WO1999010371A2 - Cyclopeptide derivatives as adhesion inhibitors - Google Patents

Cyclopeptide derivatives as adhesion inhibitors 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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PCT/EP1998/005161
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German (de)
French (fr)
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WO1999010371A3 (en
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.)
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Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to PL98341090A priority Critical patent/PL341090A1/en
Priority to SK213-2000A priority patent/SK2132000A3/en
Priority to JP2000507697A priority patent/JP2001514186A/en
Priority to BR9811992-3A priority patent/BR9811992A/en
Priority to AU95319/98A priority patent/AU734829B2/en
Priority to CA002301182A priority patent/CA2301182A1/en
Priority to EP98948833A priority patent/EP1007545A2/en
Priority to KR1020007001430A priority patent/KR20010022828A/en
Publication of WO1999010371A2 publication Critical patent/WO1999010371A2/en
Publication of WO1999010371A3 publication Critical patent/WO1999010371A3/en
Priority to NO20000860A priority patent/NO20000860D0/en

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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

Abstract

Compounds of formula (I), in which X, A, B and C have the meanings given in Claim 1, as well as their salts, can be used as integrin inhibitors, in particular for the prevention and treatment of circulatory diseases, thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, in pathological conditions maintained and propagated by angiogenesis, and for tumour therapy.

Description

CYCLOPEPTIDDERIVATE ALS ADHÄSIONSINHIBITOREN CYCLOPEPTID DERIVATIVES AS ADHESION INHIBITORS
Die Erfindung betrifft Verbindungen der FormelThe invention relates to compounds of the formula
Figure imgf000003_0001
Figure imgf000003_0001
worinwherein
Gly, Ala oder NH-NH-CO,Gly, Ala or NH-NH-CO,
wobei die genannten Aminosäuren auch derivatisiert sein können,the amino acids mentioned can also be derivatized,
B einen Rest der Formel IIB is a radical of formula II
N' N '
H yy „RH yy "R
N NN N
I HI H
(CO)m (CO) m
Figure imgf000003_0002
Figure imgf000003_0002
-(CO)p-(CH2)q-(CO)r- oder -(CO)p-CH=CH-(CO)r-- (CO) p- (CH 2 ) q - (CO) r - or - (CO) p -CH = CH- (CO) r -
m, p, r jeweils unabhängig voneinander 0 oder 1 ,m, p, r each independently of one another 0 or 1,
n, q jeweils unabhängig voneinander 1 , 2, 3 oder 4, R1 und R2 jeweils unabhängig voneinander H oder Alkyl,n, q each independently of one another 1, 2, 3 or 4, R 1 and R 2 are each independently of one another H or alkyl,
R1 und R2 zusammen auch oder
Figure imgf000004_0001
Figure imgf000004_0002
R 1 and R 2 together also or
Figure imgf000004_0001
Figure imgf000004_0002
R7, R8, R9,R 7 , R 8 , R 9 ,
R ,10 jeweils unabhängig voneinander H, Alkyl, Ar, OR , Hai, NO2,R, 10 each independently of one another H, alkyl, Ar, OR, shark, NO 2 ,
NR6R6', NHCOR6, CN, NHSO2R6, COOR6 oder COR6,NR 6 R 6 ' , NHCOR 6 , CN, NHSO 2 R 6 , COOR 6 or COR 6 ,
H, Hai, Alkyl oder Ar,H, shark, alkyl or Ar,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch R3, R4 oder R5 substituiertes Phenyl oder unsubstituiertes Naphthyl,Ar is unsubstituted or mono-, di- or trisubstituted by R 3 , R 4 or R 5 phenyl or unsubstituted naphthyl,
R3, R4, R5 jeweils unabhängig voneinander R6, OR6, Hai, NO2, NR6R6', NHCOR6, CN, NHSO2R6, COOR6 oder COR6,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 ,
R6, R6' jeweils unabhängig voneinander H, Alkyl, Phenyl oder Ben- zyl, undR 6 , R 6 ' each independently of one another are H, alkyl, phenyl or benzyl, and
Hai F, Cl, Br oder IShark F, Cl, Br or I
bedeuten,mean,
wobei, sofern es sich um Reste optisch aktiver Aminosäuren und Aminosäurederivate handelt, sowohl die D- als auch die L-Formen einge- schlössen sind,where, in the case of residues of optically active amino acids and amino acid derivatives, both the D and the L forms are included,
sowie deren Salze.as well as their salts.
Ähnliche Verbindungen cyclischer Peptide sind z.B. aus DE 43 10 643 oder EP 0 683 173 bekannt. Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.Similar compounds of cyclic peptides are known, for example, from DE 43 10 643 or EP 0 683 173. 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-, ß3- oder ß5-lntegrin-Rezeptoren mit Liganden hemmen, wie z. B. die Bindung von Fibrinogeπ an den ß3- Integrinrezeptor. Besondere Wirksamkeit zeigen die Verbindungen im Fall der Integrine αvßι, αvß3, αvßs, ocnbß3 sowie αvßβ und αvß_. Diese Wirkung kann z.B. nach der Methode nachgewiesen werden, die von J.W. Smith et al. in J. Biol. Chem. 265, 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 α v -, ß 3 - or ß 5 -integrin receptors with ligands, such as. B. the binding of Fibrinogeπ to the ß 3 - integrin receptor. The compounds show particular effectiveness in the case of the integrins α v ßι, α v ß3, αvßs, ocn b ß3 and α v ßβ and α 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).
Die Abhängigkeit der Entstehung von Angiogenese von der Wechselwirkung zwischen vaskulären Integrinen und extrazelluiären Matrixproteinen ist von P.C. Brooks, R.A. Clark und D.A. Cheresh in Science 264, 569-71 (1994) beschrieben.The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 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, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier und D.A. Cheresh in Cell 79, 1157-64 (1994) beschrieben.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 and D.A. Cheresh in Cell 79, 1157-64 (1994).
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: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 evidenced by the following observations:
Die Verbreitung von Tumorzellen von einem lokalen Tumor in das vaskulä- re System erfolgt durch die Bildung von Mikroaggregaten (Mikrothromben) durch Wechselwirkung der Tumorzellen mit Blutplättchen. Die Tumorzel- len 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. Da die Bildung der Mikrothromben durch Fibrinogenbindung an die Fibri- nogenrezeptoren auf aktivierten Blutplättchen vermittelt wird, können die GPIIa/lllb-Antagonisten als wirksame Metastase-Hemmer angesehen werden.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.
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden, insbesondere zur Pro- phylaxe und/oder Therapie von Erkrankungen des Kreislaufs, Thrombose, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Tumorerkrankungen, osteolytischen Krankheiten wie Osteoporo- se, pathologisch angiogenen Krankheiten wie z. B. Entzündungen, oph- thalmologischen Krankheiten, diabetischer Retinopathie, makularer Dege- neration, Myopia, okularer Histoplasmose, rheumatischer Arthritis, Osteo- arthritis, rubeotischem Glaukom, ulcerativer Colitis, Morbus Crohn, Athe- rosklerose, Psoriasis, Angiogenese und Restenose nach Aπgioplastie, vi- raler Infektion, bakterieller Infektion, Pilzinfektion, bei akutem Nierenver- sagen und bei der Wundheilung zur Unterstützung der Heilungsprozesse.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. inflammation, 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.
