CA2093770C - Aspartic acid derivatives, their preparation and use - Google Patents

Aspartic acid derivatives, their preparation and use Download PDF

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CA2093770C
CA2093770C CA002093770A CA2093770A CA2093770C CA 2093770 C CA2093770 C CA 2093770C CA 002093770 A CA002093770 A CA 002093770A CA 2093770 A CA2093770 A CA 2093770A CA 2093770 C CA2093770 C CA 2093770C
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CA2093770A1 (en
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Otmar Klingler
Gerhard Zoller
Melitta Just
Bernd Jablonka
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Sanofi Aventis Deutschland GmbH
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Cassella AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215Radicals derived from nitrogen analogues of carbonic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06104Dipeptides with the first amino acid being acidic
    • C07K5/06113Asp- or Asn-amino acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0802Tripeptides with the first amino acid being neutral
    • C07K5/0804Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/582Recycling of unreacted starting or intermediate materials

Abstract

Aspartic acid derivatives of the formula (see formula I) in which X denotes, for example, (see formula II) and R denotes, for example, cyclohexylamino, have useful pharmacological properties. In particular, they have the ability to inhibit the binding of fibrinogen, fibronectin and von Willebrand factor to integrin receptors. They also inhibit platelet aggregation, metastasis of carcinoma cells and osteoclast formation on bone surfaces and are useful in prophylaxis and therapy of, for example, arterial vascular diseases and in the treatment of tumors.

Description

2fl~37'~~
Ref.3506 Dr. Eu/L10872 Asoartic acid derivatives their~preparation and use The invention relates to aspartic acid derivatives of the general formula I
HN=i-X-NH-iH-CHZ-COOH (I) in which X denotes -NH- ( CHZ ) ~ \ CO-i~---CHZ°CO-, -N CH?
-f--A ' C 0-CHZ-(~CHZ)k -NH- ( CH2 )m~CO--t'1-CH? CO-, -NH-(CH2)fi ' (?-CHI-CO-.
A denotes -(CHZ)m , -O- or a direct bond, n denotes a number from 1 to 4, k denotes a number from 0 to 7, m denotes a number from 0 to 4, R denotes -ORl, -N-R3, -NH-R,, Rz Rl denotes hydrogen, C1-CZgalkyl, C3-C28cycloalkyl, phenyl, where the Cl-C28alkyl, the C3-CZecycloalkyl or the phenyl is unsubstituted or mono- or polysubetituted by identical or different radicals from the series consisting of hydroxyl, carboxyl, C1-C,alkoxy-carbonyl, arylmethoxycarbonyl, carboxamido, C1-C,alkylamino-~I

carbonyl, amino, mercapto, C1-C,,alkoxy, C3-Cecycloalkyl, imida-zolyl, indolyl, pyrrolidinyl, hydroxypyrrolidinyl, halogen, phenyl or phenoxy, each of which is unsubstituted or mono-substituted or polysubstituted by hydroxyl, C1-C4alkyl, halogen, vitro or trifluoromethyl, C3-Celalkyl interrupted one or more times by -O- and (C3-Celalkoxy)carbonyl interrupted one ore more times by -0-;
R2 and R3 independently of one another denoted hydrogen, R1 or, together with the nitrogen to which they are bonded, a 5- or 6-membered, saturated heterocyclic ring which can additionally contain -0- or -NRS-, or RZ denotes hydrogen and R' denotes a radical of the formula iH~-0-CO-(CH?)p-CH3 -CH-CQ-O-CH
CH?-0-CO-(CH2)q-CH3 or -CH-CO-0-iH2 CH-0-CO-(CH~)p-CH3 CH2-0-CO-(CHZ)q-CH3 R' denotes the radical of an amino acid or of a dipeptide, in which the peptide bond can also be reduced to -NH-CHZ-, R5 denotes hydrogen, C1-C,,alkyl, phenyl, C1-Cdalkylphenyl, C1-C,,alkoxyphenyl, R6 denotes hydrogen, C1-C4alkyl, phenyl, phenyl(C1-C,,)alkyl, p and q independently of one another denote a number from 1 to 20, and their physiologically tolerable salts.
The invention also relates to the processes for the preparation of the compounds of the formula I, their use as pharmaceutically active substances, pharmaceutical compositions and methods of making the compositions as well as commercial packages containing the compound or compositions of the invention.
i The alkyl and alkoxy radicals representing R1, R2, R3 and R5 can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals.
2a zu93~~o Examples of suitable C1-CZealkyl radicals are:
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tridecyl, heptadecyl, nonadecyl, eicosyl, docosyl, tricosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl, sec-butyl, tart-butyl, tert-pentyl, isohexyl. Unbranched C1-CZealkyl radicals are preferred.
Of the C3-CZecycloalkyl radicals, C3-Cealkyl radicals (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), in particular cyclopentyl and cyclohexyl, are preferred.
Halogen can be, for example, fluorine, chlorine, bromine or iodine, of which fluorine, chlorine and bromine are preferred.
The C3-C8lalkyl interrupted one or more times by oxygen preferably contains the group H3C0 -fCHZCHZO --~_ where x is a number from 1 to 40.
The (C3-Celalkoxy)carbonyl interrupted one or more times by oxygen preferably contains the group H3C0 --(-CHZCH2O -.j~xCO-where x is a number from 1 to 40.
The C3-Cecycloalkyl radicals can in particular also be substituted by a carboxyl group.
The aryl radical in the arylmethoxycarbonyl radical can be, for example, an a- or p-naphthyl radical or in particular a phenyl radical.
A phenyl or phenoxy radical acting for R1, RZ or R' or a phenyl or phenoxy radical acting as a substituent for Rl, RZ or R' can be, for example, mono-, di- or trisubstituted, if this is possible for steric reasons or for stability reasons. In the case of nitro substitution, as a rule only one nitro group, if appro-priate in addition to other substituents, is present.
The imidazole radical is in particular a 4-imidazole radical. The indolyl radical is in particular a 3-indolyl radical.
2U93'~'~~l Suitable substituted phenyl radicals are, for example, 3,5-dibromo-4-hydroxyphenyl.
Ri and R', together with the nitrogen to which they are bonded, can also form a 5- or 6-membered saturated, heterocyclic ring which can additionally contain -O- or -N(Rs)-. Examples of radicals of this type are 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 4-(C1-C'alkyl)piperazin-1-yl, in particular 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl, 4-(C1-C'alkoxy)-piperazin-1-yl.
Hydrogen is preferred for RZ.
R' represents the radical of a natural or unnatural amino acid or of a dipeptide, this radical formally being formed by removal of an NH2 group from the amino acid or the dipeptide.
Radicals of p-amino acids and in particular of a-amino acids are preferred. The radicals R' can be derived, for example, from the following amino acids, which, if they are chiral, can be present in the D- or L-form (cf. Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry, volume XV/1 and 2, Stuttgart, 1974):
Aad, Abu, Abu, ABz, 2ABz, aAca, Ach, Acp, Adpd, Ahb, Aib, ~9Aib, Ala, pAla, oAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Hai, Bph, Can, Cit, Cys, (Cys)Z, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hero, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, ~9Lys, aLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, P=o, oPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, pThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Tbg, Npg, Chg, Cha, Thia, 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, 2-(p-chlorophenyl)aminoacetic acid.
The radical R' can also be derived from a dipeptide, it being possible for these dipeptidea to contain, ae components, natural or unnatural amino acids. In addition, the radicals R' of the natural or unnaturatl amino acids and dipeptides can also be present as esters or amides, such as, for example, the methyl ester, ethyl amide, semicarbazide or ~r-amino-(C'-C~)alkyl amide.

