WO2001014338A1 - NOVEL INTEGRIN αVβ3 INHIBITORS - Google Patents

NOVEL INTEGRIN αVβ3 INHIBITORS 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)
French (fr)
Inventor
Alfred Jonczyk
Oliver Schadt
Simon Goodman
Original Assignee
Merck Patent Gmbh
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Publication date
Priority to BR0013504-6A priority Critical patent/BR0013504A/en
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to CA002382850A priority patent/CA2382850A1/en
Priority to PL00352989A priority patent/PL352989A1/en
Priority to EP00953158A priority patent/EP1206454A1/en
Priority to SK228-2002A priority patent/SK2282002A3/en
Priority to AU65705/00A priority patent/AU6570500A/en
Priority to MXPA02001861A priority patent/MXPA02001861A/en
Priority to HU0203697A priority patent/HUP0203697A3/en
Priority to KR1020027001419A priority patent/KR20020016651A/en
Priority to JP2001518427A priority patent/JP2003507458A/en
Publication of WO2001014338A1 publication Critical patent/WO2001014338A1/en
Priority to NO20020886A priority patent/NO20020886D0/en
Priority to HK03101785.4A priority patent/HK1049666A1/en

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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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Abstract

The invention relates to novel compounds of formula (I) which are biologically active when present as ligands of the integrin alpha v beta 3: X-Y-Z-R<1>-CH2-R<2>(R<4>)-CH2-CO-R<5> wherein the meaning of X, Y, Z, R<1>, R<2>, R<4> and R<5> is given in Claim 1. The invention also relates to the physiologically acceptable salts and solvates of said compounds.

Description

Neue Inhibitoren des Integrins αvß3 New inhibitors of the integrin α v ß 3
Die Erfindung betrifft neuartige Verbindungen der FormelThe invention relates to novel compounds of the formula
X-Y-Z-R1-CH2-R2(R4)-CH2-CO-R5 XYZR 1 -CH 2 -R 2 (R 4 ) -CH 2 -CO-R 5
worinwherein
X H2N-C(=NH)-, H2N-C(=NH)-NH-, A-C(=NH)-NH-, Het1- oderXH 2 NC (= NH) -, H 2 NC (= NH) -NH-, AC (= NH) -NH-, Het 1 - or
Het1-NH-, wobei die primären Aminogruppen auch mit konventionellenHet 1 -NH-, the primary amino groups also with conventional
Aminoschutzgruppen versehen sein können,Amino protective groups can be provided,
Y -(CH2)n- , ,Y - (CH 2 ) n - ,,
Figure imgf000002_0001
worin eine, zwei, drei oder vier Methylengruppen durch N, O und/oder S ersetzt sein können,
Figure imgf000002_0001
in which one, two, three or four methylene groups can be replaced by N, O and / or S,
Z fehlt, -O-, -NH-, -NA-, -CH(OH)-, -CH(OA)-, -CHA-,Z is missing, -O-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-,
-CA2- oder -S-,-CA 2 - or -S-,
R1 unsubstituiertes oder ein-, zwei- oder dreifach durch F, Cl, Br, A, OA, OCF3 oder CN substituiertes Phenylen,R 1 is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF 3 or CN,
R2 N, CH oder CA,R 2 N, CH or CA,
R3 H, F, Cl, Br, A, OA oder OCF3,R 3 H, F, Cl, Br, A, OA or OCF 3 ,
R4 ein- oder mehrfach durch F, Cl, Br, A, Aryl, OA, SA, CO-A,R 4 one or more times by F, Cl, Br, A, aryl, OA, SA, CO-A,
CN, COOA, CONH2, CONHA, CONA2 oder NO2 substituiertes Phenyl, Naphthyl oder Het2,CN, COOA, CONH 2 , CONHA, CONA 2 or NO 2 substituted phenyl, naphthyl or Het 2 ,
R5 OH, OA, NH2, NHA oder NA2, Het1 einen ein- oder zweikernigen Heterocyclus mit 1 bis 4 N-R 5 OH, OA, NH 2 , NHA or NA 2 , Het 1 is a mono- or dinuclear heterocycle with 1 to 4 N-
Atomen, der unsubstituiert oder ein- oder zweifach durch NH2 substituiert sein kann,Atoms which may be unsubstituted or mono- or disubstituted by NH 2 ,
Het einen aromatischen ein- oder zweikernigen Heterocyclus mitHas an aromatic mono- or dinuclear heterocycle with
1 bis 3 N-, O- und / oder S-Atomen, der unsubstituiert oder ein- oder zweifach durch F, Cl, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONH2, CONHA, CONA2 oder N02 substituiert sein kann,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,
Aryl unsubstituiertes oder ein- oder mehrfach durch Hai, A, OA,Aryl unsubstituted or one or more times by shark, A, OA,
OH, CO-A, CN, COOA, COOH, CONH2, CONHA, CONA2 oder NO2 substituiertes Phenyl oder Naphthyl,OH, CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 or NO 2 substituted phenyl or naphthyl,
A Alkyl mit 1-12 C-Atomen,A alkyl with 1-12 C atoms,
n 1 , 2, 3, 4, 5 oder 6n 1, 2, 3, 4, 5 or 6
m, o jeweils unabhängig voneinander 0, 1 , 2, 3, 4, 5 oder 6,m, o each independently of one another 0, 1, 2, 3, 4, 5 or 6,
bedeuten,mean,
mit der Maßgabe, daß R4 ≠ ein einfach durch A oder Aryl substituierter Phenyl- oder Naphthyirest ist,with the proviso that R 4 ≠ is a phenyl or naphthyi radical which is simply substituted by A or aryl,
sowie deren physiologisch unbedenklichen Salze und Solvate.and their physiologically acceptable salts and solvates.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.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.
Es wurde gefunden, daß die Verbindungen der Formel I und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologische Eigenschaften besitzen. Vor allem wirken sie als Integrin-Inhibitoren, wobei sie insbesondere die Wechselwirkungen der αv-Integrin-Rezeptoren mit Liganden hemmen. Besondere Wirksamkeit zeigen die Verbindungen im Fall der Integrine αvß3 und αvßs- Ganz besonders wirksam sind die Verbindungen als Adhäsionsrezeptor-Antagonisten für den Rezeptor α ß3 . Diese Wirkung kann z.B. nach der Methode nachgewiesen werden, die von J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 und 12267- 12271 (1990) beschrieben wird.It has been found that 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 αv integrin receptors with ligands. The compounds show particular effectiveness in the case of integrins αvß3 and α v ßs- The compounds are particularly effective as adhesion receptor antagonists for the receptor α 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).
Die Inhibierung der Vitronectin-Bindung an den Rezeptor α ß3 wurde fürThe inhibition of vitronectin binding to the receptor α ß 3 was for
3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-buttersäure experimentell bewiesen.3- (4-Fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid has been experimentally proven.
B. Felding-Habermann und D.A. Cheresh beschreiben in Curr. Opin. Cell. Biol. 5, 864 (1993) die Bedeutungen der Integrine als Adhäsionsrezeptoren für die unterschiedlichsten Phänomene und Krankheitsbilder, speziell in Bezug auf den Rezeptor αvßß.B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the meanings of integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially with regard to the receptor αvß ß .
Andere Inhibitoren des Integrins αvß3 sind in der EP 0820988 beschrieben. Vitronectinrezeptor-Antagonisten sind auch beschrieben in der WO 97/24124 und in EP 0820991.Other inhibitors of the integrin α v β 3 are described in EP 0820988. Vitronectin receptor antagonists are also described in WO 97/24124 and in EP 0820991.
Die Abhängigkeit der Entstehung von Angiogenese von der Wechselwirkung zwischen vaskulären Integrinen und extrazellulären Matrix- proteinen ist von P.C. Brooks, R.A. Clark und D.A. Cheresh in ScienceThe dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins has been described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science
264, 569-71 (1994) beschrieben.264, 569-71 (1994).
Die Möglichkeit der Inhibierung dieser Wechselwirkung und damit zum Einleiten von Apoptose (programmierter Zelltod) angiogener vaskulärer Zellen durch ein cyclisches Peptid ist von P.C. Brooks, A.M. Montgomery,The possibility of inhibiting this interaction and thus inducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide has been discussed by P.C. Brooks, A.M. Montgomery,
M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier und D.A. Cheresh in Cell 79, 1157-64 (1994) beschrieben.M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79, 1157-64 (1994).
Der experimentelle Nachweis, daß auch die erfindungsgemäßen Verbin- düngen die Anheftung von lebenden Zellen auf den entsprechendenThe experimental proof that the compounds according to the invention also adhere living cells to the corresponding ones
Matrixproteinen verhindern und dementsprechend auch die Anheftung von Tumorzellen an Matrixproteine verhindern, kann in einem Zelladhäsions- test erbracht werden, der analog der Methode von F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995) durchgeführt wird. P.C. Brooks et al. beschreiben in J. Clin. Invest. 96, 1815-1822 (1995) αvß3 -Antagonisten zur Krebsbekämpfung und zur Behandlung tumorinduzierter angiogener Krankheiten.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) α v ß3 antagonists for combating cancer and for treating tumor-induced angiogenic diseases.
Die erfindungsgemäßen Verbindungen der Formel I können daher als Arzneimittelwirkstoffe insbesondere zur Behandlung von Tumorerkrankungen, Osteoporosen, osteolytischen Erkrankungen sowie zur Unterdrückung der Angiogenese eingesetzt werden.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.
Verbindungen der Formel I, die die Wechselwirkung von Integrinrezep- toren und Liganden, wie z. B. von Fibrinogen an den Fibrinogenrezeptor (Glycoprotein llb/llla) blockieren, verhindern als GPIIb/llla-Antagonisten die Ausbreitung von Tumorzellen durch Metastase. Dies wird durch folgende Beobachtungen belegt: Die Verbreitung von Tumorzellen von einem lokalen Tumor in das vaskuläre System erfolgt durch die Bildung von Mikroaggregaten (Mikrothromben) durch Wechselwirkung der Tumorzellen mit Blutplättchen. Die Tumorzellen sind durch den Schutz im Mikroaggregat abgeschirmt und werden von den Zellen des Immunsystems nicht erkannt. Die Mikroaggregate können sich an Gefäßwandungen festsetzen, wodurch ein weiteres Eindringen von Tumorzellen in das Gewebe erleichtert wird.Compounds of formula I, the interaction of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein llb / llla) prevent GPIIb / llla antagonists from spreading tumor cells through metastasis. This is confirmed by the following observations: The spread of tumor cells from a local tumor into the vascular system occurs through the formation of micro-aggregates (microthrombi) through the interaction of the tumor cells with platelets. The tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system. The micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue.
