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WO1999010371A2 - Derives de cyclopeptide utilises comme inhibiteurs d'adherence - Google Patents

Derives de cyclopeptide utilises comme inhibiteurs d'adherence Download PDF

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Publication number
WO1999010371A2
WO1999010371A2 PCT/EP1998/005161 EP9805161W WO9910371A2 WO 1999010371 A2 WO1999010371 A2 WO 1999010371A2 EP 9805161 W EP9805161 W EP 9805161W WO 9910371 A2 WO9910371 A2 WO 9910371A2
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Prior art keywords
formula
compounds
acid
compound
salts
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Application number
PCT/EP1998/005161
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German (de)
English (en)
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WO1999010371A3 (fr
Inventor
Günter Hölzemann
Simon Goodman
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Merck Patent Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to PL98341090A priority Critical patent/PL341090A1/xx
Priority to EP98948833A priority patent/EP1007545A2/fr
Priority to SK213-2000A priority patent/SK2132000A3/sk
Priority to KR1020007001430A priority patent/KR20010022828A/ko
Priority to AU95319/98A priority patent/AU734829B2/en
Priority to JP2000507697A priority patent/JP2001514186A/ja
Priority to CA002301182A priority patent/CA2301182A1/fr
Priority to BR9811992-3A priority patent/BR9811992A/pt
Publication of WO1999010371A2 publication Critical patent/WO1999010371A2/fr
Publication of WO1999010371A3 publication Critical patent/WO1999010371A3/fr
Priority to NO20000860A priority patent/NO20000860L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to compounds of the formula
  • amino acids mentioned can also be derivatized
  • R 1 and R 2 are each independently of one another H or alkyl
  • R 1 and R 2 together also or
  • R, 10 each independently of one another H, alkyl, Ar, OR, shark, NO 2 ,
  • Ar is unsubstituted or mono-, di- or trisubstituted by R 3 , R 4 or R 5 phenyl or unsubstituted naphthyl,
  • R 3 , R 4 , R 5 each independently of one another R 6 , OR 6 , shark, NO 2 , NR 6 R 6 ' , NHCOR 6 , CN, NHSO 2 R 6 , COOR 6 or COR 6 ,
  • R 6 , R 6 ' each independently of one another are H, alkyl, phenyl or benzyl, and
  • 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 -, ß 3 - or ß 5 -integrin receptors with ligands, such as. B. the binding of Fibrinoge ⁇ to the ß 3 - integrin receptor.
  • the compounds show particular effectiveness in the case of the integrins ⁇ v ß ⁇ , ⁇ v ß3, ⁇ vßs, ocn b ß3 and ⁇ v ß ⁇ and ⁇ v ß_. This effect can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990).
  • micro-aggregates 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. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIa / IIIb antagonists can be regarded as effective metastasis inhibitors.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of circulatory diseases, thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as Osteoporosis, pathologically angiogenic diseases such as B.
  • ophthalmic diseases diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, angiogenesis and restenosis viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing to support the healing processes.
  • 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 demonstrated by the method described by P. Valentin-Weigund et al., In Infection and Immunity, 2851-2855 (1988).
  • the compounds of the formula I are inhibitors of fibrinogen binding and thus ligands of the fibrinogen receptors on platelets, they can be used as diagnostics for the detection and localization of thrombi in the vascular system in vivo, provided that they are substituted, for example, by a radioactive or UV-detectable residue.
  • the compounds of the formula I as inhibitors of fibrinogen binding, can also be used as effective tools for studying the metabolism of
  • Platelets at different stages of activation or from intracellular signal mechanisms of the fibrinogen receptor are used.
  • the detectable unit of a "label" to be incorporated for example isotope labeling by 3 H, allows the mechanisms mentioned to be investigated after binding to the receptor.
  • Trt trityl (triphenylmethyl).
  • amino acids can occur in several enantiomeric forms, then above and below, for. B. as a component of the compounds of formula I, all these forms and also their mixtures (z. B. the DL forms) included. Furthermore, the amino acids, e.g. B. as part of compounds of formula I, provided with corresponding protective groups known per se.
  • 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.
  • Amino acids the configuration of which is not specifically specified, have the (S) or (L) configuration.
  • 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
  • radicals X, A, B, C, R 1 , R 2 , m, n, p, q and Z have the meanings given in the formulas I, II and III, unless expressly stated otherwise.
  • X preferably represents H, shark or alkyl, in particular H, CI or CH 3 .
  • alkyl has 1-6 C atoms and preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also also 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- or 1, 2,2-trimethylpropyl.
  • Alkyl is particularly preferably methyl.
  • R 7 , R 8 R 9 and R 10 are preferably H.
  • amino acids and amino acid residues mentioned can also be derivatized, the N-methyl, N-ethyl, N-propyl, N-benzyl or C ⁇ -
  • Methyl derivatives are preferred.
  • R 6 and R 6 are preferably, for example, H, methyl or ethyl, furthermore benzyl or phenyl.
  • OR 6 preferably means, for example, hydroxy or methoxy.
  • COR 6 is alkanoyl and preferably means formyl, acetyl, propionyl,
  • Butyryl, pentanoyl or hexanoyl is butyryl, pentanoyl or hexanoyl.
  • Ar 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-
  • Amino protecting group preferably means acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc, Mtr or benzyl.
  • the compounds of formula I have at least two chiral centers and can therefore exist in different stereoisomeric forms. Formula I encompasses all of these forms.
  • 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 la, Ib and Ic, which correspond to formula I and in which
  • 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.
  • the compounds of formula I can be, for example, as follows
  • Compounds of formula I can preferably be obtained by cyclization of compounds of formula III under the conditions of peptide synthesis. It is convenient to work according to customary methods of peptide synthesis, such as those e.g. in Houben-Weyl, 1.c, volume 15/11,
  • the reaction is preferably carried out in the presence of a dehydrating agent, e.g. a carbodiimide such as DCCI or EDCI, further e.g. Propane-phosphonic anhydride (see Angew. Chem. 92, 129 (1980)), diphenylphosphorylazide or 2-ethoxy-N-ethoxycarbonyl-1, 2-dihydroquinoline, in an inert solvent, e.g.
  • a dehydrating agent e.g. a carbodiimide such as DCCI or EDCI
  • EDCI e.g. Propane-phosphonic anhydride
  • diphenylphosphorylazide or 2-ethoxy-N-ethoxycarbonyl-1, 2-dihydroquinoline e.g.
  • a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents, at temperatures between about -10 and 40, preferably between 0 and 30 ° .
  • a reaction time is between a few minutes and 14 days depending on the conditions used.
  • derivatives of compounds of the formula III preferably a preactivated carboxylic acid, or a carboxylic acid halide, a symmetrical or mixed anhydride or an active ester can also be used.
