IL104960A - 4-oxo-2-thioxoimidazolidine derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

4-oxo-2-thioxoimidazolidine derivates have the general formula (I), in which R?1 to R?4 and Y have the definition given in the description. Also disclosed is a process for preparing these derivates and their use as inhibitors of thrombocyte aggregation, of the formation of carcinoma cell metastases and of the binding of osteoclalsts to bone surfaces.

Description

it-0xo-2-thioxoimidazolidine derivatives, their preparation and pharmaceutical compositions containing them CASSELLA AKTIENGESELLSCHAFT C: 889808 The present invention relates to 4-oxo-2-thioxoimidazolidine derivatives , their preparation and their use as inhibitors of blood platelet. ggregation.

Hydantoin derivatives with platelet aggregation-inhibiting activity are described in EP-A 449,079 which corresponds to IL 97657, as well as in the German Patent Application 4,126,277. Further research has shown that the compounds of the present invention are also potent inhibitors of blood platelet aggregation.

The present invention relates to compounds of the general formula I caciH H i I 0 CH? — Y — N H — C — { > S RJ in whic Y denotes -(CH2)aj-C0-/ where m stands for a whole number from 1 to 4, or R1 denotes -(CH2)n-NH-X, where n stands for a whole number from 1 to 6, -(CH2)p-CeH<-NH-X, -(CH2)p-C6H,-C(=NH) -NH2 or -(CH2)p-CeHil-CH2-srH-X/ where p in each case stands for 1 or 2, \ \ t where, however, CE-R can also be replaced by C=CH-C6H4-X ; / . ■ / X1 denotes -NH2, -C¾NHX or -C(=NH)-NH2; X denotes hydrogen, ( C^-C8) -alkyl or a radical of the formula II R ' -NH-C=N-R ' ' ^11^ I where R' and R", independently of each other, stand for hydrogen or ( C Cg) -alkyl; R2 denotes hydrogen or (C^Cg) -alkyl; R3 denotes hydrogen or phenyl; R* denotes hydrogen, -COOR3 or -CO-NH-R5; R5 denotes hydrogen, or ( x-C2a ) -alkyl which is optionally - 1 - n radicals from the series comprising hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-(C1-Cla) -alkylaminocarbonyl, amino- (C2-C ) -alkylaminocarbonyl, amino- (Cj-C3) alk lphenyl- ( ^-C,) - alky 1 aminocarbonyl, (Cy-C^) -alkylcarbonylamino- (Cj-Ca) -alkyl- phenyl- (C -C3) -alkylaininocarbonyl , (Ci~C a) -alkylcarbonylajiino- {C2-Cllt ) -alky laminocarbonyl , phenyl- ( Cl-Ca ) -alkoxycarbonyl , amino , "mercapto, (C1-C1a) -alkoxy , (Cr-C1a) -alkoxycarbonyl, (C3-Ca) -cyclo-alkyl, halogen, nitro, trif luoromethyl or a radical Rs; R6' denotes phenyl, phenyl-(C1-C8)-alkyl, a mono- or bicyclic, 5- to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated, and which can contain, as the hetero element, one, two or three identical or different nitrogen, oxygen or sulphur atoms, or a radical R7, where the phenyl radical, and independently thereof the heterocyclic radical, can optionally be substituted once or more ' than once by identical or different radicals from the series comprising ( CrCia) -alkyl, {C^- ^) -alkoxy, halogen, nitro or tri- f luoromethyl ; R7 denotes -NRaR9, -ORa, -SRa, an amino acid side chain, a natural or unnatural amino acid residue, as well as their esters and amides, where free functional groups can optionally be protected by protective groups which are customary in peptide chemistry, or denotes a radical -COR7; R8 denotes hydrogen, (C2-C18)-alkyl, phenyl-(CrC8)-alkyl, (CrC18)-alkylcarbonyl, (C1-C18)-alkoxycarbonyl, phenylcarbonyl, phenyl-(CrC8)-alkylcarbonyl, phenyl-(C1-C18)-alkoxycarbonyl,which can optionally be substituted by an amino group, or a natural or unnatural amino acid residue; and R9 denotes hydrogen, (C1-C18)-alkyl, phenyl or phenyl-(C1-C8)-alkyl; as well as their physiologically tolerable salts. ra ca s w c are pre erre are met y , e y , n-propy , i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl. The same applies to radicals such as alkoxy, alkoxycarbonyl or aralkyl.

(C3-Ca) -cycloalkyl radicals are, in particular, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and eyelooctyl, which radicals may, however, also be substituted by, for example, (Ci-C^,) -alkyl . 4-Methylcyclohexyl and 2 , 3-dimethyl-cyclopentyl are examples of substituted cycloalkyl radicals.

