4 independently; aryl optionally substituted with one or more R 5 independently and/or fused to a C3-C 1 0 cycloalkane; or heteroaryl optionally substituted with one or more R 5 independently and/or fused to a C3-C10 cycloalkane;
  • R 2 may be connected to R 3 or R 7 by a saturated or unsaturated bridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms, or sulphur atoms independently, or a valence bond, thus forming a ring, said ring may be fused to an aryl or heteroaryl, optionally substituted by one or more R 5 independently;
  • R 4 is cycloalkyl; aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently; amino optionally substituted with one or more R 6 independently; -SO-R 6 ; -SO2-R 6 ; -CO-R 6 ; -COO-R 6 , - CONH-R 6 ; -CON(R 6 ) 2 ; -O-R 6 ; -S-R 6 ; carboxy; acetamido; cyano; nitro; halogen; hydroxy; trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl; R 5 is halogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylamino, C1-C10 dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl, trifluorometh
  • R 6 is C1-C10 alkyl, C 2 -C 10 alkenyl, C 2 -C ⁇ o-alkynyl, C 3 -C 10 -cycloalkyl, C5-C10 cycloalkenyl where any one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally be substituted with aryl optionally substituted with one or more R 5 independently or heteroaryl optionally substituted with one or more R 5 independently; benzyl, phenethyl; aryl optionally substituted with one or more R 5 independently; or heteroaryl optionally substituted with one or more R 5 independently R 7 is H; C 1 -C 1 0 alkyl optionally substituted with one or more R 4 independently; C 2 -
  • R 2 is H; C 1 -C 1 0 alkyl optionally substituted with R 4 ; C2-C10 alkenyl optionally substituted with R 4 ; C 2 -C ⁇ o-alkynyl optionally substituted with R 4 ; aryl optionally substituted with one or more R 5 independently; or heteroaryl optionally substituted with one or more R 5 independently;
  • R 2 is H or C 1 -C10 alkyl optionally substituted with R 4 .
  • Another preferred embodiment is represented by the compounds of the invention wherein R 2 is H.
  • R 3 is H; C 1 -C 1 0 alkyl optionally substituted with R 4 ; C 2 -C10 alkenyl optionally substituted with R 4 ; C 2 -C ⁇ o-alkynyl optionally substituted with R 4 ; C3-C10 cycloalkyl optionally substituted with R 4 ; aryl optionally substituted with one or more R 5 independently and/or fused to a C3-C 1 0 cycloalkane; or heteroaryl optionally substituted with one or more R 5 independently and/or fused to a C3-C10 cycloalkane;
  • R 3 is H; C 1 -C 1 0 alkyl optionally substituted with R 4 ; or aryl optionally substituted with one or more R 5 independently and/or fused to a C3-C10 cycloalkane.
  • R 3 is C 1 -C 1 0 alkyl optionally substituted with R 4 .
  • R 4 is cycloalkyl; aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently; -SO-R 6 ; -S0 2 -R 6 ; - CO-R 6 ; -COO-R 6 ; -O-R 6 ; -S-R 6 ;
  • R 4 is aryl optionally substituted with one or more R 5 independently; heteroaryl optionally substituted with one or more R 5 independently; -CO-R 6 ; -COO-R 6 ; -O-R 6 ; -S- R 6 ;
  • R 4 is aryl optionally substituted with one or more R 5 independently;
  • R 4 is -COO-R 6 , -O-R 6 , or -S-R 6 ;
  • Another preferred embodiment is represented by the compounds of the invention wwhheerreeiinn RR 55 iiss hhaallooggeenn,, CC11--CC1100 alkyl, C1-C10 alkoxy, C ⁇ -C ⁇ 0 alkylamino, C1-C10 dialkylamino, benzyl, or benzyloxy.
  • R 5 is halogen, C1-C10 alkyl, or C1-C10 alkoxy.
  • R 6 is C 1 -C 1 0 alkyl, C 2 -C 10 alkenyl optionally substituted with R 4 ; C 2 -C ⁇ o-alkynyl optionally substituted with R 4 ; benzyl, aryl optionally substituted with one or more R 5 independently, or heteroaryl optionally substituted with one or more R 5 independently.
  • nn RR 66 iiss C 1 -C 1 0 alkyl, benzyl, or aryl optionally substituted with one or more R 5 independently.
  • the invention also relates to methods for preparing the above-mentioned compounds. These methods comprise (1) and (2) described below:
  • the compounds of the present invention may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • a further aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for treating a condition which may be regulated or normalised via inhibition of DPP-IV.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for treatment of metabolic disorders.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for blood glucose lowering.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for treatment of Type II diabetes
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment of impaired glucose tolerance (IGT).
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment of impaired fasting glucose (IFG).
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for prevention of hyperglycemia.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for delaying the progression of impaired glucose tolerance (IGT) to Type II diabetes.
  • ITT impaired glucose tolerance
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for delaying the progression of non-insulin requiring Type II diabetes to insulin requiring Type II diabetes.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for increasing the number and/or the size of beta cells in a mammalian subject.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for treatment of beta cell degeneration, in particular apoptosis of beta cells.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment of disorders of food intake.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment of obesity.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for appetite regulation or induction of satiety.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment of dyslipidemia.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for treatment of functional dyspepsia, in particular irritable bowel syndrome.
  • a further aspect of the invention is a method for treating the conditions mentioned above by administering to a subject in need thereof an effective amount of a compound of the invention.
  • the invention furthermore relates to the use of a compound according to the present invention for the preparation of a medicament for use in the treatment of diabetes in a regimen which additionally comprises treatment with another antidiabetic agent.
  • the antidiabetic agent is insulin or GLP-1 or any analogue or derivative thereof.
  • the antidiabetic agent is a non-peptidyl hypoglycaemic agent, preferably an oral hypoglycaemic agent.
  • Oral hypoglycaemic agents are preferably selected from the group consisting of sulfonylureas, non-sulphonylurea insulin secretagogues, biguanides, thiazolidinediones, alpha glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potasium channel openers, insulin sensitizers, hepatic enzyme inhibitors, glucose uptake modulators, compounds modifying the ' lipid metabolism, compounds lowering food intake, and agents acting on the ATP-dependent potassium channel of the ⁇ -cells.
  • sulfonylureas tolbutamide, glibenclamide, glipizide and gliclazide are preferred.
  • non-sulphonylurea insulin secretagogues repaglinide and nateglinide are preferred.
  • metformin is preferred.
  • troglitazone Among the thiazolidinediones, troglitazone, rosiglitazone and ciglitazone are preferred.
  • acarbose is preferred.
  • glibenclamide glipizide
  • gliclazide gliclazide
  • repaglinide glibenclamide
  • 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, 9 th Fri 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 which 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 which 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.
  • the pharmaceutical 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.
  • 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. If 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, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound 250 mg
  • 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. For example, in the treatment of adult humans, 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. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. 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. Generally, 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.
  • prodrugs will be functional derivatives of a compound af the invention which are readily convertible in vivo into a compound af 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, 1985.
  • the invention also encompasses active metabolites of a compound of the invention.
  • 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 is
  • Assay buffer 50 mM Tris pH7.4, 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
  • 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 HbA1c 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 sensitiser compounds.