  • residues for activating the carboxy group in typical acylation reactions are described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart).
  • Activated esters are conveniently formed in situ, e.g. B. by adding HOBt or N-hydroxysuccinimide.
  • the reaction is usually carried out in an inert solvent, when using a carboxylic acid halide in the presence of an acid-binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
  • an acid-binding agent preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
  • an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal preferably potassium, sodium, calcium or cesium, can also be favorable.
  • the starting materials of formula III are usually new. They can be produced by known methods of peptide synthesis.
  • the compounds of the formulas I can also be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which, 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 linked to an N- Atom is attached, carry an amino protecting group, e.g. B. those which correspond to the formula I, but instead of an NH 2 group contain an NHR 'group (in which R' is an amino protecting group, for example Boc or CBZ).
  • starting materials are preferred which carry a hydroxyl protective group instead of the H atom of a hydroxyl group, for. B. those which correspond to the formula I, but instead of a hydroxyphenyl group contain an R "o-phenyl group (in which R" is a hydroxy 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 at other locations in the molecule. 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. It encompasses 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; Aryioxyaikanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichiorethoxycarbonyl, Boc, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc; Arylsuifonyl such as Mtr.
  • Preferred amino protective groups are Boc and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups.
  • the nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxyl protecting groups include benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • the COOH group is preferably protected in the form of its tert-butyl ester. The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - z. 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.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, and halogenated hydrocarbons such as
  • Dichloromethane 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.
  • reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups Boc, OtBu 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 15th -30 °.
  • the trityl group is used to protect the amino acids histidine, asparagine, glutamine and cysteine.
  • the cleavage takes place with TFA / 10% thiophenol, the trityl group being cleaved from all the amino acids mentioned; when using TFA / anisole or TFA / thioanisole, only the trityl group is cleaved from histidine, asparagine and glutamine, whereas it remains on the cysteine side chain.
  • 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, conveniently on a support such as coal).
  • a catalyst e.g. B. a noble metal catalyst such as palladium, conveniently on a support such as coal.
  • 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 at 5 to 10
  • 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, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric 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.
  • Salts with physiologically unacceptable acids e.g. 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.
  • 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 di isopropyl ammonium salts, monoethanol, diethanol or diisopropyl ammonium salts, cyclohexyl, dicyclohexylammonium salts, dibenzylethylene diammonium salts, further z. B. salts with arginine or lysine.
  • 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 further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteric (e.g. 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, glycerol triacetate, 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, furthermore 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 contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, e.g. B. one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, 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. CO 2 or chlorofluorocarbons).
  • the active ingredient is expediently used in micronized form, one or more additional physiologically tolerable
  • Solvents may be present, e.g. B. ethanol. Inhalation solutions can be administered using standard inhalers.
  • the compounds of formula I and their physiologically acceptable salts can act as integrin inhibitors in the control of diseases, in particular diseases of the circulatory system, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, apoplexy, angina pectoris, tumors, osteoporosis, inflammation, infections and restenosis after angiopiasty be used.
  • diseases in particular diseases of the circulatory system, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, apoplexy, angina pectoris, tumors, osteoporosis, inflammation, infections and restenosis after angiopiasty be used.
  • the compounds of formula I according to claim 1 and / or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumors or rheumatoid arthritis.
  • the substances according to the invention can generally be administered in analogy to other known, commercially available peptides, 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.
  • the compounds of the formula I can be used as integrin ligands for the preparation of columns for affinity chromatography for the purification of integrins.
  • the ligand i.e. a compound of formula I is activated via an anchor function, e.g. the free carboxy group is covalently coupled to a polymeric support.
  • Suitable polymeric carrier materials are the polymeric solid phases known per se in peptide chemistry with preferably hydrophilic properties, for example cross-linked poly sugars such as cellulose, Sepharose or Sephadex R , acrylic amide, polymer based on polyethylene glycol or tentacle polymers R.
  • the materials for affinity chromatography for integrin purification are produced under conditions such as those for the condensation of
  • Amino acids are common and known per se.
  • the compounds of the formula I contain at least two chiral centers and can therefore be in racemic or 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, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid. Enantiomer separation using a column filled with an optically active separating agent (e.g.
  • 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. All temperatures above and below are given in ° C. Room temperature means 22 ° C.
  • customary work-up means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ether or dichloromethane, and the organic phase is separated off , the organic phase dries over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel and / or by crystallization.
  • RT retention time (minutes) with HPLC in the following systems:
  • the diastereomers are preferably separated under the stated conditions.
  • Example 4 Example 4:
  • 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 is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O 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.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner 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
  • each capsule contains 20 mg of the active ingredient.
  • Example I Inhalation spray