Da die Bildung der Mikrothromben durch Fibrinogenbindung an die Fibrino- genrezeptoren auf aktivierten Blutplättchen vermittelt wird, können die GPIIb/llla-Antagonisten als wirksame Metastase-Hemmer angesehen werden.Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIb / llla antagonists can be regarded as effective metastasis inhibitors.
Verbindungen der Formel I hemmen neben der Bindung von Fibrinogen, Fibronectin und des von Willebrand-Faktors an den Fibrinogenrezeptor der Blutplättchen auch die Bindung weiterer adhäsiver Proteine, wie Vitro- nectin, Kollagen und Laminin, an die entsprechenden Rezeptoren auf der Oberflache verschiedener Zelltypen. Sie verhindern insbesondere dieIn 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
Entstehung von Blutplättchenthromben und können daher zur Behandlung von Thrombosen, Apoplexie, Herzinfarkt, Entzündungen und Arterio- sklerose eingesetzt werden.Formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.
Die Eigenschaften der Verbindungen können auch nach Methoden nachgewiesen werden, die in der EP-A1-0 462 960 beschrieben sind. Die Hemmung der Fibrinogenbindung an den Fibrinogenrezeptor kann nach der Methode nachgewiesen werden, die in der EP-A1-0 381 033 angegeben ist.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.
Die thrombozytenaggregationshemmende Wirkung läßt sich in vitro nach der Methode von Born (Nature 4832, 927-929, 1962) nachweisen. Die Hemmung der Knochenresorption durch die erfindungsgemäßen Verbindungen kann mit Hilfe eines Osteoclasten-Resorptionstests analog WO 95/32710 erfolgen.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.
Gegenstand der Erfindung sind demgemäß Verbindungen der Formel I nach Anspruch 1 und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels zur Verwendung als Integrin-Inhibitor. Gegenstand der Erfindung sind insbesondere Verbindungen der Formel I nach Anspruch 1 und/oder ihrer unbedenklichen Salze zur Herstellung eines Arzneimittels zur Bekämpfung von pathologisch angiogenen Erkrankungen, Tumoren, Osteoporose, Entzündungen und Infektionen.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.
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden, zur Prophylaxe und/oderThe compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, for prophylaxis and / or
Therapie von Thrombose, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Tumorerkrankungen, osteolytischen Krankheiten wie Osteoporose, Hypercalcämie, pathologisch angiogenen Krankheiten wie z. B. Entzündungen, ophthalmologischen Krankheiten, diabetischer Retinopathie, makularer Degeneration, Myopia, okularer Histoplasmose, rheumatischer Arthritis, Osteoarthritis, rubeotischem Glaukom, ulcerativer Colitis, Morbus Crohn, Atherosklerose, Psoriasis, Restenose nach Angioplastie, viraler Infektion, bakterieller Infektion, Pilzinfektion, bei akutem Nierenversagen und bei der Wundheilung zur Unterstützung der Heilungsprozesse.Therapy of 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.
Die Verbindungen der Formel I können als antimikrobiell wirkende Substanzen bei Operationen eingesetzt werden, wo Biomaterialien, Implantate, Katheter oder Herzschrittmacher verwendet werden. Dabei wirken sie antiseptisch. Die Wirksamkeit der antimikrobiellen Aktivität kann durch das von P. Valentin-Weigund et al. in Infection and Immunity, 2851-2855 (1988) beschriebene Verfahren nachgewiesen werden.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).
Gegenstand der Erfindung sind auch die Hydrate und Solvate, z.B. Alkoholate, dieser Verbindungen.The invention also relates to the hydrates and solvates, e.g. Alcoholates, these compounds.
Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß manThe 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) eine Verbindung der Formel I aus einem ihrer funktionellen Derivate durch Behandeln mit einem solvolysierenden, reduzierenden oder hydrogenolysierenden Mittel in Freiheit setzt, odera) releases a compound of formula I from one of its functional derivatives by treatment with a solvolysing, reducing or hydrogenolysing agent, or
b) einen Rest X und/oder R5 in einen anderen Rest X und/oder R5 umwandelt,b) converts a radical X and / or R 5 into another radical X and / or R 5 ,
indem man beispielsweisefor example by
i) eine Aminogruppe durch Umsetzung mit einem amidinierenden Mittel in eine Guanidinogruppe umwandelt, ii) einen Ester verseift, iii) ein Hydroxyamidin durch Hydrierung in ein Amidin überführt,i) converting an amino group into a guanidino group by reaction with an amidifying agent, ii) saponifying an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation,
und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or converts a base or acid of the formula I into one of its salts.
Die Verbindungen der Formel I können ein chirales Zentrum besitzen und können daher in mehreren stereoisomeren Formen auftreten. Alle diese Formen (z. B. D- und L-Formen) und deren Gemische (z. B. die DL- Formen) sind in der Formel I eingeschlossen. In die erfindungsgemäßen Verbindungen sind auch sogenannte Prodrug- Derivate eingeschlossen, d. h. mit z. B. Alkyl- oder Acylgruppen, Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßen Verbindungen gespalten werden.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.
Die vor- und nachstehend aufgeführten Abkürzungen stehen für:The abbreviations listed above and below stand for:
Ac AcetylAc Acetyl
BOC tert.-ButoxycarbonylBOC tert-butoxycarbonyl
CBZ oder Z BenzyloxycarbonylCBZ or Z benzyloxycarbonyl
DCCI DicyclohexylcarbodiimidDCCI dicyclohexylcarbodiimide
DMF DimethylformamidDMF dimethylformamide
EDCI N-Ethyl-N,N'-(dimethylaminopropyl)-carbodiimidEDCI N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide
Et EthylEt ethyl
Fmoc 9-FluorenylmethoxycarbonylFmoc 9-fluorenylmethoxycarbonyl
HOBt 1-HydroxybenzotriazolHOBt 1-hydroxybenzotriazole
Me MethylMe methyl
Mtr 4-Methoxy-2,3,6-thmethylphenyl-sulfonylMtr 4-methoxy-2,3,6-thmethylphenylsulfonyl
HONSu N-HydroxysuccinimidHONSu N-hydroxysuccinimide
OBut tert.-ButylesterOBut tert-butyl ester
Oct OctanoylOct octanoyl
OMe MethylesterOMe methyl ester
OEt EthylesterOEt ethyl ester
POA PhenoxyacetylPOA phenoxyacetyl
TFA TrifluoressigsäureTFA trifluoroacetic acid
Trt Trityl (Triphenylmethyl).Trt trityl (triphenylmethyl).
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, wie z.B. A, gleich oder verschieden sein können, d.h. unabhängig voneinander sind.For the entire invention it applies that all residues that occur several times, such as A, may be the same or different, i.e. are independent of each other.
A ist Alkyl und hat 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 oder 12 C-Atome und steht vorzugsweise für Methyl, Ethyl, Propyl, Isopropyl, Butyl, lsobutyl, sek.-Butyl oder tert.-Butyl, ferner auch für Pentyl, 1-, 2- oder 3-Methylbutyl, 1 ,1- , 1 ,2- oder 2,2-Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1- , 2- , 3- oder 4- Methylpentyl, 1 ,1- , 1 ,2- , 1 ,3- , 2,2- , 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methylpropyl, 1-Ethyl-2-methylpropyl, 1 ,1 ,2-, 1 ,2,2- Trimethylpropyl, Heptyl, Octyl, Nonyl oder Decyl, Undecyl oder Dodecyl. A bedeutet auch durch Halogen substituiertes Alkyl, vorzugsweise CF3.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, preferably CF 3 .
X ist vorzugsweise z.B. Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1- yl, lmidazol-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 oder 2-Amino-pyridin-6-yl.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 ist vorzugsweise z.B. Ethylen, Propylen oder Butylen.Y is preferably e.g. Ethylene, propylene or butylene.
Z ist vorzugsweise z.B. O. R1 ist vorzugsweise z.B. 1 ,4-Phenylen.Z is preferably, for example, O. R 1 is preferably, for example, 1,4-phenylene.
R2 ist vorzugsweise z.B. CH oder N, ganz besonders bevorzugt CH.R 2 is preferably, for example, CH or N, very particularly preferably CH.
R4 ist vorzugsweise z.B. ein- oder mehrfach durch F substituiertes Phenyl.R 4 is preferably, for example, phenyl which is mono- or polysubstituted by F.
R5 ist vorzugsweise z.B. OH.R 5 is preferably, for example, OH.
Het1 ist vorzugsweise unsubstituiertes oder ein- oder zweifach durch A,Het 1 is preferably unsubstituted or mono- or disubstituted by A,
NHA und/oder NH2 substituiertes 1-, 2- oder 3-Pyrrolyl, 1-, 2, 4- oder 5- Imidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1 ,2,3-Triazo -, -4- oder -5-yl, 1 ,2,4- Triazol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 3- oder 4-Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 1-, 2-, 4- oder 5-NHA and / or NH 2 substituted 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5- imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4- Pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazo -, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-
Benzimidazolyl, 1-, 3-, 4-, 5-, 6- oder 7-Benzopyrazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, 4-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, 4-, 5-, 6-, 7- oder 8-Cinnolinyl, 2-, 4-, 5-, 6-, 7- oder 8-Chinazolinyl, 1 H-lmidazo[4,5-b]pyridin- 2-yl oder 1 ,8-Naphthyridin-7-yl. Die heterocyclischen Reste können auch teilweise oder vollständig hydriert sein.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.
Het1 kann also z. B. auch bedeuten 2,3-Dihydro-1-, -2-, -3-, -4- oder -5- pyrrolyl, 2,5-Dihydro-1-, -2-, -3-, -4- oder -5-pyrrolyl, 1-, 2- oder 3-Pyrroli- dinyl, Tetrahydro-1-, -2- oder -4-imidazolyl, 4,5-Dihydro-imidazol-2-yl, 2,3- Dihydro-1-, -2-, -3-, -4- oder -5-pyrazolyl, Tetrahydro-1-, -3- oder -4- pyrazolyl, 1 ,4-Dihydro-1-, -2-, -3- oder -4-pyridyl, 1 ,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5- oder -6-pyridyl, 1-, 2-, 3- oder 4-Piperidinyl, Hexahydro-1-, -3- oder -4-pyridazinyl, Hexahydro-1-, -2-, -4- oder -5-pyrimidinyl, 1-, 2- oder 3- Piperazinyl, 1 ,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- oder -8-chinolyl, 1 ,2,3,4-Tetrahydro-1 -,-2-,-3-, -4-, -5-, -6-, -7- oder -8-isochinolyl oderHet 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, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3 , 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, -2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl or
1 ,2,3,4-Tetrahydro-1 ,8-naphthyridin-7-yl. Hydrierte oder teilhydrierte Het -Reste können zusätzlich durch =NH oder Carbonylsauerstoff substituiert sein.1, 2,3,4-tetrahydro-1,8-naphthyridin-7-yl. Hydrogenated or partially hydrogenated Het radicals can additionally be substituted by = NH or carbonyl oxygen.
