CA2130174C - 4-oxo-2 thioxoimidazolidine derivatives as inhibitors of blood platelet aggregation - Google Patents
4-oxo-2 thioxoimidazolidine derivatives as inhibitors of blood platelet aggregation Download PDFInfo
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Abstract
The present invention relates to 4-oxo-2-thioxo-imidazolidine derivates of the general formula I
(see formula I) in which R1 to R4 and Y are defined as indicated in the description, processes for their preparation and their use as inhibitors of blood platelet aggregation, the metastasis of carcinoma cells and the binding of osteo-clasts to bone surfaces.
(see formula I) in which R1 to R4 and Y are defined as indicated in the description, processes for their preparation and their use as inhibitors of blood platelet aggregation, the metastasis of carcinoma cells and the binding of osteo-clasts to bone surfaces.
Description
4-oxo-2-thioxoimidazolidine derivatives The present invention relates to 4-oxo-2-thioxoimidazolidine derivatives, their preparation and their use as inhibitors of blood platelet aggregation.
Hydantoin derivat~_ves with platelet aggregation-inhibiting activity are desc::ribed in EP-A 449,079, as well as in the published German Patent Appli<~ati<an D13-A 41 26 277.
Further research has shown that the compounds of the present invention are also potent inhibitors cf ~:~lood platelet aggregation.
According to one aspect of the pre;~ent invention, there is provided a compound of the general :Formula I
H
0 CHz R 1 -_ C _~\
N _..__ Y ___._ N H ___.___ C ~_. R4 ( I ) R z N ~;
R:3 wherein: Y denotes -(CHZ)m-CO-, where m stands for 1 or 2, or _. _ ___ ~~_% ;
Ri denotes - (CH2) n-NH-X, whex:e n stands for a whole number from 1 to 6, - (CHZ) r,-C6H4-NH-X, - (CH2) ~-C6H4-C (=NH) -NHZ or - (CHZ)p-C6H4-CHZ-NH-X, where p in each case stands for 1 or 2, where, however H R1 can also be replaced by C .--- CH -- C6H4 -1_.
X1 denotes -NHX, -CHzNHX or -C (=NH) -NH?; X denotes hydrogen, (Cl-C6)-alkyl or a radical of the formula II
R ~_.- N H _ .__ ~ -_- N .._.._ R , , ( I I ) where R' and R " , independently of each other, stand for hydrogen or (C1-C6) -alkyl; R~' denotes hydrogen or (C1-C6) -alkyl; R3 denotes hydrogen or phenyl; R4 denotes hydrogen or -CO-NH-R5, where -NH-RS stands for an a-amino acid residue or its c~-amino- (C'y>>-Ca) -alkyl amide; anal a physiologically tolerated salt thereof.
The present invention relates to compounds of the general formula I
COOH
H
p CH2 R 1-__ ~ __ ;
~N __._ ~ ___._. N H __ _ C ___ R4 ( I ) i N
y,S R 3 in which Y denotes -(CH2)~,-CO-, where m stands for a whole number from 1 to 4, or 2 0 ~~~ __. ~ p _..._......
R1 denotes -(CHz)n-NH-X, where n stands for a whole number from 1 to 6, - (CH2) P-C6H4-NH-X, - (CH2) P-C6H4-C (=NH) -NH2 or - (CHz)p-C6H4-CHZ-NH-X, where p in each case stands for 1 or 2, where, however, -la-CH R1 can also be replaced by C ==- CH ---- C6H4 --X1 ;
Xl denotes -NHX, -CHZNHX or --C (=NH) -N~-i2;
X denotes hydrogen, (C1-C6) -alkyl or a radical of the formula II
R ~-_ N H -_ C ~_.:: N .__ ____. R . . ( I I ) where R' and R " , independently of each other, stand for hydrogen or (C1-C6) -alkyl;
R~ denotes hydrogen or (C~-C~) -alkyl;
R3 denotes hydrogen or phenyl;
R4 denotes hydrogen, -COORS or -CO-NH-RS;
RS denotes hydrogen, or (C1-(~2a) -alkyl which i.s optionally -lb_ w ' substituted once or more than once by identical or different iadicals from the series comprising hydroxyl, hydroxycarbonyl, J aminocarbonyl, mono- or di-(C1-Cue)-alkylaminocarbonyl, amino-( Cz-Cia ) -alkylaminocarbonyl, amino- ( C1-C3 ) alkylphenyl- ( C1-C3 ) -alkylaminocarbonyl, (C1-C1B)-alkyl.carbonylamino-(C1-C3)-alkyl-phenyl-(C:-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarbonylamino-(G2-G14)-alkylaminOCarbOnyl, phenyl-(C1-C8)-alkoxycarbonyl, amino, mercapto, ( C1-Cl~ ) -alkoxy, ( C1-C18 ) -alkoxycarbonyl, ( C3-Ca ) -cyclo-alkyl,.>halogen, vitro, trifluoromethyl or a radical R6;
R° denotes ( C6-C,a ) -aryl , ( CB-Cla ) -aryl- ( C1-Ce ) -alkyl, a mono- or bi-cyclic, 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 R', where the aryl radical, and independently thereof the y ,.
heterocyclic radical, can optionally be substituted once or more than once by identical or different radicals from the series comprising (C:-Clay-alkyl, (C1-C18)-alkoxy, halogen, vitro or tri-fluoromethyl;
R' denotes -NR8R9, -OR&, -SRe, an amino acid side chain, a natural or unnatural amino acid residue, an imino acid residue, an optionall y N- ( C:-GB ) -alkylated or ( C6-C~a ) -aryl- ( C1-Ce ) -alkyl ated azaam:.no acid residue or dipeptide residue, in which the peptide bond can be reduced to NH-CHZ, as well as their esters and amides, where free functional groups can optionally be substituted by' hydrogen oz hydroxymethyl or be protected by protective groups which are customary in peptide chemistry, or a radical -COR'' in which R'' is defined as R';
Re denotes hydrogen, ( CZ-C18 ) -alkyl, ( Ce-Cla ) -aryl- ( Cl-Cg) -alkyl, 3 0 ( Cl-Cl8 ) -alkylcarbonyl, ( Cl-C18 ) -alkoxycarbonyl, ( Gs-Cla ) -aryl-carbonyl, ( CB-Cla ) -aryl- ( C~-Ce ) -alkylcarbonyl, ( C6-C~a ) -aryl- ( Cl-Cla ) ' alkoxycarbonyl, which can optionally be substituted by an amino group, or a natural or unnatural amino acid residue, an imino acid residue, an optionally N- ( C1-CB ) -alkylated or ( CB-Clay-aryl-(Cl-Ce)-alkylated azaamino acid residue or a dipeptide residue, in which the peptide bond can be reduced to NH-CH2; and R9 denotes hydrogen, ( C1-C~,e ) -alkyl, ( Cg-Cla ) -aryl or ( CB-Cla ) -aryl-( Ci-C$ ) -alkyl ;
as well as their physiologically tolerated salts -21 ~Oi'~-~
Alkyl radicals may be straight-chain or branched. Alkyl "radicals which are preferred are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl. The same applies to radicals such as alkoxy, alkoxycarbonyl or aralkyl.
(C3-Ce)-cycloalkyl radicals are, in particular, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, which radicals may, however, also be substituted by, for example, (C1-C~)-alkyl. 4-Methylcyclahexyl and 2,3-dimethyl-cyclopentyl are examples of substituted cycloalkyl radicals.
1O f Examples of (C6-C14)-aryl groups are phenyl, naphthyl, biphenylyl or fluorenyl, and phenyl and naphthyl are preferred.
The same applies to radicals such as aralkyl or ar-ylcarbonyl.
Aralkyl radicals are, in particular, benzyl as well as Z- and 2-naphthylmethyl, which radicals may also be substituted. Examples 1,5 of substituted aralkyl radicals are halobenzyl or (C1-C4)-alkoxybenzyl.
- xf phenyl is substituted twine, 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.
20 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, 25 quinazolinyl, cinnolinyl or a benzo-fused, cyclapenta-, cyclohexa- or cyclohepta-fused derivative of these radicals.
These heterocycles may be substituted on a nitrogen atom . by oxide, (Cl-C~)-alkyl, a.g. methyl or ethyl, phenyl or phenyl-i (C1-C4)-alkyl, e.g. benzyl, and/or on one or more carbon atoms by 30 (C1-C4)-alkyl, halogen, hydroxyl, (G1-C4)-alkoxy, e.g. methoxy, phenyl-(C1-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, 35 4-imidazolyl, methyl-imidazolyl, e.g. 1-.methyl-2-, 4- or' 5-3.midazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, 2-pyrazinyl, 2-, 4- ar 5-pyramidinyl, 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, 3 ..