~0~3'~'~Q
Functional groups of the amino acid and dipeptide radi-cals R' can be present in protected form. Suitable protective groups such as, for example, urethane protective groups, carboxyl protective groups and side-chain protective groups are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 and in Biillesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. The following may in particular be mentioned: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NOZ), Z(Halp), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
-N(RZ)R3 and in particular -NH-R' is preferred for R. The radical -N ( RZ r R' in particular denotes an amino- ( C1-C8 ) alkyl-diphenyl radical, an amino-(C3-C8)cycloalkyl radical or an amino-(C1-Ca)-alkyl radical. The amino-(C3-Ce)cycloalkyl radical can in this case also be substituted on the cycloalkyl radical, in particular by a carboxyl group. The amino-(C1-Ca)alkyldiphenyl radical is in particular an ~, ~-diphenylalkylamine radical, very particularly preferably a 3,3-diphenylpropylamine radical. Par-ticularly preferably, the radical -NH-R' representing R represents the valine, phenylalanine or phenylglycine radical, which is formed by removal of a hydrogen atom from the amino group of valine, phenylalanine or phenylglycine.
Hydrogen, phenyl, benzyl, methyl or isopropyl are pre-ferred for RB.
2 and in particular 3 are preferred for k. A number from 14 to 16 is preferred for p and q.
The radicals representing X preferably contain 1,4- or 1,3-phenylene, 1,4-cyclohexylene, p-piperidinyl or 3-pyrrolidinyl.
1 is preferred for n and 1 or 2 are preferred for m.
Particularly preferred radicals X are:
-NH-CHZ ~ ~ CO-i-CHI-C0-, -NH-CH2--.~.-CO-i-CHI-CO-, ~o~~~~~
-NH-CHZCH2 ~ ' 0-CHZ-CO-.
-N~-A ~ ' C0- , -N~A ~ ' , ' CO- , ~N
CO-A ~ ' Preferred compounds of the formula I are those which contain one and in particular several of the preferred radicals or groups.
Physiologically tolerable salts of the compounds of the general formula I are in particular pharmaceutically utilisable or non-toxic salts.
The carboxyl group of the compounds of the formula I can form salts with alkali metals or-alkaline earth metals, such as, for example, Na, R, Mg and Ca, and also with physiologically tolerable organic amines, such as, for example, triethylamine and tris(2-hydroxyethyl)amine.
Compounds of the general formula I can also form salts on the basic amidino group or guanidino group with inorganic acids and with organic carboxylic or sulphonic acids.
Compounds of the formula I can be prepared by 2093"~"~0 a' reacting a compound of the general formula II
HN=C-7-COOH
NH2 (II) in which Z denotes 'f---A ' , CH2-i~CH2)k -NH-(CH2)m ~ C CH?- , -NH-(CH?)n 1 CO-i-CH7-, -NH- ( CHZ ) m-E- -f-C0- i -CHI- , ~/' CH3 and A, n and m have the meanings already mentioned, with a com-pound of the general formula III
H2N- i H-CHZ-COOH ( I I I ) COR
in which R has the meaning already mentioned, or bj reacting a compound of the general formula IIa HN~C-Z1-COOH (IIa) NHZ
-which Z° denotes -NH- ( CHz ) n ' r -NH- ( CHz ) m ~ r and n and m have the meaning already mentioned, with a compound of the general formula IIIa H- i -CHz-CO-NH- i -CHz-COON ( I I Ia ) in which R has the meaning already mentioned, or c) reacting a compound of the general formula Ia HN=C-X-NH-CH-CHz-COY1 (Ia) NHz COON
in which X has the meaning already mentioned at the beginning and Y1 denotes a protective group, with a compound of the formula IV
HR (IV) in which R has the meaning already mentioned at the beginning, and then removing the protective group, and by optionally con-verting the compound of the formula I into a physiologically tolerable salt.
The reactions fnr the preparation of the compounds of the formula I according to the invention are in principle acylation reactions. They are carried out according to known principles, in particular according to the known methods of peptide chemistry (cf., for example, Houben-Weyl, Methoden der organischen Chemie, (Methods of Organic Chemistry, vol. 15/2 (1974); Ullmanns Enzyklop~die der techn. Chemie, (Ullman's Encylopedia of Indus-trial Chemistry, 4th edition, vol. 19, pp. 542-548). Groups present which are not intended to react are protected by protec-tive groups which are removed again after the reaction. All protective groups can be used which are stable under the 2093'~'~0 zthesis conditions and can be removed again after the synthesis of the compounds according to the invention. Suitable amino protective groups are, for example (the customary abbreviations are in brackets): benzyloxycarbonyl (Z), tert-butoxycarbonyl (Hoc), 3,5-dimethoxyphenylisopropoxycarbonyl (Ddz), 2-(4-biphenyl)-iso-propoxycarbonyl (Bpoc), trityl (Trt), methyl-sulphonylethoxy-carbonyl (Msc), 9-fluorenylmethylcarbonyl (Fmoc).
Guanidino groups can be protected, for example, with NOZ
groups or with methoxytrimethylbenzenesulphonyl (Mtr) groups.
Methyl or ethyl esters, tert-butyl esters, allyl, benzyl or nitrobenzyl esters are used as carboxyl protective groups.