Examples of (C6-C1 ) -aryl groups are phenyl, naphthyl, biphenylyl or fluorenyl, and phenyl and naphthyl are preferred. The same applies to radicals such as aralkyl or arylcarbonyl . Aralkyl radicals are, in particular, benzyl as well as 1- and 2-naphthylmethyl , which radicals may also be substituted. Examples of substituted aralkyl radicals are halobenzyl or (Cj-C4)-alkoxybenzyl .

If phenyl is substituted twice, the substituents may be in the 1,2, 1,3 or 1,4 position in relation to each other. The 1,3 and the 1,4 positions are preferred.

Examples of heterocycles in the sense of the above definitions are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindazolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl , quinoxalinyl, quinazolinyl, cinnolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohep -fused derivative of these radicals.

These heterocycles may be substituted on a nitrogen atom by oxide, (C1-C7) -alkyl, e.g. methyl or ethyl, phenyl or phenyl-(Cx-C4) -alkyl, e.g. benzyl, and/or on one or more carbon atoms by (Ci-C -alkyl, halogen, hydroxyl, (Ci-CJ -alkoxy, e.g. methoxy, phenyl-(Ci-C -alkoxy, e.g. benzyloxy or oxo, and partially or completed saturated.

Examples of such radicals are 2- or 3-pyrrolyl, phenyl-pyrrolyl, e.g. 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methyl-imidazolyl, e.g. l-methyl-2-, 4- or 5-imidazolyl, 1, 3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-or 5-indolyl, substituted 2-indolyl, e.g. 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4, 5-dimethyl-2-indolyl, hepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-iso- quinolyl, 1-oxo-l, 2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or benothiazolyl. Examples of partially hydrogenated or completely hydrogenated heterocyclic rings are dihydropyridinyl , pyrrolidinyl , e.g. 2-, 3- or 4-N-methylpyrrolidinyl, piperazinyl, morpholinyl , thio- morpholinyl, tetrahydrothienyl, benzodioxolanyl .

Halogen stands for fluorine, chlorine, bromine or iodine, in particular for fluorine or chlorine.

Natural and unnatural amino acids may, if they are chiral, be present in the D or L form. a-Amino acids are preferred. Examples which may be mentioned are (cf . Houben-Weyl, Methoden der organischen Chemie (Methods of organic chemistry) Volume XV/1 and 2, Stuttgart, 1974): Aad, Abu SAbu, ABz, 2ABz, Aca, Ach, Acp, Adpd, Ahb, Aib, j3Aib, Ala, /SAla, AAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2,. Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Pel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu,- hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, ^Lys, ALys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, Thi, Thr, Thy, Thx, Tia, Tie, 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.

Amino acid side-chains are understood to mean side-chains of natufal or unnatural amino acids. Azaa ino acids are natural or unnatural amino acids in which the central component -CHR-or -CH2- is replaced by -NR- or -NH-.

Suitable imino acid residues are, in particular, radicals from heterocycles from the following group: Pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydro-quinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1 ]heptane-3-carboxylic acid; 2-azabicyclo- boxylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro-( bxcyclo [ 2.2.1] heptane ) -2 , 3-pyrrolidine-5-carboxylic acid; spiro-( bxcyclo [2.2.2] octane ) -2 , 3-pyrrolidine-5-carboxylic acid ; 2-azatricyclo[ 4.3.0. l6'9]decane-3-carboxylic acid; decahydrocyclo-hepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c] pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-l-carboxylic acid; 2 , 3 , 3a, , 6a-hexa-hydrocyclopenta[b]pyrrole-2-carboxylic acid; 2, 3, 3a, 4 , 5, 7a-hexa-hydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid; hydroxyproline-2-carboxylic acid; which may all be optionally substituted (see the following formulae) : US-A 4,344,949 which corresponds to IL 63,806, US-A 4,374,847, US-A 4,350,704 which corresponds to IL 62,294, EP-A 29,488, EP-A 31,741 which corresponds to IL 63,940, EP-A 46,953, EP-A 49,605 which corresponds to IL 63;806, EP-A 49,658 which corresponds to IL 63,940, EP-A 50,800, EP-A 51,020 which corresponds to IL 64,075, EP-A 52,870, EP-A 79,022 which corresponds to IL 84,056, EP-A 84,164 which corresponds to IL 67,572, EP-A 89,637 which corresponds to IL 68,199, EP-A 90,341, EP-A 90,362 which corresponds to IL 68,267, EP-A 105,102, EP-A 109,020 which corresponds to IL 70,207 and IL 80,105, EP-A 111,873 which corresponds to IL 70,446 and IL 83,917, EP-A 271,865 which corresponds to IL 84,841 and EP-A 344,682 which corresponds to IL 90,482.

