EP1208088A2 - Fluorenderivate als integrininhibitoren - Google Patents

Fluorenderivate als integrininhibitoren

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Publication number
EP1208088A2
EP1208088A2 EP00956284A EP00956284A EP1208088A2 EP 1208088 A2 EP1208088 A2 EP 1208088A2 EP 00956284 A EP00956284 A EP 00956284A EP 00956284 A EP00956284 A EP 00956284A EP 1208088 A2 EP1208088 A2 EP 1208088A2
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
atoms
solvates
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00956284A
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German (de)
English (en)
French (fr)
Inventor
Wolfgang Stähle
Simon Goodman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1208088A2 publication Critical patent/EP1208088A2/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings

Definitions

  • the invention relates to compounds of the formula I.
  • R 2 H CO-R 7 , CO-OR 7 , CONHR 7 , CONA " 2 or S0 2 R 7 ,
  • R 4 , R 5 each independently of one another H, Hai, N0 2 , NHR 7 , NA " 2 ,
  • R 6 is a mono- or dinuclear heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by shark,
  • R 7 H, A, Ar or Aralk A is unsubstituted or mono-, di- or trisubstituted by R alkyl with 1-15 C- or cycloalkyl with 3-15 C-atoms and in which one, two or three methylene groups can be replaced by N, O and / or S,
  • R 8 shark NO 2 , NHA ', NA " 2 , OA', phenoxy, CO-A ', S0 3 A', CN,
  • Ar unsubstituted or mono-, di- or trisubstituted by alkyl with 1-6 C atoms and / or R 8 mono- or dinuclear aromatic ring system with 0, 1, 2, 3 or 4 N-, O- and / or S -atoms,
  • Aralk unsubstituted or mono-, di- or trisubstituted by R substituted aralkylene with 7-14 C atoms and in which one, two or three methylene groups can be replaced by N, O and / or S,
  • n each independently of one another 0, 1, 2, 3 or 4
  • vitronectin antagonists are known from WO 97/24124.
  • Bicyclic fibrinogen antagonists are described, for example, in WO 96/18602.
  • 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 and solvates have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the ⁇ -IgG receptors with ligands.
  • the compounds are particularly effective in the case of the integrins ⁇ vß 3 and ⁇ ßs. They are particularly effective
  • Active pharmaceutical ingredients are used in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for the suppression of angiogenesis.
  • compounds of the formula I In addition to the binding of fibrinogen, fibronectin and the 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
  • the antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
  • the invention accordingly relates to the compounds of the formula I and their physiologically acceptable salts and solvates as medicaments.
  • the invention further relates to said medicaments as inhibitors for combating diseases which are based on the expression and pathological function of ⁇ v ⁇ 3 and ⁇ v ⁇ 5 integrin receptors.
  • the invention also relates to medicaments as GPIIb / llla antagonists for combating thromboses, heart attacks, coronary heart diseases and arteriosclerosis, and the medicaments as ⁇ v integrin inhibitors for combating pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors and osteoporosis and rheumatoid arthritis.
  • 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, pathologically angiogenic diseases such as B. inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, uicerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after infection with infection, viral infection, viral infection, viral infection in acute kidney failure and in wound healing to support the healing processes.
  • osteolytic diseases such as osteoporosis
  • pathologically angiogenic diseases such as B. inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma,
  • 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 determined by that of P.Valentin-Weigund et al., In Infection and Immunity, 2851-2855
  • the invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts and solvates, characterized in that
  • the invention further relates to a process for the preparation of compounds of the formula I as claimed in claim 1, in which R 1 is OH and R 2 , R 3 , R 4 , R 5 , m and n have the meanings given in claim 1, and their salts and solvates, characterized in that a compound of formula II
  • R 1 is O-alkyl having 1-6 C atoms and R 2 , R 3 , R 4 , R 5 , m and n have the meanings given in claim 1, saponified and then decarboxylated.
  • the compounds of formula I have at least one 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.
  • prodrug derivatives are also included in the compounds according to the invention, i. H. with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
  • Solvates of the compounds are also included in the compounds according to the invention. Below that are addition connections with e.g. Understand water (hydrates) or alcohols such as methanol or ethanol.
  • Trt trityl (triphenylmethyl)
  • Preferred compounds of the formula I are those in which the radical - (CH 2 ) n -R 3 is in the 2-position and the radical - (CH 2 ) m -CH (NHR 2 ) -COR 1 in the 7-position of the fluorene- Ring system substituted.
  • Alkyl preferably means 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, as well as, for example, trifluoromethyl or pentafluoroethyl.
  • a ' is preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl or hexyl.
  • A preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
  • Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl,
  • Alkylene preferably means methylene, ethylene, propylene, butylene,
  • Pentylene also hexylene, heptylene, ocytylene, nonylene or decylene.
  • Aralk is aralkylene and preferably means alkylenephenyl and is e.g. preferably benzyl or phenethyl.
  • CO-A ' is alkanoyl or cycloalkanoyl and preferably means formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, pentadecanoyl, pentadecanoyl, pentadecanoyl, pentadecanoyl, pentadecanoyl, pentadecanoyl and preferably means formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecan
  • Preferred substituents R 8 for alkyl, Ar, cycloalkyl and aralk are preferably, for example, shark, N0 2 , NH 2 , NHA ", such as methylamino, NA" 2 , such as dimethylamino, methoxy, phenoxy, acyl such as formyl or acetyl, CN , NHCOA ', such as acetamido, COOA', such as COOH or methoxycarbonyl, CONA ' 2 or S0 2 A', in particular, for example, F, Cl, hydroxy, Methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.
  • alkyl, alkylene and cycloalkyl radicals one, two or three methylene groups can each be replaced by N, O and / or S.
  • Ar-CO is aroyl and preferably means benzoyl or naphthoyl.
  • Ar is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-
  • Ar furthermore preferably denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazoi-1-, -4- or -5-yl, 1 , 2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3 - or - 5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-
  • R 6 is a mono- or dinuclear heterocycle, preferably 2- or 3-
  • the heterocyclic radicals can also be partially or completely hydrogenated.
  • R 5 can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-
  • R 6 very particularly preferably denotes 1 H-imidazol-2-yl, 4,5-dihydro-1 H-imidazol-2-yl, 5-oxo-4,5-dihydro-1 H-imidazol-2-yl, thiazole -2-yl, 1 H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1 H-tetrazol-5-yl, 2-imino-imidazolidin-4-one, 5-yl, 1-alkyl -1,5-dihydro-imidazol-4-one-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl.
  • R 1 means in particular, for example, hydroxyl, methoxy, ethoxy, NH 2 , NHMe,
  • R 1 very particularly preferably denotes OH or OEt.