21~~3~.'~-~
- 1-benzyl-2~ or 3-iadolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclo apta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-iso - quinolyl, 1-oxo-1,2-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, morphalinyl, 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. «-Amino acids are pre-ferred. Examples which may be mentioned are (cf. Houben-Weyl, Methoden der organischen Chemie (Methods of organic chemistry) ~-'S Volume XV/1 and 2, Stuttgart, 1974):
,:
Aad, Abu 6Abu, ABz, 2AB2, Aca, Ach, Acp, Adpd, Ahb, Alb, pAib, Ala, pAla, oAla, 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, Da.SU, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hP~o, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Tse, Tva, ISyn, Lant, Lcn, Leu, Lsg, Lys, pLys, ALys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, afro, 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, This, 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, 2-(p-chloroghenyl)aminoacetic acid.
.~1 Amino acid side-chains are understood to mean side-chains of natux'~al or unnatural amino acids. Azaamino 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; decahydraisoquinoline-3-carboxylic acid; octahydroindale-2-carboxylic acid; decahydro-quinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2--carbc~xylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid;
2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo-- 4 ...
- f3.1.0]hexane-3-carboxylic acid; 2-azaSpirO[4.4]nonane-3-car-,~xylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro-y (bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro-(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;
2-azatricyclo[4.3Ø16~~]decane-3-carboxylic acid; decahydrocyclo-hepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a,4,6a-hexa-hydrocydlopenta[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 option-ally substituted (see the following formulae)c ' ' ~ ~..~- ; ~~ ~ 3 t ~ C r -_ Cn.
CV
~A_ t~.0 i '.' '.
\ ' ~ I f .~_ .. v , a ~°' ~°'~,~- ; va" ' t t ' ..
* ~_ ~CO°' ; ~IEC.~.~ i , N ' ' I
~ x1 * .,_ ~ ~\~~~iC~- i .1 N
N f N
I~CO- ; ~C~-I
~~co- ; ' . Cvv~- ; c~
N ~ .~i~l' td I t t H~
NCB- ~ ~~" , I t t ~~.s~~.~=
The heterocycles on which the abovementioned residues are eased are known, for example, from US-A 4,344,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488;
EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800;
EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637;
EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020;
EP-A 111,873; EP-A 271,865 and EP-A 344,682.
Dipeptides may contain as components natural or unnatural amino acids, ixnino 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 w-amino-( C4-CB ) -al kylamide .
Functional groups of the amino acids, imino acids and ?5 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 Hiillesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. Particular mention may be made of: Aloc, Pyoc, Fznoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NOz),Z(Haln), Bobz, Iboc, Adpoc, Mboo, Acm, tart.-Butyl, OHzl, 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 toler-ated organic amines, such as, for example, triethylamine and Tris- ( 2-hydraxy-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, sul-phuric acid or.phosphoxic acid, and with organic carboxylic or sulphonic acids, such as, for example, acetic acid, citric said, benzoic acid, malefic acid, fumaric acid, tartaric acid and p-toluenesulphonic acid.
° 6 ..
~~J~~~~~
_ Preferred compounds of the general formula I are those in '~ :l.ch y~denotes -(CHZ)m-CO-, where m stands for 1 or 2, or n ~
R1 denotes -CHZ-C6H,-NH-C ( =NH ) -~tfiz; -CHZ-CgHb-C ( =NH ) -NHZ or -CHZ-C6H4-CHz, ~2~
RZ denotes hydrogen or methyl;
R' denotes hydrogen; and R° denotes -CO-NH-Rs, where -NH-RS stands for an a-amino acid residue or its ~-amino-(CZ-C9)-alkylamide.
In this context, the valine residue, the phenylalanine residue or the phenylglycine residue are particularly preferred :~,i a-amino acid residues standing for -D1H-R5.
The ~-aminobutylamide is a particularly preferred ~-amino- ( CZ-Ce ) -.alkylamide .
The compounds according to the invention of the general formula I may be prepared by fragment condensation of a compound of the general foxzaula III
H
~~~~~0 R 1--C~
N-Y-°''J H ( I I I ) R x°N°°°~C
S
with a compound of the general formula TV
COOH
CHZ
(IV) HzN°-i°R4 where the radicals R~ to R° and Y' are defined as indicated above.
The methods of peptide chemistzy which are known per se are advantageously used for the condensation of the compounds of the general. fo~noula III with those of the general foz:anula IV ( sae e.g. Houben Weyl, Methoden dex organischen Cheynie, Volume 15/1 ~d 15/2, Stuttgart, 1974).
For this, it is necessary as a rule that amino groups ~~JO~'~
contained in Rl and R' are protected by reversible protective -:.pups. The same applies to the carboxyl groups of the compound - of the general formula IV, which are preferably present as benzyl esters ox tart-butyl esters. Protection of amino groups is unnecessary if the amino groups which are to be generated are present as vitro or cyano groups and are only formed by hydrogen-ation after the coupling.
.After the coupling, the protective groups which are presents are eliminated in a suitable manner. For example, NOZ
1Q groups (guanidino protection), benzyloxycarbonyl groups and benzyl esters may be removed by hydrogenation. Protective groups of the tart-butyl type are cleaved under acid conditions, while the 9-fluorenylmethyloxycarbonyl residue is removed by secondary amines.
The starting compounds of the general fornula III may be obtained as follows:
Reaction of amino acids, N-alkylami.no acids or, preferably, theirmethyl, ethyl, benzyl or tart-butyl esters, for example a compound of the general formula V
RZ..NH-CH-C00CH3 (V) , with an isolthiocyanatoalkanecarboxylic acid ester, for example of the general formula VI
S°C 'N- ( ~z ) m-COOCH3 ( VI ) r in which Rl, RZ and m are defined as indicated above, results in thiourea derivatives, for example of the general formula VII
(VIT), .. CH300C-( CHZ ) rti-NH-C-N---CH-COOCH3 which, by heating with acid to hydrolyse the ester functionalities, cyclise to compounds of the general formula IIIa H
R 1 °- i "°~
N°tCHZ)~--COOH (Ills).
R 2~
S
g -, . 2.~~0i'~~
During the thiourea synthesis, guanidino groups can be _~loc?~ed by protective groups, such as NOZ or Mtr. Amino groups in the side chain must likewise be present in protected forte (for example as Boc or Z derivatives) or still be in the form of an NOZ
or cyano functionality, which can later be reduced to the atn.no group or, in the case of the cyano group, also be converted into the formamidino group.
Compounds of the general formula IIIb d H COOH
R '~"~ / ' ( IIIb ) N
R 2-N"°.~C
S
can be obtained in an analogous manner if, instead of isothio-cyanatoalkanecarboxylic acid esters, the~isothiocyanates of the atninobenzoic acid esters are employed.
Compounds of the general formula IIIc H
' /
(IIIc) N~-Y--0 H
R z-N---S
1S can be obtained in analogy with Granacher and Landolt, Helv.
Chim. Acta 10 (1927) 808 by reacting thiohydantains of the general formula VIII
H
H-C--~
N-Y-off (VIII) R Z'°N°
S
with aldehydes of the general formula IX
/~' Ho (IX). f.
x1 The guanylation of the amino functionality may be carried out with the following reagentsa 1. O~Methylisothiourea (S. Weirs and H. Krommer, Claemiker Zeitung 98 (1974) 617-618), _ g _ w ~ ~~.~~1"~
7. S-Methylisethiourea (R. F. Borne, M.L. Foryester and I.W.
.:esters, J. Med. Chem. 20 (1977) 771-776), 3. Vitro-S-methylisothiourea (L. S. Hafner and R.E. Evans, J. Org.
Chem. 24 (1959) 1157), 4. Formamidinosulphonic acid (R. Rim, Y.-T. Lin and H.S. Mosher, Tetrah. 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 ) . ~
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, 'S Phaxmazie 29 (19?4) 12-55). An additional method for preparing formamidines is the addition of HzS onto the cyano group, followed by a methylation of the resulting thioamide and subsequent reac-tion 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 physio-logically tolerated salts can be administered as medicines on their own, in mixtures with each other, or in the form of phar-maceutical 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 O.S 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, gran-ules, hard and soft gelatin capsules, solutions, syrups,~emul-sions or suspensions or aerosol mixtures. Adaai.nistration can, however, also take place rectally, e.g. in the form of sup-positories, 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 2,1~01'~~
'sprays.
The preparation of the pharmaceutical products takes place in a manner known per se in which pharmaceutically inert inorganic or organic excipients are used. For example, lactose, carp starch or derivatives thereof, talc, stearic acid or its salts etc., may be used for the preparation of pills, tablets, coated tablets and haxd gelatin capsules. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semiso.~;a.d 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 injec-tions are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable excipients for microcapsules or implants are copolymers of glycolic acid and lactic acid.
s Resides the active substances and excipients, the phar-maceutical 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 asmotic 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-ergacristine, nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol, bencyclane, cinnarizine, naftidrofuryl, raubasine and vincamine; positive isotropic 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, mol.'sidomine and verapamil; ,B-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 ONS-active substances, such as pirlindole, sulphide, etc.