Dipeptides may contain as components natural or unnatural amino acids, imino acids and azaamino acids. Furthermore, the natural or unnatural amino acids, imino acids, azaamino acids and dipeptides may also be present as esters or amides, such as, for example, methyl ester, ethylamide, semicarbazide or ω-amino- (C -C8) -alkylamide.

Functional groups of the amino acids, imino acids and dipeptides may be present in protected form. Suitable protective groups, such as, for example, urethane protective groups, car-boxyl 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. Particular mention may be made of: Aloe, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (N02) , Z (HalJ , Bobz, Iboc, Adpoc, Mboc, Acm, tert. -Butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt .

Physiologically tolerated salts of the compounds of the general formula I are, in particular, pharmaceutically usable or non-toxic salts.

Such salts are formed, for example, from those compounds of the general formula I which contain acidic groups, e.g. car-boxyl, with alkali metals or alkaline earth metals, such as, for example, Na, K, Mg and Ca, as well as with physiologically tolerated organic amines, such as, for example, triethylamine and Tris- ( 2-hydroxy-ethyl) -amine.

Compounds of the general formula I which contain basic groups, e.g. an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydrochloric acid, sulphuric acid or phosphoric acid, and with organic carboxylic or sulphonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulphonic acid.

Y denotes - (CH2)o-C0-, where m stands for 1 or 2, or R1 denotes -CH2-C6H4-NH-C(=NH)-NH2; -CH2-C6H<-C ( =NH) -NH2 or -CH2-C6H4-CH2-NH2; R2 denotes hydrogen or methyl; R3 denotes hydrogen; and R* denotes -CO-NH-R5, where -NH-R5 stands for an a-amino acid residue or its (d-amino-(C2-C8) -alkylamide .

In this context, the valine residue, the phenylalanine residue or the phenylglycine residue are particularly preferred a-amino acid residues standing for -NH-R3.

The 4-aminobutylamide is a particularly preferred ω-amino- (C2-Ca) -alkylamide .

The compounds according to the invention of the general formula I may be prepared by fragment condensation of a compound of the general formula III with a compound of the general formula IV COOH I where the radicals R1 to R4 and Y are defined as indicated above.

The methods of peptide chemistry which are known per se are advantageously used for the condensation of the compounds of the general formula III with those of the general formula IV (see e.g. Houben eyl, Methoden der organischen Chemie, Volume 15/1 and 15/2, Stuttgart, 1974).

For this, it is necessary as a rule that amino groups groups . e same app es o e car oxy groups o t e compound of the general formula IV, which are preferably present as benzyl esters or tert-butyl esters . Protection of amino groups is unnecessary if the amino groups which are to be generated are present as nitro or cyano groups and are only formed by hydrogen-ation after the coupling.

After the coupling, the protective groups which aire present are eliminated in a suitable manner. For example, N02 groups (guanidino protection), benzyloxycarbonyl groups and benzyl esters may be removed by hydrogenation . Protective groups of the tert-butyl type are cleaved under acid conditions, while the 9-fluorenylmethyloxycarbonyl residue is removed by secondary amines .

The starting compounds of the general formula III may be obtained as follows: Reaction of amino acids, N-alkylamino acids or, preferably, theirmethyl, ethyl, benzyl or tert-butyl esters, for example a compound of the general formula V R1 R2-NH-CH-COOCH3 ^ ' with an isolthiocyanatoalkanecarboxylic acid ester, for example of the general formula VI S=C=N- ( CH2)m-COOCH3 (VI ) , in which R1, R2 and m are defined as indicated above, results in thiourea derivatives, for example of the general formula VII S R2 R1 11 I I (vii) , CH3OOC- ( CH2 ) m-NH-C-N CH-COOCH3 which, by heating with acid to hydrolyse the ester functionalities, cyclise to compounds of the general formula Ilia blocked by protective groups, such as N02 or Mtr. Amino groups in the side chain must likewise be present in protected form (for example as Boc or Z derivatives) or still be in the form of an N02 or cyano f nctionality, which can later be reduced to the amino group or, in the case of the cyano group, also be converted into the formamidino group.

Compounds of the general formula Illb can be obtained in an analogous manner if, instead of isothio- cyanatoalkanecarboxylic acid esters, the isothiocyanates of the aminoben2oic acid esters are employed.

Compounds of the general formula IIIc S can be obtained in analogy with Granacher and Landolt, Helv.