  • R 2 preferably denotes, for example, H, acetyl, propionyl, aminocarbonyl, N, N-dimethylaminocarbonyl, alkoxycarbonyl such as, for example, pentyloxycarbonyl,
  • Alkylsulfonyi such as e.g. Methylsulfonyl, ethylsulfonyl, propylsulfonyl,
  • R 2 very particularly preferably denotes 2,2-dimethylpropoxycarbonyl or butylsulfonyl.
  • R 4 and R 5 very particularly preferably denote H.
  • 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.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • m denotes 1; in le) m 1 and R 1 OH; iinn I Iff)) mean RR 1 'OH, R 2 CO-OR 7 or S0 2 R 7 and m 1; in ig) R 1 denotes OH, R 2 CO-OR 7 or S0 2 R 7 and RR 7 'alkyl with 1-6 C atoms and m 1; in Ih) R 1 OH,
  • R 7 alkyl with 1-6 C atoms
  • R 4 , R 5 are H, m 1 and n are 2, 3 or 4;
  • 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 hydroxyl protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" is a
  • Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
  • the release of the amidino group from its oxadiazole derivative can e.g. by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel).
  • a catalyst e.g. Raney nickel
  • Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. Hydrogenolysis is usually done with
  • Temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar.
  • amino protecting group is generally known and refers to groups which are suitable for protecting an amino group from chemical Protect (block) settlements that are easily removable after the desired chemical reaction has been performed elsewhere in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protecting groups according to the desired
  • 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.
  • acyl groups are 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 such as Mtr.
  • Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • the amino protective group is split off, depending on the protective group used, 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
  • 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. Mixtures of the abovementioned solvents are also suitable. 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 gap tion are expediently 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 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, advantageously on a support such as coal).
  • a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support 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 such as hexane, petroleum 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-butanoi or tert-butanol; Ethers such as diethyl ether, diisopropyl ether,
  • Hydrocarbons such as hexane, petroleum 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,
  • Tetrahydrofuran (THF) or dioxane 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 such as nitromethane or nitrobenzene; Esters such as ethyl acetate, water or mixtures of the solvents mentioned.
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (digly
  • a radical R 1 , R 2 and / or R 3 into another radical R 1 , R 2 and / or R 3 .
  • a carboxylic acid ester can be converted into a carboxylic acid.
  • the conversion of a cyano group into an amidino group takes place by reaction with e.g. Hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. Pd / C.
  • a catalyst such as e.g. Pd / C.
  • 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) converting the nitrile with an alcohol, for example ethanol in the presence of HCl, into the corresponding imidoester and treating it with ammonia, or c) reacting the nitrile with lithium bis (thmethylsilyl) amide and the product then hydrolyzed.
  • an alkylating agent for example CH 3 I
  • 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 that provide physiologically acceptable salts are suitable for this implementation.
  • 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.
  • Base be converted into one of their physiologically acceptable metal or ammonium salts.
  • Suitable salts are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, e.g. B. the dimethyl, diethyl or diisopropyl ammonium salts, monoethanol, diethanol or diisopropylammonium salts, cyclohexyl, dicyclohexylammonium salts, di- benzylethylenediammonium salts, further 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.
  • Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent.
  • Suitable release agents are e.g. optically active acids, such as the D and L forms of tartaric acid,
  • Enantiomer separation using a column filled with an optically active separating 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.
  • optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention furthermore relates to pharmaceutical preparations containing at least one medicament, comprising at least one compound of the formula I and / or one of its physiologically acceptable salts, and, if appropriate, excipients and / or auxiliaries and, where appropriate, other active ingredients.
  • medicaments comprising at least one compound of the formula I and / or one of its physiologically acceptable salts, and, if appropriate, excipients and / or auxiliaries and, where appropriate, other active ingredients.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (eg oral), parenteral, topical application or for application in the form of an inhalation spray and do not react with the new compounds, for example water, vegetable oils , Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin acetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral use , for topical application of ointments, creams or powder.
  • 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 auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active ingredients, e.g. B. one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active ingredients, e.g. 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. C0 2 or chlorofluorocarbons).
  • a propellant gas or propellant gas mixture e.g. C0 2 or chlorofluorocarbons.
  • the active ingredient is expediently used in micronized form, with one or more additional physiologically tolerable ones
  • Solvents may be present, e.g. B. ethanol. Inhalation solutions can be administered using standard inhalers.
  • the invention thus also relates to the use of compounds of the formula I and / or their physiologically acceptable
  • Salts and solvates for the manufacture of a medicament for combating diseases which are based on the expression and pathological function of ⁇ v ß 3 and ⁇ v ßs integrin receptors.
  • the invention furthermore relates to the use of compounds of the formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for combating pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, rheumatic arthritis, restenoses, and diabetic retinopathy.
  • the substances according to the invention can generally be administered in analogy to other known, commercially available integrin inhibitors, but in particular in analogy to the compounds 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 administered per dosage unit.
  • the daily dosage is preferably between about 0.01 and 2 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, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Parenteral administration is preferred.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of 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
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • 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
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP00956284A 1999-08-07 2000-07-26 Fluorenderivate als integrininhibitoren Withdrawn EP1208088A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19937394 1999-08-07
DE19937394A DE19937394A1 (de) 1999-08-07 1999-08-07 Fluorenderivate
PCT/EP2000/007153 WO2001010841A2 (de) 1999-08-07 2000-07-26 Fluorenderivate als integrin inhibitoren