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 Aktivi- tat kann durch das von P. Valentin-Weigund et al., in Infection and Im- munity, 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 demonstrated by the method described by P. Valentin-Weigund et al., In Infection and Immunity, 2851-2855 (1988).
Da die Verbindungen der Formel I Inhibitoren der Fibrinogenbindung und damit Liganden der Fibrinogenrezeptoren auf Blutplättchen darstellen, können sie als Diagnostika zur Detektion und Lokalisierung von Thromben im vaskulären System in vivo verwendet werden, sofern sie beispielsweise durch einen radioaktiven oder UV-detektierbaren Rest substituiert werden.Since 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.
Die Verbindungen der Formel I können als Inhibitoren der Fibrinogenbin- düng auch als wirksame Hilfsmittel zum Studium des Metabolismus vonThe compounds of the formula I, as inhibitors of fibrinogen binding, can also be used as effective tools for studying the metabolism of
Blutplättchen in unterschiedlichen Aktivierungsstadien oder von intrazellu- lären Signalmechanismen des Fibrinogenrezeptors verwendet werden. Die detektierbare Einheit eines einzubauenden "Labels" , z.B. eine Isotopenmarkierung durch 3H, erlaubt es, nach Bindung an den Rezeptor, die genannten Mechanismen zu untersuchen.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.
Die vor- und nachstehend aufgeführten Abkürzungen von Aminosäureresten stehen für die Reste folgender Aminosäuren:The abbreviations of amino acid residues listed above and below stand for the residues of the following amino acids:
Ala AlaninAla alanine
NH2 H3C— CH— COOHNH 2 H 3 C - CH - COOH
Arg ArgininArg arginine
Figure imgf000007_0001
Figure imgf000007_0001
Gly GlycinGly glycine
H2N-CH— COOHH 2 N-CH-COOH
Ferner bedeuten nachstehend:Furthermore, below mean:
Ac AcetylAc Acetyl
Boc tert.-Butoxycarbonyl CBZ oder Z Benzyloxycarbonyl DCCI DicyclohexylcarbodiimidBoc tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide
DMAP 4-DimethylaminopyridinDMAP 4-dimethylaminopyridine
DMF DimethylformamidDMF dimethylformamide
EDCI N-Ethyl-N,N'-(dimethylaminopropyl)-carbodiimidEDCI N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide
Et EthylEt ethyl
FCA FluoresceincarbonsäureFCA fluorescein carboxylic acid
Fmoc 9-Fluorenylmethoxycarbonyl HOBt 1 -HydroxybenzotriazolFmoc 9-fluorenylmethoxycarbonyl HOBt 1 -hydroxybenzotriazole
HONSu N-HydroxysuccinimidHONSu N-hydroxysuccinimide
MBHA 4-Methyl-benzhydrylaminMBHA 4-methyl-benzhydrylamine
Me MethylMe methyl
Mtr 4-Methoxy-2,3,6-trimethylphenyl-sulfonylMtr 4-methoxy-2,3,6-trimethylphenyl sulfonyl
NMM N-MethylmorpholinNMM N-methylmorpholine
OBzl BenzylesterOBzl benzyl ester
Oct OctanoylOct octanoyl
OEt EthylesterOEt ethyl ester
OMe MethylesterOMe methyl ester
OtBu tert.-ButylesterOtBu tert-butyl ester
POA PhenoxyacetylPOA phenoxyacetyl
Sal SalicyloylSal salicyloyl
TFA TrifluoressigsäureTFA trifluoroacetic acid
Trt Trityl (Triphenylmethyl).Trt trityl (triphenylmethyl).
Sofern die vorstehend genannten Aminosäuren in mehreren enantiomeren Formen auftreten können, so sind vor- und nachstehend, z. B. als Bestandteil der Verbindungen der Formel I, alle diese Formen und auch ihre Gemische (z. B. die DL-Formen) eingeschlossen. Ferner können die Aminosäuren, z. B. als Bestandteil von Verbindungen der Formel I, mit entsprechenden an sich bekannten Schutzgruppen versehen sein.If the above-mentioned 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.
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.So-called 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.
Hierzu gehören auch bioabbaubare Polymerderivate der erfindungs- gemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 115, 61-67 (1995) beschrieben ist.This also includes biodegradable polymer derivatives of the compounds according to the invention. B. in Int. J. Pharm. 115, 61-67 (1995).
Aminosäuren, deren Konfiguration nicht speziell angegeben ist, weisen die (S)- oder (L)-Konfiguration auf. Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß manAmino 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
(a) eine Verbindung der Formel III(a) a compound of formula III
H-Z-OHH-Z-OH
worinwherein
Figure imgf000009_0001
Figure imgf000009_0001
bedeutet,
Figure imgf000009_0002
means
Figure imgf000009_0002
und X, A, B und C die in Anspruch 1 angegebenen Bedeutungen haben,and X, A, B and C have the meanings given in claim 1,
oder ein reaktionsfähiges Derivat einer Verbindung der Formel IM mit einem cyclisierenden Mittel behandelt, oderor treating a reactive derivative of a compound of the formula IM with a cyclizing agent, or
b) eine Verbindung der Formel I aus einem ihrer funktionellen Derivate durch Behandeln mit einem solvolysierenden oder hydrogenolysie- renden Mittel in Freiheit setzt,b) liberates a compound of the formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
und/oder daß man eine basische oder saure Verbindung der Formel I durch Behandeln mit einer Säure oder Base in eines ihrer Salze überführt.and / or that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base.
Vor- und nachstehend haben die Reste X, A, B, C, R1, R2, m, n, p, q und Z die bei den Formeln I, II und III angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist.Above and below, the 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.
In den vorstehenden Formeln steht X vorzugsweise für H, Hai oder Alkyl, insbesondere für H, CI oder CH3.In the above formulas, X preferably represents H, shark or alkyl, in particular H, CI or CH 3 .
In den vorstehenden Formeln hat Alkyl 1-6 C-Atome und steht vorzugs- weise für Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, 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-methylproρyl, 1 ,1 ,2- oder 1 ,2,2-Tri- methylpropyl. Besonders bevorzugt steht Alkyl für Methyl.In the above formulas, 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.
R7, R8 R9 und R10 bedeuten vorzugsweise H.R 7 , R 8 R 9 and R 10 are preferably H.
Die genannten Aminosäuren und Aminosäurereste können auch derivati- siert sein, wobei die N-Methyl-, N-Ethyl-, N-Propyl-, N-Benzyl- oder Cα-The amino acids and amino acid residues mentioned can also be derivatized, the N-methyl, N-ethyl, N-propyl, N-benzyl or C α -
Methylderivate bevorzugt sind.Methyl derivatives are preferred.