Suitable sulphur protective groups for mercapto radicals present in the molecule are, for example, benzyl (Hzl), p-methoxybenzyl (Mbzl), trityl (Trt) or acetamidomethyl (Acm).
The conditions for the introduction and removal of the protective groups are known from peptide chemistry (cf., for example, Houben-Weyl loc. cit., Ullmanns loc. cit.).
N02 groups (guanidino protection), benzyloxycarbonyl groups and benzyl ester groups are removed, for example, by hydrogenation. Protective groups of the tert-butyl type are removed by acidic hydrolysis.
The conditions for forming the peptide bond are also known from peptide chemistry (cf., for example Houben-Weyl loc.
cit., Ullmanns loc. cit.).
In the formation of the amide or peptide bond,,a direct removal of water in the reaction of the amino component with the -COON-containing component is possible by means of addition of suitable condensing agents, the reaction being carried out in anhydrous medium. Expediently, however, activation of the car-boxyl group is carried out before or during the reaction. The activation of the carboxyl group can be carried out, for example, by the-azide method or the mixed anhydride method. In the mixed anhydride method, for example, half esters of carbonic acid are used. The activation of the carboxyl group by the carbodiimide method, far example using dicyclohexylcarbodiimide (DCC), is particularly convenient, it being possible to carry out the reaction in a one-pot process. Expediently, the carbodiimide method is combined with the active ester method, i.e. an N-hydroxy compound forming an active ester, such as, for example, g ~Q9~'~'~~
hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt), is employed additionally to a carbodiimide. The use of HOBt or HOObt in combination with a carbodiimide, in particular DCC, is pre-y ferred.
The reactions are expediently carried out in a suitable inert solvent or dispersant, such as, for example, water, methanol, ethanol, acetonitrile, an amide, such as dimethyl-formamide or dimethylacetamide, N-methylpyrrolidone, methylene chloride or an ether, such as tetrahydrofuran, or a mixture of various solvents or dispersants.
The reactions can in principle be carried out at tempera-tures between -10°C and the boiling point of the salvent or dispersant used. In many cases, the reaction is carried out at 0 to 50°C, in particular at 0 to 30°C and preferably at 0 to room temperature.
In the preparation of the compounds of the formula I, the starting components and the activating agent or activating agent mixture optionally used are normally employed in approximately equimolar amounts.
The compounds of the fonaula I according to the invention form acid addition salts with inorganic or organic acids. Acids suitable for the formation of acid addition salts of this type are, for example: hydrogen chloride, hydrogen bromide, naphtha-lenedisulphonic acids, in particular naphthalene-1,5-disulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, glycolic, sorbic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, malefic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, nicotinic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. The acid addition salts are prepared as usual by combination of the components, expediently in a suitable solvent, or diluent.
Carboxyl groups in the compounds of the formula I can form salts by combining in a known manner with hydroxides, such as, for example, sodium hydroxide, potassium hydroxide, rubidium hydroxide, lithium hydroxide,, magnesium hydroxide, calcium hydroxide or organic amines.
The starting compounds of the formulae II and IIa can be 2fl93'~'~0 ~._epared from the corresponding amino compounds by guanylation or nitroguanylation. The amino compounds are known or can be pre-pared from the corresponding known starting compounds by cus-tomary methods. The following reagents can be reused for guanyl-ation and nitroguanylation:
1. 0-methylisothiourea (S. Weirs and H. Krommer, Chemiker Zeitung 98 (1974) 617-618);
2. S-methylisothiourea (R.F. aorne, M.L. Forrester and I.W. Waters, J. Med. Chem. 20 (1977) 771-776);
3. vitro-S-methylisothiourea (L. S. Hafner and R.F. Evans, J. Org. Chem. 24 (1959) 1157);
4. formamidinesulphonic acid (R. Kim, Y.-T. Lin and H.S. Mosher, Tetrahedron Lett. 29 (1988) 3183-3186);
5. 3,5-dimethyl-1-pyrazolylformamidinium nitrate (F. L. Scott, D. G. 0'Donovan and J.Reilly, J.Amer.Chem. Soc. 75 (1953) 4053-4054 ) .
The starting compounds of the formulae III and IIIa are synthesised stepwise from known compounds in a known manner, as a rule from the C-terminal end. The peptide couplings can be car-ried out using the known coupling methods of peptide chemistry.
The compounds of the formula III can be prepared in a manner known per se, for example, by reaction of a compound of the general formula IIIb Fi2N-CH-CH2-COOY2 (IIIb) ~oOH
with a compound HR.
The compounds of the formula IIIa can be prepared in a known manner, for example, by reaction of a compound of the general formula IIIc H2N-CH-CH2-COOY2 (IIIc) COR
where Y denotes hydrogea or a suitable protective group, with a sarcosine (HN(CH3)CHZCOOH) protected in a suitable manner.