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Abstract

L'invention concerne des inhibiteurs sélectifs à activité thérapeutique agissant sur l'enzyme DPP-IV. L'invention concerne des composés hétérocycliques insaturés à substitution en 2, avec un atome d'azote de la chaîne hétérocyclique fixé via une liaison amide ou peptidique à un acide aminé ou un dérivé d'acide aminé. Les composés considérés sont des inhibiteurs puissants et sélectifs de l'enzyme DPP-IV, et ils sont efficaces pour traiter des affections susceptibles d'être régulées ou normalisées à travers l'inhibition de l'enzyme considérée.
PCT/DK2001/000045 2000-01-24 2001-01-22 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv WO2001055105A1 (fr)

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AU2001228309A AU2001228309A1 (en) 2000-01-24 2001-01-22 N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv
EP01946849A EP1254113A1 (fr) 2000-01-24 2001-01-22 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
JP2001555047A JP2003520849A (ja) 2000-01-24 2001-01-22 酵素ｄｐｐ−ｉｖの阻害剤であるｎ−置換２−シアノピロールおよび−ピロリン
AU2001233622A AU2001233622A1 (en) 2000-02-25 2001-02-20 Inhibition of beta cell degeneration
EP01905634A EP1259246A2 (fr) 2000-02-25 2001-02-20 Inhibition de la degenerescence des cellules beta
JP2001561331A JP2003523396A (ja) 2000-02-25 2001-02-20 ベータ細胞変性の抑制
PCT/DK2001/000115 WO2001062266A2 (fr) 2000-02-25 2001-02-20 Inhibition de la degenerescence des cellules beta
US09/790,002 US7064145B2 (en) 2000-02-25 2001-02-21 Inhibition of beta cell degeneration

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