The dose may vary within wide limits and must be adjusted 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 dally 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 I5 0.5 to 10 mg, o~ 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 glyco-proteins (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). Besides this, they inhibit the binding of otaer 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 chronic-ally 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 prophyla~is after lysis and dilatation (PTCA), unstable angina pectoris, transient ischaemic attacks, stroke, coronary bypass operation including reocclusion .,~rophylax~a in association with bypass, pulmonary emboli pe rkaeral arterial occlusive disease and dissecting aneurysm; in the therapy of venous and microcirculatory vascular diseases, such as deep vein thrombosis, disseminating intravascular coagulation, S 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 circul-ation;fa further application is during cancer operations and also in association with cancer prophylaxis. Furthermore, os'ceoporosis can be prevented by inhibition of the binding of osteoclasts to the bone surf ace.
The compounds are examined in particular for their inhib-itory effect on blood platelet aggregation and the adhesion of t~5 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 NM~t zo spectra.
Example 1:
(S-(S)-(3-Guanid:i.nopropyl)-4-oxo-2-thioxoimi.dazolidin-3-yl)-acetyl-L-aspartyl-Z-phenylglycine la: Z-Arg-(Mtr)-OCH~
p 1.S ml (20 mmol) of thionyl chloride are slowly added dropwise at 0°C to ~r suspension of 8.5 g (16 mmol) of Z-Arg-(Mtr)-OH in 100 ml of methanol. The mixture is allowed to warm to zoom tempera-ture and is stirred fax a further 15 hours. After concentrating (10.2 g), the material is freeze-dried and used directly for ' 30 further reaction.
i 1b: H-Arg-(Mt~)-OCH3 hydrochloride 10 g (18.7 mBaol) of Z-Arg-(Mtr)-~Cx3 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 35 dropwise addition of methanolic hydrochloric acid. The catalyst is removed by filtration and the filtrate is concentrated.
Yield: 8 g lc : N- ( 1-Methoxycarbo.nyl -2 ~ S ) - ( 3 -Mtr-guanid:inopropyl ) ethyl ) -N'-methoxycarbonylmethylthic>urea 5 g (11.4 mmol) of H-Arg--(Mtr)-OCH-s hydrochloride are dissolved in 40 ml of dimethylformam:Lde. 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 residuf=_ is dissolved in methylene chloride and extracted with a ciilut~e solution of potassium hydrogen sulphate. After drying, t:he organic solution is concentrated.
Yield: 4.4 g (72%) 1d: (5- (S) - (3-Guanidinopropyl) --4-oxo-2-t~hioxoimidazolidin-3-yl) -acetic acid 4 g (7.5 mol) of N- (1-~methoxycarbonyl-2 (S) - (3-Mtr-guanidinopropyl)ethyl)-N'-methoxycarbonylmethyl thiourea are heated under reflux for 20 minutes irr 40 ml of 6 N
hydrochloric acid. The mixture is then concentrated, mixed with water/methanol, separated from the inso7Luble residue and concentrated. For purification, the substance is chromatographed on SephadexT"" LH20 with a homogeneous mixture of butanol/glacial acetic ac°id/water.
Yield: 1.9 g (92%) 1e: (5-(S)-(3-Guanidinopropyl)--4-oxo-2-thioxoimidazolidin-3-yl)-acetyl-L-aspartyl(OtBu)-L-phenylglycine-OtBu 127 mg (1.l mmol) of N-ethylmorpho7.ine and 250 mg (1.21 mmol) of DCC are added at 0°C to a solution of 300 mg 1. 4 (1.1 mmol) of (5- (S) - (3-guanidinopropyl) -4-oxo-2-thioxoimidazolidin-3-yl)acet;ic acid, 472 mg (1.l mmol) of H-Asp (OtBu) -phen.ylglycine-Ot:.Bu hydrochloride and 148 mg (1 . 1 mmol) of hydroxybenzotriazole in 10 ml of dimethylformamide.
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 furthE=r reaction.
14a ~;~ ~OlP~r 1f: (5-{S)-(3-Guani.dinopropyl)-~-oxo-2-thi.oxoimidazolidin-3-yl)-.etyl-L-aspartyl-L-phenylglycine 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 9S$ trifluoroacetic acid at room temperature for 3 hours with occasional shaking, and the mixture is then concentrated. Fox purification, the crude product is chromato-graphed on Sephadex LH20 with an homogeneous mixture of butanol/-glacia7~r acetic acid/raater.
Yield: 222 mg Melting point: 170°C
~a~DZS = 11.8° (c = 0.255, water) Mass spectrum: M + 1 peak at 522 Example 2:
{ 5-- ( S, R ) - ( 4-f oryn~m~ dinobenzyl ) -4-ozo--2-thiozoixaidazolidin-3-yl ) -acetyl-L-aspartyl-L-phenylglycine la) N-(2-(4-Form.i.dinoplaenyl)-1-methoxycarbonyleth~l)-N' (methoxycar3~onylmethyl)thiourea 1.3 ml (10 moral) 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 3.sothiocyanatoacetate in 25 ml. of dimethylformamide. To complete the reaction, a further 0.35 ml of methyl 2S isothiocyanatoacetate is added later. The mixture is left ~to stand at +~°C over the weekend and then concentrated and, far purification, chromatographed on Sephadex LH20 with an homogeneous mixture of butanol/glacial acetic acid/water.
Yield: 2.7 g 2b> (5-(S,R)-(4-Fox~amidinobenzyl)-4-oao-2-thioxoimidazolidin-3-yl)acetic acid 2.5 g of N-(2-(4-fo~namidinophenyl)-1-methoxycarbonyleth~l)-N'-{methoxycarbonylmethyl)thiourea are heated under reflex 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 pFI
is adjusted to 5-S with Na~3C03 and the solution is left to stand t 4°C overnight. On the next day the precipitate is filtered off 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-tart-butyl ester of (5-(S,R)-(4-fo~a~dinobenzyl)-4-oxo-2-thioxoimidazolida.n-3-yl)acetyl-L-aspartyl-L-phenylglycine hydrochloride 430 mg of DCC are added at 0°C to a suspension of 650 mg (2 mmo1) of (5-(S,R)-(4-formamidinobenxyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetic acid, 830 mg of S-Asp(OtDu)-phenylglycine-OtHu hydro-chloride and 270 mg of hydroxybenzo~triazole in 4 ml of dimethyl-formamide. The mixture is stirred at 0°C for 1 hour and subse-quently at room temperature for 2 hours. The precipitated urea is '.'15 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 2 0 2d: ( 5- ( S, R) - ( 4-~'o~-~n~~~ dinobenzyl ) -4-oxo-2-thioxoimidazolid~.n-3-yl)acetyl-L-aspartyl-L-phenylglycine 1.2 g of di-tart-butyl ester of (5-(S,R)-(4-formamidinobenzyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine hydrochloride axe stirred with. 15 ml of 90~ trifluoroacetic acid 25 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.
30 Yield: 280 mg [a]DZB a +15.7° (c = 1, 90~ acetic acid) The following compounds may be prepared in analogy with the examples described above:
J ~ ~ ~l Example 3:
\5-(S)-(3-opropyl)-4-oxo-2-thioaoimidazolidixe-3-yl)benzoyl-L-aspartyl-h-phenylglycine FAE-MS 5 4 2 ( M+Fi ) +
Eple 4:
(5-(4-Guanidinobenzyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-h-aspartyl-L-saline FAB-MS 5~3 6 ( M+Fi ) +
Ezample 5:
(5-(4-Fo~aidi.nobenzylidene)-4-ozo-2-thioxoi,aaidazolidin-3-yl)-acetyl-~.-aspartyl-I~-tryptophan FAB-MS 606 (M+H)+
,_ ) Eple 6:
3-(5-(S,R)-(4-Formamidinobenzyl)-4-ozo-2-thiozo.i.neidazolidin-3-yl)propionyl-L-aspartyl-L-phenylalanine(4-aminobutyl)amide FAH-MS 6 5 3 ( M+~~ ) +
Example 7:
(5-(4-Amy.nomethylbenzylidene)-4-oao-2-thioxoimidazol.idin-3-yl)-acetyl-L-aspartyl-L-lysine FAH-MS 535 (M+H)+
Example 8:
3-(5-Gaanidinouatethyl-~-oxo-2-thioaoimidazolidin-3-yl)benzoyl-Ie-aspartyl-D-phenylglycine FAS-MS 556 (M+H)+
Examg,le 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 carbo.cymethylcellulose 0.6 g Polyoxyethylene stearate g.s.
bore glycerol 0.6 to 2 g Aroma substances q.s.