zoo37~0 Starting compounds of the formula Ia are synthesised analogously to the compounds according to the invention. The starting compounds of the formula IV are known or can be prepared by known methods.
The novel aspartic acid derivatives of the formula I
according to the invention and their physiologically tolerable salts have the ability to inhibit the binding of fibrinogen, fibronectin and of von Willebrand factor to integrin receptors.
Integrins are cell membrane glycoproteins and mediate cell adhesion by interaction with a large number of extracelluar proteins, such as fibronectin, laminin, fibrinogen, collagen, vitronectin, and von Willebrand factor or with other cell mem-brane proteins, such as, for example, ICAM-1. An important receptor of the integrin family is glycoprotein IIb/IIIa locali-sed on blood platelets (fibrinogen receptor) - a key protein in platelet-platelet interaction and thrombus formation. A central fragment in the receptor recognition sequence of these proteins is the tripeptide Arg-Gly-Asp (E.Ruoslahti and M.D. Pierschbacher, Science 238 (1987) 491-497; D.R Phillips, I.F. Charo, L.V. Parise and L.A. Fitzgerald, Blood 71 (1988) 831-843).
The compounds of the general formula I according to the invention and their physiologically tolerable salts inhibit platelet aggregation, metastasis of carcinoma cells and osteo-clast formation on bone surfaces.
The compounds of the formula I and'their physiologically acceptable salts can therefore be administered to humans as medicines per se on their own, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral use and which contain, as active constituent, an effective dose of at least one compound of the formula I or of a salt thereof, in addition to one or more customary pharma-ceutically innocuous excipients, fillers or diluents and option-ally one or more additives.
The medicines cmn be administered orally, for example in the form of tablets, fi7.m tablets, coated tablets, hard and soft gelatine capsules, microcapsules, granules, powders, pellets, solutions, syrups, emulsions, suspensions, aerosols, foams, pills or pastilles. Administration can also be carried out, however, re~tally, for example in the form of suppo~i~~~i~ ~ ~or parenter-aw_y, for example in the form of injection solutions, or per-cutaneously, for example in the form of ointments, creams, gels, pastes, aerosols, foams, powders, tinctures, liniments or so-y called transdermal therapeutic systems (TTS) or nasally, for example in the form of nasal sprays.
The pharmaceutical preparations can be prepared in a manner known per se using pharmaceutically inert inorganic or organic auxiliaries, excipients, fillers or diluents. For the preparation of pills, tablets, film tablets, coated tablets and the pellet or granule fillings of hard gelatin capsules, calcium phosphates, lactose, sorbitol, mannitol, starches, prepared starches, chemically modified starches, starch hydrolysates, cellulose, cellulose derivatives, synthetic polymers, talc etc., for example, can be used. The excipients or diluents for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable excipients or diluents for the preparation of solutions and syrups are, for example, water, polyols, solutions of sucrose, dextrose, glucose, etc. Suitable excipients for the preparation of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils. Suitable exci-pients or diluents for ointments, creams and pastes are, for example, natural petroleum jelly, synthetic petroleum jelly, viscous and mobile paraffins, fats, natural or hardened vegetable and animal oils, neutral oils, waxes, wax alcohols, polyethylene .. ,. ;;7 glycols, polyacrylic acid, silicone gels, etc. Suitable excipients for microcapsules or implants are, for example, copolymers of glycolic acid and lactic acid.
Apart from the active compounds and diluents or exci-pients, the pharmaceutical preparations can additionally contain, in a manner known per se, one or more additives or auxiliaries, such as, for example, diaintegrants, binders, lubricants, wetting agents, stabilisers', emulsifiers, preservatives, sweeteners, colorants, flavourings or aromatisers, buffer substances, and also solvents or solubilisers, solution accelerators, antifoams, salt-forming agents, gel-forming agents, thickeners, flow regulators, absorbents, agents for achieving a depot effect or agents, in particular salts, for changing the osmotic pressure, 2093"x'70 sting agents or antioxidants, etc. They can also contain two or more compounds of the formula I or their pharmalogically accept-able acid addition salts and additionally one or more other therapeutically active substances.
Other therapeutically active substances of this type are, for example, agents promoting the circulation, such as dihydro-ergocristine, nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol, bencyclan, cinnarizine, naftidrofuryl, raubasine and vincamine; positively inotropic compounds, such as digoxin, acetyldigoxin, metildigoxin and lanthanoglycosides;
coronary dilators, such as carbochromen; dipyramidol, nifedipine and perhexiline; antianginal compounds, such as isosorbide dini-trates, isosorbide mononitrates, glycerol nitrates, molsidomine and verapamil; p-blockers, such as propranolol, oxprenolol, atenolol, metaprolol and penbutolol. The compounds may moreover be combined with other nootropic substances, such as, for example, piracetam, or CNS-active substances, such as pirlindol, sulpiride, etc.
The content of the active compound or the active com-pounds of the formula I in the pharmaceutical preparations can vary within wide limits and is, for example, 0.05 to 15% by weight, preferably 0.05 to 20% by weight. In solid presentation forms, such as coated tablets, tablets, etc., the content of one or more active compounds of the formula I is in many cases 2 to 20% by weight. Liquid presentation forms, such as drops, emul-sions and injection solutions often contain 0.05 to 2% by weight, preferably 0.05 to 1% by weight, of one or more active compounds of the formula I. The content of one or more active compounds of the formula I in the pharmaceutical preparations can optionally be partially replaced, for example up to 50% by weight, prefer-ably to 5 to 40% by weight, by one or more other therapeutically active substances.
The compounds of the formula ~, their physiologically acceptable salts and the pharmaceutical preparations which con-tain the compounds of the formula I or their physiologically acceptable salts as active compounds, can be employed in humans for the prophylaxis and therapy of, for example, arterial vas-cular diseases, such as acute myocardial infarct in combination with lysis therapy, post-infarct treatment, secondary prevention 2093"70 c myocardial infarct, reocclusion prophylaxis after lysis and dilatation, unstable angina pectoris, transitory ischaemic attacks, strokes, coronary bypass operation and reocclusion prophylaxis of bypass, pulmonary embolism, peripheral arterial occlusive diseases, dissecting aneurysm, for the therapy of venous and microcirculatory vascular disorders, such as deep vein thrombosis, disseminated intravascular clotting, post-operative and post-partum trauma, surgical or infectious shock, septicaemia, for therapy in hyperreactive platelet diseases, thrombotic thrombocytopenic purpura, preeclampsia, premenstrual syndrome, dialysis, extracorporeal circulation, and also in inflammations and in the treatment of tumours and the inhibition of osteoclast formation on the bone surface.
The dose can vary within wide limits and is to be adapted to the individual conditions in each individual case. In general, in the case of oral administration a daily dose of about 0.1 to 1 mg/kg, preferably 0.3 to 0.5 mg/kg, of body weight is appro-priate to achieve effective results, in the case of intravenous administration the daily dose is in general about 0.01 to 0.3 mg/kg, preferably 0.05 to 0.1 mg/kg, of body weight. The daily dose is normally divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations.
In some cases, depending on individual behaviour, it may be necessary to deviate upwards or downwards from the given daily dose. Pharmaceutical preparations_normally contain 0.2 to 50 mg, preferably 0.5 to 10 mg, of active compound of the general for-mula I or one of its pharmaceutically acceptable acid addition salts per dose.
The compounds of the formula I are in particular tested for their inhibiting action in blood platelet aggregation and the adhesion of fibrinogen to blood platelets. The measurement of aggregation and the binding of ~'I-fibrinogen is carried out on filtered, plasma-free human platelets. Platelet activation is effected by means of ADP or thrombin.
As a functional test, the inhibition of aggregation of filtered human platelets is measured after ADP or thrombin stimu-lation by the compounds according to the invention. The ICso value of inhibition is given.