Chim. Acta 10 (1927) 808 by reacting thiohydantoins of the general formula VIII 5 with aldehydes of the general formula IX The guanylation of the amino functionality may be carried out with the following reagents: 1. O-Methylisothiourea (S. Weiss and H. Krommer, Chemiker Zeitung 98 (1974) 617-618), Waters, J. Med. Chem. 20 (1977) 771-776), 3. Nitro-S-methylisothiourea (L.S. Hafner and R.E . Evans, J. Org. Chem. 24 (1959) 1157), 4. Formamidinosulphonic acid (K. Kim, Y.-T. Lin and H.S. Mosher, Tetrah. Lett. 29 (1988) 3183-3186), 5. 3 , 5-Dimethyl-l-pyrazolylformamidinium nitrate (F.L. Scott, D.G. 0'Donovan and J. Reilly, J. Amer. Chem. Soc. 75 (1953) 4053- 4054).

Formamidines can be prepared from the corresponding cyano compounds by addition of alcohols (e.g. methanol or ethanol) in acid anhydrous medium (e.g. dioxane, methanol or ethanol) and subsequent treatment with ammonia in alcohols (e.g. isopropanol, methanol or ethanol) (G. Wagner, P. Richter and Ch. Garbe, Pharmazie 29 (1974) 12-55). An additional method for preparing formamidines is the addition of H2S onto the cyano group, followed by a methylation of the resulting thioamide and subsequent reaction with ammonia (East German Patent No. 235 866) .

The starting peptides of the general formula IV are as a rule built up step-wise from the C-terminal end. Peptide linkings can be carried out using the coupling methods known in peptide chemistry.

The compounds of the general formula I and their physiologically tolerated salts can be administered as medicines on their own, in mixtures with each other, or in the form of pharmaceutical preparations which permit enteral or parenteral use and which contain, as the active component, an effective dose of at least one compound of the general formula I or a salt thereof, together-with customary pharmaceutically acceptable excipients and additives. The preparations normally contain about 0.5 to 90 % by weight of the therapeutically active compound.

The medicines can be administered orally, e.g. in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. Administration can, however, also take place rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of solutions for injection or microcapsules, percutaneously, e.g. in the form of ointments or tinctures, or nasally, e.g. in the form of nasal' e preparat on o e p armaceut ca pro ucts ta es place in a manner known per se in which pharmaceutically inert inorganic or organic excipients are used. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc., may be used for the preparation of pills, tablets, coated tablets and hard gelatin capsules. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc.

Suitable excipients for the preparation of solutions and syrups are e.g. water, sucrose, invert sugar, glucose, polyols, etc. Suitable excipients for the preparation of solutions for injections are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable excipients for microcapsules or implants are copolymers of glycolic acid and lactic acid.

Besides the active substances and excipients, the pharmaceutical products can also contain additives, such as, for example, fillers, extenders, disintegrants , binders, lubricants, wetting agents, stabilisers, emulsifiers, preservatives, sweeten-ers, colorants, flavorings or aromatising agents, thickeners, diluents and buffering substances, as well as solvents or solub-ilisers or agents for achieving a depot effect, and salts for changing the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of the general for-mula I or their physiologically tolerated salts and additionally one or more other therapeutically active substances .

Other therapeutically active substances of this type are, for example, bloodflow-promoting agents, such as dihydro-ergocristine, nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol, bencyclane, cinnarizine, naftidrofuryl, raubasine and vincamine; positive inotropic compounds, such as digoxin, acetyldigoxin, metildigoxin and lanato-glycosides; coronary dilators, such as carbochromen, dipyridamole, nifedipine and perhexiline; anti-anginal compounds, such as isosorbide dinitrate, isosorbide mononitrate, glycerol nitrate, molsidomine and verapamil 0-blockers, such as propranolol, oxprenolol, atenolol, metoprolol and penbutolol. In addition, the compounds may be combined with other substances with nootropic activity, such as, for example, piracetam, or with CNS-active substances, e o vary w n w e s an mus e a us e in each separate case to the individual circumstances . In general, a daily dose of about 0.1 to 1 mg/kg, preferably 0.3 to 0.5 mg/kg, of body weight is appropriate for achieving effective results in the case of oral administration, while 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, in particular in the case of the administration of larger quantities, divided into several, e.g. 2, 3 or 4, part doses. Where appropriate, it can be necessary, in each case depending on the individual circumstances, to deviate upwards or downwards from the daily dose indicated.

Pharmaceutical products normally contain 0.2 to 50 mg, preferably 0.5 to 10 mg, of active substance of the general formula I, or of one of its physiologically tolerated salts, per dose.