Weiter bevorzugt sind insbesondere die Methyl-, Ethyl, Propyl, Butyl, tert.- Butyl, Neopentyl- oder Benzylester der Seitenketten-carboxy-gruppe, ferner auch Derivate von Arginin, das an der -NH-C(=NH)-NH2 -Gruppe mit einem Acetyl-, Benzoyl-, Methoxycarbonyl- oder Ethoxycarbonylrest substituiert sein kann. R6 und R6 bedeuten vorzugsweise z.B. H, Methyl oder Ethyl, ferner Benzyl oder Phenyl.Further preferred are in particular the methyl, ethyl, propyl, butyl, tert-butyl, neopentyl or benzyl ester of the side chain carboxy group, and also derivatives of arginine which is attached to the -NH-C (= NH) -NH 2 Group can be substituted with an acetyl, benzoyl, methoxycarbonyl or ethoxycarbonyl radical. R 6 and R 6 are preferably, for example, H, methyl or ethyl, furthermore benzyl or phenyl.
OR6 bedeutet bevorzugt z.B. Hydroxy oder Methoxy. COR6 ist Alkanoyl und bedeutet vorzugsweise Formyl, Acetyl, Propionyl,OR 6 preferably means, for example, hydroxy or methoxy. COR 6 is alkanoyl and preferably means formyl, acetyl, propionyl,
Butyryl, Pentanoyl oder Hexanoyl.Butyryl, pentanoyl or hexanoyl.
Ar ist unsubstituiertes, vorzugsweise - wie angegeben - monosub- stituiertes Phenyl, im einzelnen bevorzugt Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-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-
Isopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Trifluor- methylphenyl, o-, m- oder p-Hydroxyphenyi, o-, m- oder p-Nitrophenyl, o-, m- oder p-Aminophenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-(Trifluormethoxy)-phenyl, o-, m- oder p- Cyanphenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Carboxyphenyl, o-, m- oder p-Methoxycarbonylphenyl, o-, m- oder p- Ethoxycarbonylphenyl, o-, m- oder p-Benzyloxycarbonylphenyl, o-, m- oder p-(Carboxymethyloxy)-phenyl, o-, m- oder p- (Methoxycarbonyl- methyloxy)-phenyl, o-, m- oder p-(Methoxycarbonyl-ethyloxy)-phenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p-(N-Ethylamino)- phenyl, o-, m- oder p-(N,N-Diethylamino)-phenyl, o-, m- oder p-Fluor- phenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-(Difluormethoxy)-phenyl, o-, m- oder p-(Fluormethoxy)-phenyl, o-, m- oder p-Formylphenyl, o-, m- oder p-Acetylphenyl, o-, m- oder p-Propionyl- phenyl, o-, m- oder p- Butyrylphenyl, o-, m- oder p-Pentanoylphenyl, o-, m- oder p-( Methylsulfonamido)-phenyl, o-, m- oder p-Phenoxyphenyl, o-, m- oder p-Methylthiophenyl, o-, m- oder p-Methylsulfinylphenyl, o-, m- oder p- Methylsulfonylphenyl oder Naphthyl.Isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyi, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p- (trifluoromethoxy) -phenyl, o-, m- or p- cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p- ethoxycarbonylphenyl, o-, m- or p-benzyloxycarbonylphenyl, o-, m- or p- (carboxymethyloxy) -phenyl, o-, m- or p- (methoxycarbonyl-methyloxy) -phenyl, o-, m- or p- (methoxycarbonyl-ethyloxy) phenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (difluoromethoxy) phenyl, o-, m- or p- (fluoromethoxy) phenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-Pr opionylphenyl, o-, m- or p-butyrylphenyl, o-, m- or p-pentanoylphenyl, o-, m- or p- (methylsulfonamido) phenyl, o-, m- or p-phenoxyphenyl, o- , m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl or naphthyl.
Aminoschutzgruppe bedeutet vorzugsweise Acetyl, Propionyl, Butyryl, Phenylacetyl, Benzoyl, Toluyl, POA, Methoxycarbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, Boc, 2-lodethoxycarbonyl, CBZ ("Carbo- benzoxy"), 4-Methoxybenzyloxycarbonyl, Fmoc, Mtr oder Benzyl. Die Verbindungen der Formel I besitzen mindestens zwei chirale Zentren und können daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen.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.
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. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln la, Ib und Ic ausgedrückt werden, die der Formel I entsprechen und worinAccordingly, 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
in la X H, Alkyl oder Hai,in la X H, alkyl or shark,
R1, R2 H, m 0, n 3,R 1 , R 2 H, m 0, n 3,
P. r 1 , und q 2 oder 3, undP. r 1, and q 2 or 3, and
in lb X H, Alkyl oder Hai,in lb X H, alkyl or shark,
R1, R2 H, m 0, n 3,R 1 , R 2 H, m 0, n 3,
P 1 , r 0, und q 1 , undP 1, r 0, and q 1, and
in Ic X H, Alkyl oder Hai,in Ic X H, alkyl or shark,
R1 und R2 zusammen oder
Figure imgf000012_0001
Figure imgf000012_0002
m 1 n 2R 1 and R 2 together or
Figure imgf000012_0001
Figure imgf000012_0002
m 1 n 2
P- r 1 , und q 2P- r 1, and q 2
bedeuten; 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.mean; 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.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.
Die Verbindungen der Formel I können beispielsweise nach den folgendenThe compounds of formula I can be, for example, as follows
Schemata 1 und 2 hergestellt werden: Schemes 1 and 2 are produced:
Schema 1:Scheme 1:
Figure imgf000014_0001
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0002
LA Schema 2:LA Scheme 2:
Figure imgf000015_0001
Figure imgf000015_0001
IXIX
Figure imgf000015_0002
XII
Figure imgf000015_0002
XII
Figure imgf000015_0003
Figure imgf000015_0003
XIV IB Der wichtige 3-Amino-3-(3-nitro-phenyl)propionsäure-Baustein aus Schema 1 wird hergestellt nach J. Org. Chem. 25, 1758 (1960) aus 3 Nitro- benzaldehyd, Malonsäure und Ammoniumacetat. Bei der Synthese von analogen Verbindungen verwendet man die entsprechenden Nitrobenzal- dehyd-Derivate.XIV IB The important 3-amino-3- (3-nitro-phenyl) propionic acid building block from scheme 1 is produced according to J. Org. Chem. 25, 1758 (1960) from 3 nitrobenzaldehyde, malonic acid and ammonium acetate. The corresponding nitrobenzaldehyde derivatives are used in the synthesis of analogous compounds.
Verbindungen der Formel I können vorzugsweise durch Cyclisierung von Verbindungen der Formel III unter den Bedingungen einer Peptidsynthese erhalten werden. Dabei arbeitet man zweckmäßig nach üblichen Metho- den der Peptidsynthese, wie sie z.B. in Houben-Weyl, 1.c, Band 15/11,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,
Seiten 1 bis 806 (1974) beschrieben sind.Pages 1 to 806 (1974).