Het2 ist vorzugsweise unsubstituiertes oder einfach durch F, Cl, Br, A, OA oder OCF3 substituiertes 2,3-, 2,4- 2,5- oder 3,4-Thienyl, 2,3-, 2,4-, 2,5- oder 3,4-Pyrrolyl, 2,4-, 2,5- oder 4,5-lmidazolyl, 2,3-, 2,4-, 2,6- oder 3,5- Pyridyl, 2,4-, 2,5-, 2,6-, 4,5- oder 5,6-Pyrimidinyl.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 bedeutet vorzugsweise 2,3,4,5 oder 6, ganz besonders bevorzugt bedeutet n 3, 4 oder 5. m und o bedeuten vorzugsweise, jeweils unabhängig voneinander, 0,1 oder 2, ganz besonders bevorzugt bedeuten sie 0.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.
"ein- oder mehrfach" substituiert bedeutet ein-, zwei-, drei- oder vierfach substituiert.“One or more times” substituted means one, two, three or four times substituted.
Aryl ist unsubstituiertes, vorzugsweise - wie angegeben - monosubstituier- tes Phenyl, im einzelnen bevorzugt Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-lsopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Cyanphenyl, o-, m- oder p- Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p- Methylthiophenyl, o-, m- oder p-Methylsulfinylphenyl, o-, m- oder p- Methylsulfonylphenyl, o-, m- oder p-Aminophenyl, o-, m- oder p-Methyl- aminophenyl, o-, m- oder p-Dimethylaminophenyl, o-, m- oder p-Nitro- phenyl, o-, m- oder p-Acetylphenyl, o-, m- oder p-Methoxycarbonylphenyl, o-, m- oder p-Aminocarbonylphenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4- , 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5- Dibromphenyl, 2-Chlor-3-methyl-, 2-Chlor-4-methyl-, 2-Chlor-5- methyl-, 2-Chlor-6-methyl-, 2-Methyl-3-chlor-, 2-Methyl-4-chlor-, 2-Methyl- 5-chlor-, 2-Methyl-6-chlor-, 3-Chlor-4-methyl-, 3-Chlor-5-methyl- oder 3- Methyl-4-chlorphenyl, 2-Brom-3-methyl-, 2-Brom-4-methyl-, 2-Brom-5- methyl-, 2-Brom-6-methyl-, 2-Methyl-3-brom-, 2-Methyl-4-brom-, 2-Methyl- 5-broιm-, 2-Methyl-6-brom-, 3-Brom-4-methyl-, 3-Brom-5-methyl- oder 3-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- methylthiophenyl, o-, m- or p- Methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonylphenyl, more preferably 2,3-, 2,4-, 2, 5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2 -Chlor-5-methyl-, 2-chloro-6- methyl, 2-methyl-3-chloro, 2-methyl-4-chloro, 2-methyl-5-chloro, 2-methyl-6-chloro, 3-chloro-4-methyl, 3- Chloro-5-methyl or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl , 2-methyl-3-bromo, 2-methyl-4-bromo, 2-methyl 5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl, 3-bromo 5-methyl- or 3-
Methyl-4-bromphenyl, 2,4- oder 2,5-Dinitrophenyl, 2,5- oder 3,4-Dimeth- oxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder 3,4,5-Trichlorphenyl, 2,4,6-Tri- tert.-Butylphenyl, 2,5-Dimethylphenyl, p-lodphenyl, 4-Fluor-3-chlorphenyl, 4-Fluor-3,5-dimethylphenyl, 2-Fluor-4-bromphenyl, 2,5-Difluor-4-brom- phenyl, 2,4-Dichlor-5-methylphenyl, 3-Brom-6-methoxyphenyl, 3-Chlor-6- methoxyphenyl, 2-Methoxy-5-methylphenyl, 2,4,6-Triisopropylphenyl.Methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimeth- oxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tritert-butylphenyl , 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2 , 4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 2,4,6-triisopropylphenyl.
Aminoschutzgruppe bedeutet vorzugsweise Formyl, Acetyl, Propionyl, Butyryl, Phenylacetyl, Benzoyl, Toluyl, POA, Methoxycarbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, BOC, 2-lodethoxycarbonyl, CBZ ("Carbobenzoxy"), 4-Methoxybenzyloxycarbonyl, FMOC, Mtr oderAmino 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
Benzyl.Benzyl.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejenigen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat.Accordingly, 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.
Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln la bis Im ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochSome preferred groups of compounds can be expressed by the following sub-formulas Ia to Im, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in a) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1-yl, lmidazol-2-ylamino, Benzimidazol-2-ylamino, 4,5-Dihydro- imidazol-2-ylamino, 2-Amino-imidazol-5- ylamino, 2-Amino-pyhdin-6-yiamino, 2-in a) X 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-pyhdin-6-yiamino, 2-
Amino-imidazol-5-yl oder 2-Amino-pyridin-6-yl bedeutet;Amino-imidazol-5-yl or 2-aminopyridin-6-yl;
in b) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1-yl, lmidazol-2-ylamino,in b) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,
Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino, Y -(CH2)n-, n 2, 3 oder 4 bedeuten; in c) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1-yl, lmidazol-2-ylamino, Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino,Benzimidazol-2-ylamino or 4,5-dihydroimidazol-2-ylamino, 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 -(CH2)n- n 2, 3 oder 4 bedeuten;Y is - (CH 2 ) n - n 2, 3 or 4;
in d) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1-yl, lmidazol-2-ylamino, Benzimidazol-2-ylamino oder 4,5-Dihydro imidazol-2-ylamino,in d) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazol-2-ylamino,
Y -(CH2)n- n 2, 3 oder 4,Y - (CH 2 ) n - n 2, 3 or 4,
Z O bedeuten;Z is O;
in e) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1 -yl, lmidazol-2-ylamino,in e) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,
Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino,Benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,
Y -(CH2)n- n 2, 3 oder 4,Y - (CH 2 ) n - n 2, 3 or 4,
Z O,Z O,
R2 N oder CH bedeuten;R 2 is N or CH;
in f) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1 -yl, lmidazol-2-ylamino,in f) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,
Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino,Benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,
Y -(CH2)n- n 2, 3 oder 4, Z O, R2 N oder CH, R4 ein- oder mehrfach durch F, Cl, Br, OA,Y - (CH 2 ) n - n 2, 3 or 4, ZO, R 2 N or CH, R 4 one or more times by F, Cl, Br, OA,
OCF3, -CO-A, CN, COOA, CONH2 oder NO2 substituiertes Phenyl bedeuten;OCF 3 , -CO-A, CN, COOA, CONH 2 or NO 2 are substituted phenyl;
in g) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1 -yl, lmidazol-2-ylamino,in g) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,
Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino,Benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,
Y -(CH2)n- n 2, 3 oder 4,Y - (CH 2 ) n - n 2, 3 or 4,
Z O,Z O,
R2 N oder CH,R 2 N or CH,
R4 ein- oder mehrfach durch F, Cl, Br, OA oderR 4 one or more times by F, Cl, Br, OA or
OCF3 substituiertes Phenyl,OCF 3 substituted phenyl,
R5 OA oder OH bedeuten;R 5 is OA or OH;
in h) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazσl-1-yl, lmidazol-2-ylamino,in h) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazσl-1-yl, imidazol-2-ylamino,
Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino,Benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,
Y -(CH2)n- n 2, 3 oder 4, Z O,Y - (CH 2 ) n - n 2, 3 or 4, ZO,
R2 N oder CH,R 2 N or CH,
R4 ein- oder mehrfach durch F substituiertes Phenyl,R 4 phenyl which is substituted once or several times by F,
R5 OA oder OH bedeuten;R 5 is OA or OH;
in i) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1 -yl, lmidazol-2-ylamino, Benzimidazol-2-ylamiπo oder 4,5-Dihydro- imidazol-2-ylamino,in i) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,
Y -(CH2)n- n 2, 3 oder 4,Y - (CH 2 ) n - n 2, 3 or 4,
Z O,Z O,
R2 N oder CH,R 2 N or CH,
R4 ein- oder mehrfach durch Hai, A oder Aryl, substituiertes Phenyl,R 4 is phenyl substituted one or more times by shark, A or aryl,
R5 OA oder OH bedeuten mit der Maßgabe, daß R4 ≠ ein einfach durch A oder Aryl substituierter Phenyl- oder Naphthylrest ist;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;
in k) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1 -yl, lmidazol-2-ylamino,in k) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,
Benzimidazol-2-ylamino oder 4,5-Dihydro imidazol-2-ylamino,Benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y -(CH2)„- n 2, 3 oder 4,Y - (CH 2 ) „- n 2, 3 or 4,
Z 0,Z 0,
R2 N oder CH,R 2 N or CH,
R4 durch Hai und Aryl substituiertes Phenyl,R 4 phenyl substituted by shark and aryl,
R5 OA oder OH bedeuten mit der Maßgabe, daß R4 ≠ ein einfach durch A oder Aryl substituierter Phenyl- oder Naphthylrest ist;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;
in I) X Pyhmidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1-yl, lmidazol-2-ylamino, Benzimidazol-2-ylamino oder 4,5-Dihydro- imidazol-2-ylamino, Y -(CH2)n- n 2, 3 oder 4,in I) X pyhmidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino, Y - (CH 2 ) n - n 2, 3 or 4,
Z O,Z O,
R2 N oder CH,R 2 N or CH,
R4 durch Hai und Aryl substituiertes Phenyl,R 4 phenyl substituted by shark and aryl,
R5 OA oder OH, Aryl ein-, zwei- oder dreifach durch Hai, A, OA,R 5 OA or OH, aryl one, two or three times by shark, A, OA,
CF3, CN oder N02 substituiertes Phenyl bedeuten mit der Maßgabe, daß R4 ≠ ein einfach durch A oder Aryl substituierter Phenyl- oder Naphthylrest ist;CF 3 , CN or N0 2 substituted phenyl with the proviso that R 4 ≠ is a phenyl or naphthyl radical which is simply substituted by A or aryl;
in m) X Pyrimidin-2-ylamino, Pyridin-2-ylamino, lmidazol-1 -yl, lmidazol-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 oder 2-Amino-pyridin-6- yi,in m) X 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-yi,
Y -(CH2)„- n 2, 3 oder 4,Y - (CH 2 ) „- n 2, 3 or 4,
Z O, R2 N oder CH,ZO, R 2 N or CH,
R4 ein- oder mehrfach durch Hai, A oder Aryl, substituiertes Phenyl,R 4 is phenyl substituted one or more times by shark, A or aryl,
Ra OA oder OH bedeuten mmiitt ddeerr MM∑aßgabe, daß R4 ≠ ein einfach durch A oder Aryl substituierter Phenyl- oder Naphthylrest ist.R a OA or OH means that the R 4 ≠ is a phenyl or naphthyl radical which is simply substituted by A or aryl.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt. Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Verbindungen der Formel I aus einem ihrer funktioneilen Derivate durch Behandeln mit einem solvolysierenden oder hydrogenolysierenden Mittel in Freiheit setzt.If desired, 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.