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  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Molecular Biology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés de la formule (I) dans laquelle X, A, B et C ont la signification mentionnée dans la revendication 1. L'invention concerne également leurs sels et peuvent s'utiliser comme inhibiteurs d'intégrine, notamment pour assurer la prophylaxie et le traitement d'affections de la circulation, en cas de thrombose, d'infarctus, de maladies cardiaques coronariennes, d'artériosclérose, en cas de phénomènes pathologiques entretenus ou propagés par angiogenèse et dans la thérapie tumorale.
PCT/EP1998/005161 1997-08-23 1998-08-14 Derives de cyclopeptide utilises comme inhibiteurs d'adherence WO1999010371A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
PL98341090A PL341090A1 (en) 1997-08-23 1998-08-14 Cyclic derivatives of peptides as adhesion inhibitors
EP98948833A EP1007545A2 (fr) 1997-08-23 1998-08-14 Derives de cyclopeptide utilises comme inhibiteurs d'adherence
SK213-2000A SK2132000A3 (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives as adhesion inhibitors
KR1020007001430A KR20010022828A (ko) 1997-08-23 1998-08-14 유착 억제제로서의 시클로펩티드 유도체
AU95319/98A AU734829B2 (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives
JP2000507697A JP2001514186A (ja) 1997-08-23 1998-08-14 接着インヒビターとしてのシクロペプチド誘導体
CA002301182A CA2301182A1 (fr) 1997-08-23 1998-08-14 Derives de cyclopeptide utilises comme inhibiteurs d'adherence
BR9811992-3A BR9811992A (pt) 1997-08-23 1998-08-14 Derivados de ciclopeptìdeos
NO20000860A NO20000860L (no) 1997-08-23 2000-02-22 Syklopeptidderivater som adhesjonsinhibitorer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19736772A DE19736772A1 (de) 1997-08-23 1997-08-23 Cyclopeptidderivate
DE19736772.0 1997-08-23