' ference: G.A. Mar uerie et al., J.
g ~~~~.~~h~m. 254 ( 1979 ) , The Ri value of the inhibition of binding of lzsl_fibrinogen after stimulation with ADP (10 gym) is given.
Reference: J.S. Bennett and G. Vilaire, J. Clin. Invest. 64, (1979), 1393-1401 E. Rornecki et al., J. Hiol. Chem. 256 (1981), 5695-5701 G.A. Marguerie et al., J. Biol. Chem. 254 (1979), 5357-5363 G.A. Marguerie et al., J. Biol. Chem. 255 (1980), 154-161 In the testing of the inhibition of fibrinogen formation and the inhibition of aggregation, the following results are obtained for the compounds of the following examples:
Inhibition of platelet Inhibition of fibrinogen Example aggregation binding ADP (~M) Thrombin (pM) R~ (pM) 9 2 2 1.8 12 8 4 3.1 14 4.5 1.5 0.8 ". not measured In the examples below, the following abbreviations, inter alia, are used:
Asp = aspartic acid Val = ~ valine Bn = benzyl HOBt = 1-hydroxybenzotriazole DMF = dimethylformamide DCC = dicyclohexylcarbodiimida DCH = dicyclohexylurea Sarc = sarcosine I

E X A M P I. E S
Example 1:
p-(4-(N-Ani.dinopiperidinyl)ethyl)benzoyl-L-aspartyl-L-valine ay p-(4-(Nitroamidinopineridinyllmethvl)benzoic acid 3.42 g (25.3 mmol) of vitro-S-methylisothiourea are added at 0°C
with stirring to a solution of 4.96 g (22,6 mmol) of p-(4-piperi- .
dinylmethyl)benzoic acid and 1.81 g (45.2 mmol) of NaOH in 50 ml of water. After stirring at room temperature for 24 h, the mix-ture is acidified to pH = 1 with conc. HC1. The precipitate is filtered off, washed with water and dried.
Yield: 6.13 q .(89%);
melting point: 260 to 261°C (dec).
b1 n-(4-N-Nitroamidinopiperidi,nullmethvllbenzoyl-Asn(OBn.)-Val-OBn 0.83 q (3.64 mmol) of DCC are added at 0°C to a solution of 1.11 g (3.64 mmol) of p-(4-(nitroamidinopiperidinyl)methyl)-benzoic acid, 1.50 g (3.64 mmol) of H2N-Asp(OBn)-Val-OBn and 0.49 g (3.64 nunol) of HOBt in 25 ml of.DMF. After stirring at 0°C
for 4 h, the mixture is stirred at room temperature for a further 12 h. The precipitated DCH is filtered oft and the residue is purified by chromatography.
Yield. 2.43 g (95%), still contains some DCH;
melting point: 60 to 75°C.
c 1 p- (,4-N-Ami.dinopit~eridinyl l methyl ) benzoyl-L-aspartvl-L-valine .
2.29 g (3.27.mmol) of p-(4-(N-nitroamidinopiperidinyl)methyl)-benzoyl-Asp(OBn)-Val-OHn are dissolved in 20 ml of methanol/10 ml of DMF and treated with 0.25 g of Pd/C (10 %): After hydrogena-tion at room temperature fox 6 h, 20 m1 of water and 20 ml of .glacial acetic.acid are,added and the mixture is hydrogenated for a further 1.5 h. The catalyst is filtered off and the residue is chromatographed on "Sephadex LH-20 (methanol).
Yield: 1.47 g (94%); ., melting point: 260 to 270°C; , [a]D = -5.5° (c = 1 in glacial acetic acid) am:ale 2: ~~g3770 p-(4-(H-Aaidinopiperidinyl)methyl)benzoy -aspartyl-cyclohexylaaide a) 0-(4-(N-Nitroamidinoniperidin~llmethyl]benzoyl-Aso(OHnI-cyclo-hex~lamide Analogously to lb), 1.51 g (4.93 mmol) of p-(4-(nitroamidino-piperidinyl)methyl)benzoic acid are allowed to react with 1.50 g (4.93 mmol) of HZN-Asp(OHn)cyclohexylamide.
Yield: 2.3 g (79%);
melting point: 70 to 75°C.
b 1 p- ( 4-N-Ami.dino~pigeridinyl l meth~,rl_]~ benzoyl-L-as~artyl cyclo hexylamide 2.1 g (3.54 mmol) of p-(4-N-nitroamidinopiperidinyl)methyl)-benzoyl-Asp(OBn)cyclohexylamide are hydrogenated analogously to lc).
Yield: 1.6 g (82%);
melting point: 220 to 225°C;
[a]D = -5.8° (c = 1.2 in glacial acetic acid) Example 3:
p-(4-~i-Amidinopiperidinyl)methyl)benzoyl-L-aspartyl-3,3-diphenyl-propylaaide a 't t 0 -3 dichenyloroovlamide Analogously to lb), 1.1 g (3.6 mmol) of p-(4-(nitroamidinopiperi-dinyl)methyl)benzoic acid are allowed to react with 1.50 g (3.6 mmol) of HZN-Asp(OHn)-3,3-diphenylpropylamide.
Yield: 2.15 g (85%) of acetate;
melting point: 90 to 100°C.
1~ 1 n- ( 4-N-Ami.dinog~,peridinyl f methy enzoyl-L-asgart~rl-3 , 3-d=Dhenvl Dropyl ate!; de 1.97 g (2.8 mmol) of p-(4-(N-nitroamidinopiperidinyl)methyl)-benzoyl-Asp(OHn)-3,3-diphenylpropylamide are hydrogenated analo-gously to lc).
Yield: 1.57 g (89%) of acetate;