Bevorzugte Ausgangsstoffe für die Solvolyse bzw. Hydrogenolyse sind solche, die sonst der Formel I entsprechen, aber anstelle einer oder mehrerer freier Amino- und/oder Hydroxygruppen entsprechende geschützte Amino- und/oder Hydroxygruppen enthalten, vorzugsweise solche, die anstelle eines H-Atoms, das mit einem N-Atom verbunden ist, eine Aminoschutzgruppe tragen, insbesondere solche, die anstelle einer HN-Gruppe eine R'-N-Gruppe tragen, worin R' eine Aminoschutzgruppe bedeutet, und/oder solche, die anstelle des H-Atoms einer Hydroxygruppe eine Hydroxyschutzgruppe tragen, z.B. solche, die der Formel I entsprechen, jedoch anstelle einer Gruppe -COOH eine Gruppe -COOR" tragen, worin R" eine Hydroxyschutzgruppe bedeutet.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.
Es können auch mehrere - gleiche oder verschiedene - geschützte Amino- und/oder Hydroxygruppen im Molekül des Ausgangsstoffes vorhanden sein. Falls die vorhandenen Schutzgruppen voneinander verschieden sind, können sie in vielen Fällen selektiv abgespalten werden.Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.
Der Ausdruck "Aminoschutzgruppe" ist allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Aminogruppe vor chemischen Um- Setzungen zu schützen (zu blockieren), die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an anderen Stellen des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind insbesondere unsubstituierte oder substituierte Acyl-, Aryl-, Aralkoxymethyl- oder Aralkylgruppen. Da die Aminoschutzgruppen nach der gewünschten Reaktion (oder Reaktionsfolge) entfernt werden, ist ihre Art und Größe im übrigen nicht kritisch; bevorzugt werden jedoch solche mit 1-20, insbesondere 1-8 C-Atomen. Der Ausdruck "Acylgruppe" ist im Zusammenhang mit dem vorliegenden Verfahren in weitestem Sinne aufzufassen. Er umschließt von aliphatischen, araliphatischen, aromatischen oder hetero- cyclischen Carbonsäuren oder Sulfonsäuren abgeleitete Acylgruppen sowie insbesondere Alkoxycarbonyl-, Aryloxycarbonyl- und vor allem Aralkoxycarbonylgruppen. Beispiele für derartige Acylgruppen sind Formyl oder Alkanoyl wie Acetyl, Propionyl, Butyryl; Aralkanoyl wie Phenylacetyl; Aroyl wie Benzoyl oder Toluyl; Aryloxyalkanoyl wie POA; Alkoxycarbonyl wie Methoxycarbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, BOC, 2-lodethoxycarbonyl; Aralkyloxycarbonyl wie CBZ ("Carbobenzoxy"), 4-The term "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. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially Aralkoxycarbonyl groups. Examples of such 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-
Methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl wie Mtr. Bevorzugte Aminoschutzgruppen sind BOC und Mtr, ferner CBZ, Fmoc, Benzyl, Formyl und Acetyl.Methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl, formyl and acetyl.
Die Abspaltung der Aminoschutzgruppe gelingt - je nach der benutztenThe amino protective group can be split off, depending on the one used
Schutzgruppe - z. B. mit starken Säuren, zweckmäßig mit TFA oder Perchlorsäure, aber auch mit anderen starken anorganischen Säuren wie Salzsäure oder Schwefelsäure, starken organischen Carbonsäuren wie Trichloressigsäure oder Sulfonsäuren wie Benzol- oder p-Toluolsulfon- säure. Die Anwesenheit eines zusätzlichen inerten Lösungsmittels ist möglich, aber nicht immer erforderlich. Als inerte Lösungsmittel eignen sich vorzugsweise organische, beispielsweise Carbonsäuren wie Essigsäure, Ether wie Tetrahydrofuran oder Dioxan, Amide wie DMF, haloge- nierte Kohlenwasserstoffe wie Dichlormethan, ferner auch Alkohole wie Methanol, Ethanol oder Isopropanol, sowie Wasser. Ferner kommenProtecting 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. The presence of an additional inert solvent is possible, but not always necessary. 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. Come further
Gemische der vorgenannten Lösungsmittel in Frage. TFA wird vorzugsweise im Überschuß ohne Zusatz eines weiteren Lösungsmittels verwendet, Perchlorsäure in Form eines Gemisches aus Essigsäure und 70 %iger Perchlorsäure im Verhältnis 9:1. Die Reaktionstemperaturen für die Spal- tung liegen zweckmäßig zwischen etwa 0 und etwa 50°, vorzugsweise arbeitet man zwischen 15 und 30° (Raumtemperatur).Mixtures of the aforementioned solvents in question. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
Die Gruppen BOC, OBut und Mtr können z. B. bevorzugt mit TFA in Dichlormethan oder mit etwa 3 bis 5n HCI in Dioxan bei 15-30° abgespalten werden, die FMOC-Gruppe mit einer etwa 5- bis 50 %igen Lösung von sek. Aminen, wie Dimethylamin, Diethylamin oder Piperidin in DMF bei 15- 30°.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 °.
Hydrogenolytisch entfernbare Schutzgruppen (z. B. CBZ oder Benzyl) können z. B. durch Behandeln mit Wasserstoff in Gegenwart eines Katalysators (z. B. eines Edelmetallkatalysators wie Palladium, zweckmäßig auf einem Träger wie Kohle) abgespalten werden. Als Lösungsmittel eignen sich dabei die oben angegebenen, insbesondere z. B. Alkohole wie Methanol oder Ethanol oder Amide wie DMF. Die Hydrogenolyse wird in der Regel bei Temperaturen zwischen etwa 0 und 100° und Drucken zwischen etwa 1 und 200 bar, bevorzugt bei 20-30° und 1-10 bar durchgeführt. Eine Hydrogenolyse der CBZ-Gruppe gelingt z. B. gut an 5 bis 10 %igem Pd/C in Methanol oder mit Ammoniumformiat (anstelle von Wasserstoff) an Pd/C in Methanol/DMF bei 20-30°.Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) 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. 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 °.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan,Suitable inert solvents are e.g. Hydrocarbons like hexane,
Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan, Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono- methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylen- glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wiePetroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds like
Nitromethan oder Nitrobenzol; Ester wie Ethylacetat, Wasser oder Gemische der genannten Lösungsmittel.Nitromethane or nitrobenzene; Esters such as ethyl acetate, water or mixtures of the solvents mentioned.
Weiterhin ist es möglich, einen Ester der Formel I zu verseifen. Zweckmäßig erfolgt dies durch Solvolyse oder Hydrogenolyse, wie oben angegeben, z.B. mit LiOH in Methanol, NaOH oder KOH in Dioxan-Wasser bei Temperaturen zwischen 0 und 60° C, vorzugsweise zwischen 10 und 40° C.It is also possible to saponify an ester of the formula I. This is conveniently done by solvolysis or hydrogenolysis, as indicated above, e.g. with LiOH in methanol, NaOH or KOH in dioxane water at temperatures between 0 and 60 ° C, preferably between 10 and 40 ° C.
Die Umwandlung einer Cyangruppe in eine Amidinogruppe erfolgt durch Umsetzung mit z.B. Hydroxylamin und anschließender Reduktion des N- Hydroxyamidins mit Wasserstoff in Anwesenheit eines Katalysators wie z.B. Pd/C. Ferner ist es möglich, eine konventionelle Aminoschutzgruppe durch Wasserstoff zu ersetzen, indem die Schutzgruppe, wie oben beschrieben, solvolytisch oder hydrogenolytisch abgespalten wird oder daß man eine durch eine konventionelle Schutzgruppe geschützte Aminogruppe durch Solvolyse oder Hydrogenolyse in Freiheit setzt.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.
Zur Herstellung von Verbindungen der Formel I, worin X H2N-C(=NH)-NH- bedeutet, kann man eine entsprechende Aminoverbindung mit einem amidinierenden Mittel behandeln. Als amidinierendes Mittel ist 1-Amidino- 3,5-dimethylpyrazol (DPFN) bevorzugt, das insbesondere in Form seines Nitrats eingesetzt wird. Man arbeitet zweckmäßig unter Zusatz einer Base wie Triethylamin oder Ethyl-diisopropylamin in einem inerten Lösungsmittel oder Lösungsmittelgemisch, z.B. Wasser/Dioxan bei Temperaturen zwischen 0 und 120 °C, vorzugsweise zwischen 60 und 120 °C.To prepare compounds of the formula I in which XH 2 is NC (= NH) -NH-, a corresponding amino compound can be treated with an amidizing agent. Preferred amidinizing agent is 1-amidino-3,5-dimethylpyrazole (DPFN), which is used in particular in the form of its nitrate. It is advantageous to work with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example water / dioxane, at temperatures between 0 and 120 ° C., preferably between 60 and 120 ° C.