The compounds according to the invention of the formula I have the ability to inhibit the cell-cell adhesion which is based on the interaction of Arg-Gly-Asp-containing proteins, such as fibronectin, fibrinogen or the von Willebrand factor, with the so-called integrins. Integrins are transmembrane glycoproteins and receptors for Arg-Gly-Asp-containing cell matrix glycoproteins (E. Ruoslahti and M.D. Pierschbacher, Science 238 (1987) 491-497; D.R. Phillips, I. P. Charo, L.V. Parise and L.A.

Fitzgerald, Blood 71 (1988) 831-843). Besides this, they inhibit the binding of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types.

The compounds according to the invention of the general formula I inhibit platelet aggregation, the metastasis of carcinoma cells and the binding of osteoclasts to bone surfaces.

The thiohydantoin derivatives of the general formula I are used acutely where there is danger of thrombosis and chronically in the prevention of arteriosclerosis and thrombosis, e.g. in the therapy and prophylaxis of arterial vascular diseases, such as in acute myocardial infarction, secondary prevention of myocardial infarction, reocclusion prophylaxis after lysis and dilatation (PTCA), unstable angina pectoris, transient ischaemic attacks, stroke, coronary bypass operation including reocclusion pheral arterial occlusive disease and dissecting aneurysm; in the therapy of venous and microcirculatory vascular diseases, such as deep vein thrombosis, disseminating intravascular coagulation, post operative and post-partum trauma, surgical or infectious shock and septicaemia or in diseases with hyperreactive platelets, thrombotic thrombocytopenic purpura, pre-eclampsia, pre-menstrual syndrome and dialysis or extracorporeal circulation; a further application is during cancer operations and also in association with cancer prophylaxis. Furthermore, osteoporosis can be prevented by inhibition of the binding of osteoclasts to the bone surface.

The compounds are examined in particular for their inhibitory effect on blood platelet aggregation and the adhesion of fibrinogen to blood platelets. Use is made of filtered blood platelets from human donor blood which are activated with ADP or thrombin.

Examples; The products were identified by the mass spectra and/or NMR spectra.

Example 1: ( 5- (S ) - ( 3-Guanidinopropyl ) -4-oxo-2-thioxoiinidazolidin-3-yl ) -acetyl-L-aspartyl-L-phenylglycine la: Z-Arg-(Mtr)-OCH3 1.5 ml (20 mmol) of thionyl chloride are slowly added dropwise at 0°C to a- suspension of 8.5 g (16 mmol) of Z-Arg- (Mt ) -OH in 100 ml of methanol. The mixture is allowed to warm to room temperature and is stirred for a further 15 hours. After concentrating (10.2 g), the material is freeze-dried and used directly for further reaction. lb: H-Arg-(Mtr) -OCH3 hydrochloride 10 g (18.7 mmol) of Z-Arg- (Mtr) -OCH3 are dissolved in 150 ml of methanol. After addition of 1 g of 10% Pd on carbon, the mixture is stirred at room temperature and the pH is adjusted to 4.5 by dropwise addition of methanolic hydrochloric acid. The catalyst Yield: 8 g lc : N- ( l-Methoxycarbonyl-2 ( S ) - { 3-Mtr-guanidinopropyl ) ethyl ) -N '- methoxycarbonylmethylthiourea 5 g (11.4 mmol) of H-Arg- (Mtr) -OCH3 hydrochloride are dissolved in 40 ml of dimethylfor amide. After addition of 1.45 ml (11.4 mmol) of N-ethylmorpholine, 1.5 g (11.4 mmol) of methyl isothiocyanato-acetate are slowly added dropwise. The mixture is stirred for 15 hours at room temperature and concentrated, and the residue is dissolved in methylene chloride and extracted with a dilute solution of potassium hydrogen sulphate. After drying, the organic solution is concentrated.

Yield: 4.4 g (72%) Id: ( 5- ( S ) - ( 3-Guanidinopropyl) -4-oxo-2-thioxoimidazolidin-3-yl) -acetic acid 4 g (7.5 mol) of N- ( l-methoxycarbonyl-2 (S )-( 3-Mtr-guanidinopropyl ) ethyl ) -N ' -methoxycarbonylmethyl thiourea are heated under reflux for 20 minutes in 40 ml of 6 N hydrochloric acid. The mixture is then concentrated, mixed with water/methanol, separated from the insoluble residue and concentrated. For purification, the substance is chromatographed on Sephadex LH20 with a homogeneous mixture of butanol/glacial acetic acid/water.

