WO2001014338A1 - NOUVEAUX INHIBITEURS DE L'INTEGRINE αVβ¿3? - Google Patents

NOUVEAUX INHIBITEURS DE L'INTEGRINE αVβ¿3? Download PDF

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Publication number
WO2001014338A1
WO2001014338A1 PCT/EP2000/007591 EP0007591W WO0114338A1 WO 2001014338 A1 WO2001014338 A1 WO 2001014338A1 EP 0007591 W EP0007591 W EP 0007591W WO 0114338 A1 WO0114338 A1 WO 0114338A1
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Prior art keywords
ylamino
phenyl
compounds
acid
formula
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PCT/EP2000/007591
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German (de)
English (en)
Inventor
Alfred Jonczyk
Oliver Schadt
Simon Goodman
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Merck Patent Gmbh
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Priority to PL00352989A priority Critical patent/PL352989A1/xx
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to SK228-2002A priority patent/SK2282002A3/sk
Priority to EP00953158A priority patent/EP1206454A1/fr
Priority to JP2001518427A priority patent/JP2003507458A/ja
Priority to KR1020027001419A priority patent/KR20020016651A/ko
Priority to MXPA02001861A priority patent/MXPA02001861A/es
Priority to AU65705/00A priority patent/AU6570500A/en
Priority to BR0013504-6A priority patent/BR0013504A/pt
Priority to HU0203697A priority patent/HUP0203697A3/hu
Priority to CA002382850A priority patent/CA2382850A1/fr
Publication of WO2001014338A1 publication Critical patent/WO2001014338A1/fr
Priority to NO20020886A priority patent/NO20020886L/no
Priority to HK03101785.4A priority patent/HK1049666A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the invention relates to novel compounds of the formula
  • Amino protective groups can be provided,
  • Z is missing, -O-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-,
  • R 1 is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF 3 or CN,
  • R 4 one or more times by F, Cl, Br, A, aryl, OA, SA, CO-A,
  • Het 1 is a mono- or dinuclear heterocycle with 1 to 4 N-
  • Atoms which may be unsubstituted or mono- or disubstituted by NH 2 may be unsubstituted or mono- or disubstituted by NH 2 ,
  • N 1 to 3 N, O and / or S atoms which are unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF 3 , -CO-A, CN, COOA, CONH 2 , CONHA, CONA 2 or N0 2 can be substituted,
  • n 1, 2, 3, 4, 5 or 6
  • R 4 ⁇ is a phenyl or naphthyi radical which is simply substituted by A or aryl
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the ⁇ v integrin receptors with ligands.
  • the compounds show particular effectiveness in the case of integrins ⁇ vß3 and ⁇ v ßs-
  • the compounds are particularly effective as adhesion receptor antagonists for the receptor ⁇ ß 3 . This effect can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
  • Preventing matrix proteins and accordingly also preventing tumor cells from attaching to matrix proteins can be performed in a cell adhesion test which is carried out analogously to the method by F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995). PC Brooks et al. describe in J. Clin. Invest. 96, 1815-1822 (1995) ⁇ v ß3 antagonists for combating cancer and for treating tumor-induced angiogenic diseases.
  • the compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis.
  • the GPIIb / llla antagonists can be regarded as effective metastasis inhibitors.
  • compounds of the formula I In addition to the binding of fibrinogen, fibronectin and von Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as vitonectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent that
  • Formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.
  • the properties of the compounds can also be demonstrated by methods which are described in EP-A1-0 462 960.
  • the Inhibition of fibrinogen binding to the fibrinogen receptor can be detected using the method specified in EP-A1-0 381 033.
  • the antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
  • the bone resorption can be inhibited by the compounds according to the invention with the aid of an osteoclast absorption test analogous to WO 95/32710.
  • the invention accordingly relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a medicament for use as an integrin inhibitor.
  • the invention relates in particular to compounds of the formula I according to Claim 1 and / or their harmless salts for the production of a medicament for combating pathologically angiogenic diseases, tumors, osteoporosis, inflammation and infections.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, for prophylaxis and / or
  • thrombosis myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, hypercalcaemia, pathologically angiogenic diseases such as B. Inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, infection, pilutectomy, acne infection, viral infection Kidney failure and wound healing to support the healing process.
  • B. Inflammation ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, athe
  • the compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect.
  • the effectiveness of the antimicrobial activity can be by P. Valentin-Weigund et al. methods described in Infection and Immunity, 2851-2855 (1988).
  • the invention also relates to the hydrates and solvates, e.g. Alcoholates, these compounds.
  • the invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
  • a) releases a compound of formula I from one of its functional derivatives by treatment with a solvolysing, reducing or hydrogenolysing agent, or
  • the compounds of formula I can have a chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula I. So-called prodrug derivatives are also included in the compounds according to the invention, ie with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I which in Organism can be quickly split into the active compounds of the invention.
  • Trt trityl (triphenylmethyl).