Zur Herstellung eines Amidins der Formel I (X = -C(=NH)-NH2) kann man an ein Nitril der Formel I (X = CN) Ammoniak anlagern. Die Anlagerung erfolgt bevorzugt mehrstufig, indem man in an sich bekannter Weise a) das Nitril mit H2S in ein Thioamid umwandelt, das mit einem Alkylierungs- mittel, z.B. CH3I, in den entsprechenden S-Alkyl-imidothioester übergeführt wird, welcher seinerseits mit NH3 zum Amidin reagiert, b) das Nitril mit einem Alkohol, z.B. Ethanol in Gegenwart von HCI in den entsprechenden Imidoester umwandelt und diesen mit Ammoniak behandelt, oder c) dasTo produce an amidine of the formula I (X = -C (= NH) -NH 2 ), ammonia can be added to a nitrile of the formula I (X = CN). 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
Nitril mit Lithium-bis-(trimethylsilyl)-amid umsetzt und das Produkt anschließend hydrolysiert.Reacting nitrile with lithium bis (trimethylsilyl) amide and then hydrolyzing the product.
Weiterhin bevorzugt ist die Freisetzung der Verbindungen der Formel I aus einer oxydierten Vorstufe, indem man z.B. einen Oxy-Heterocyclus mit einem Reduktionsmittel wie z.B. Phosphortrichlorid in einem inerten Lösungsmittel reduziert.It is further preferred to release 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.
Ferner kann man freie Aminogruppen in üblicher Weise mit einem Säure- chlorid oder -anhydrid acylieren oder mit einem unsubstituierten oder substituierten Alkylhalogenid alkylieren, zweckmäßig in einem inerten Lösungsmittel wie Dichlormethan oder THF und /oder in Gegenwart einer Base wie Triethylamin oder Pyridin bei Temperaturen zwischen -60 und +30°. Eine Base der Formel I kann mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenklicheFurthermore, 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. For this implementation, acids are particularly suitable, the physiologically harmless ones
Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Ortho- phosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfon- säure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfon- säure, p-Toluolsulfonsäure, Naphthalin-mono- und Disulfonsäuren, Lauryl- schwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und /oder Aufreinigung der Verbindungen der Formel I verwendet werden.Deliver salts. 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.
Andererseits kann eine Säure der Formel I durch Umsetzung mit einer Base in eines ihrer physiologisch unbedenklichen Metall- oder Ammoniumsalze übergeführt werden. Als Salze kommen dabei insbesondere die Natrium-, Kalium-, Magnesium-, Calcium- und Ammoniumsalze inOn the other hand, an acid of formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base. In particular, the sodium, potassium, magnesium, calcium and ammonium salts come in as salts
Betracht, ferner substituierte Ammoniumsalze, z. B. die Dimethyl-, Diethyl- oder Diisopropyl-ammoniumsalze, Monoethanol-, Diethanol- oder Diiso- propylammoniumsalze, Cyclohexyl-, Dicyclohexyiammoniumsalze, Di- benzylethylendiammoniumsalze, weiterhin z. B. Salze mit Arginin oder Lysin.Consider further substituted 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.
Die Verbindungen der Formel I enthalten ein oder mehrere chirale Zentren und können daher in racemischer oder in optisch-aktiver Form vorliegen. Erhaltene Racemate können nach an sich bekannten Methoden mecha- nisch oder chemisch in die Enantiomeren getrennt werden. Vorzugsweise werden aus dem racemischen Gemisch durch Umsetzung mit einem optisch aktiven Trennmittel Diastereomere gebildet. Als Trennmittel eignen sich z.B. optisch aktive Säuren, wie die D- und L-Formen von Weinsäure, Diacetylweinsäure, Dibenzoylweinsäure, Mandelsäure, Äpfelsäure, Milchsäure oder die verschiedenen optisch aktiven Camphersulfonsäuren wie ß- Camphersulfonsäure. Vorteilhaft ist auch eine Enantiomerentrennung mitThe 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 β-camphorsulfonic acid. Enantiomer separation with is also advantageous
Hilfe einer mit einem optisch aktiven Trennmittel (z.B. Dinitrobenzoyl- phenylglycin) gefüllten Säule; als Laufmittel eignet sich z.B. ein Gemisch Hexan/Isopropanol/Acetonitril, z.B. im Volumenverhältnis 82:15:3.Using a column filled with an optically active release agent (e.g. dinitrobenzoylphenylglycine); a suitable solvent is e.g. a mixture of hexane / isopropanol / acetonitrile, e.g. in the volume ratio 82: 15: 3.
Natürlich ist es auch möglich, optisch aktive Verbindungen der Formel I nach den oben beschriebenen Methoden zu erhalten, indem man Ausgangsstoffe verwendet, die bereits optisch aktiv sind.Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
Die Erfindung umfaßt nicht nur die genannten Verbindungen sondern auch Mischungen und Zubereitungen, welche neben diesen erfindungsgemäßen Verbindungen auch andere pharmakologische Wirkstoffe oder Adjuvantien enthalten, die die primäre pharmakologische Wirkung der erfindungsgemäßen Verbindungen in gewünschter Weise beinflussen können. Diese können als Therapeutika, Diagnostika oder als Reagenzien Verwendung finden. Sie können an Mensch oder Tier lokal oder systemisch, oral, intravenös, intraperitoneal, intramuskulär, subkutan, transdermal, nasal, buccal, oder iontophoretisch gegeben werden, das schließt Formulierungen in Suspensionen, Emulsionen oder Lösungen, Liposomen, Salben, Pasten, bioabbaubaren Polymeren oder als Nanopartikel, Tabletten, Kapseln oder Pillen, Granulate oder Puder, als Aerosol zum Inhalieren, als intranasale Tropfen oder Sprays ein. Auch eine Kombination der neuen Produkte mit anderen Techniken, wie Chirurgie, Bestrahlung, Diagnose, Radiotherapie, photodynamischerThe 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. They can be given to humans or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally, or iontophoretically, which includes formulations in suspensions, emulsions or solutions, liposomes, ointments, pastes, biodegradable polymers or as nanoparticles, tablets, capsules or pills, granules or powder, as an aerosol for inhalation, as intranasal drops or sprays. Also a combination of the new products with other techniques, such as surgery, radiation, diagnosis, radiotherapy, photodynamic
Therapie und Gentherapie, sowie mit anderen Medikamenten ist möglich. Solche Medikamente können z.B. aus den Gebieten Herzkreislauf, Zentralnervensystem oder der Onkologie stammen. Es können Tumormittel sein, wie Angiogeneseinhibitoren oder Cytostatika, Chemotherapeutika der Gruppen alkylierende Agenzien, Antibiotika, Antimetaboliten, Biologika und Immunmodulatoren, Hormone und derenTherapy and gene therapy, as well as with other drugs is possible. Such 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
Antagonisten, Senfgasderivaten, Alkaloiden und anderen, wobei dieseAntagonists, mustard gas derivatives, alkaloids and others, these
Substanzen niedermolekular und hochmolekular sein können. Es könnenSubstances can be low molecular weight and high molecular weight. It can
Lipide, Kohlehydrate oder Proteine sein. Darunter fallen auch Zytokine,Lipids, carbohydrates or proteins. This includes cytokines,
Toxine, Fusionsproteine, monoklonale Antikörper und Vaccine.Toxins, fusion proteins, monoclonal antibodies and vaccines.
Gegenstand der Erfindung sind demgemäß Verbindungen der oben und unten sowie in den Ansprüchen definierten Formeln einschließlich ihrer physiologisch unbedenklichen Salze als Arzneimittel, Diagnostika oderThe 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
Reagenzien.Reagents.
Gegenstand der Erfindung sind insbesondere entsprechende Arzneimittel als Inhibitoren zur Bekämpfung von Erkrankungen, die mittelbar oder unmittelbar auf einer Expression des αvß3 -Integrinrezeptors beruhen, insbesondere also bei pathologisch angiogenen Erkrankungen, Thrombosen, Herzinfarkt, koronaren Herzerkrankungen, Arteriosklerose, Tumoren, Osteoporose, Entzündungen, Infektionen sowie zur Beeinflussung von Wundheilungsprozessen.The invention relates in particular to corresponding medicaments as inhibitors for combating diseases which are based directly or indirectly on expression of the α v β 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.
Gegenstand sind auch entsprechende pharmazeutische Zubereitungen, welche mindestens ein Arzneimittel der Formel I sowie gegebenenfalls Träger- und/oder Hilfsstoffe enthalten.Corresponding pharmaceutical preparations which contain at least one medicament of the formula I and, if appropriate, carriers and / or auxiliaries are also an object.
Ferner ist Gegenstand der Erfindung die Verwendung der Verbindungen und/oder ihre physiologisch unbedenklichen Salze gemäß der Ansprüche und der Beschreibung zur Herstellung eines Arzneimittels zur Bekämpfung von Erkrankungen, die mittelbar oder unmittelbar auf einer Expression des αvß3 -Integrinrezeptors beruhen, insbesondere also bei pathologisch angiogenen Erkrankungen, Thrombosen, Herzinfarkt, koronaren Herzerkrankungen, Arteriosklerose, Tumoren, Osteoporose, Entzündungen, Infektionen sowie zur Beeinflussung von Wundheilungsprozessen. Die erfindungsgemäßen Arzneimittel bzw. sie enthaltende pharmazeutische Zubereitungen können in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganischeThe 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 α v β 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
Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale, topische Applikation oder für eine Applikation in Form eines Inhalation-Substances in question that are suitable for enteral (e.g. oral), parenteral, topical application or for an application in the form of an inhalation
Sprays eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohole, Alkylenglykole,Sprays are suitable and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols,
Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver,Polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. In particular, tablets, pills, coated tablets, capsules, powders,
Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Supposi- torien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Kon- servierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und /oder mehrere weitere Wirkstoffe enthalten, z. B. ein oder mehrere Vitamine. Für die Applikation als Inhalationsspray können Sprays verwendet werden, die den Wirkstoff entweder gelöst oder suspendiert in einem Treibgas oder Treibgasgemisch (z. B. CO2 oder Fluorchlorkohlenwasserstoffen) enthalten. Zweckmäßig verwendet man den Wirkstoff dabei in mikronisierter Form, wobei ein oder mehrere zusätzliche physiologisch verträgliche Lösungsmittel zugegen sein können, z. B. Ethanol. Inhalationslösungen können mit Hilfe üblicher Inhalatoren verabreicht werden.Granules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, for topical use ointments, creams or powders. 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. For the application as an inhalation spray, 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). 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.
Die erfindungsgemäßen Substanzen können in der Regel in Analogie zu anderen bekannten, im Handel befindlichen Präparaten (z.B. beschrieben in der US-A-4 472 305 ) verabreicht werden, vorzugsweise in Dosierungen zwischen etwa 0,05 und 500 mg, insbesondere zwischen 0,5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugs- weise zwischen etwa 0,01 und 20 mg/kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von derThe 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. However, 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
Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die parenterale Applikation ist bevorzugt.Elimination rate, drug combination and severity of the disease to which the therapy applies. Parenteral administration is preferred.