2~.~0~."~-~
Water 'emineralised or distilled) to 100 ml Example B
Tablets may be prepared according to the following formulation:
Active substance 2 mg Lactose 50 mg Corn starch 30 mg Soluble starch 4 mg Magnesium stearate 4 mg ______ 100 mg Example C
-.1 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 Examble D
The following formulation is suitable for the preparation of coated tablets:
Active substance 3 mg Corn starch 100 mg Lactose 55 mg ''~S Dibasic calcium phosphate 30 mg Soluble-starch 3 mg Magnesium stearate 5 mg Colloidal silicica 4 mg 200 mg p Example E
Coated tablets containing an active substance according to the invention and another therapeutically active substance:
Active substance 6 mg hropranolol 40 mg T ~:C tOSe 90 mg porn starch 90 mg Dibasic calcium phosphate 34 mg Soluble starch 3 mg Magnesium stearate 3 mg Colloidal silicica 4 mg 270 mg Example F
~.0 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 'i..5 Corn starch 90 mg Dibasic calcium phosphate 30 mg Soluble starch 3 mg.
Magnesium stearate 3 mg Colloidal silicica 4 mg 20 ______ 200 mg Example G
Capsules containing an active substance according to the inven~-tion and another therapeutically active substance:
25 Active substance 5 mg Nicergoline 5 mg Corn starch 185 mg 195 mg 30 EXamb,3.e H
Solutions for injection with 1 mg of active substance peg ml may be prepared according to the following formula:
Active substance 1.0 mg Polyethylene glycol 400 0.3 mc~
35 Sodium chloride 2.7 mg Water for injection to 1 ml _ 1g _ Pharmacological data:
~~J~~~~
vhe inhibition of the binding of fibrinogen to its receptor (glycoprotein IIb/IIIa) by the compounds according to the invention is examined on intact, gel-filtered humaa~ platelets.
The K1 value for the inhibition of the binding of lasl-fibrinogen following stimulation with ADP (10 ~,M) is indicated.
Literature: J.S. Bennett and G. Vilaire, J. Clin. Invest. 64 (1979), 7.393-1401 E. Kornecki et al., J. Biol. Chem. 256 (1981), G.A. Marguerie et al., J. Biol. Chem. 254 (1979), 5357.-5363 G.A. Marguerie et al., J. Biol. Chem.. 255 (1980), 1.54-161 _i Example Ki (uMl=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 ICso value far the inhibition is given.
Literature: G.A. Marguerie et al., J. Biol. Chew. 254 (1979), Examule Ira ADP-stimulated Thrombin-stimulated 0.5 0.1 2 0.55 0.2 y
Hydantoin derivat~_ves with platelet aggregation-inhibiting activity are desc::ribed in EP-A 449,079, as well as in the published German Patent Appli<~ati<an D13-A 41 26 277.
Further research has shown that the compounds of the present invention are also potent inhibitors cf ~:~lood platelet aggregation.
According to one aspect of the pre;~ent invention, there is provided a compound of the general :Formula I
H
0 CHz R 1 -_ C _~\
N _..__ Y ___._ N H ___.___ C ~_. R4 ( I ) R z N ~;
R:3 wherein: Y denotes -(CHZ)m-CO-, where m stands for 1 or 2, or _. _ ___ ~~_% ;
Ri denotes - (CH2) n-NH-X, whex:e n stands for a whole number from 1 to 6, - (CHZ) r,-C6H4-NH-X, - (CH2) ~-C6H4-C (=NH) -NHZ or - (CHZ)p-C6H4-CHZ-NH-X, where p in each case stands for 1 or 2, where, however H R1 can also be replaced by C .--- CH -- C6H4 -1_.
X1 denotes -NHX, -CHzNHX or -C (=NH) -NH?; X denotes hydrogen, (Cl-C6)-alkyl or a radical of the formula II
R ~_.- N H _ .__ ~ -_- N .._.._ R , , ( I I ) where R' and R " , independently of each other, stand for hydrogen or (C1-C6) -alkyl; R~' denotes hydrogen or (C1-C6) -alkyl; R3 denotes hydrogen or phenyl; R4 denotes hydrogen or -CO-NH-R5, where -NH-RS stands for an a-amino acid residue or its c~-amino- (C'y>>-Ca) -alkyl amide; anal a physiologically tolerated salt thereof.
The present invention relates to compounds of the general formula I
COOH
H
p CH2 R 1-__ ~ __ ;
~N __._ ~ ___._. N H __ _ C ___ R4 ( I ) i N
y,S R 3 in which Y denotes -(CH2)~,-CO-, where m stands for a whole number from 1 to 4, or 2 0 ~~~ __. ~ p _..._......
R1 denotes -(CHz)n-NH-X, where n stands for a whole number from 1 to 6, - (CH2) P-C6H4-NH-X, - (CH2) P-C6H4-C (=NH) -NH2 or - (CHz)p-C6H4-CHZ-NH-X, where p in each case stands for 1 or 2, where, however, -la-CH R1 can also be replaced by C ==- CH ---- C6H4 --X1 ;
Xl denotes -NHX, -CHZNHX or --C (=NH) -N~-i2;
X denotes hydrogen, (C1-C6) -alkyl or a radical of the formula II
R ~-_ N H -_ C ~_.:: N .__ ____. R . . ( I I ) where R' and R " , independently of each other, stand for hydrogen or (C1-C6) -alkyl;
R~ denotes hydrogen or (C~-C~) -alkyl;
R3 denotes hydrogen or phenyl;
R4 denotes hydrogen, -COORS or -CO-NH-RS;
RS denotes hydrogen, or (C1-(~2a) -alkyl which i.s optionally -lb_ w ' substituted once or more than once by identical or different iadicals from the series comprising hydroxyl, hydroxycarbonyl, J aminocarbonyl, mono- or di-(C1-Cue)-alkylaminocarbonyl, amino-( Cz-Cia ) -alkylaminocarbonyl, amino- ( C1-C3 ) alkylphenyl- ( C1-C3 ) -alkylaminocarbonyl, (C1-C1B)-alkyl.carbonylamino-(C1-C3)-alkyl-phenyl-(C:-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarbonylamino-(G2-G14)-alkylaminOCarbOnyl, phenyl-(C1-C8)-alkoxycarbonyl, amino, mercapto, ( C1-Cl~ ) -alkoxy, ( C1-C18 ) -alkoxycarbonyl, ( C3-Ca ) -cyclo-alkyl,.>halogen, vitro, trifluoromethyl or a radical R6;
R° denotes ( C6-C,a ) -aryl , ( CB-Cla ) -aryl- ( C1-Ce ) -alkyl, a mono- or bi-cyclic, 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 R', where the aryl radical, and independently thereof the y ,.
heterocyclic radical, can optionally be substituted once or more than once by identical or different radicals from the series comprising (C:-Clay-alkyl, (C1-C18)-alkoxy, halogen, vitro or tri-fluoromethyl;
R' denotes -NR8R9, -OR&, -SRe, an amino acid side chain, a natural or unnatural amino acid residue, an imino acid residue, an optionall y N- ( C:-GB ) -alkylated or ( C6-C~a ) -aryl- ( C1-Ce ) -alkyl ated azaam:.no acid residue or dipeptide residue, in which the peptide bond can be reduced to NH-CHZ, as well as their esters and amides, where free functional groups can optionally be substituted by' hydrogen oz hydroxymethyl or be protected by protective groups which are customary in peptide chemistry, or a radical -COR'' in which R'' is defined as R';
Re denotes hydrogen, ( CZ-C18 ) -alkyl, ( Ce-Cla ) -aryl- ( Cl-Cg) -alkyl, 3 0 ( Cl-Cl8 ) -alkylcarbonyl, ( Cl-C18 ) -alkoxycarbonyl, ( Gs-Cla ) -aryl-carbonyl, ( CB-Cla ) -aryl- ( C~-Ce ) -alkylcarbonyl, ( C6-C~a ) -aryl- ( Cl-Cla ) ' alkoxycarbonyl, which can optionally be substituted by an amino group, or a natural or unnatural amino acid residue, an imino acid residue, an optionally N- ( C1-CB ) -alkylated or ( CB-Clay-aryl-(Cl-Ce)-alkylated azaamino acid residue or a dipeptide residue, in which the peptide bond can be reduced to NH-CH2; and R9 denotes hydrogen, ( C1-C~,e ) -alkyl, ( Cg-Cla ) -aryl or ( CB-Cla ) -aryl-( Ci-C$ ) -alkyl ;
as well as their physiologically tolerated salts -21 ~Oi'~-~
Alkyl radicals may be straight-chain or branched. Alkyl "radicals which are preferred are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl. The same applies to radicals such as alkoxy, alkoxycarbonyl or aralkyl.