Die Reaktion gelingt vorzugsweise in Gegenwart eines Dehydratisierungs- mittels, z.B. eines Carbodiimids wie DCCI oder EDCI, ferner z.B. Propan- phosphonsäureanhydrid (vgl. Angew. Chem. 92, 129 (1980)), Diphenyl- phosphorylazid oder 2-Ethoxy-N-ethoxycarbonyl-1 ,2-dihydrochinolin, in einem inerten Lösungsmittel, z.B. einem halogenierten Kohlenwasserstoff wie Dichlormethan, einem Ether wie Tetrahydrofuran oder Dioxan, einem Amid wie DMF oder Dimethylacetamid, einem Nitril wie Acetonitril, in Di- methylsulfoxid oder in Gegenwart dieser Lösungsmittel, bei Temperaturen zwischen etwa -10 und 40, vorzugsweise zwischen 0 und 30°. Um die intramolekulare Cyclisierung vor der intermolekularen Peptidbindung zu fördern, ist es zweckmäßig, in verdünnten Lösungen zu arbeiten. Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen.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 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 ° . In order to promote intramolecular cyclization before intermolecular peptide binding, it is advisable to work in dilute solutions. The reaction time is between a few minutes and 14 days depending on the conditions used.
Anstelle von Verbindungen der Formel III können auch Derivate von Verbindungen der Formel III, vorzugsweise eine voraktivierte Carbonsäure, oder ein Carbonsäurehalogenid, ein symmetrisches oder gemischtes An- hydrid oder ein Aktivester eingesetzt werden. Derartige Reste zur Aktivierung der Carboxygruppe in typischen Acylierungsreaktionen sind in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben. Aktivierte Ester werden zweckmäßig in situ gebildet, z. B. durch Zusatz von HOBt oder N-Hydroxysuccinimid. Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, bei Verwendung eines Carbonsäurehalogenids in Gegenwart eines säurebindenden Mittels vorzugsweise einer organischen Base wie Triethylamin, Dimethylanilin, Pyridin oder Chinolin. Auch der Zusatz eines Alkali- oder Erdalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugsweise des Kaliums, Natriums, Calci- ums oder Cäsiums kann günstig sein.Instead of compounds of the formula III, 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. Such 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. The addition of 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.
Die Ausgangsstoffe der Formel III sind in der Regel neu. Sie können nach bekannten Methoden der Peptidsynthese hergestellt werden.The starting materials of formula III are usually new. They can be produced by known methods of peptide synthesis.
Die Verbindungen der Formeln I können ferner erhalten werden, indem man sie aus ihren funktionellen Derivaten durch Solvolyse, insbesondere Hydrolyse, oder durch Hydrogenolyse in Freiheit setzt.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.
Bevorzugte Ausgangsstoffe für die Solvolyse bzw. Hydrogenolyse sind solche, die anstelle einer oder mehrerer freier Amino- und/oder Hydroxy- gruppen entsprechende geschützte Amino- und/oder Hydroxygruppen enthalten, vorzugsweise solche, die anstelle eines H-Atoms, das mit einem N-Atom verbunden ist, eine Aminoschutzgruppe tragen, z. B. solche, die der Formel I entsprechen, aber anstelle einer NH2-Gruppe eine NHR'- Gruppe (worin R' eine Aminoschutzgruppe bedeutet, z. B. Boc oder CBZ) enthalten.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).
Ferner sind Ausgangsstoffe bevorzugt, die anstelle des H-Atoms einer Hydroxygruppe eine Hydroxyschutzgruppe tragen, z. B. solche, die der Formel I entsprechen, aber anstelle einer Hydroxyphenylgruppe eine R"O- phenylgruppe enthalten (worin R" eine Hydroxyschutzgruppe bedeutet).Furthermore, 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).
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. Der Ausdruck "Aminoschutzgruppe" ist allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Aminogruppe vor chemischen Umsetzungen 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, insbe- sondere 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 Aral- koxycarbonylgruppen. Beispiele für derartige Acylgruppen sind Alkanoyl wie Acetyl, Propionyl, Butyryl; Aralkanoyl wie Phenylacetyl; Aroyl wie Ben- zoyl oder Toluyl; Aryioxyaikanoyl wie POA; Alkoxycarbonyl wie Methoxy- carbonyl, Ethoxycarbonyl, 2,2,2-Trichiorethoxycarbonyl, Boc, 2- lodethoxycarbonyl; Aralkyloxycarbonyl wie CBZ ("Carbobenzoxy"), 4- Methoxybenzyloxycarbonyl, Fmoc; Arylsuifonyl wie Mtr. Bevorzugte Aminoschutzgruppen sind Boc und Mtr, ferner CBZ, Fmoc, Benzyl und Acetyl.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. 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 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. The term "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. Examples of such 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.
Der Ausdruck "Hydroxyschutzgruppe" ist ebenfalls allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Hydroxygruppe vor chemischen Umsetzungen zu schützen, die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an anderen Stellen des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind die oben genannten unsubstituierten oder substituierten Aryl-, Aralkyl- oder Acylgruppen, ferner auch Alkylgruppen. Die Natur und Größe der Hydroxy- schutzgruppen ist nicht kritisch, da sie nach der gewünschten chemischen Reaktion oder Reaktionsfolge wieder entfernt werden; bevorzugt sind Gruppen mit 1-20, insbesondere 1-10 C-Atomen. Beispiele für Hydroxy- schutzgruppen sind u.a. Benzyl, p-Nitrobenzoyl, p-Toluolsulfonyl, tert.- Butyl und Acetyl, wobei Benzyl und tert.-Butyl besonders bevorzugt sind. Die COOH-Gruppe wird bevorzugt in Form ihrer tert.-Butylester geschützt. Das In-Freiheit-Setzen der Verbindungen der Formel I aus ihren funktionellen Derivaten gelingt - je nach der benutzten Schutzgruppe - z. B. mit starken Säuren, zweckmäßig mit TFA oder Perchlorsäure, aber auch mit anderen starken anorganischen Säuren wie Salzsäure oder Schwefel- säure, starken organischen Carbonsäuren wie Trichloressigsäure oderThe term "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. Examples of 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
Sulfonsäuren wie Benzol- oder p-Toluolsulfonsäure. 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, haiogenierte Kohlenwasserstoffe wieSulfonic 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, and halogenated hydrocarbons such as
Dichlormethan, ferner auch Alkohole wie Methanol, Ethanol oder Isopro- panol, sowie Wasser. Ferner kommen 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.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.
Die Reaktionstemperaturen für die Spaltung liegen zweckmäßig zwischen etwa 0 und etwa 50°, vorzugsweise arbeitet man zwischen 15 und 30° (Raumtemperatur).The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
Die Gruppen Boc, OtBu 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 Di- methylamin, Diethylamin oder Piperidin in DMF bei 15-30°.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 °.
Die Tritylgruppe wird zum Schutz der Aminosäuren Histidin, Asparagin, Glutamin und Cystein eingesetzt. Die Abspaltung erfolgt, je nach gewünschtem Endprodukt, mit TFA / 10% Thiophenol, wobei die Tritylgruppe von allen genannten Aminosäuren abgespalten wird, bei Einsatz von TFA / Anisol oder TFA / Thioanisol wird nur die Tritylgruppe von Histidin, Aspa- ragin und Glutamin abgespalten, wogegen sie an der Cystein-Seitenkette verbleibt.The trityl group is used to protect the amino acids histidine, asparagine, glutamine and cysteine. Depending on the desired end product, 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.