Vor- und nachstehend sind alle Temperaturen in °C angegeben.All temperatures above and below are given in ° C.
Die HPLC-Analysen (Retentionszeit Rt) erfolgten in den folgenden Systemen:The HPLC analyzes (retention time Rt) were carried out in the following systems:
Säule 3 μm Silica-Rod mit einem 210-Sekunden Gradienten von 20 bis 100 % Wasser / Acetonitril / 0,01 % Trifluoressigsäure, bei 2,2 ml/minColumn 3 μm silica rod with a 210-second gradient from 20 to 100% water / acetonitrile / 0.01% trifluoroacetic acid, at 2.2 ml / min
Fluss und Detektion bei 220 nm.Flow and detection at 220 nm.
Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ FAB (Fast Atom Bombardment) (M + H) +
Beispiel 1example 1
Synthese von 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]- phenyl}-buttersäureSynthesis of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid
835 mg Mg werden in 5 ml abs. THF suspendiert. Anschließend wird tropfenweise eine Lösung von 2,0 g 4-Benzyloxybenzylchlorid in 5 ml abs. Tetra hydrofu ran zugegeben. Nach vollendeter Zugabe wird die trübe Lösung noch 1 Stunde bei Raumtemperatur gerührt, anschließend eine Lösung von 1 ,73 g 2-Cyan-3-(4-fluorphenyl)-acrylsäureethylester in 10 ml abs. Toluol zugegeben und 16 Stunden unter Rückfluß gekocht. Das Lösungsmittel wird entfernt und nach üblicher Aufarbeitung erhält man 4- (4-Benzyloxy-phenyl)-2-cyan-3-(4-fluorphenyl)-buttersäureethylester ("AA"). 8,27 g "AA" werden in einer Mischung aus 80 ml Essigsäure und 80 ml konz. HCI suspendiert und anschließend 16 Stunden unter Rückfluß gekocht. Nach üblicher Aufarbeitung erhält man 4-(4-Hydroxyphenyl)-3-(4- fluorphenyl)-buttersäure ("AB").835 mg Mg are abs. In 5 ml. THF suspended. Then a solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. Tetra hydrofuran ran added. When the addition is complete, the cloudy solution is stirred for a further 1 hour at room temperature, then a solution of 1, 73 g of 2-cyano-3- (4-fluorophenyl) acrylic acid ester in 10 ml abs. Toluene added and refluxed for 16 hours. The solvent is removed and, after customary working up, 4- (4-benzyloxyphenyl) -2-cyan-3- (4-fluorophenyl) butyric acid ethyl ester ("AA") is obtained. 8.27 g of "AA" are concentrated in a mixture of 80 ml of acetic acid and 80 ml. HCl suspended and then refluxed for 16 hours. After the usual work-up, 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) butyric acid ("AB") is obtained.
Eine Lösung 1 ,0 g "AB" in 10 ml abs. Methanol wird mit 0,4 ml Thionyl- chlorid versetzt und 16 Stunden bei Raumtemperatur gerührt. Nach üblicher Aufarbeitung erhält man 4-(4-Hydroxyphenyl)-3-(4-fluorphenyl)- buttersäuremethylester ("AC").A solution 1.0 g "AB" in 10 ml abs. 0.4 ml of thionyl chloride is added to methanol and the mixture is stirred at room temperature for 16 hours. After customary working up, 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) butyric acid methyl ester ("AC") is obtained.
Zu einer Suspension von 0,4 g "AC", 0,5 g 3-(1-Oxy-pyridin-2-ylamino)- propan-1-ol und 1 ,23 g polymergebundenem Triphenylphosphin (Beladung ca. 3 mmol/g) in 17 ml abs. THF tropft man 0,62 ml Diethylazadicarboxylat und rührt 16 Stunden nach. Nach Filtration und Entfernung des Lösungsmittels wird über HPLC gereinigt. Man erhält 3-(4-Fluorphenyl)-4-{4-[3-(1- oxypyridin-2-ylamino)-propoxy]-phenyl}-buttersäuremethylester ("AD").To a suspension of 0.4 g "AC", 0.5 g 3- (1-oxy-pyridin-2-ylamino) propan-1-ol and 1.23 g polymer-bound triphenylphosphine (loading approx. 3 mmol / g ) in 17 ml abs. THF is added dropwise to 0.62 ml of diethyl azadicarboxylate and stirring is continued for 16 hours. After filtration and removal of the solvent, it is purified by HPLC. 3- (4-Fluorophenyl) -4- {4- [3- (1- oxypyridin-2-ylamino) propoxy] phenyl} butyric acid methyl ester ("AD") is obtained.
Eine Lösung von 0,45 g "AD" in 30 ml Chloroform wird mit 0,59 g Phosphortrichlorid versetzt, 2 Stunden bei Raumtemperatur und weitere 2 Stunden unter Rückfluß gerührt. Nach üblicher Aufarbeitung wird der Rückstand in 15 ml Methanol mit 0,2 g Lithiumhydroxid versetzt und 16 Stunden bei Raumtemperatur gerührt. Nach Entfernung des Lösungsmittels wird mit 0,66 ml Trifluoressigsäure versetzt und über HPLC gereinigt. Man erhält 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)- propoxy]-phenyl}-buttersäure, TrifluoracetatA solution of 0.45 g of "AD" in 30 ml of chloroform is mixed with 0.59 g of phosphorus trichloride, stirred for 2 hours at room temperature and for a further 2 hours under reflux. After the usual workup, the residue in 15 ml of methanol is mixed with 0.2 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by HPLC. This gives 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, trifluoroacetate
Figure imgf000025_0001
Testerqebnis der αyß3-lnhibierunq durch 3-(4-Fluorphenyl)-4-(4-f3-(pyridin- 2-ylamino)-propoxyl-phenyl>-buttersäure
Figure imgf000025_0001
Test results of the α 3 inhibition by 3- (4-fluorophenyl) -4- (4-f3- (pyridin-2-ylamino) -propoxyl-phenyl> -butyric acid
Für den Vitronectin-Bindungstest ist der IC50-Wert angegeben, d.h. die Konzentration in nMol/Liter, die 50 % der Vitronectin-Bindung an den entsprechenden isolierten Rezeptor inhibiert (Methode von Smith et al., J. Biol. Chem. 265, 12267-71 ,1990). IC5o vß3: 10.The 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). IC 5 o VSS 3: 10th
Die pharmakologischen Daten beweisen die antagonistische Aktivität der erfindungsgemäßen Verbindung für den Rezeptor αyß3-The pharmacological data demonstrate the antagonistic activity of the compound according to the invention for the receptor αyß 3 -
Analog dem oben beschriebenen Syntheseschema werden nachstehende Verbindungen erhaltenThe following compounds are obtained analogously to the synthesis scheme described above
3-(4-Fluorphenyl)-4-{4-[2-(pyrimidin-2-ylamino)-ethoxy]-phenyl}- buttersäure, Trifluoracetat;3- (4-fluorophenyl) -4- {4- [2- (pyrimidin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate;
3-(4-Fluorphenyl)-4-{4-[3-(pyrimidin-2-ylamino)-propoxy]-phenyl}- buttersäure, Trifluoracetat;3- (4-fluorophenyl) -4- {4- [3- (pyrimidin-2-ylamino) propoxy] phenyl} butyric acid, trifluoroacetate;
3-(4-Fluorphenyl)-4-{4-[4-(pyrimidin-2-ylamino)-butoxy]-phenyl}- buttersäure, Trifluoracetat;3- (4-fluorophenyl) -4- {4- [4- (pyrimidin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate;
3-(4-Fluorphenyl)-4-{4-[2-(pyridin-2-ylamino)-ethoxy]-phenyl}-buttersäure,3- (4-fluorophenyl) -4- {4- [2- (pyridin-2-ylamino) -ethoxy] -phenyl} -butyric acid,
Trifluoracetat;trifluoroacetate;
3-(4-Fluorphenyl)-4-{4-[4-(pyridin-2-ylamino)-butoxy]-phenyl}-buttersäure, Trifluoracetat;3- (4-fluorophenyl) -4- {4- [4- (pyridin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate;
3-(4-Fluorphenyl)-4-{4-[3-(imidazol-1-yl)-propoxy]-phenyl}-buttersäure;3- (4-fluorophenyl) -4- {4- [3- (imidazol-1-yl) propoxy] phenyl} -butyric acid;
3-(4-Fluorphenyl)-4-{4-[3-(4,5-dihydro-1/- -imidazol-2-ylamino)-propoxy]- phenylj-buttersäure; 3-(4-Fluorphenyl)-4-{4-[3-(imidazol-2-ylamino)-propoxy]-phenyl}- buttersäure;3- (4-fluorophenyl) -4- {4- [3- (4,5-dihydro-1 / - -imidazol-2-ylamino) propoxy] phenylj-butyric acid; 3- (4-fluorophenyl) -4- {4- [3- (imidazol-2-ylamino) propoxy] phenyl} butyric acid;
3-(4-Fluorphenyl)-4-{4-[3-(benzimidazol-2-ylamino)-propoxy]-phenyl}- buttersäure;3- (4-fluorophenyl) -4- {4- [3- (benzimidazol-2-ylamino) propoxy] phenyl} butyric acid;
3-(4-Fluorphenyl)-4-{4-[3-(2-amino-pyridin-6-yl-amino)-propoxy]-phenyl}- buttersäure,3- (4-fluorophenyl) -4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid,
3-(4-Fluorphenyl)-4-{4-[3-(2-amino-imidazol-5-yl-amino)-propoxy]-phenyl}- buttersäure.3- (4-fluorophenyl) -4- {4- [3- (2-aminoimidazol-5-ylamino) propoxy] phenyl} butyric acid.