(C3-Ce)-cycloalkyl radicals are, in particular, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, which radicals may, however, also be substituted by, for example, (C1-C~)-alkyl. 4-Methylcyclahexyl and 2,3-dimethyl-cyclopentyl are examples of substituted cycloalkyl radicals.
1O f Examples of (C6-C14)-aryl groups are phenyl, naphthyl, biphenylyl or fluorenyl, and phenyl and naphthyl are preferred.
The same applies to radicals such as aralkyl or ar-ylcarbonyl.
Aralkyl radicals are, in particular, benzyl as well as Z- and 2-naphthylmethyl, which radicals may also be substituted. Examples 1,5 of substituted aralkyl radicals are halobenzyl or (C1-C4)-alkoxybenzyl.
- xf phenyl is substituted twine, 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.
20 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, 25 quinazolinyl, cinnolinyl or a benzo-fused, cyclapenta-, cyclohexa- or cyclohepta-fused derivative of these radicals.
These heterocycles may be substituted on a nitrogen atom . by oxide, (Cl-C~)-alkyl, a.g. methyl or ethyl, phenyl or phenyl-i (C1-C4)-alkyl, e.g. benzyl, and/or on one or more carbon atoms by 30 (C1-C4)-alkyl, halogen, hydroxyl, (G1-C4)-alkoxy, e.g. methoxy, phenyl-(C1-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, 35 4-imidazolyl, methyl-imidazolyl, e.g. 1-.methyl-2-, 4- or' 5-3.midazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, 2-pyrazinyl, 2-, 4- ar 5-pyramidinyl, 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, 3 ..
21~~3~.'~-~
- 1-benzyl-2~ or 3-iadolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclo apta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-iso - quinolyl, 1-oxo-1,2-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, morphalinyl, 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. «-Amino acids are pre-ferred. Examples which may be mentioned are (cf. Houben-Weyl, Methoden der organischen Chemie (Methods of organic chemistry) ~-'S Volume XV/1 and 2, Stuttgart, 1974):
,:
Aad, Abu 6Abu, ABz, 2AB2, Aca, Ach, Acp, Adpd, Ahb, Alb, pAib, Ala, pAla, oAla, 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, Da.SU, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hP~o, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Tse, Tva, ISyn, Lant, Lcn, Leu, Lsg, Lys, pLys, ALys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, afro, 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, This, 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, 2-(p-chloroghenyl)aminoacetic acid.
.~1 Amino acid side-chains are understood to mean side-chains of natux'~al or unnatural amino acids. Azaamino 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; decahydraisoquinoline-3-carboxylic acid; octahydroindale-2-carboxylic acid; decahydro-quinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2--carbc~xylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid;
2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo-- 4 ...
- f3.1.0]hexane-3-carboxylic acid; 2-azaSpirO[4.4]nonane-3-car-,~xylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro-y (bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro-(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;
2-azatricyclo[4.3Ø16~~]decane-3-carboxylic acid; decahydrocyclo-hepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a,4,6a-hexa-hydrocydlopenta[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 option-ally substituted (see the following formulae)c ' ' ~ ~..~- ; ~~ ~ 3 t ~ C r -_ Cn.
CV
~A_ t~.0 i '.' '.
\ ' ~ I f .~_ .. v , a ~°' ~°'~,~- ; va" ' t t ' ..
* ~_ ~CO°' ; ~IEC.~.~ i , N ' ' I
~ x1 * .,_ ~ ~\~~~iC~- i .1 N
N f N
I~CO- ; ~C~-I
~~co- ; ' . Cvv~- ; c~
N ~ .~i~l' td I t t H~
NCB- ~ ~~" , I t t ~~.s~~.~=
The heterocycles on which the abovementioned residues are eased are known, for example, from US-A 4,344,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488;
EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800;
EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637;
EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020;
EP-A 111,873; EP-A 271,865 and EP-A 344,682.
Dipeptides may contain as components natural or unnatural amino acids, ixnino 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 w-amino-( C4-CB ) -al kylamide .
Functional groups of the amino acids, imino acids and ?5 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 Hiillesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. Particular mention may be made of: Aloc, Pyoc, Fznoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NOz),Z(Haln), Bobz, Iboc, Adpoc, Mboo, Acm, tart.-Butyl, OHzl, 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 toler-ated organic amines, such as, for example, triethylamine and Tris- ( 2-hydraxy-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, sul-phuric acid or.phosphoxic acid, and with organic carboxylic or sulphonic acids, such as, for example, acetic acid, citric said, benzoic acid, malefic acid, fumaric acid, tartaric acid and p-toluenesulphonic acid.
° 6 ..
~~J~~~~~
_ Preferred compounds of the general formula I are those in '~ :l.ch y~denotes -(CHZ)m-CO-, where m stands for 1 or 2, or n ~
R1 denotes -CHZ-C6H,-NH-C ( =NH ) -~tfiz; -CHZ-CgHb-C ( =NH ) -NHZ or -CHZ-C6H4-CHz, ~2~
RZ denotes hydrogen or methyl;
R' denotes hydrogen; and R° denotes -CO-NH-Rs, where -NH-RS stands for an a-amino acid residue or its ~-amino-(CZ-C9)-alkylamide.
In this context, the valine residue, the phenylalanine residue or the phenylglycine residue are particularly preferred :~,i a-amino acid residues standing for -D1H-R5.
The ~-aminobutylamide is a particularly preferred ~-amino- ( CZ-Ce ) -.alkylamide .
The compounds according to the invention of the general formula I may be prepared by fragment condensation of a compound of the general foxzaula III
H
~~~~~0 R 1--C~
N-Y-°''J H ( I I I ) R x°N°°°~C
S
with a compound of the general formula TV
COOH
CHZ
(IV) HzN°-i°R4 where the radicals R~ to R° and Y' are defined as indicated above.
The methods of peptide chemistzy which are known per se are advantageously used for the condensation of the compounds of the general. fo~noula III with those of the general foz:anula IV ( sae e.g. Houben Weyl, Methoden dex organischen Cheynie, Volume 15/1 ~d 15/2, Stuttgart, 1974).
For this, it is necessary as a rule that amino groups ~~JO~'~
contained in Rl and R' are protected by reversible protective -:.pups. The same applies to the carboxyl groups of the compound - of the general formula IV, which are preferably present as benzyl esters ox tart-butyl esters. Protection of amino groups is unnecessary if the amino groups which are to be generated are present as vitro or cyano groups and are only formed by hydrogen-ation after the coupling.
.After the coupling, the protective groups which are presents are eliminated in a suitable manner. For example, NOZ
1Q groups (guanidino protection), benzyloxycarbonyl groups and benzyl esters may be removed by hydrogenation. Protective groups of the tart-butyl type are cleaved under acid conditions, while the 9-fluorenylmethyloxycarbonyl residue is removed by secondary amines.
The starting compounds of the general fornula III may be obtained as follows:
Reaction of amino acids, N-alkylami.no acids or, preferably, theirmethyl, ethyl, benzyl or tart-butyl esters, for example a compound of the general formula V
RZ..NH-CH-C00CH3 (V) , with an isolthiocyanatoalkanecarboxylic acid ester, for example of the general formula VI
S°C 'N- ( ~z ) m-COOCH3 ( VI ) r in which Rl, RZ and m are defined as indicated above, results in thiourea derivatives, for example of the general formula VII
(VIT), .. CH300C-( CHZ ) rti-NH-C-N---CH-COOCH3 which, by heating with acid to hydrolyse the ester functionalities, cyclise to compounds of the general formula IIIa H
R 1 °- i "°~
N°tCHZ)~--COOH (Ills).
R 2~
S
g -, . 2.~~0i'~~
During the thiourea synthesis, guanidino groups can be _~loc?~ed by protective groups, such as NOZ or Mtr. Amino groups in the side chain must likewise be present in protected forte (for example as Boc or Z derivatives) or still be in the form of an NOZ
or cyano functionality, which can later be reduced to the atn.no group or, in the case of the cyano group, also be converted into the formamidino group.
Compounds of the general formula IIIb d H COOH
R '~"~ / ' ( IIIb ) N
R 2-N"°.~C
S
can be obtained in an analogous manner if, instead of isothio-cyanatoalkanecarboxylic acid esters, the~isothiocyanates of the atninobenzoic acid esters are employed.
Compounds of the general formula IIIc H
' /
(IIIc) N~-Y--0 H
R z-N---S
1S can be obtained in analogy with Granacher and Landolt, Helv.
Chim. Acta 10 (1927) 808 by reacting thiohydantains of the general formula VIII
H
H-C--~
N-Y-off (VIII) R Z'°N°
S
with aldehydes of the general formula IX
/~' Ho (IX). f.
x1 The guanylation of the amino functionality may be carried out with the following reagentsa 1. O~Methylisothiourea (S. Weirs and H. Krommer, Claemiker Zeitung 98 (1974) 617-618), _ g _ w ~ ~~.~~1"~
7. S-Methylisethiourea (R. F. Borne, M.L. Foryester and I.W.
.:esters, J. Med. Chem. 20 (1977) 771-776), 3. Vitro-S-methylisothiourea (L. S. Hafner and R.E. Evans, J. Org.