Publications (2)

Publication Number Publication Date
WO1999010371A2 true WO1999010371A2 (fr) 1999-03-04
WO1999010371A3 WO1999010371A3 (fr) 1999-05-27

Family

ID=7839977

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/005161 WO1999010371A2 (fr) 1997-08-23 1998-08-14 Derives de cyclopeptide utilises comme inhibiteurs d'adherence

Country Status (18)

Country Link
EP (1) EP1007545A2 (fr)
JP (1) JP2001514186A (fr)
KR (1) KR20010022828A (fr)
CN (1) CN1267306A (fr)
AR (1) AR013650A1 (fr)
AU (1) AU734829B2 (fr)
BR (1) BR9811992A (fr)
CA (1) CA2301182A1 (fr)
DE (1) DE19736772A1 (fr)
HU (1) HUP0003500A3 (fr)
ID (1) ID23952A (fr)
NO (1) NO20000860L (fr)
PL (1) PL341090A1 (fr)
RU (1) RU2200166C2 (fr)
SK (1) SK2132000A3 (fr)
TW (1) TW477793B (fr)
WO (1) WO1999010371A2 (fr)
ZA (1) ZA987558B (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA43823C2 (uk) * 1992-07-06 2002-01-15 Мерк Патент Геселлшафт Міт Бесшренктер Хафтунг ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ ДЛЯ ІНГІБУВАННЯ ІНТЕГРИН <font face="Symbol">a</font><sub>V</sub><font face="Symbol">b</font><sub>3</sub>-ОПОСЕРЕДКОВАНОЇ КЛІТИННОЇ АДГЕЗІЇ КЛІТИН ССАВЦІВ, СПОСІБ ЛІКУВАННЯ ТА ПРОФІЛАКТИКИ ЗАХВОРЮВАННЯ, АСОЦІЙОВАНОГО З ПОРУШЕННЯМ АДГЕЗІЇ КЛІТИН, СПОСІБ БЛОКУВАННЯ ЗВ'ЯЗУВАННЯ ФІБРИНОГЕНОМ ІНТЕГРИНУ, КОМПОЗИЦІЯ ДЛЯ ЗАГОЄННЯ РАН
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
DE4310643A1 (de) * 1993-04-01 1994-10-06 Merck Patent Gmbh Cyclische Adhäsionsinhibitoren
DE4415310A1 (de) * 1994-04-30 1995-11-02 Merck Patent Gmbh Cyclopeptide
JPH07316193A (ja) * 1994-05-24 1995-12-05 Asahi Glass Co Ltd ペプチド誘導体およびその用途

Also Published As

Publication number Publication date
DE19736772A1 (de) 1999-02-25
ID23952A (id) 2000-06-08
WO1999010371A3 (fr) 1999-05-27
ZA987558B (en) 1999-02-23
KR20010022828A (ko) 2001-03-26
NO20000860D0 (no) 2000-02-22
BR9811992A (pt) 2000-09-05
SK2132000A3 (en) 2000-09-12
NO20000860L (no) 2000-02-22
HUP0003500A3 (en) 2001-12-28
CN1267306A (zh) 2000-09-20
PL341090A1 (en) 2001-03-26
RU2200166C2 (ru) 2003-03-10
JP2001514186A (ja) 2001-09-11
CA2301182A1 (fr) 1999-03-04
AR013650A1 (es) 2001-01-10
AU9531998A (en) 1999-03-16
TW477793B (en) 2002-03-01
EP1007545A2 (fr) 2000-06-14
AU734829B2 (en) 2001-06-21
HUP0003500A2 (hu) 2001-02-28

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