Beispiel 2Example 2
Synthese von (4-Fluorphenyl-{4-[3-(pyridin-2-ylamino)-propoxy]-benzyl}- amino)-essigsäureSynthesis of (4-fluorophenyl- {4- [3- (pyridin-2-ylamino) propoxy] benzyl} amino) acetic acid
40,0 g 4-Hydroxybenzaldehyd werden unter Schutzgasatmosphäre in 400 ml abs. THF gelöst, mit 55,1 g Dihydropyran und 13,7 g Pyridinium-p- toluolsulfonat versetzt und über Nacht bei Raumtemperatur gerührt. Das Lösungsmittel wird am Rotationsverdampfer entfernt, der Rückstand wie üblich aufgearbeitet und man erhält 4-(Tetrahydro-pyran-2-yloxy)- benzaldehyd ("BA") als farbloses Öl.40.0 g of 4-hydroxybenzaldehyde in a protective gas atmosphere in 400 ml of abs. THF dissolved, mixed with 55.1 g dihydropyran and 13.7 g pyridinium p-toluenesulfonate and stirred overnight at room temperature. The solvent is removed on a rotary evaporator, the residue is worked up as usual and 4- (tetrahydro-pyran-2-yloxy) benzaldehyde ("BA") is obtained as a colorless oil.
Eine Lösung von 2,0 g "BA" in 20 ml abs. Methanol wird mit 1 ,17 g 4- Fluoranilin versetzt und 3 Stunden bei 60° gerührt. Bei Raumtemperatur werden 0,79 g Natriumcyanoborhydrid zugegeben und die Reaktionslösung 16 Stunden unter Rückfluß gekocht. Nach Entfernung des Lösungsmittels, üblicher Aufarbeitung und Reinigung durch Chromatographie erhält man 4-Fluorphenyl-[4-(tetrahydro-pyran-2-yloxy)-benzyl]- amin ("BB") als farblose Flüssigkeit.A solution of 2.0 g "BA" in 20 ml abs. 1, 17 g of 4-fluoroaniline are added to methanol and the mixture is stirred at 60 ° for 3 hours. 0.79 g of sodium cyanoborohydride are added at room temperature and the reaction solution is refluxed for 16 hours. After removal of the solvent, customary work-up and purification by chromatography, 4-fluorophenyl- [4- (tetrahydro-pyran-2-yloxy) benzyl] amine ("BB") is obtained as a colorless liquid.
8,0 g "BB" und 10,36 g Bromessigsäuremethylester werden unter N2- Atmosphäre in 100 ml abs. THF gelöst, mit 12,0 g Kaliumcarbonat versetzt und 16 Stunden unter Rückfluß gekocht. Nach Entfernung des Lösungs- mittels, üblicher Aufarbeitung und Reinigung durch Chromatographie erhält man {[4-Fluorphenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amino}- essigsäuremethylester ("BC") als farblosen Feststoff.8.0 "BB" g and 10.36 g of methyl bromoacetate are N 2 - abs ml atmosphere in 100th THF dissolved, mixed with 12.0 g of potassium carbonate and boiled under reflux for 16 hours. After removal of the solvent, usual work-up and purification by chromatography man {[4-fluorophenyl] - [4- (tetrahydro-pyran-2-yloxy) benzyl] amino] - methyl acetate ("BC") as a colorless solid.
Eine Lösung von 0,5 g "BC" in 25 ml Methanol und 5 ml Dichlormethan wird mit 2,76 ml konz. HCI versetzt und 5 Minuten bei Raumtemperatur gerührt. Nach Entfernen der Lösungsmittel und üblicher Aufarbeitung wird der Rückstand zusammen mit 0,47 g 3-(1-Oxypyridin-2-ylamino)-propan-1- ol in 16 ml abs. THF gelöst und anschließend mit 1 ,17 g polymerem Triphenylphosphin (Beladung ca. 3 mmol/g) versetzt. Anschließend werden 0,62 ml Diethylazadicarboxylat zugetropft. Die Suspension wird dann 16 Stunden bei Raumtemperatur gerührt. Nach Filtration und Entfernung des Lösungsmittels wird über HPLC gereinigt. Man erhält ({4- [3-(1-Oxy-pyridin-2-ylamino)-propoxy]-benzyl}-(4-fluorphenyl)-amino)- essigsäuremethylester ("BD").A solution of 0.5 g "BC" in 25 ml methanol and 5 ml dichloromethane is concentrated with 2.76 ml. HCI added and stirred for 5 minutes at room temperature. After removal of the solvent and usual work-up, the residue together with 0.47 g of 3- (1-oxypyridin-2-ylamino) propan-1-ol in 16 ml of abs. THF dissolved and then mixed with 1.17 g of polymeric triphenylphosphine (loading about 3 mmol / g). Then 0.62 ml of diethyl azadicarboxylate are added dropwise. The suspension is then stirred for 16 hours at room temperature. After filtration and removal of the solvent, it is purified by HPLC. This gives ({4- [3- (1-oxy-pyridin-2-ylamino) propoxy] benzyl} - (4-fluorophenyl) amino) methyl acetate ("BD").
Eine Lösung von 0,44 g "BD" in 30 ml Chloroform wird mit 0,57 g Phosphortrichlorid versetzt, 2 Stunden bei Raumtemperatur und weitere 2 Stunden unter Rückfluß gerührt. Nach üblicher Aufarbeitung wird der Rückstand in 15 ml Methanol mit 0,27 g Lithiumhydroxid versetzt und 16 Stunden bei Raumtemperatur gerührt. Nach Entfernung desA solution of 0.44 g of "BD" in 30 ml of chloroform is mixed with 0.57 g of phosphorus trichloride, stirred for 2 hours at room temperature and for a further 2 hours under reflux. After the usual work-up, the residue in 15 ml of methanol is mixed with 0.27 g of lithium hydroxide and stirred at room temperature for 16 hours. After removing the
Lösungsmittels wird mit 0,66 ml Trifluoressigsäure versetzt und über HPLC gereinigt. Man erhält ((4-Fluorphenyl)-{4-[3-(pyridin-2-ylamino)-propoxy]- benzyl}-amino)-essigsäure, BistrifluoracetatSolvent is mixed with 0.66 ml of trifluoroacetic acid and purified by HPLC. This gives ((4-fluorophenyl) - {4- [3- (pyridin-2-ylamino) propoxy] - benzyl} amino) acetic acid, bistrifluoroacetate
Figure imgf000028_0001
Figure imgf000028_0001
Analog erhält man die nachstehenden VerbindungenThe following compounds are obtained analogously
((4-Fluorphenyl)-{4-[2-(pyrimidin-2-ylamino)-ethoxy]-benzyl}-amino)- essigsäure, ((4-Fluorphenyl)-{4-[3-(pyrimidin-2-ylamino)-propoxy]-benzyl}-amino)- essigsäure,((4-fluorophenyl) - {4- [2- (pyrimidin-2-ylamino) ethoxy] benzyl} amino) - acetic acid, ((4-fluorophenyl) - {4- [3- (pyrimidin-2-ylamino) propoxy] benzyl} amino) - acetic acid,
((4-Fluorphenyl)-{4-[4-(pyrimidin-2-ylamino)-butoxy]-benzyl}-amino)- essigsäure,((4-fluorophenyl) - {4- [4- (pyrimidin-2-ylamino) butoxy] benzyl} amino) - acetic acid,
((4-Fluorphenyl)-{4-[2-(pyridin-2-ylamino)-ethoxy]-benzyl}-amino)- essigsäure,((4-fluorophenyl) - {4- [2- (pyridin-2-ylamino) ethoxy] benzyl} amino) - acetic acid,
((4-Fluorphenyl)-{4-[4-(pyridin-2-ylamino)-butoxy]-benzyl}-amino)- essigsäure,((4-fluorophenyl) - {4- [4- (pyridin-2-ylamino) butoxy] benzyl} amino) - acetic acid,
((4-Fluorphenyl)-{4-[3-(imidazol-1-yl)-propoxy]-benzyl}-amino)- essigsäure,((4-fluorophenyl) - {4- [3- (imidazol-1-yl) propoxy] benzyl} amino) - acetic acid,
((4-Fluorphenyl)-{4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)-propoxy]- benzyl}-amino)-essigsäure,((4-fluorophenyl) - {4- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] benzyl} amino) acetic acid,
((4-Fluorphenyl)-{4-[3-(imidazol-2-ylamino)-propoxy]-benzyl}-amino)- essigsäure,((4-fluorophenyl) - {4- [3- (imidazol-2-ylamino) propoxy] benzyl} amino) - acetic acid,
((4-Fluorphenyl)-{4-[3-(benzimidazol-2-ylamino)-propoxy]-benzyl}- amino)-essigsäure.((4-fluorophenyl) - {4- [3- (benzimidazol-2-ylamino) propoxy] benzyl} amino) acetic acid.
Beispiel 3Example 3
Analog Beispiel 1 erhält man nachstehende VerbindungenAnalogously to Example 1, the following compounds are obtained
3-(3-Chlor-4-phenyl)-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]- phenyl}-buttersäure,3- (3-chloro-4-phenyl) phenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,
Figure imgf000029_0001
Figure imgf000029_0001
3-(2-Brom-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure, 3-(3,4-Dichlor-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure, 3-(4-Brom-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure,3- (2-bromophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, 3- (3,4-dichlorophenyl) -4- {4 - [3- (pyridin-2-ylamino) propoxy] phenyl} - butyric acid, 3- (4-bromophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,
3-(2,3-Dichlor-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure, 3-(2,4-Dichlor-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure,3- (2,3-dichlorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, 3- (2,4-dichlorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,
3-(3-Brom-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure,3- (3-bromo-phenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,
3-(2,6-Difluor-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure,3- (2,6-difluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,
3-(3,5-Dichlor-phenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure. 3- (3,5-dichlorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)- propoxy]-phenyl}-buttersäure und 5 g Dinatriumhydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2- ylamino)-propoxy]-phenyl}-buttersäure mit 100 g Sojalecithin und 1400 gA mixture of 20 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid is melted with 100 g of soy lecithin and 1400 g
Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.Cocoa butter, pour into molds and let cool. Each suppository contains 20 mg of active ingredient.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2- ylamino)-propoxy]-phenyl}-buttersäure, 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.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.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]- phenyl}-buttersäure mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: TablettenExample E: tablets
Ein Gemisch von 1 kg 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)- propoxy]-phenyl}-buttersäure, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.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.
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid are filled into hard gelatin capsules in a conventional manner so that each capsule contains 20 mg of the active ingredient ,
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)- propoxy]-phenyl}-buttersäure in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophiiisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff.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.