Yield: 1.9 g (92%) le: ( 5- (S ) - ( 3-Guanidinopropyl) -4-oxo-2-thioxoijiiidazolidin-3-yl) -acetyl-L-aspartyl (OtBu) -L-phenylglycine-OtBu 127 mg fl.l mmol) of N-ethylmorpholine and 250 mg (1.21 mmol) of DCC are added at 0°C to a solution of 300 mg (1.1 mmol) of (5-( S ) - ( 3-guanidinopropyl ) -4-oxo-2-thioxoimidazolidin-3-yl ) acetic acid, 472 mg (1.1 mmol) of H-Asp(OtBu) -phenylglycine-OtBu hydrochloride and 148 mg (1.1 mmol) of hydroxybenzotriazole in 10 ml of dimethyIformamide. The mixture is stirred at 0°C for 1 hour and subsequently at room temperature for 5 hours. The precipitated urea is filtered off with suction, the filtrate is concentrated and the crude product is used directly for further reaction. acety - -asparty -L-p eny g yc ne 700 mg of (5-(S) -( 3-guanidinopropyl) -4-oxo-2-thioxoimidazolidin- 3-yl) acetyl-L-aspartyl (OtBu) -L-phenylglycine-OtBu are left to stand with 5 ml of 95% trifluoroacetic acid at room temperature for 3 hours with occasional shaking, and the mixture is then concentrated. For purification, the crude product is chromato-graphed on Sephadex LH20 with an homogeneous mixture of butanol/-glacial acetic acid/water.

Yield: 222 mg Melting point: 170 eC [a]D25 = 11.8" (c = 0.255, water) Mass spectrum: M + 1 peak at 522 Example 2: (5-(S,R)-(4-formamidinobenzyl) -4-oxo-2-thioxoimidazolidin-3-yl) -acetyl-L-aspartyl-L-phenylglycine la) N-(2-( -Formamidinophenyl) -1-methoxycarbonylethyl) -N'- (methoxycarbonylmethyl)thiourea 1.3 ml (10 mmol) of N-ethylmorpholine in 3 ml of dimethylformamide are slowly added dropwise at room temperature to a solution of 2.93 g (10 mmol) of the methyl ester of 4-formamidinophenylalanine dihydrochloride and 1.3 g (10 mmol) of methyl isothiocyanatoacetate in 25 ml of dimethylformamide . To complete the reaction, a further 0.35 ml of methyl isothiocyanatoacetate is added later. The mixture is left to stand at +4°C over the weekend and then concentrated and, for purification, chromatographed on Sephadex LH20 with an homogeneous mixture of butanol/glacial acetic acid/water.

Yield: 2.7 g 2b: (5-(S,R)-(4-Formamidinobenzyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetic acid 2.5 g of N- (2- (4-formamidinophenyl) -1-methoxycarbonylethyl)-N' -(methoxycarbonylmethyl) thiourea are heated under reflux for 30 minutes in 10 ml of 6 N hydrochloric acid. The mixture is then concentrated and the residue is mixed with 50 ml of water. The pH is adjusted to 5-6 with NaHC03 and the solution is left to stand with suction, washed with a small quantity of cold water and dried under high vacuum.

Yield: 1.79 g Melting point: 280-283°C (decomp.) 2c: Di-tert-butyl ester of (5-(S,R)-(4-formamidinobenzyl)-4-oxo- 2-thioxoimi dazolidin-3-yl) acetyl-L-aspartyl-L-phenylglycine hydrochloride 430 mg of DCC are added at 0°C to a suspension of 650 mg (2 mmol) of ( 5- ( S , R) - ( 4-formamidinobenzyl ) -4-oxo-2-thioxoimidazolidin-3- yl) acetic acid, 830 mg of H-Asp(OtBu) -phenylglycine-OtBu hydrochloride and 270 mg of hydroxybenzotriazole in 4 ml of dimethyl- formamide. The mixture is stirred at 0°C for 1 hour and subsequently at room temperature for 2 hours. The precipitated urea is filtered off with suction, the filtrate is concentrated and the crude product is chromatographed on silica gel in a mixture of methylene chloride, methanol, glacial acetic acid and water in the proportions 90:10:1:1.