  • A is alkyl and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl or tert-butyl, also for pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1 -methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2-, 1, 2,2- Trimethylpropyl, heptyl, octyl, nonyl or decyl, undecyl or dodecyl.
  • A also means alkyl substituted by halogen,
  • X is preferably e.g. Pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydro-imidazol-2-ylamino, 2-amino-imidazol-5- ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl.
  • Y is preferably e.g. Ethylene, propylene or butylene.
  • Z is preferably, for example, O.
  • R 1 is preferably, for example, 1,4-phenylene.
  • R 2 is preferably, for example, CH or N, very particularly preferably CH.
  • R 4 is preferably, for example, phenyl which is mono- or polysubstituted by F.
  • R 5 is preferably, for example, OH.
  • Het 1 is preferably unsubstituted or mono- or disubstituted by A,
  • Benzimidazolyl 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4 -, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8 -Quinazolinyl, 1 H-imidazo [4,5-b] pyridin-2-yl or 1,8-naphthyridin-7-yl.
  • the heterocyclic radicals can also be partially or completely hydrogenated.
  • Het 1 can, for. B. also mean 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 4,5-dihydro-imidazol-2-yl, 2,3-dihydro- 1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4- pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4 -Piperidinyl,
  • Het 2 is preferably unsubstituted or simply substituted by F, Cl, Br, A, OA or OCF 3 2,3-, 2,4- 2,5- or 3,4-thienyl, 2,3-, 2,4- , 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2nd , 4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl.
  • n is preferably 2, 3, 4, 5 or 6, very particularly preferably n is 3, 4 or 5.
  • m and o are preferably, in each case independently of one another, 0.1 or 2, very particularly preferably they are 0.
  • One or more times substituted means one, two, three or four times substituted.
  • Aryl is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o -, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p- Ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- methylthioph
  • Amino protecting group preferably means formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Y is - (CH 2 ) n -, n is 2, 3 or 4; in c) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,
  • Y is - (CH 2 ) n - n 2, 3 or 4;
  • Z is O
  • R 2 is N or CH
  • OCF 3 , -CO-A, CN, COOA, CONH 2 or NO 2 are substituted phenyl;
  • R 4 one or more times by F, Cl, Br, OA or
  • R 5 is OA or OH
  • R 5 is OA or OH
  • R 4 is phenyl substituted one or more times by shark, A or aryl,
  • R 5 is OA or OH with the proviso that R 4 ⁇ is a phenyl or naphthyl radical which is simply substituted by A or aryl;
  • R 5 is OA or OH with the proviso that R 4 ⁇ is a phenyl or naphthyl radical which is simply substituted by A or aryl;
  • R 5 OA or OH, aryl one, two or three times by shark, A, OA,
  • R 4 ⁇ is a phenyl or naphthyl radical which is simply substituted by A or aryl;
  • R 4 is phenyl substituted one or more times by shark, A or aryl,
  • R a OA or OH means that the R 4 ⁇ is a phenyl or naphthyl radical which is simply substituted by A or aryl.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxy protecting group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule is. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially Aralkoxycarbonyl groups.
  • acyl groups are formyl or alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy”), 4-
  • Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl, formyl and acetyl.
  • the amino protective group can be split off, depending on the one used
  • Protecting group - e.g. B. with strong acids suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid.
  • strong acids suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid.
  • strong acids suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water.
  • carboxylic acids such as acetic acid
  • ethers such as tetrahydrofuran or dioxane
  • amides such as DMF
  • halogenated hydrocarbons such as dichloromethane
  • alcohols such as methanol, ethanol or isopropanol, and water.
  • reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of sec. Amines such as dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
  • Hydrogenolytically removable protective groups can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, appropriately a carrier such as coal) can be split off.
  • a catalyst z. B. a noble metal catalyst such as palladium, appropriately a carrier such as coal
  • Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.
  • Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
  • Suitable inert solvents are e.g. Hydrocarbons like hexane,
  • the conversion of a cyano group into an amidino group takes place by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd / C. It is also possible to replace a conventional amino protecting group with hydrogen by splitting off the protecting group as described above, solvolytically or hydrogenolytically, or by having one amino group protected by a conventional protective group is released by solvolysis or hydrogenolysis.
  • amidinizing agent is 1-amidino-3,5-dimethylpyrazole (DPFN), which is used in particular in the form of its nitrate.
  • DPFN 1-amidino-3,5-dimethylpyrazole
  • the addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H 2 S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH 3 I, which in turn reacts with NH 3 to form the amidine, b) converts the nitrile with an alcohol, for example ethanol in the presence of HCl, into the corresponding imidoester and treats it with ammonia, or c) that
  • the compounds of the formula I from an oxidized precursor by, for example, an oxy heterocycle with a reducing agent such as e.g. Reduced phosphorus trichloride in an inert solvent.
  • a reducing agent such as e.g. Reduced phosphorus trichloride in an inert solvent.