Beispiel I: Inhalations-SprayExample I: Inhalation spray
Man löst 14 g 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]- phenyl}-buttersäure in 10 I isotonischer NaCI-Lösung und füllt die Lösung in handelsübliche Sprühgefäße mit Pump-Mechanismus. Die Lösung kann in Mund oder Nase gesprüht werden. Ein Sprühstoß (etwa 0,1 ml) entspricht einer Dosis von etwa 0,14 mg. 14 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid are dissolved in 10 l of isotonic NaCl solution and the solution is filled into commercially available spray vessels a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

Patentansprüche claims
1. Verbindungen der Formel I1. Compounds of formula I.
X-Y-Z-R1-CH2-R2(R4)-CH2-CO-R5 XYZR 1 -CH 2 -R 2 (R 4 ) -CH 2 -CO-R 5
worinwherein
X H2N-C(=NH)-, H2N-C(=NH)-NH-, A-C(=NH)-NH-, Het1- oder Het1-NH-, wobei die primären Aminogruppen auch mit konventionellen Aminoschutzgruppen versehen sein können,XH 2 NC (= NH) -, H 2 NC (= NH) -NH-, AC (= NH) -NH-, Het 1 - or Het 1 -NH-, whereby the primary amino groups can also be provided with conventional amino protective groups .
Y -(CH2)n- ,Y - (CH 2 ) n -,
Figure imgf000033_0001
worin eine, zwei, drei oder vier Methylengruppen durch N, O und/oder S ersetzt sein können,
Figure imgf000033_0001
in which one, two, three or four methylene groups can be replaced by N, O and / or S,
Z fehlt, -0-, -NH-, -NA-, -CH(OH)-, -CH(OA)-, -CHA-,Z is missing, -0-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-,
-CA2- oder -S-,-CA 2 - or -S-,
R1 unsubstituiertes oder ein-, zwei- oder dreifach durch F,R 1 is unsubstituted or one, two or three times by F,
Cl, Br, A, OA, OCF3 oder CN substituiertes Phenylen,Cl, Br, A, OA, OCF 3 or CN substituted phenylene,
R2 N, CH oder CA,R 2 N, CH or CA,
R3 H, F, Cl, Br, A, OA oder OCF3,R 3 H, F, Cl, Br, A, OA or OCF 3 ,
R4 ein- oder mehrfach durch F, Cl, Br, A, Aryl, OA, SA, CO-R 4 one or more times by F, Cl, Br, A, aryl, OA, SA, CO-
A, CN, COOA, CONH2, CONHA, CONA2 oder N02 substituiertes Phenyl, Naphthyl oder Het2,A, CN, COOA, CONH 2 , CONHA, CONA 2 or N0 2 substituted phenyl, naphthyl or Het 2 ,
Rb OH, OA, NH2, NHA oder NA2, Het1 einen ein- oder zweikernigen Heterocyclus mit 1 bis 4R b OH, OA, NH 2 , NHA or NA 2 , Het 1 is a mono- or dinuclear heterocycle with 1 to 4
N-Atomen, der unsubstituiert oder ein- oder zweifach durch NH2 substituiert sein kann,N atoms, which can be unsubstituted or substituted once or twice by NH 2 ,
Het2 einen aromatischen ein- oder zweikernigen Heterocyclus mit 1 bis 3 N-, O- und / oder S-Atomen, der unsubstituiert oder ein- oder zweifach durch F, Cl, Br, A, OA, SA, OCF3, -CO-A, CN, COOA, CONH2, CONHA, CONA2 oder NO2 substituiert sein kann,Het 2 is an aromatic mono- or dinuclear heterocycle with 1 to 3 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF 3 , -CO -A, CN, COOA, CONH 2 , CONHA, CONA 2 or NO 2 can be substituted,
Aryl unsubstituiertes oder ein- oder mehrfach durch Hai, A,Aryl unsubstituted or one or more times by shark, A,
OA, OH, CO-A, CN, COOA, COOH, CONH2, CONHA, CONA2 oder NO2 substituiertes Phenyl oder Naphthyl,OA, OH, CO-A, CN, COOA, COOH, CONH 2 , CONHA, CONA 2 or NO 2 substituted phenyl or naphthyl,
A Alkyl mit 1 -12 C-Atomen,A alkyl with 1-12 carbon atoms,
n 1 , 2, 3, 4, 5 oder 6n 1, 2, 3, 4, 5 or 6
m, o jeweils unabhängig voneinander 0, 1 , m, o each independently 0, 1,
2, 2,
3, 4, 5 oder 6,3, 4, 5 or 6,
bedeuten,mean,
mit der Maßgabe, daß R4 ≠ ein einfach durch A oder Aryl substituierter Phenyl- oder Naphthylrest ist,with the proviso that R 4 ≠ is a phenyl or naphthyl radical which is simply substituted by A or aryl,
sowie deren physiologisch unbedenklichen Salze und Solvate.and their physiologically acceptable salts and solvates.
Verbindungen nach Anspruch 1Compounds according to claim 1
a) 3-(4-Fluorphenyl)-4-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}- buttersäure; b) 3-(4-Fluorphenyl)-4-{4-[3-(2-amino-pyridin-6-yl-amino)-propoxy]- phenyl}-buttersäure, c) 3-(4-Fluorphenyl)-4-{4-[3-(2-amino-imidazol-5-yl-amino)- propoxy]-phenyl}-buttersäurea) 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid; b) 3- (4-fluorophenyl) -4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid, c) 3- (4-fluorophenyl) -4- {4- [3- (2-aminoimidazol-5-ylamino) propoxy] phenyl} butyric acid
sowie deren physiologisch unbedenklichen Salze und Solvate.and their physiologically acceptable salts and solvates.
Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß manA process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that
a) eine Verbindung der Formel I aus einem ihrer funktionellen Derivate durch Behandeln mit einem solvolysierenden, reduzierenden oder hydrogenolysierenden Mittel in Freiheit setzt, odera) releases a compound of formula I from one of its functional derivatives by treatment with a solvolysing, reducing or hydrogenolysing agent, or
b) einen Rest X und/oder R5 in einen anderen Rest X und/oder R5 umwandelt,b) converts a radical X and / or R 5 into another radical X and / or R 5 ,
indem man beispielsweisefor example by
i) eine Aminogruppe durch Umsetzung mit einem amidinierenden Mittel in eine Guanidinogruppe umwandelt,i) converting an amino group into a guanidino group by reaction with an amidinizing agent,
ii) einen Ester verseift,ii) saponifying an ester,
iii) ein Hydroxyamidin durch Hydrierung in ein Amidin überführt,iii) converting a hydroxyamidine into an amidine by hydrogenation,
und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or converts a base or acid of the formula I into one of its salts.
4. Verbindungen der Formel I gemäß Anspruch 1 und die Verbindungen gemäß Anspruch 2 sowie deren physiologisch unbedenklichen Salze und Solvate als Arzneimittel. 4. Compounds of formula I according to claim 1 and the compounds according to claim 2 and their physiologically acceptable salts and solvates as medicaments.
5. Arzneimittel nach Anspruch 4 als Inhibitor zur Bekämpfung von Erkrankungen, die auf einer Expression und pathologischen Funktion von αvß3 Integrinrezeptoren beruhen.5. Medicament according to claim 4 as an inhibitor for combating diseases which are based on an expression and pathological function of α v ß 3 integrin receptors.
6. Arzneimittel nach Anspruch 5 zur Bekämpfung von Thrombosen, Herzinfarkt, koronaren Herzerkrankungen, Arteriosklerose, Tumoren, Osteoporose, Fibrösen, Entzündungen, Infektionen, Psoriasis sowie zur Beeinflussung von Wundheilungsprozessen.6. Medicament according to claim 5 for combating thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis, inflammation, infection, psoriasis and for influencing wound healing processes.
7. Pharmazeutische Zubereitung, enthaltend mindestens ein Arzneimittel gemäß einem der Ansprüche 5 bis 6 sowie gegebenenfalls Träger- und/oder Hilfsstoffe und gegebenenfalls andere Wirkstoffe.7. Pharmaceutical preparation containing at least one medicament according to one of claims 5 to 6 and optionally carriers and / or auxiliaries and optionally other active substances.
8. Verwendung von Verbindungen gemäß der Ansprüche 1 bis 2 und/oder ihre physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels zur Bekämpfung von Erkrankungen, die auf einer Expression und pathologischen Funktion von αvß3 Integrinrezeptoren beruhen.8. Use of compounds according to claims 1 to 2 and / or their physiologically acceptable salts for the manufacture of a medicament for combating diseases which are based on the expression and pathological function of α v β 3 integrin receptors.
9. Verwendung nach Anspruch 8 zur Herstellung eines Arzneimittels zur Bekämpfung pathologischer Vorgängen, die durch Angiogenese unterhalten oder propagiert werden.9. Use according to claim 8 for the manufacture of a medicament for combating pathological processes which are maintained or propagated by angiogenesis.
10. Verwendung nach Anspruch 8 zur Herstellung eines Arzneimittels zur Bekämpfung von Thrombosen, Herzinfarkt, koronaren Herzerkrankungen, Arteriosklerose, Tumoren, Osteoporose, Fibrösen,10. Use according to claim 8 for the manufacture of a medicament for combating thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis,
Entzündungen, Infektionen, Psoriasis sowie zur Beeinflussung vonInflammation, infections, psoriasis and for influencing
Wundheilungsprozessen. Wound healing processes.
PCT/EP2000/007591 1999-08-24 2000-08-04 NOVEL INTEGRIN αVβ3 INHIBITORS WO2001014338A1 (en)

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AU65705/00A AU6570500A (en) 1999-08-24 2000-08-04 Novel integrin alphavbeta3 inhibitors
CA002382850A CA2382850A1 (en) 1999-08-24 2000-08-04 Novel inhibitors of the integrin .alpha.v.beta.3
PL00352989A PL352989A1 (en) 1999-08-24 2000-08-04 Novel integrin alphav
EP00953158A EP1206454A1 (en) 1999-08-24 2000-08-04 NOVEL INTEGRIN ALPHAvBETA3 INHIBITORS
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
BR0013504-6A BR0013504A (en) 1999-08-24 2000-08-04 Alfav beta3 integrin inhibitors
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HU0203697A HUP0203697A3 (en) 1999-08-24 2000-08-04 Novel integrin alphavbetha3 inhibitors, pharmaceutical compositions containing them and their use
NO20020886A NO20020886D0 (en) 1999-08-24 2002-02-22 Novel integrin <alfa> v <beta> 3 inhibitors
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US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
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HUE053620T2 (en) * 2016-11-08 2021-07-28 Bristol Myers Squibb Co Pyrrole amides as alpha v integrin inhibitors

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Cited By (3)

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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 (en) * 2004-10-14 2006-04-27 Pharmacia Corporation Biphenyl integrin antagonists

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HUP0203697A2 (en) 2003-03-28
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CA2382850A1 (en) 2001-03-01
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