Hydrogenolytisch entfernbare Schutzgruppen (z. B. CBZ oder Benzyl) können z. B. durch Behandeln mit Wasserstoff in Gegenwart eines Kata- lysators (z. B. eines Edelmetallkatalysators wie Palladium, zweckmäßig auf einem Träger wie Kohle) abgespalten werden. Als Lösungsmittel eig- nen 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 durch- geführt. Eine Hydrogenolyse der CBZ-Gruppe gelingt z. B. gut an 5 bis 10Hydrogenolytically 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, conveniently on a support such as coal). Suitable as a solvent NEN 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 at 5 to 10
%igem Pd/C in Methanol oder mit Ammomiumformiat (anstelle von Wasserstoff) an Pd/C in Methanol/DMF bei 20-30°.% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
Eine Base der Formel I kann mit einer Säure in das zugehörige Säure- additionssalz 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 unbedenkliche 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 heterocyc- lische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessig- säure, 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.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. In particular, 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.
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 in Betracht, ferner substituierte Ammoniumsalze, z. B. die Dimethyl-, Diethyl- oder Di- isopropyl-ammoniumsaize, Monoethanol-, Diethanol- oder Diisopropyl- ammoniumsalze, Cyclohexyl-, Dicyclohexylammoniumsalze, Dibenzyl- ethylendiammoniumsalze, weiterhin z. B. Salze mit Arginin oder Lysin.On 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. 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.
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung pharmazeutischer Zubereitungen, insbesondere auf nichtchemischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gege- benenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.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.
Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enteraie (z.B. orale), parenterale, topische Applikation oder für eine Applikation in Form eines Inhalation-Sprays eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohole, Alkylenglyko- le, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lac- tose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen An- wendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Sup- positorien, 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 Hiifsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgato- ren, 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 mikronisier- ter Form, wobei ein oder mehrere zusätzliche physiologisch verträglicheThese preparations can be used as medicinal products in human or veterinary medicine. 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. 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, one or more additional physiologically tolerable
Lösungsmittel zugegen sein können, z. B. Ethanol. Inhalationslösungen können mit Hilfe üblicher Inhalatoren verabreicht werden.Solvents may be present, e.g. B. ethanol. Inhalation solutions can be administered using standard inhalers.
Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können als Integrininhibitoren bei der Bekämpfung von Krankheiten, insbesondere von Erkrankungen des Kreislaufs, Thrombosen, Herzinfarkt, koronaren Herzerkrankungen, Arteriosklerose, Apoplexie, Angina pectoris, Tumoren, Osteoporose, Entzündungen, Infektionen und Restenose nach Angiopiastie verwendet werden.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.
Die Verbindungen der Formel l nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze finden auch Verwendung bei pathologischen Vorgängen, die durch Angiogenese unterhalten oder propagiert werden, insbesondere bei Tumoren oder rheumatoider Arthritis.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.
Dabei können die erfindungsgemäßen Substanzen in der Regel in Analogie zu anderen bekannten, im Handel befindlichen Peptiden, insbesondere aber in Analogie zu den in der US-A-4 472 305 beschriebenen Verbindungen 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 vorzugsweise zwischen etwa 0,01 und 2 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 der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die parenterale Applikation ist bevorzugt. Ferner können die Verbindungen der Formel I als Integrinliganden zur Herstellung von Säulen für die Affinitätschromatographie zur Reindarstellung von Integrinen verwendet werden.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. 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, 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. Furthermore, 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.
Der Ligand, d.h. eine Verbindung der Formel I, wird dabei über eine Ankerfunktion, z.B. die freie Carboxygruppe an einen polymeren Träger kovalent gekuppelt.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.
Als polymere Trägermaterialien eignen sich die an sich in der Peptid- chemie bekannten polymeren festen Phasen mit vorzugsweise hydro- philen Eigenschaften, beispielsweise quervernetzte Polyzucker wie Cellu- lose, Sepharose oder SephadexR, Acryiamide, Polymer auf Polyethylen- glykolbasis oder TentakelpolymereR.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.
Die Herstellung der Materialien für die Affinitätschromatographie zur Inte- grinreinigung erfolgt unter Bedingungen wie sie für die Kondensation vonThe materials for affinity chromatography for integrin purification are produced under conditions such as those for the condensation of
Aminosäuren üblich und an sich bekannt sind.Amino acids are common and known per se.
Die Verbindungen der Formel I enthalten mindestens zwei chirale Zentren und können daher in racemischer oder in optisch-aktiver Form vorliegen. Erhaltene Racemate können nach an sich bekannten Methoden mechanisch 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 mit 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.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. dinitrobenzoylphenylglycine) is also advantageous; 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. Vor- und nachstehend sind alle Temperaturen in °C angegeben. Raumtemperatur bedeutet 22 °C. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ether oder Dichlormethan, trennt die organische Phase ab, trocknet die organische Phase über Natriumsulfat, filtriert, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation. RT = Retentionszeit (Minuten) bei HPLC in den folgenden Systemen: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. All temperatures above and below are given in ° C. Room temperature means 22 ° C. In the examples below, "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:
Säule: Lichrosorb® RP 18 (250 x 4; 5 μm);Column: Lichrosorb ® RP 18 (250 x 4; 5 μm);
Eluent A: 0,1 % TFA in WasserEluent A: 0.1% TFA in water
Eluent B: 0,1 % TFA in 90 % Acetonitril, 10 % WasserEluent B: 0.1% TFA in 90% acetonitrile, 10% water
Fluß: 1 ml/minFlow: 1 ml / min
Gradient: 20 - 95 % B / 50 minGradient: 20 - 95% B / 50 min
Detektion bei 215 nm.Detection at 215 nm.
Die Trennung der Diastereomeren erfolgt vorzugsweise unter den angegebenen Bedingungen.The diastereomers are preferably separated under the stated conditions.
Massenspektrometrie (MS): FAß (Fast Atom Bombardment) (M+H)+ Mass spectrometry (MS): FASS (Fast Atom Bombardment) (M + H) +
Beispiel 1 :Example 1 :
Figure imgf000024_0001
Figure imgf000024_0001
8S,14S-IB Svnthese der zu cyclisierenden Verbindung Analog Schema 1 wird (3R,S)-3-Amino-3-(4-methyl-3-nitro-phenyl)- propionsäuremethylester (3R.S-IX) synthetisiert. Dieser Ester wird nach bekannter Methode in die Enantiomeren gespalten und (3S)-3-Amino-3-(4- methyl-3-nitro-phenyl)-propionsäuremethylester (3S-IX) anschließend analog Schema 2 zur Mtr-geschützten Verbindung 3S-Amino-3-(3-{3-[1- (carboxy-methyl-carbamoyl)-4-guanidino-1 S-butylcarbamoyl]-propionyl- amino}-4-methyl-phenyl)-propionsäuremethylester (S.S-XIV) umgesetzt.8S, 14S-IB Synthesis of the compound to be cyclized Analogously to Scheme 1, (3R, S) -3-amino-3- (4-methyl-3-nitro-phenyl) propionate (3R.S-IX) is synthesized. This ester is split into the enantiomers by a known method and methyl (3S) -3-amino-3- (4-methyl-3-nitro-phenyl) propionate (3S-IX) is then analogous to Scheme 2 for the Mtr-protected compound 3S- Amino-3- (3- {3- [1- (carboxymethyl-carbamoyl) -4-guanidino-1 S-butylcarbamoyl] -propionyl-amino} -4-methyl-phenyl) -propionic acid methyl ester (SS-XIV) .