2093'~'~0 m~.tting point: 160 to 175°C;
[aJD = -6.4° (c = 1.1 in glacial acetic acid) The following were prepared analogously:
Example 4:
p-(4-N-Amidinopiperidinyl)methyl)benzoyl-L-aspartyl-isopropyl-aaide Melting point: 206 to 208°C;
[a]o° _ + 5.6° (c = 1.2 in glacial acetic acid) Example 5:
p-(2-Guanidinoethyl)phenoxyacetyl-L-aspartyl-cyclohexylamide a~g- ~( 2-Nitroguanidinoethyl t ~ ha enoxyacetyl-L-Asp ( OBn 1-c~clohexyl-amide Analogously to lb), 1.48 g (5.26 mmol) of p-(2-nitroguanidino-ethyl)phenoxy acetic acid are allowed to react with 1.60 g (5.26 mmol) of HZN-Asp(OBn)cyclohexylamide.
Yield: 2.51 g (84%);
melting point: 140 to 144°C.
b1 n-(2-Guanidinoethvllnhenoxvacetvl-L-aspartvl-cvclohexv~amide 1.4 g (2.46 mmol) of p-(2-nitroguanidinoethyl)phenoxyacetyl-L-Asp(OHn)cyclohexylamide are hydrogenated analogously to lc).
Yield: 0.6 g (56%);
melting point: 215 to 219°C;
[a]o° _ +4° (c ~ 1 in glacial acetic aaid).
The following were prepared analogously to Example 5:
Exam le 6:
p-(2-Gnanidinoethyl)phenoxyacetyl-L-aspartyl-3,3-diphenylpropyl-aude melting point: 194°C (dec.);
[a]o ~ +3.5° (c ~ 1.1 in glacial acetic acid) _ 2093'~'~0 F mole 7:
p-(2-Guanidinoethyl)phenoxyacetyl-L-aspartyl-D,L-~-phenyl-p-alanine ethyl ester [a]o° _ +9.1° (c = 1 in glacial acetic acid) Example 8:
p-(2-Guanidinoethyl)phenoxyacetyl-L-aspartyl-amido-cyclohexan-1-carboxylic acid Melting point: 190 to 199°C;
[a]D = -4.8° (c = 1.2 in glacial acetic acid) Example 9:
p-Guanidino~ethylbenzoylsarcosyl-Z-as~yl-3.3-diphenYlpr~l-a~' de enzovl-Sarc-Asn(OBn1-3.3-dinhenvlDrocvl-Analogously to lb), 0.59 g (2.48 mmol) of p-nitroguanidinomethyl-benzoic acid is allowed to react with 1.21 g (2.48 mmol) of HZN-Sarc-Asp-(OBn)-3,3-diphenylpropylamide. __ Yield: 1.37 g (78%).
b1 o-.Guanidinomethylbenzoyrlsarcosyl-L-aspartyl-3.3-diphenyluro-pylamide 1.25 g (1.77 mmol) of p-nitroguanidinoethylbenzoyl-Sarc-Asp-(OHn)-3,3-diphsnylpropylamide are hydrogenated analogously to lc).
Yield: 0.60 g (54%);
melting point: 180 to 195°C;
[a]o° _ -17.6° (c = 1 in glacial acetic acid) E~ple 10 p-Guanidina~ethylbenzoylsarcosyl-L-aspartyl-aaido-cyclohexane-1-carboxylic acid Melting point: 180 to 185°C;
[a]D = -25.8° (c = 1 in glacial acetic acid) zoo3~~0 _E mple 11:
traps-4-Guanidinomethylcyclohexanecarboxylsarcosyl-L-aspartyl-amido-cyclohexane-1-carboxylic acid al Benzvl traps-4-nitroQUanidinomethylcyclohexanecarboxyl-Sarc-Asp(OBn1-amido~clohexane-1-carboxylate Analogously to lb), 0.48 g (1.96 mmol) of traps-4-nitroguanidino-methylcyclohexane-1-carboxylic acid is allowed to react with 1.00 g (1.96 mm:ol) of benzyl HZN-Sarc-Asp(OBn)amidocyclohexane-i-carboxylate.
Yield: 1.25 g (87%).
traps-4-Guanidinomethvlcvclohexanecarboxvlsarcosvl-L-asnartvl-am~.d' ocyclohexane-1-carboxylic acid 1.13 g (1.54 mmol) of benzyl traps-4-Nitroguanidinomethylcyclo hexanecarboxyl-Sarc-Asp(OBn)-amidocyclohexane-1-carboxylate are hydrogenated analogously to lc).
Yield: 0.83 g (94%);
melting point: 210 to 220°C;
[a]D = -24.6° (c = 1.1 in glacial acetic acid) Example 12:
traps-4-Guanidinossethylcyclohezanecarboxylsarcosyl-L-aspartyl-benzhydrylamide [a]p° _ -22.8° (c = 1.1 in glacial acetic acid) Example 13:
p-(2-Guanidinoethyl)phenoxyacetyl-L-aspartyl-D,L-~-phenyl-~9-alanine a) 8-(2-Nitroguanidinoethyll hg_enoxyacetyl-L-Asg(OBn1-D,L-B-~yl-9-alanine benzyl ester Analogously to lb), 0.92 g (3.26 msiol) of p-(2-nitroguanidino-ethyl)phenoxy acetic acid is allowed to react with 1. 5 g (3.26 nm:ol) of HZN-Asp(OBn)-D,L-p-phenyl-p-alanine benzyl ester.
Yield: 1.28 g (54%).