Chem. 24 (1959) 1157), 4. Formamidinosulphonic acid (R. Rim, Y.-T. Lin and H.S. Mosher, Tetrah. 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 ) . ~
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, 'S Phaxmazie 29 (19?4) 12-55). An additional method for preparing formamidines is the addition of HzS onto the cyano group, followed by a methylation of the resulting thioamide and subsequent reac-tion 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 physio-logically tolerated salts can be administered as medicines on their own, in mixtures with each other, or in the form of phar-maceutical 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 O.S 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, gran-ules, hard and soft gelatin capsules, solutions, syrups,~emul-sions or suspensions or aerosol mixtures. Adaai.nistration can, however, also take place rectally, e.g. in the form of sup-positories, 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 2,1~01'~~
'sprays.
The preparation of the pharmaceutical products takes place in a manner known per se in which pharmaceutically inert inorganic or organic excipients are used. For example, lactose, carp starch or derivatives thereof, talc, stearic acid or its salts etc., may be used for the preparation of pills, tablets, coated tablets and haxd gelatin capsules. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semiso.~;a.d 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 injec-tions are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable excipients for microcapsules or implants are copolymers of glycolic acid and lactic acid.
s Resides the active substances and excipients, the phar-maceutical 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 asmotic 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-ergacristine, nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol, bencyclane, cinnarizine, naftidrofuryl, raubasine and vincamine; positive isotropic 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, mol.'sidomine and verapamil; ,B-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 ONS-active substances, such as pirlindole, sulphide, etc.
The dose may vary within wide limits and must be adjusted 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 dally 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 I5 0.5 to 10 mg, o~ 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 glyco-proteins (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). Besides this, they inhibit the binding of otaer 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 chronic-ally 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 prophyla~is after lysis and dilatation (PTCA), unstable angina pectoris, transient ischaemic attacks, stroke, coronary bypass operation including reocclusion .,~rophylax~a in association with bypass, pulmonary emboli pe rkaeral arterial occlusive disease and dissecting aneurysm; in the therapy of venous and microcirculatory vascular diseases, such as deep vein thrombosis, disseminating intravascular coagulation, S 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 circul-ation;fa further application is during cancer operations and also in association with cancer prophylaxis. Furthermore, os'ceoporosis can be prevented by inhibition of the binding of osteoclasts to the bone surf ace.
The compounds are examined in particular for their inhib-itory effect on blood platelet aggregation and the adhesion of t~5 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 NM~t zo spectra.
Example 1:
(S-(S)-(3-Guanid:i.nopropyl)-4-oxo-2-thioxoimi.dazolidin-3-yl)-acetyl-L-aspartyl-Z-phenylglycine la: Z-Arg-(Mtr)-OCH~
p 1.S ml (20 mmol) of thionyl chloride are slowly added dropwise at 0°C to ~r suspension of 8.5 g (16 mmol) of Z-Arg-(Mtr)-OH in 100 ml of methanol. The mixture is allowed to warm to zoom tempera-ture and is stirred fax a further 15 hours. After concentrating (10.2 g), the material is freeze-dried and used directly for ' 30 further reaction.
i 1b: H-Arg-(Mt~)-OCH3 hydrochloride 10 g (18.7 mBaol) of Z-Arg-(Mtr)-~Cx3 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 35 dropwise addition of methanolic hydrochloric acid. The catalyst is removed by filtration and the filtrate is concentrated.
Yield: 8 g lc : N- ( 1-Methoxycarbo.nyl -2 ~ S ) - ( 3 -Mtr-guanid:inopropyl ) ethyl ) -N'-methoxycarbonylmethylthic>urea 5 g (11.4 mmol) of H-Arg--(Mtr)-OCH-s hydrochloride are dissolved in 40 ml of dimethylformam:Lde. 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 residuf=_ is dissolved in methylene chloride and extracted with a ciilut~e solution of potassium hydrogen sulphate. After drying, t:he organic solution is concentrated.
Yield: 4.4 g (72%) 1d: (5- (S) - (3-Guanidinopropyl) --4-oxo-2-t~hioxoimidazolidin-3-yl) -acetic acid 4 g (7.5 mol) of N- (1-~methoxycarbonyl-2 (S) - (3-Mtr-guanidinopropyl)ethyl)-N'-methoxycarbonylmethyl thiourea are heated under reflux for 20 minutes irr 40 ml of 6 N
hydrochloric acid. The mixture is then concentrated, mixed with water/methanol, separated from the inso7Luble residue and concentrated. For purification, the substance is chromatographed on SephadexT"" LH20 with a homogeneous mixture of butanol/glacial acetic ac°id/water.
Yield: 1.9 g (92%) 1e: (5-(S)-(3-Guanidinopropyl)--4-oxo-2-thioxoimidazolidin-3-yl)-acetyl-L-aspartyl(OtBu)-L-phenylglycine-OtBu 127 mg (1.l mmol) of N-ethylmorpho7.ine and 250 mg (1.21 mmol) of DCC are added at 0°C to a solution of 300 mg 1. 4 (1.1 mmol) of (5- (S) - (3-guanidinopropyl) -4-oxo-2-thioxoimidazolidin-3-yl)acet;ic acid, 472 mg (1.l mmol) of H-Asp (OtBu) -phen.ylglycine-Ot:.Bu hydrochloride and 148 mg (1 . 1 mmol) of hydroxybenzotriazole in 10 ml of dimethylformamide.
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 furthE=r reaction.
14a ~;~ ~OlP~r 1f: (5-{S)-(3-Guani.dinopropyl)-~-oxo-2-thi.oxoimidazolidin-3-yl)-.etyl-L-aspartyl-L-phenylglycine 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 9S$ trifluoroacetic acid at room temperature for 3 hours with occasional shaking, and the mixture is then concentrated. Fox purification, the crude product is chromato-graphed on Sephadex LH20 with an homogeneous mixture of butanol/-glacia7~r acetic acid/raater.
Yield: 222 mg Melting point: 170°C
~a~DZS = 11.8° (c = 0.255, water) Mass spectrum: M + 1 peak at 522 Example 2:
{ 5-- ( S, R ) - ( 4-f oryn~m~ dinobenzyl ) -4-ozo--2-thiozoixaidazolidin-3-yl ) -acetyl-L-aspartyl-L-phenylglycine la) N-(2-(4-Form.i.dinoplaenyl)-1-methoxycarbonyleth~l)-N' (methoxycar3~onylmethyl)thiourea 1.3 ml (10 moral) 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 3.sothiocyanatoacetate in 25 ml. of dimethylformamide. To complete the reaction, a further 0.35 ml of methyl 2S isothiocyanatoacetate is added later. The mixture is left ~to stand at +~°C over the weekend and then concentrated and, far purification, chromatographed on Sephadex LH20 with an homogeneous mixture of butanol/glacial acetic acid/water.
Yield: 2.7 g 2b> (5-(S,R)-(4-Fox~amidinobenzyl)-4-oao-2-thioxoimidazolidin-3-yl)acetic acid 2.5 g of N-(2-(4-fo~namidinophenyl)-1-methoxycarbonyleth~l)-N'-{methoxycarbonylmethyl)thiourea are heated under reflex 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 pFI
is adjusted to 5-S with Na~3C03 and the solution is left to stand t 4°C overnight. On the next day the precipitate is filtered off 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-tart-butyl ester of (5-(S,R)-(4-fo~a~dinobenzyl)-4-oxo-2-thioxoimidazolida.n-3-yl)acetyl-L-aspartyl-L-phenylglycine hydrochloride 430 mg of DCC are added at 0°C to a suspension of 650 mg (2 mmo1) of (5-(S,R)-(4-formamidinobenxyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetic acid, 830 mg of S-Asp(OtDu)-phenylglycine-OtHu hydro-chloride and 270 mg of hydroxybenzo~triazole in 4 ml of dimethyl-formamide. The mixture is stirred at 0°C for 1 hour and subse-quently at room temperature for 2 hours. The precipitated urea is '.'15 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 2 0 2d: ( 5- ( S, R) - ( 4-~'o~-~n~~~ dinobenzyl ) -4-oxo-2-thioxoimidazolid~.n-3-yl)acetyl-L-aspartyl-L-phenylglycine 1.2 g of di-tart-butyl ester of (5-(S,R)-(4-formamidinobenzyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine hydrochloride axe stirred with. 15 ml of 90~ trifluoroacetic acid 25 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.