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EP1208088A2 true EP1208088A2 (de) 2002-05-29

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JP (1) JP2003506439A (cs)
KR (1) KR20020012631A (cs)
CN (1) CN1368962A (cs)
AR (1) AR025042A1 (cs)
AU (1) AU6828600A (cs)
BR (1) BR0013083A (cs)
CA (1) CA2380981A1 (cs)
CZ (1) CZ2002298A3 (cs)
DE (1) DE19937394A1 (cs)
HK (1) HK1049006A1 (cs)
HU (1) HUP0202464A3 (cs)
MX (1) MXPA02001297A (cs)
NO (1) NO20020592L (cs)
PL (1) PL353054A1 (cs)
SK (1) SK1402002A3 (cs)
WO (1) WO2001010841A2 (cs)
ZA (1) ZA200201873B (cs)

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KR101102808B1 (ko) * 2010-04-13 2012-01-05 윤태삼 라이저 인장 장치
US8574899B2 (en) 2010-12-22 2013-11-05 Vladimir B Serikov Methods for augmentation collection of placental hematopoietic stem cells and uses thereof

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JPH04506350A (ja) * 1989-06-22 1992-11-05 ノバ　ファーマスーティカル　コーポレイション 炎症の処置用の医薬組成物及び炎症の処置方法
IL113196A0 (en) * 1994-03-31 1995-06-29 Bristol Myers Squibb Co Imidazole derivatives and pharmaceutical compositions containing the same
EP0889877B1 (en) * 1996-03-29 2001-08-29 G.D. Searle & Co. META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTEGRIN ANTAGONISTS OR INHIBITORS
DE19654483A1 (de) * 1996-06-28 1998-01-02 Merck Patent Gmbh Phenylalanin-Derivate
CA2214931A1 (en) * 1996-09-26 1998-03-26 Henry Uhlman Bryant Tetrahydrobenzo-a-fluorene compounds and method of use

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See references of WO0110841A2 *

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SK1402002A3 (en) 2002-06-04
ZA200201873B (en) 2003-08-27
CZ2002298A3 (cs) 2002-04-17
JP2003506439A (ja) 2003-02-18
AR025042A1 (es) 2002-11-06
NO20020592D0 (no) 2002-02-06
BR0013083A (pt) 2002-04-23
PL353054A1 (en) 2003-10-06
AU6828600A (en) 2001-03-05
KR20020012631A (ko) 2002-02-16
CN1368962A (zh) 2002-09-11
WO2001010841A3 (de) 2001-09-07
HUP0202464A3 (en) 2003-02-28
CA2380981A1 (en) 2001-02-15
MXPA02001297A (es) 2004-07-16
DE19937394A1 (de) 2001-02-08
WO2001010841A2 (de) 2001-02-15
HK1049006A1 (zh) 2003-04-25
HUP0202464A2 (hu) 2002-12-28
NO20020592L (no) 2002-04-04

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