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between - 60 and + 30 °.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids are particularly suitable, the physiologically harmless ones
  • So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, methanesulfonic acid, methanesulfonic acid - Acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • an acid of formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base.
  • the sodium, potassium, magnesium, calcium and ammonium salts come in as salts
  • ammonium salts e.g. B. the dimethyl, diethyl or diisopropyl ammonium salts, monoethanol, diethanol or diisopropylammonium salts, cyclohexyl, dicyclohexyiammonium salts, dibenzylethylenediammonium salts, z. B. salts with arginine or lysine.
  • the compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se.
  • the racemic mixture is preferably reacted with a optically active release agent diastereomers formed.
  • Suitable release agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • Enantiomer separation with is also advantageous
  • a suitable solvent is e.g. a mixture of hexane / isopropanol / acetonitrile, e.g. in the volume ratio 82: 15: 3.
  • optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
  • the invention includes not only the compounds mentioned but also mixtures and preparations which, in addition to these compounds according to the invention, also contain other pharmacological active ingredients or adjuvants which can influence the primary pharmacological action of the compounds according to the invention in a desired manner. These can be used as therapeutic agents, diagnostic agents or as reagents.
  • drugs can come from the fields of cardiovascular, central nervous system or oncology. They can be tumor agents, such as angiogenesis inhibitors or cytostatics, chemotherapeutics from the group alkylating agents, antibiotics, Antimetabolites, biologicals and immunomodulators, hormones and their
  • Substances can be low molecular weight and high molecular weight. It can be
  • Lipids Lipids, carbohydrates or proteins. This includes cytokines,
  • Toxins fusion proteins, monoclonal antibodies and vaccines.
  • the invention accordingly relates to compounds of the formulas defined above and below and in the claims, including their physiologically acceptable salts as medicaments, diagnostics or
  • the invention relates in particular to corresponding medicaments as inhibitors for combating diseases which are based directly or indirectly on expression of the ⁇ v ⁇ 3 integrin receptor, in particular in the case of pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis. Inflammation, infections and to influence wound healing processes.
  • the invention furthermore relates to the use of the compounds and / or their physiologically acceptable salts according to the claims and the description for the manufacture of a medicament for combating diseases which are based directly or indirectly on expression of the ⁇ v ⁇ 3 integrin receptor, in particular therefore in pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammation, infections and for influencing wound healing processes.
  • the pharmaceuticals according to the invention or pharmaceuticals containing them Preparations can be used in human or veterinary medicine.
  • Organic or inorganic are used as carriers
  • Sprays are suitable and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols,
  • carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, z. B. one or more vitamins.
  • sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant gas mixture (e.g. CO 2 or chlorofluorocarbons).
  • a propellant gas or propellant gas mixture e.g. CO 2 or chlorofluorocarbons
  • the active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically acceptable solvents to be present, for. B. ethanol.
  • Inhalation solutions can be administered using standard inhalers.
  • the substances according to the invention can generally be administered in analogy to other known, commercially available preparations (for example described in US Pat. No. 4,472,305), preferably in doses between about 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit.
  • the daily dosage is preferably between about 0.01 and 20 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, gender, on the diet, on the time and route of administration, on which
  • Elimination rate, drug combination and severity of the disease to which the therapy applies are preferred.
  • HPLC analyzes (retention time Rt) were carried out in the following systems:
  • IC 50 value is given for the vitronectin binding test, ie the concentration in nmoles / liter which inhibits 50% of the vitronectin binding to the corresponding isolated receptor (method of Smith et al., J. Biol. Chem. 265, 12267-71, 1990).
  • Example A Injection glasses
  • a solution of 100 g of 3- (4-fluorophenyl) -4- ⁇ 4- [3- (pyridin-2-ylamino) propoxy] phenyl ⁇ butyric acid and 5 g of disodium hydrogenphosphate is dissolved in 3 l of double-distilled water with 2N Hydrochloric acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • Cocoa butter pour into molds and let cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of 3- (4-fluorophenyl) -4- ⁇ 4- [3- (pyridin-2-ylamino) propoxy] phenyl ⁇ butyric acid, 9.38 g of NaH 2 PO 4 • 2 H 2 O, 28.48 g Na 2 HPO 4 • 12 H 2 O and 0.1 g benzalkonium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • a mixture of 1 kg of 3- (4-fluorophenyl) -4- ⁇ 4- [3- (pyridin-2-ylamino) propoxy] phenyl ⁇ butyric acid, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg Talc and 0.1 kg of magnesium stearate are compressed into tablets in the usual way, such that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • a solution of 1 kg of 3- (4-fluorophenyl) -4- ⁇ 4- [3- (pyridin-2-ylamino) propoxy] phenyl ⁇ butyric acid in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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  • Cardiology (AREA)
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Abstract