30 Yield: 280 mg [a]DZB a +15.7° (c = 1, 90~ acetic acid) The following compounds may be prepared in analogy with the examples described above:
J ~ ~ ~l Example 3:
\5-(S)-(3-opropyl)-4-oxo-2-thioaoimidazolidixe-3-yl)benzoyl-L-aspartyl-h-phenylglycine FAE-MS 5 4 2 ( M+Fi ) +
Eple 4:
(5-(4-Guanidinobenzyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-h-aspartyl-L-saline FAB-MS 5~3 6 ( M+Fi ) +
Ezample 5:
(5-(4-Fo~aidi.nobenzylidene)-4-ozo-2-thioxoi,aaidazolidin-3-yl)-acetyl-~.-aspartyl-I~-tryptophan FAB-MS 606 (M+H)+
,_ ) Eple 6:
3-(5-(S,R)-(4-Formamidinobenzyl)-4-ozo-2-thiozo.i.neidazolidin-3-yl)propionyl-L-aspartyl-L-phenylalanine(4-aminobutyl)amide FAH-MS 6 5 3 ( M+~~ ) +
Example 7:
(5-(4-Amy.nomethylbenzylidene)-4-oao-2-thioxoimidazol.idin-3-yl)-acetyl-L-aspartyl-L-lysine FAH-MS 535 (M+H)+
Example 8:
3-(5-Gaanidinouatethyl-~-oxo-2-thioaoimidazolidin-3-yl)benzoyl-Ie-aspartyl-D-phenylglycine FAS-MS 556 (M+H)+
Examg,le 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 carbo.cymethylcellulose 0.6 g Polyoxyethylene stearate g.s.
bore glycerol 0.6 to 2 g Aroma substances q.s.
2~.~0~."~-~
Water 'emineralised or distilled) to 100 ml Example B
Tablets may be prepared according to the following formulation:
Active substance 2 mg Lactose 50 mg Corn starch 30 mg Soluble starch 4 mg Magnesium stearate 4 mg ______ 100 mg Example C
-.1 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 Examble D
The following formulation is suitable for the preparation of coated tablets:
Active substance 3 mg Corn starch 100 mg Lactose 55 mg ''~S Dibasic calcium phosphate 30 mg Soluble-starch 3 mg Magnesium stearate 5 mg Colloidal silicica 4 mg 200 mg p Example E
Coated tablets containing an active substance according to the invention and another therapeutically active substance:
Active substance 6 mg hropranolol 40 mg T ~:C tOSe 90 mg porn starch 90 mg Dibasic calcium phosphate 34 mg Soluble starch 3 mg Magnesium stearate 3 mg Colloidal silicica 4 mg 270 mg Example F
~.0 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 'i..5 Corn starch 90 mg Dibasic calcium phosphate 30 mg Soluble starch 3 mg.
Magnesium stearate 3 mg Colloidal silicica 4 mg 20 ______ 200 mg Example G
Capsules containing an active substance according to the inven~-tion and another therapeutically active substance:
25 Active substance 5 mg Nicergoline 5 mg Corn starch 185 mg 195 mg 30 EXamb,3.e H
Solutions for injection with 1 mg of active substance peg ml may be prepared according to the following formula:
Active substance 1.0 mg Polyethylene glycol 400 0.3 mc~
35 Sodium chloride 2.7 mg Water for injection to 1 ml _ 1g _ Pharmacological data:
~~J~~~~
vhe inhibition of the binding of fibrinogen to its receptor (glycoprotein IIb/IIIa) by the compounds according to the invention is examined on intact, gel-filtered humaa~ platelets.
The K1 value for the inhibition of the binding of lasl-fibrinogen following stimulation with ADP (10 ~,M) is indicated.
Literature: J.S. Bennett and G. Vilaire, J. Clin. Invest. 64 (1979), 7.393-1401 E. Kornecki et al., J. Biol. Chem. 256 (1981), G.A. Marguerie et al., J. Biol. Chem. 254 (1979), 5357.-5363 G.A. Marguerie et al., J. Biol. Chem.. 255 (1980), 1.54-161 _i Example Ki (uMl=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 ICso value far the inhibition is given.
Literature: G.A. Marguerie et al., J. Biol. Chew. 254 (1979), Examule Ira ADP-stimulated Thrombin-stimulated 0.5 0.1 2 0.55 0.2 y
Claims (10)
1. A compound of the general formula I
wherein:
Y denotes -(CH2)m-CO-, where m stands for 1 or 2, or ;
R1 denotes -(CH2)n-NH-X, where n stands for a whole number from 1 to 6, -(CH2)p-C6H4-NH-X, -(CH2)p-C6H4-C(=NH)-NH2 or -(CH2)p-C6H4-CH2-NH-X, where p in each case stands for 1 or 2, where, however can also be replaced by ;
X1 denotes -NHX, -CH2NHX or -C(=NH)-NH2;
X denotes hydrogen, (C1-C6)-alkyl or a radical of the formula II
where R' and R'' , independently of each other, stand for hydrogen or (C1-C6)-alkyl;
R2 denotes hydrogen or (C1-C6)-alkyl;
R3 denotes hydrogen or phenyl;
R4 denotes hydrogen or -CO-NH-R5, where -NH-R5 stands for an .alpha.-amino acid residue or its .omega.-amino-(C2-C8)-alkylamide;
or a physiologically tolerated salt thereof.
wherein:
Y denotes -(CH2)m-CO-, where m stands for 1 or 2, or ;
R1 denotes -(CH2)n-NH-X, where n stands for a whole number from 1 to 6, -(CH2)p-C6H4-NH-X, -(CH2)p-C6H4-C(=NH)-NH2 or -(CH2)p-C6H4-CH2-NH-X, where p in each case stands for 1 or 2, where, however can also be replaced by ;
X1 denotes -NHX, -CH2NHX or -C(=NH)-NH2;
X denotes hydrogen, (C1-C6)-alkyl or a radical of the formula II
where R' and R'' , independently of each other, stand for hydrogen or (C1-C6)-alkyl;
R2 denotes hydrogen or (C1-C6)-alkyl;
R3 denotes hydrogen or phenyl;
R4 denotes hydrogen or -CO-NH-R5, where -NH-R5 stands for an .alpha.-amino acid residue or its .omega.-amino-(C2-C8)-alkylamide;
or a physiologically tolerated salt thereof.
2. The compound or salt according to claim 1, wherein:
R1 denotes -CH2-C6H4-NH-C(=NH)-NH2; -CH2-C6H4-C(=NH)-NH2 or -CH2-C6H4-CH2-NH2;
R2 denotes hydrogen or methyl; and R3 denotes hydrogen.
R1 denotes -CH2-C6H4-NH-C(=NH)-NH2; -CH2-C6H4-C(=NH)-NH2 or -CH2-C6H4-CH2-NH2;
R2 denotes hydrogen or methyl; and R3 denotes hydrogen.
3. The compound or salt according to claim 1 or 2, wherein -NH-R5 is valine, phenylalanine or phenylglycine.
4. The compound or salt according to any one of claims 1 to 2, wherein the .omega.-amino-(C2-C8)-alkylamide is 4-aminobutylamide.
5. A process for preparing a compound of any one of claims 1 to 4, wherein a fragment condensation of a compound of the general formula III
with a compound of the general formula IV
where the radicals R1 to R4 and Y are defined as indicated in claim 1, is carried out.
with a compound of the general formula IV
where the radicals R1 to R4 and Y are defined as indicated in claim 1, is carried out.
6. The compound or salt of the general formula I
according to any one of claims 1 to 4 for use as an inhibitor of one or more of platelet aggregation, of metastasis of carcinoma cells and of binding of osteoclasts to bone surfaces.
according to any one of claims 1 to 4 for use as an inhibitor of one or more of platelet aggregation, of metastasis of carcinoma cells and of binding of osteoclasts to bone surfaces.
7. A pharmaceutical composition comprising one or more compounds of the general formula I according to any one of claims 1 to 4 or a physiologically tolerated salt thereof, as active substance together with a pharmaceutically acceptable excipient.
8. The pharmaceutical composition according to claim 7, further comprising one or more substances selected from a bloodflow promoting agent, a positive inotropic compound, a coronary dilator, an anti-anginal compound, a beta blocker, a substance with nootropic activity and a CNS-active substance.
9. A process for the preparation of a pharmaceutical composition comprising one or more compounds of the general formula I according to any one of claims 1 to 4 or a physiologically tolerated salt thereof, wherein said one or more compounds or salts are brought into a suitable administration form together with a pharmaceutically acceptable excipient.