CyclisierungCyclization
616 mg der Mtr-geschützten Verbindung 3S-Amino-3-(3-{3-[1-(carboxy- methyl-carbamoyl)-4-guanidino-1 S-butylcarbamoyl]-propionylamino}-4- methyl-phenyl)-propionsäuremethylester (S.S-XIV) werden in 80 ml DMF gelöst und mit 800 ml Dichlormethan verdünnt. Danach wird auf -20 °C gekühlt und nacheinander 300 mg EDCI, 98 mg DMAP und 0,176 ml NMM zugegeben. Es wird auf Raumtemperatur erwärmt und über Nacht gerührt. Die Lösung wird eingeengt und der Rückstand in 200 ml halbgesättigte NaHCO3-Lösung eingerührt. Der Niederschlag wird abgesaugt und gewaschen. Man erhält 400 mg Substanz, die durch präparative HPLC gereinigt werden. Nach der Chromatographie erhält man 44 mg der Mtr-geschützten cyclischen Verbindung (8S, 14S)-[8-(3-Guanidinopropyl)-18-methyl- 3,6,9, 12-tetraoxo-2,7, 10, 13-tetraazabicyclo[13.3.1 ]nonadeca- 1 (18),15(19),16-trien-14-yl]-essigsäuremethylester, RT 26.1 ; FAB 716.616 mg of the Mtr-protected compound 3S-amino-3- (3- {3- [1- (carboxymethyl-carbamoyl) -4-guanidino-1 S-butylcarbamoyl] -propionylamino} -4-methyl-phenyl) - Methyl propionate (SS-XIV) are dissolved in 80 ml DMF and diluted with 800 ml dichloromethane. It is then cooled to -20 ° C. and 300 mg of EDCI, 98 mg of DMAP and 0.176 ml of NMM are added in succession. It is warmed to room temperature and stirred overnight. The solution is concentrated and the residue is stirred into 200 ml of semi-saturated NaHCO 3 solution. The precipitate is filtered off and washed. 400 mg of substance are obtained, which are purified by preparative HPLC. After chromatography, 44 mg of the Mtr-protected cyclic compound (8S, 14S) - [8- (3-guanidinopropyl) -18-methyl-3,6,9, 12-tetraoxo-2,7, 10, 13- tetraazabicyclo [13.3.1] nonadeca- 1 (18), 15 (19), 16-trien-14-yl] -acetic acid methyl ester, RT 26.1; FAB 716.
Verseifung und Abspaltung der Mtr-SchutzqruppeSaponification and separation of the Mtr protection group
Durch Verseifung in KOH/Methanol erhält man die Mtr-geschützte cy- clische Verbindung (8S,14SH8-(3-Guanidinopropyl)-18-methyl-3,6,9,12- tetraoxo-2,7, 10, 13-tetraazabicyclo[13.3.1 ]nonadeca-1 (18), 15(19), 16-trien- 14-yl]-essigsäure. 25 mg dieser Verbindung werden anschließend in 4,3 ml 98%iger Trifluoressigsäure gelöst und über Nacht bei Raumtemperatur gerührt. Die Lösung wird einrotiert und durch präparative HPLC gereinigt. Es werden 9,5 mg (8S,14S)-[8-(3-Guanidinopropyl)-18-methyl-3,6,9,12- tetraoxo-2,7, 10, 13-tetraazabicyclo[13.3.1 ]nonadeca-1 (18), 15(19), 16-trien- 14-yl]-essigsäure (8S.14S-IB) erhalten, RT 20.2; FAB 490. Beispiele 2-3:Saponification in KOH / methanol gives the Mtr-protected cyclic compound (8S, 14SH8- (3-guanidinopropyl) -18-methyl-3,6,9,12-tetraoxo-2,7, 10, 13-tetraazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16-trien-14-yl] acetic acid, 25 mg of this compound are then dissolved in 4.3 ml of 98% trifluoroacetic acid and stirred overnight at room temperature The solution is spun in and purified by preparative HPLC, 9.5 mg (8S, 14S) - [8- (3-guanidinopropyl) -18-methyl-3,6,9,12-tetraoxo-2,7, 10, 13-tetraazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16-trien-14-yl] -acetic acid (8S.14S-IB) obtained, RT 20.2; FAB 490. Examples 2-3:
Figure imgf000026_0001
Figure imgf000026_0001
Beispiel 2 (q = 2):Example 2 (q = 2):
Ausgehend von 85 mg der Mtr-geschützten Verbindung (8S,14S)-2-(8-(3- Guanidinopropyl)-3,6,9, 12-tetraoxo-2,7, 10, 13-tetraazabicyclo[13.3.1 ]- nonadeca-16,18,19-trien-14-yl)-essigsäure erhält man in Analogie zu Beispiel 1 durch Umsetzung mit 14,7 ml 98%iger Trifluoressigsäure 13 mg (8S, 14S)-2-(8-(3-Guanidinopropyl)-3,6,9, 12-tetraoxo-2,7, 10, 13-tetraaza- bicyclo[13.3.1]nonadeca-16,18,19-trien-14-yl)-essigsäure; RT 17,2; FAB 476.Starting from 85 mg of the Mtr-protected compound (8S, 14S) -2- (8- (3-guanidinopropyl) -3,6,9, 12-tetraoxo-2,7, 10, 13-tetraazabicyclo [13.3.1] - Nonadeca-16,18,19-trien-14-yl) acetic acid is obtained analogously to Example 1 by reaction with 14.7 ml of 98% trifluoroacetic acid 13 mg (8S, 14S) -2- (8- (3rd -Guanidinopropyl) -3,6,9, 12-tetraoxo-2,7, 10, 13-tetraazabicyclo [13.3.1] nonadeca-16,18,19-trien-14-yl) acetic acid; RT 17.2; FAB 476.