L'invention concerne de nouveaux composés de formule (I) : X-Y-Z-R1-CH2-R?2(R4)-CH¿2-CO-R5, qui exercent une activité biologique en tant que ligands de l'intégrine α¿v?β3. Dans la formule (I), X, Y, Z, R?1, R2, R4 et R5¿ ont la signification indiquée dans la revendication 1. L'invention concerne également les sels et solvates physiologiquement tolérables desdits composés.
PCT/EP2000/007591 1999-08-24 2000-08-04 NOUVEAUX INHIBITEURS DE L'INTEGRINE αVβ¿3? WO2001014338A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
MXPA02001861A MXPA02001861A (es) 1999-08-24 2000-08-04 Nuevos inhbidores de la integrina alfav beta3.
SK228-2002A SK2282002A3 (en) 1999-08-24 2000-08-04 Integrin alpha'v'beta'3' inhibitors, process for the preparation and use thereof and pharmaceutical composition comprising same
EP00953158A EP1206454A1 (fr) 1999-08-24 2000-08-04 NOUVEAUX INHIBITEURS DE L'INTEGRINE ALPHAvBETA3
JP2001518427A JP2003507458A (ja) 1999-08-24 2000-08-04 新規なインテグリンαｖβ３阻害剤
KR1020027001419A KR20020016651A (ko) 1999-08-24 2000-08-04 신규한 인테그린 αｖβ３억제제
PL00352989A PL352989A1 (en) 1999-08-24 2000-08-04 Novel integrin alphav
AU65705/00A AU6570500A (en) 1999-08-24 2000-08-04 Novel integrin alphavbeta3 inhibitors
CA002382850A CA2382850A1 (fr) 1999-08-24 2000-08-04 Nouveaux inhibiteurs de .alpha.v.beta.3
HU0203697A HUP0203697A3 (en) 1999-08-24 2000-08-04 Novel integrin alphavbetha3 inhibitors, pharmaceutical compositions containing them and their use
BR0013504-6A BR0013504A (pt) 1999-08-24 2000-08-04 Inibidores da integrina alfav beta3
NO20020886A NO20020886L (no) 1999-08-24 2002-02-22 Nye integrin- <alfa>v<beta>3-inhibitorer
HK03101785.4A HK1049666A1 (zh) 1999-08-24 2003-03-12 新型整合蛋白αVβ3抑制劑