k g- ( 2-Guanidinoethyl ) ohenoxyacetyl-L- ~ ~ ~ ~yl~D~ L-9_,phenyl-,B,-a an' a 1.24 g (1.71 mmol) of p-(2-nitroguanidinoethyl)phenoxyacetyi-L-Asp(OBn)-D,L-~9-phenyl-~9-alanine benzyl ester are hydrogenated analogously to lc).
Yield: 0.58 g (68%);
melting point: 155 to 175°C;
[a]D° = 0.03° (c = 1 in glacial acetic acid) Example 14:
p-(4-N-Amidinopiperidinyloxy)beazoyl-L-aspartyl-L-valine ~p(4-N-Nitroamidino.~ineridinvloxvlbenzoyl-L-As~l_OBn1-L-Val-OBn Analogously to lb), 0.3 g ( = 0.97 mmol) of p-(4-N-nitroamidino-piperidinyloxy)benzoic acid is allowed to react with 0.4 g (0.97 mmol) of H2N-Asp(OBn)-Val-OBn.
Yield: 0.55 g (81%).
4-N-Amidinocineridinvloxvbenzovl-L-asnartvl-L-valine 0.36 g (0.51 mmol) of p-(4-N-nitroamidinopiperidinyloxy)benzoyl-L-Asp(OBn)-L-Val-OBn is hydrogenated analogously to lc).
Yield: 0.23 g (94%);
melting point: 150°C.
Examgle 15:
p-4-%1-Asidinopiperidi.nylbenzoyl-L-aspartyl-L-valine ai n-4-NitroamidinopiDeridinylben~c~yl-Asg,(OBn1-L-Val-OHn Analogously to lb), 2.5 g (8.55 mmol) of p-4-nitroamidino-piperidinylbenzoic acid are allowed to react with 3.56 g (8.55 meal) of H2N-Asp(OBn)-Val-OBn.
Yield: 1.92 g (25%).
b1 n-4-N-Amidinonineridinvlhen2ovl-L-asnartvl-L-valine Analogously to lc), 0.42 g (0.61 mmol) of p-4-nitroamidino-piperidinylbenzoyl-Asp(OBn)-L-Val-OBn is hydrogenated.
Yield: 0.14 g (41%);
melting point: 190°C (dec.).

F m,.gle 16:
p-(3-1~-Asiidinopyrvolidinyloxy)benzoyl-L-aspartyl-L-valine aJ ~-(3-N-Nitroamidinogyrvolidin,~iloxylbenzoyl-L-AspsOBnl-L-Val-Analogously to lb), 0.29 g (0.99 mmol) of p-(3-N-nitroamidino-pyrvolidinyloxy)benzoic acid is allowed to react with 0.41 g (0.99 mmol) of HZN-Asp(OHn)-Val-OHn.
Yield: 0.63 g (92%).
~,L p-l3-N-Amidinogyrvolidinyl~lbenzoyl-L-aspartyl-L-valine 0.63 g (0.92 mmol) of p-(3-N-nitroamidinopyrvolidinyloxy)benzoyl-L-Asp(OBn)-L-Val-OBn is hydrogenated analogously to lc).
Yield: 0.11 g (27%);
melting point: 250°C;
[a]o = -5.95° (C = 0.84 in methanol/water 2:1).
The following examples A to H relate to pharmaceutical preparations.
Examgle A
Emulsions containing 3 mg of active compound per 5 ml can be prepared according to the following recipe:
Active compound 0.06 g Neutral oil q s Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q. s.

Pure glycerol 0.6 to 2 g Flavourings q. s.

Water (demineralised or distilled) to 100 ml Example H
Tablets can be prepared according to the following formula-tion~
Active compound 2 mg Lactose 60 mg 1~~-' ze starch ~ ~ ~s~~
Soluble starch 4 m( Ig Magnesium stearate 4 me 100 mg Example C
The following composition is suitable for the production of soft gelatine capsules containing 5 mg of active compound per capsule:
Active compound 5 mg Mixture of triglycerides of coconut oil 51 0 mg Capsule contents 155 mg Exams3e D
The following formulation is suitable for the production of coated tablets:
Active compound 3 mg Maize starch 100 mg Lactose 55 mg sec. Calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 5 mg Colloidal silica 4 ma 200 mg Ex~ple E
Coated tablets, containing a compound according to the invention and another therapeutically active substance:
Active compound 6 mg Propanolol 40 mg Lactose 90 mq Maize starch 90 mg sec. Calcium phosphate 34 mg Soluble starch 3 m9 Magnesium stearate 3 mg Colloidal silica 270 mg zo93~~0 Coated tablets, containing a compound according to the invention and another therapeutically active substance:
Active compound 5 mg Pirlindol 5 mg Lactose 60 mg Maize starch 90 mg sec. Calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 3 mg Colloidal silica 4 me 200 mg Example C
Capsules, containing an active compound according to the invention and another therapeutically active substance:
Active compound 5 mg Nicergoline 5 mg Maize starch 185 mq, 195 mg Ex~ple H
Injection solutions containing 1 mg of active compound per ml can be prepared according to the following recipes Active compound 1.0 mg Polyethylmnm glycol X100 0.3 mg Sodium chloride . 2.7 mg Water for injection purposes to 1 ml