10. The process according to claim 9, further comprising adding one or more substances selected from a bloodflow promoting agent, a positive inotropic compound, a coronary dilator, an anti-anginal compound, a beta blocker, a substance with nootropic activity and a CNS-active substance.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4207254.9 | 1992-03-07 | ||
| DE4207254A DE4207254A1 (en) | 1992-03-07 | 1992-03-07 | 4-oxo-2-thioxoimidazolidin DERIVATIVES |
| PCT/EP1993/000424 WO1993018057A1 (en) | 1992-03-07 | 1993-02-24 | 4-oxo-2 thioxoimidazolidine derivates as inhibitors of blood platelet aggregation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2130174A1 CA2130174A1 (en) | 1993-09-16 |
| CA2130174C true CA2130174C (en) | 2003-09-09 |
Family
ID=6453475
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002130174A Expired - Lifetime CA2130174C (en) | 1992-03-07 | 1993-02-24 | 4-oxo-2 thioxoimidazolidine derivatives as inhibitors of blood platelet aggregation |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0629211B1 (en) |
| JP (1) | JP3495369B2 (en) |
| KR (1) | KR100278532B1 (en) |
| AT (1) | ATE169634T1 (en) |
| AU (1) | AU665617B2 (en) |
| CA (1) | CA2130174C (en) |
| CZ (1) | CZ286327B6 (en) |
| DE (2) | DE4207254A1 (en) |
| DK (1) | DK0629211T3 (en) |
| ES (1) | ES2121993T3 (en) |
| HU (1) | HU217430B (en) |
| IL (1) | IL104960A (en) |
| SK (1) | SK107294A3 (en) |
| TW (1) | TW255888B (en) |
| WO (1) | WO1993018057A1 (en) |
| ZA (1) | ZA931537B (en) |
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| DE4228717A1 (en) * | 1992-08-28 | 1994-03-03 | Cassella Ag | Imidazolidine derivatives |
| DE4427979A1 (en) * | 1993-11-15 | 1996-02-15 | Cassella Ag | Substituted 5-ring heterocycles, their preparation and their use |
| US5849736A (en) * | 1993-11-24 | 1998-12-15 | The Dupont Merck Pharmaceutical Company | Isoxazoline and isoxazole fibrinogen receptor antagonists |
| US5563158A (en) * | 1993-12-28 | 1996-10-08 | The Dupont Merck Pharmaceutical Company | Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists |
| ZA963391B (en) * | 1995-05-24 | 1997-10-29 | Du Pont Merck Pharma | Isoxazoline fibrinogen receptor antagonists. |
| US5599829A (en) * | 1995-11-28 | 1997-02-04 | American Home Products Corporation | 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives for increasing HDL cholesterol levels |
| TW418195B (en) * | 1995-11-28 | 2001-01-11 | American Home Prod | 2-thioxo-imidazolidin-4-one derivatives |
| US5554607A (en) * | 1995-11-28 | 1996-09-10 | American Home Products Corporation | Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis |
| US5821372A (en) * | 1995-11-28 | 1998-10-13 | American Home Products Corporation | 2-thioxo-imidazolidin-4-one derivatives |
| PT796855E (en) | 1996-03-20 | 2002-07-31 | Hoechst Ag | INHIBITION OF REABSORCAO IN BONES AND ANTAGONISTS OF VITRONECTIN |
| DE19629816A1 (en) | 1996-07-24 | 1998-01-29 | Hoechst Ag | New cycloalkyl derivatives as inhibitors of bone resorption and vitronectin receptor antagonists |
| DE19629817A1 (en) * | 1996-07-24 | 1998-01-29 | Hoechst Ag | New imino derivatives as inhibitors of bone resorption and vitronectin receptor antagonists |
| US5663363A (en) * | 1996-11-21 | 1997-09-02 | American Home Products Corporation | 2-thioxo-imidazolidin-4-one derivatives |
| US5861517A (en) * | 1996-11-21 | 1999-01-19 | American Home Products Corporation | 2-thioxo-imidazolidin-4-one derivatives |
| DE19741235A1 (en) | 1997-09-18 | 1999-03-25 | Hoechst Marion Roussel De Gmbh | Novel imidazolidine derivatives, their preparation, their use and pharmaceutical compositions containing them |
| DE19741873A1 (en) * | 1997-09-23 | 1999-03-25 | Hoechst Marion Roussel De Gmbh | New 5-ring heterocycles, their preparation, their use and pharmaceutical preparations containing them |
| DE19751251A1 (en) | 1997-11-19 | 1999-05-20 | Hoechst Marion Roussel De Gmbh | Substituted imidazolidine derivatives, their manufacture, their use and pharmaceutical preparations containing them |
| DE19821483A1 (en) | 1998-05-14 | 1999-11-18 | Hoechst Marion Roussel De Gmbh | New imidazolidine derivatives useful as leukocyte adhesion and migration inhibitors and/or VLA-4 receptor antagonists for treating E.G. inflammatory and allergic disorders |
| DE19922462A1 (en) | 1999-05-17 | 2000-11-23 | Aventis Pharma Gmbh | New phenylureidobenzyl-substituted spiro-imidazolidinedione derivatives, are inhibitors of leukocyte adhesion or migration or VLA-4 receptors, useful e.g. for treating inflammatory or allergic disease |
| DE10111877A1 (en) | 2001-03-10 | 2002-09-12 | Aventis Pharma Gmbh | Novel imidazolidine derivatives, their preparation, their use and pharmaceutical compositions containing them |
| DE10137595A1 (en) | 2001-08-01 | 2003-02-13 | Aventis Pharma Gmbh | New 3-alkylaminoalkyl-imdazolidin-4-one derivatives, are VLA-4 receptor and leukocyte adhesion and/or migration inhibitors, useful e.g. for treating inflammatory, allergic, autoimmune or cardiovascular disease |
| TWI339093B (en) | 2007-08-24 | 2011-03-11 | Asustek Comp Inc | Cellular phone with shiftless motion function |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4970225A (en) * | 1990-02-13 | 1990-11-13 | Bristol-Myers Squibb Company | Imidazolidine carboxylic acids and esters as blood platelet aggregation inhibitors |
| DE4009506A1 (en) * | 1990-03-24 | 1991-09-26 | Hoechst Ag | hydantoin |
-
1992
- 1992-03-07 DE DE4207254A patent/DE4207254A1/en not_active Withdrawn
-
1993
- 1993-02-24 KR KR1019940703101A patent/KR100278532B1/en not_active IP Right Cessation
- 1993-02-24 CA CA002130174A patent/CA2130174C/en not_active Expired - Lifetime
- 1993-02-24 DE DE59308872T patent/DE59308872D1/en not_active Expired - Lifetime
- 1993-02-24 JP JP51528893A patent/JP3495369B2/en not_active Expired - Fee Related
- 1993-02-24 AU AU34988/93A patent/AU665617B2/en not_active Ceased
- 1993-02-24 DK DK93904010T patent/DK0629211T3/en active
- 1993-02-24 AT AT93904010T patent/ATE169634T1/en not_active IP Right Cessation
- 1993-02-24 WO PCT/EP1993/000424 patent/WO1993018057A1/en active IP Right Grant
- 1993-02-24 EP EP93904010A patent/EP0629211B1/en not_active Expired - Lifetime
- 1993-02-24 HU HU9402564A patent/HU217430B/en not_active IP Right Cessation
- 1993-02-24 ES ES93904010T patent/ES2121993T3/en not_active Expired - Lifetime
- 1993-02-24 CZ CZ19942166A patent/CZ286327B6/en not_active IP Right Cessation
- 1993-03-04 ZA ZA931537A patent/ZA931537B/en unknown
- 1993-03-05 IL IL10496093A patent/IL104960A/en not_active IP Right Cessation
- 1993-04-08 TW TW082102612A patent/TW255888B/zh active
-
1994
- 1994-09-07 SK SK1072-94A patent/SK107294A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP3495369B2 (en) | 2004-02-09 |
| EP0629211A1 (en) | 1994-12-21 |
| KR950700321A (en) | 1995-01-16 |
| IL104960A0 (en) | 1993-07-08 |
| HU9402564D0 (en) | 1994-11-28 |
| HU217430B (en) | 2000-01-28 |
| WO1993018057A1 (en) | 1993-09-16 |
| JPH07506567A (en) | 1995-07-20 |
| IL104960A (en) | 1996-12-05 |
| ZA931537B (en) | 1993-09-27 |
| DE59308872D1 (en) | 1998-09-17 |
| KR100278532B1 (en) | 2001-01-15 |
| HUT69716A (en) | 1995-09-28 |
| TW255888B (en) | 1995-09-01 |
| DE4207254A1 (en) | 1993-09-09 |
| AU3498893A (en) | 1993-10-05 |
| CZ216694A3 (en) | 1995-04-12 |
| ATE169634T1 (en) | 1998-08-15 |
| ES2121993T3 (en) | 1998-12-16 |
| CZ286327B6 (en) | 2000-03-15 |
| DK0629211T3 (en) | 1999-05-17 |
| SK107294A3 (en) | 1995-04-12 |
| AU665617B2 (en) | 1996-01-11 |
| CA2130174A1 (en) | 1993-09-16 |
| EP0629211B1 (en) | 1998-08-12 |
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