Yield: 1.25 g 2d: (5-(S,R)-( 4-Formamidinobenzyl ) -4-oxo-2-thioxoi mi dazolidin-3-yl) acetyl-L-aspartyl-L-phenylglycine 1.2 g of di-tert-butyl ester of ( 5- (S,R)-( 4-formamidinobenzyl) -4-oxo-2-thioxoimidazolidin-3-yl) acetyl-L-aspartyl-L-phenylglycine hydrochloride are stirred with 15 ml of 90% trifluoroacetic acid and 1.5 ml of 1 , 2-dimercaptoethanol at room temperature for 1 hour and the mixture is subsequently concentrated. The residue is partitioned between ether and water. The aqueous phase is freeze-dried and, for purification, chromatographed on Sephadex LH20 with an homogeneous mixture of butanol/glacial acetic acid/water. Yield: 280 mg [a]D26 = +15.7° (c = 1, 90% acetic acid) The following compounds may be prepared in analogy with the examples described above: 3-(5-(S) -( 3-Aminopropyl) -4-oxo-2-thioxoimidazolidin-3-yl)benzoyl L-aspartyl-L-phenylglycine FAB-MS 542 (M+H)+ Example 4: (5-(4-Guanidinobenzyl) -4-oxo-2-thioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-valine FAB-MS 536 (M+H)+ Example 5: (5-(4-Formamidinobenzylidene) -4-oxo-2-thioxoimfdazolidin-3-yl) -acetyl-L-aspartyl-L-tryptophan FAB-MS 606 (M+H)+ Example 6 : 3-(5-(S,R)-( 4-Formamidinobenzyl)-4-oxo-2-thioxoimidazolidin-3-yl)propionyl-L-aspartyl-L-phenylalanine(4-aminobutyl)amide FAB-MS 653 (M+H) + Example 7: (5-(4-Aminome hylbenzylidene)-4-oxo-2-thioxoimidazolidin-3-yl) -acetyl-L-aspartyl-L-lysine FAB-MS 535 (M+H) + Example 8: 3-(5-Guaiiidinomethyl-4-oxo-2-thioxoimidazolidin-3-yl)benzoyl-L-aspartyl-D-phenylglycine FAB-MS 556 (M+H)+ Example A Emulsions with 3 mg of active substance per 5 ml may be prepared according to the following formula: Active substance 0.06 g Neutral oil q.s.

Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s.

Pure glycerol 0.6 to 2 g Aroma substances q.s. (demineralised or distilled) to 100 ml Example B Tablets may be prepared according to the following formulation: Active substance 2 mg Lactose 60 mg Corn starch 30 mg Soluble starch 4 mg Magnesium stearate 4 mg 100 mg Example C The following composition is suitable for preparing soft gelatine capsules with 5 mg of active substance per capsule: Active substance 5 mg Mixture of triglycerides from coconut oil 150 mg Capsule content 155 mg Example D The following formulation suitable for the preparation coated tablets: Active substance 3 mg Corn starch 100 mg Lactose 55 mg Dibasic calcium phosphate 30 mg Soluble -starch 3 mg Magnesium stearate 5 mg Colloidal silicica 4 mg 200 mg Example E Coated tablets containing an active substance according to the invention and another therapeutically active substance: Active substance 6 mg Propranolol 40 mg Corn starch 90 mg Dibasic calcium phosphate 34 mg Soluble starch 3 mg Magnesium stearate 3 mg Colloidal silicica 4 mg 270 mg Example F Coated tablets containing an active substance according to the invention and another therapeutically active substance: Active substance 5 mg Pirlindole 5 mg Lactose 60 mg Corn starch 90 mg Dibasic calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 3 mg Colloidal silicica 4 mg 200 mg Example G Capsules containing an active substance according to the invention and another therapeutically active substance: Active substance 5 mg Nicergoline 5 mg Corn starch I85 m<3 195 mg Example H Solutions for injection with 1 mg of active substance per ml be prepared according to the following formula: Active substance 1·0 m9 Polyethylene glycol 400 0.3 mg Sodium chloride 2.7 mg Water for injection to 1 ml T e n ition of the binding of fibrinogen to its receptor (glycoprotein Ilb/IIIa) by the compounds according to the invention is examined on intact, gel-filtered human platelets. The K value for the inhibition of the binding of 125I-fibrinogen following stimulation with ADP (10 μΜ) is indicated.

Literature: J.S. Bennett and G. Vilaire, J. Clin. Invest. 64 (1979), 1393-1401 E. Kornecki et al., J. Biol. 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 Example Kt ( UM) , ADP stimulated 1 0.07 2 0.2 As a functional test, the inhibition of the aggregation of gel-filtered human platelets by the compounds according to the invention is measured following stimulation with ADP or thrombin. The IC50 value for the inhibition is given.