Beispiel 3 (q = 3): Ausgehend von 300 mg der Mtr-geschützten Verbindung (9S, 15S)-2-(9-(3- Guanidinopropyl)-3,7, 10,13-tetraoxo-2, 8, 11 ,14-tetraazabicyclo[14.3.1 ]- eicosan-17,19,20-trien-15-yl)-essigsäure erhält man in Analogie zu Beispiel 1 74 mg (9S,15S)-2-(9-(3-Guanidinopropyl)-3,7,10,13-tetraoxo- 2,8,11 ,14-tetraazabicyclo[14.3.1 ]eicosan-17,19,20-trien-15-yl)-essigsäure; RT 18,3; FAB 490. Beispiel 4:Example 3 (q = 3): starting from 300 mg of the Mtr-protected compound (9S, 15S) -2- (9- (3-guanidinopropyl) -3,7, 10,13-tetraoxo-2, 8, 11, 14-tetraazabicyclo [14.3.1] - eicosan-17,19,20-trien-15-yl) acetic acid is obtained analogously to Example 1, 74 mg (9S, 15S) -2- (9- (3-guanidinopropyl) -3,7,10,13-tetraoxo-2,8,11,14-tetraazabicyclo [14.3.1] eicosan-17,19,20-trien-15-yl) acetic acid; RT 18.3; FAB 490. Example 4:
Figure imgf000027_0001
Figure imgf000027_0001
Ausgehend von der Mtr-geschützten Verbindung (6S,12S)-[6-(3-Guani- dinopropyl-4,7, 10-trioxo-2,5,8, 11 -tertaazabicyclo[11.3.1 jheptadeca- 1 (17),13,15-trien-12-yl]-essigsäure erhält man in Analogie zu Beispiel 1 (6S, 12S)-[6-(3-Guanidinopropyl-4,7, 10-trioxo-2,5,8, 11 -tertaazabicyclo- [11.3.1 ]heptadeca-1 (17), 13, 15-trien-12-yl]-essigsäure.Starting from the Mtr-protected compound (6S, 12S) - [6- (3-guanidinopropyl-4,7, 10-trioxo-2,5,8, 11 -tertaazabicyclo [11.3.1 jheptadeca- 1 (17) , 13,15-trien-12-yl] acetic acid is obtained analogously to Example 1 (6S, 12S) - [6- (3-guanidinopropyl-4,7, 10-trioxo-2,5,8, 11 - tertaazabicyclo- [11.3.1] heptadeca-1 (17), 13, 15-trien-12-yl] acetic acid.
Beispiele 5-8:Examples 5-8:
Figure imgf000027_0002
ln Analogie zu Beispiel 1 werden die folgenden Verbindungen synthetisiert:
Figure imgf000027_0002
The following compounds are synthesized in analogy to Example 1:
Bsp Nr. X m n R1 und R2 Example No. X mn R 1 and R 2
H -CO-CH=CH-CO- HH -CO-CH = CH-CO- H
Cl -CO-CH2-CH2-CO- 0 HCl -CO-CH 2 -CH 2 -CO- 0 H
Figure imgf000028_0001
Figure imgf000028_0001
.H.H
CC
8 H -CO-CH2-CH2-CO- 1 II8 H -CO-CH 2 -CH 2 -CO- 1 II
.C..C.
HH
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgiäserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat 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 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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Beπzalkonium- chlorid 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 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.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: TablettenExample E: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 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 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.
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 Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I 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 Wirkstoff der Formel I in 60 l zweifach destilliertemA solution of 1 kg of active ingredient of formula I in 60 l of double distilled
Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. Beispiel I: Inhalations-SprayWater is filtered sterile, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient. Example I: Inhalation spray
Man löst 14 g Wirkstoff der Formel I 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 active ingredient of the formula I are dissolved in 10 I of isotonic NaCI solution and the solution is filled into commercially available spray vessels with 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.
Figure imgf000031_0001
Figure imgf000031_0001
worinwherein
Gly, Ala oder NH-NH-CO,Gly, Ala or NH-NH-CO,
wobei die genannten Aminosäuren auch derivatisiert sein können,the amino acids mentioned can also be derivatized,
B einen Rest der Formel IIB is a radical of formula II
.R'.R '
NN
H. yy ^H. yy ^
N NN N
I HI H
(CO)m (CO) m
Figure imgf000031_0002
Figure imgf000031_0002
-(CO)p-(CH2)q-(CO)r- oder -(CO)p-CH=CH-(CO)r-- (CO) p - (CH 2 ) q - (CO) r - or - (CO) p -CH = CH- (CO) r -
m, p, r jeweils unabhängig voneinander 0 oder 1m, p, r each independently of one another 0 or 1
n, q jeweils unabhängig voneinander 1 , 2, 3 oder 4, R und R2 jeweils unabhängig voneinander H oder Alkyl,n, q each independently of one another 1, 2, 3 or 4, R and R 2 each independently of one another are H or alkyl,
R1 und R2 zusammen auchR 1 and R 2 together also
Figure imgf000032_0001
Figure imgf000032_0001
R7, R8, R9,R 7 , R 8 , R 9 ,
R10 jeweils unabhängig voneinander H, Alkyl, Ar, OR6, Hai,R 10 each independently of one another H, alkyl, Ar, OR 6 , shark,
NO2, NR6R6', NHCOR6, CN, NHSO2R6, COOR6 oderNO 2 , NR 6 R 6 ' , NHCOR 6 , CN, NHSO 2 R 6 , COOR 6 or
COR6,COR 6 ,
X H, Hai, Alkyl oder Ar,X H, shark, alkyl or Ar,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch R3,Ar unsubstituted or single, double or triple by R 3 ,
R R44 ooddeerr R Rs substituiertes Phenyl oder unsubstituiertes Naphthyl,RR 44 ooddeerr RR s substituted phenyl or unsubstituted naphthyl,
R3, R4, R5 jeweils unabhängig voneinander R6, OR6, Hai, NO2, NR6R6', NHCOR6, CN, NHSO2R6, COOR6 oder COR6,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 ,
R6, R6 jeweils unabhängig voneinander H, Alkyl, Phenyl oderR 6 , R 6 each independently of one another are H, alkyl, phenyl or
Benzyl, undBenzyl, and
Hai F, Cl, Br oder IShark F, Cl, Br or I
bedeuten,mean,
wobei, sofern es sich um Reste optisch aktiver Aminosäuren undwhere, provided that there are residues of optically active amino acids and
Aminosäurederivate handelt, sowohl die D- als auch die L-Formen eingeschlossen sind,Amino acid derivatives, including both the D and L forms,
sowie deren Salze. as well as their salts.
2. Ein Enantiomer oder ein Diastereomer einer Verbindung der Formel gemäß Anspruch 1.2. An enantiomer or a diastereomer of a compound of the formula according to claim 1.