Claims (11)

1. An aspartic acid derivative of general formula I:

or a physiologically acceptable salt thereof, wherein:
X denotes:

wherein:
A denotes -(CH2)m-, -O- or a direct bond, k denotes a number from 0 to 7, and m denotes a number from 0 to 4, and R denotes -OR1, -NR2R3 or -NH-R4, wherein:
R1 denotes hydrogen, C1-C28alkyl, C3-C28cycloalkyl or phenyl, wherein the C1-C28alkyl, the C3-C28cycloalkyl or the phenyl is unsubstituted or mono- or polysubstituted by identical or different radicals,selected from the group consisting of hydroxyl, carboxyl, C1-C4alkoxycarbonyl, arylmethoxycarbonyl, carboxamido, C1-C4alkylaminocarbonyl, amino, mercapto, C1-C4alkoxy, C3-C8-cycloalkyl, imidazolyl, indolyl, pyrrolidinyl, hydroxypyrrolidinyl, halogen, phenyl and phenoxy, each of which is unsubstituted or monosubstituted or polysubstituted by hydroxyl, C1-C4alkyl, halogen, nitro or trifluoromethyl, C3-C81alkyl interrupted one or more times by -O- and (C3-C81alkoxy)carbonyl interrupted one or more times by -O-, R2 and R3 independently of one another denote hydrogen, R1 or, together with the nitrogen to which they are bonded, a 5-or 6-membered, saturated heterocyclic ring which can additionally contain -O- or -NR5-, or R2 denotes hydrogen and R3 denotes a radical of the general formula:

wherein:
R4 denotes a radical of an amino acid or of a dipeptide, in which the peptide bond can also be reduced to -NH-CH2-, R5 denotes hydrogen, C1-C4alkyl, phenyl, C1-C4alkylphenyl, C1-C4alkoxyphenyl, R6 denotes hydrogen, C1-C4alkyl, phenyl, phenyl(C1-C4) alkyl, and p and q independently of one another denote a number from 1 to 20.
2. A compound according to claim 1, wherein the radical X
contains 1,4- or 1,3-phenylene, p-piperidinyl or 3-pyrrolidinyl.
3. A compound according to claim 1, wherein k = 2 or 3, or m = 1 or 2.
4. A compound according to claim 1, 2 or 3, wherein R
denotes -NR2R3 or -NHR4, wherein R2, R3 and R4 are as defined in claim 1.
5. A compound according to claim 1, 2 or 3, wherein R
denotes -NHR4, where R4 represents a valine, phenylalanine or phenylglycine radical, which is formally formed by removal of the amino group from valine, phenylalanine or phenylglycine.
6. A process for the preparation of an aspartic acid derivative of the general formula I according to claim 1, which comprises:
a) reacting a compound of the general formula II:

wherein Z denotes:

wherein A and k are as defined in claim 1, with a compound of the general formula III:

wherein R is as defined in claim 1, or, if required, converting the compound of the general formula I into a physiologically acceptable salt.
7. A process according to claim 6, wherein any amino amidino, guanyl, mercapto or carboxyl group in the compounds of general formulae II and III carry protective groups which may be removed after reaction is complete.
8. Use of a compound of general formula I according to any one of claims 1 to 5, or a physiologically acceptable salt thereof, as an inhibitor of platelet aggregation, metastasis of carcinoma cells or osteoclast formation on a bone surface.
9. A pharmaceutical composition comprising an effective amount of a compound of general formula I
according to any one of claims 1 to 5, or a physiologically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
10. A method of making a pharmaceutical composition, which method comprises incorporating a compound of general formula I according to any one of claims 1 to 5, or a physiologically acceptable salt thereof, as active ingredient in the composition.
11. A commercial package comprising a compound of general formula I according to any one of claim 1 to 5, or a physiologically acceptable salt thereof, or a composition according to claim 9, together with instructions for use thereof for the inhibition of platelet aggregation, metastasis of carcinoma cells or osteoclast formation on a bone surface.
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EP0565896A2 (en) 1993-10-20
EP0565896A3 (en) 1994-01-12
ZA932535B (en) 1993-11-04
IL105355A (en) 1998-03-10
EP0784058B1 (en) 2005-10-26
KR930021605A (en) 1993-11-22
CZ49493A3 (en) 1994-02-16
AU659299B2 (en) 1995-05-11
IL105355A0 (en) 1993-08-18
HU9301071D0 (en) 1993-06-28
JPH07109256A (en) 1995-04-25
TW267158B (en) 1996-01-01
AU3683693A (en) 1993-10-14
DE4212304A1 (en) 1993-10-14
US5399570A (en) 1995-03-21
DE59310379D1 (en) 2005-12-01
ES2250980T3 (en) 2006-04-16
EP0784058A1 (en) 1997-07-16
CA2093770A1 (en) 1993-10-14
HU218206B (en) 2000-06-28
JP3504287B2 (en) 2004-03-08
CZ290280B6 (en) 2002-07-17
SK282125B6 (en) 2001-11-06
HUT64016A (en) 1993-11-29
EP0784058B8 (en) 2005-12-28
ATE307825T1 (en) 2005-11-15
SK33493A3 (en) 1994-02-02

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