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19939981.6 1999-08-24
DE19939981A DE19939981A1 (de) 1999-08-24 1999-08-24 Neue Inhibitoren des Integrins alphavß3

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JP (1) JP2003507458A (fr)
KR (1) KR20020016651A (fr)
CN (1) CN1370147A (fr)
AU (1) AU6570500A (fr)
BR (1) BR0013504A (fr)
CA (1) CA2382850A1 (fr)
CZ (1) CZ2002523A3 (fr)
DE (1) DE19939981A1 (fr)
HK (1) HK1049666A1 (fr)
HU (1) HUP0203697A3 (fr)
MX (1) MXPA02001861A (fr)
NO (1) NO20020886L (fr)
PL (1) PL352989A1 (fr)
SK (1) SK2282002A3 (fr)
WO (1) WO2001014338A1 (fr)
ZA (1) ZA200202287B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6531494B1 (en) 2001-08-29 2003-03-11 Pharmacia Corporation Gem-substituted αvβ3 antagonists
US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
WO2006043930A1 (fr) * 2004-10-14 2006-04-27 Pharmacia Corporation Antagonistes l'integrine biphenyle

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008501305A (ja) * 2003-12-03 2008-01-24 ザ スクリプス リサーチ インスティテュート インテグリンαＩＩｂβ３特異的抗体およびペプチド
LT3538528T (lt) * 2016-11-08 2021-03-10 Bristol-Myers Squibb Company Pirolo amidai, kaip alfa v integrino inhibitoriai

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08325264A (ja) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd 新規２−芳香環置換−３−フェニルプロピオン酸またはアクリル酸誘導体
WO1998018461A1 (fr) * 1996-10-30 1998-05-07 Merck & Co., Inc. Antagonistes de l'integrine
WO1999045927A1 (fr) * 1998-03-10 1999-09-16 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08325264A (ja) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd 新規２−芳香環置換−３−フェニルプロピオン酸またはアクリル酸誘導体
WO1998018461A1 (fr) * 1996-10-30 1998-05-07 Merck & Co., Inc. Antagonistes de l'integrine
WO1999045927A1 (fr) * 1998-03-10 1999-09-16 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 126, no. 9, 1997, Columbus, Ohio, US; abstract no. 117964d, page 589; XP002154889 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
US6531494B1 (en) 2001-08-29 2003-03-11 Pharmacia Corporation Gem-substituted αvβ3 antagonists
WO2006043930A1 (fr) * 2004-10-14 2006-04-27 Pharmacia Corporation Antagonistes l'integrine biphenyle

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PL352989A1 (en) 2003-09-22
CA2382850A1 (fr) 2001-03-01
NO20020886D0 (no) 2002-02-22
BR0013504A (pt) 2002-05-07
HK1049666A1 (zh) 2003-05-23
EP1206454A1 (fr) 2002-05-22
NO20020886L (no) 2002-02-22
CN1370147A (zh) 2002-09-18
DE19939981A1 (de) 2001-03-01
JP2003507458A (ja) 2003-02-25
ZA200202287B (en) 2003-08-27
HUP0203697A3 (en) 2004-04-28
HUP0203697A2 (hu) 2003-03-28
CZ2002523A3 (cs) 2002-05-15
SK2282002A3 (en) 2002-06-04
MXPA02001861A (es) 2004-09-06
KR20020016651A (ko) 2002-03-04
AU6570500A (en) 2001-03-19

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