Literature: G.A. Marguerie et al., J. Biol. Chem. 254 (1979), 5357-5363 Example IC5q ( H) ADP-stimulated Thrombin-stimulated 1 0.5 0.1 2 0.55 0.2

Claims (7)

1. 04960/2 - 21 - P a t e n t C l a i m s 1; Compounds of the general formula I in which Y denotes -(CH2)in-C0-/ where m stands for a whole number from 1 R1 denotes - ( CH2)n- H- , where n stands for a whole number from 1 to 6, -(CH2)p-C8H4- H-X, -(CH2)p-C6H4-C(= H)-NH2 or -(CH2)p-C6H4-CH2- H-X, where p in each case stands for 1 or 2, where, however, -R1 can also be replaced X1 denotes -NHX, -CH2 HX or -C(=NH) -NH2; X denotes hydrogen, (Ci-C8) -alkyl or a radical of the formula II ' -NH-C=a- ' ' i11) I where R' and R", "independently of each other, stand for hydrogen R2 denotes hydrogen or (Ci-CgJ-alkyl R3 denotes hydrogen or phenyl; R4 denotes hydrogen, -C00R5 or -CO-NH-R5; R3 denotes hydrogen, or (^-ΰ28) -alkyl which is optionally substituted once or more than once by identical or different radicals from the series comprising hydroxyl, hydroxycarbonyl , aminocarbonyl, mono- or di-fC^C^) -alkylaminocarbonyl , amino- ( C2-C14 ) -alkylaminocarbonyl , amino- ( Cj-C3 ) alkylphenyl- ( C1-C3 ) - alkylaminocarbonyl, (C1-C13) -alkylcarbonylamino- (Ci-Cj) -alkyl-nderlined phenyl- ( C1-C3 ) -alkylaminocarbonyl , ( C1-C18 ) -alkylcarbonylamino-. III.1993 (C2-C14) -alkylaminocarbonyl, phenyl- (C1-Ca) -alkoxycarbonyl , amino, rcapto, (C1-C^) -alkoxy , (C1-C1a) -alkoxycarbonyl, ( C3-Ca ) -cyclo- 104960/3 - 22 - alkyl, halogen, nitro, trif luoromethyl or a radical R6; R6 denotes phenyl, phenyl-(CrC8)-alkyl, a mono- or bicyclic, 5- to 12-membered heterocyclic ring which ca be aromatic, partially hydrogenated or completely hyd ogenated, and which can contain, as the hetero element, one, two or three identical or different nitrogen, oxygen or sulphur atoms, or a radical R7, where the phenyl radical, and independently thereof the heterocyclic radical, can optionally be substituted once or more than once by identical or different radicals from the series comprising ( ^-C^) -alkyl, (CrCia) -alkoxy, halogen, nitro or tri-f luoromethyl ; R7 denotes -NRaR3, -OR3, -SRa, an amino acid side chain, a natural or unnatural amino acid residue, as well as their esters and amides, where free functional groups can optionally be protected by protective groups which are customary in peptide chemistry, or denotes a radical -COR7; R8 denotes hydrogen, (C2-C18)-alkyl, phenyl-(C1-C8)-alkyl, (CrC18)-alkylcarbonyl, (C1-C18)-alkoxycarbonyl, phenylcarbonyl, phenyl-(C1-Cg)-alkylcarbonyl, phenyl-(CrC18)-alkoxycarbonyl,which can optionally be substituted by an amino group, or a natural or unnatural amino acid residue; and R9 denotes hydrogen, (C1-C18)-alkyl, phenyl or phenyl-(CrC8)-alkyl; as well as their physiologically tolerable salts.

2. Compounds according to Claim 1, characterised in that in the general formula I Y denotes -(CH2)m-C0-, where m stands for 1 or 2, or R1 denotes -CH2-C6H,-NH-C ( =NH ) -NH2 ; -CH2-C5H,-C ( =NH ) - H2 or -CH2-C6H^-CH2-NH2; R2 denotes hydrogen or methyl R3.denotes hydrogen; and R* denotes -CO-NH-R5, where -NH-R5 stands for an a-amino acid residue or its ω-amino- (C2-Ca) -alkylamide .

3. Compounds according to Claim 2 , characterised in that amino acid residues standing for -NH-R5 are the valine residue, the phenylalanine residue or the phenylglycine residue . .

4. Compounds according to Claim 2 , characterised in that the ω-amino- (C2-C8) -alkylamide is the 4-aminobutylamide .

5. Process for preparing compounds of Claims 1 to 4, characterised in that a fragment condensation of a compound of the general formula III with a compound of the general formula IV where the radicals R1 to R* and Y are defined as indicated in Claim 1, is carried out;

6. A compound of the general formula I of claims 1 to 4 for use as an inhibitor of platelet aggregation, metastasis of carcinoma cells and osteoclast binding to the bone surface?.

7. A pharmaceuti cal compos i ti on contai ni ng as acti ve i ngredi ent at l east one compound of formul a ( I ) i n Cl aim 1 together wi th a pharaceuti cal ly acceptabl e carri er . For the Applicants, REINHOLD COHN AND PARTNERS