3. Verbindungen der Formel I gemäß Anspruch 1 :3. Compounds of formula I according to claim 1:
a) (8S, 14S)-2-(8-(3-Guanidinopropyl)-3,6,9, 12-tetraoxo-2,7, 10,13- tetraazabicyclo[13.3.1]nonadeca-16,18,19-trien-14-yl)-essigsäure;a) (8S, 14S) -2- (8- (3-guanidinopropyl) -3,6,9, 12-tetraoxo-2,7, 10,13-tetraazabicyclo [13.3.1] nonadeca-16,18,19 -trien-14-yl) acetic acid;
b) (9S, 15S)-2-(9-(3-Guanidinopropyl)-3,7, 10, 13-tetraoxo-2,8, 11 ,14- tetraazabicyclo[14.3.1 ]eicosan-17,19,20-trien-15-yl)-essigsäure;b) (9S, 15S) -2- (9- (3-guanidinopropyl) -3,7, 10, 13-tetraoxo-2,8, 11, 14-tetraazabicyclo [14.3.1] eicosane-17,19,20 -trien-15-yl) acetic acid;
c) (8S,14S)-(8-(3-Guanidinopropyl)-18-methyl-3,6,9,12-tetraoxo- 2,7, 10, 13-tetraazabicyclo[13.3.1 ]nonadeca-1 (18), 15(19), 16-trien- 14-yl)-essigsäure;c) (8S, 14S) - (8- (3-guanidinopropyl) -18-methyl-3,6,9,12-tetraoxo-2,7, 10, 13-tetraazabicyclo [13.3.1] nonadeca-1 (18th ), 15 (19), 16-trien-14-yl) acetic acid;
d) (6S, 12S)-(6-(3-Guanidinopropyl)-4,7, 10-trioxo-2,5,8,11 - tetraazabicyclo[11.3.1 ]heptadeca-1 (17), 13, 15-trien-12-yl)- essigsaure;d) (6S, 12S) - (6- (3-guanidinopropyl) -4,7, 10-trioxo-2,5,8,11 - tetraazabicyclo [11.3.1] heptadeca-1 (17), 13, 15- trien-12-yl) - acetic acid;
sowie deren Salze.as well as their salts.
4. Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß man4. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that
(a) eine Verbindung der Formel III(a) a compound of formula III
H-Z-OH IIIH-Z-OH III
worin
Figure imgf000034_0001
wherein
Figure imgf000034_0001
bedeutet,
Figure imgf000034_0002
means
Figure imgf000034_0002
und X, A, B und C die in Anspruch 1 angegebenen Bedeutungen haben,and X, A, B and C have the meanings given in claim 1,
oder ein reaktionsfähiges Derivat einer Verbindung der Formel III mit einem cyclisierenden Mittel behandelt,or treating a reactive derivative of a compound of formula III with a cyclizing agent,
oderor
b) eine Verbindung der Formel I aus einem ihrer funktionellen Derivate durch Behandeln mit einem solvolysierenden oder hydro- genolysierenden Mittel in Freiheit setzt,b) liberates a compound of the formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenating agent,
und/oder daß man eine basische oder saure Verbindung der Formel durch Behandeln mit einer Säure oder Base in eines ihrer Salze überführt. and / or that a basic or acidic compound of the formula is converted into one of its salts by treatment with an acid or base.
5. Verfahren zur Herstellung pharmazeutischer Zubereitungen, dadurch gekennzeichnet, daß man eine Verbindung der Formel I nach Anspruch 1 und/oder eines ihrer physiologisch unbedenklichen Salze zusammen mit mindestens einem festen, flüssigen oder halbflüssigen5. A process for the preparation of pharmaceutical preparations, characterized in that a compound of formula I according to claim 1 and / or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid
Träger- oder Hilfsstoff in eine geeignete Dosierungsform bringt.Bring carrier or excipient into a suitable dosage form.
6. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der Formel I nach Anspruch 1 und/oder einem ihrer physiologisch unbedenklichen Salze.6. Pharmaceutical preparation, characterized by a content of at least one compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts.
7. Verbindungen der Formel I nach Anspruch 1 und ihre physiologisch unbedenklichen Salze als Integrininhibitoren zur Bekämpfung von Erkrankungen des Kreislaufs, Thrombosen, Herzinfarkt, koronaren Herzerkrankungen, Arteriosklerose, Apoplexie, Angina pectoris, Tumoren, Osteoporose, Entzündungen, Infektionen und Restenose nach Angioplastie.7. Compounds of formula I according to claim 1 and their physiologically acceptable salts as integrin inhibitors for combating diseases of the circulatory system, thromboses, heart attack, coronary heart diseases, arteriosclerosis, apoplexy, angina pectoris, tumors, osteoporosis, inflammation, infections and restenosis after angioplasty.
8. Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze bei pathologischen Vorgängen, die durch Angiogenese unterhalten oder propagiert werden.8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in pathological processes which are maintained or propagated by angiogenesis.
9. Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels.9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.
10. Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze bei der Bekämp- fung von Krankheiten. 10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the control of diseases.
PCT/EP1998/005161 1997-08-23 1998-08-14 Cyclopeptide derivatives as adhesion inhibitors WO1999010371A2 (en)

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
SK213-2000A SK2132000A3 (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives as adhesion inhibitors
JP2000507697A JP2001514186A (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives as adhesion inhibitors
BR9811992-3A BR9811992A (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives
AU95319/98A AU734829B2 (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives
CA002301182A CA2301182A1 (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives
EP98948833A EP1007545A2 (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives as adhesion inhibitors
KR1020007001430A KR20010022828A (en) 1997-08-23 1998-08-14 Cyclopeptide derivatives as adhesion inhibitors
NO20000860A NO20000860D0 (en) 1997-08-23 2000-02-22 Cyclopeptide derivatives as adhesion inhibitors

Applications Claiming Priority (2)

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DE19736772A DE19736772A1 (en) 1997-08-23 1997-08-23 New guanidino-substituted bi:cyclic peptide compounds
DE19736772.0 1997-08-23

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0578083A2 (en) * 1992-07-06 1994-01-12 MERCK PATENT GmbH Cyclic adhesion inhibitors
DE4310643A1 (en) * 1993-04-01 1994-10-06 Merck Patent Gmbh Cyclic adhesion inhibitors
DE4415310A1 (en) * 1994-04-30 1995-11-02 Merck Patent Gmbh Cyclopeptides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07316193A (en) * 1994-05-24 1995-12-05 Asahi Glass Co Ltd Peptide derivative and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0578083A2 (en) * 1992-07-06 1994-01-12 MERCK PATENT GmbH Cyclic adhesion inhibitors
DE4310643A1 (en) * 1993-04-01 1994-10-06 Merck Patent Gmbh Cyclic adhesion inhibitors
DE4415310A1 (en) * 1994-04-30 1995-11-02 Merck Patent Gmbh Cyclopeptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 9606 Derwent Publications Ltd., London, GB; Class B04, AN 96-055984 XP002091715 -& JP 07 316193 A (ASAHI GLASS CO LTD) , 5. Dezember 1995 *

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KR20010022828A (en) 2001-03-26
NO20000860L (en) 2000-02-22
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ZA987558B (en) 1999-02-23
DE19736772A1 (en) 1999-02-25
ID23952A (en) 2000-06-08
PL341090A1 (en) 2001-03-26
WO1999010371A3 (en) 1999-05-27
RU2200166C2 (en) 2003-03-10
CN1267306A (en) 2000-09-20
NO20000860D0 (en) 2000-02-22
SK2132000A3 (en) 2000-09-12
AU734829B2 (en) 2001-06-21
AU9531998A (en) 1999-03-16
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TW477793B (en) 2002-03-01
BR9811992A (en) 2000-09-05

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