EP0577775A1 - Peptides et pseudopeptides antithrombotiques - Google Patents

Peptides et pseudopeptides antithrombotiques

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Publication number
EP0577775A1
EP0577775A1 EP92912095A EP92912095A EP0577775A1 EP 0577775 A1 EP0577775 A1 EP 0577775A1 EP 92912095 A EP92912095 A EP 92912095A EP 92912095 A EP92912095 A EP 92912095A EP 0577775 A1 EP0577775 A1 EP 0577775A1
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EP
European Patent Office
Prior art keywords
aspartyl
substituted
compound
valine
arginine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92912095A
Other languages
German (de)
English (en)
Other versions
EP0577775A4 (fr
Inventor
Scott I. Klein
Bruce F. Molino
Mark Czekaj
Charles Gardner
Michael R. Becker
Jeffrey M. Dener
Jeffrey C. Pelletier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhone Poulenc Rorer International Holdings Inc
Original Assignee
Rhone Poulenc Rorer International Holdings Inc
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Application filed by Rhone Poulenc Rorer International Holdings Inc filed Critical Rhone Poulenc Rorer International Holdings Inc
Publication of EP0577775A1 publication Critical patent/EP0577775A1/fr
Publication of EP0577775A4 publication Critical patent/EP0577775A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/75—Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compounds having anti-thrombotic activity. More particularly, the invention relates to novel peptides and pseudopeptides that inhibit platelet aggregation and thrombus formation in mammalian blood and are useful in the prevention and treatment of thrombosis associated with disease states such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.
  • Haemostasis the biochemistry of blood coagulation, is an extremely complex and as yet not completely understood phenomena whereby normal whole blood and body tissue spontaneously arrest bleeding from injured blood vessels. Effective haemostasis requires the combined activity of vascular, platelet and plasma factors as well as a controlling mechanism to prevent excessive clotting. Defects, deficiencies, or excesses of any of these components can lead to hemorrhagic or thrombotic consequences.
  • Platelet adhesion, spreading and aggregation on extracellular matrices are central events in thrombus formation. These events are mediated by a family of platelet adhesive glycoproteins, i.e., fibrinogen, fibronectin, and von Willebrand factor.
  • Fibrinogen is a co-factor for platelet aggregation, while fibronectin supports platelet attachments and spreading reactions, and von Willebrand factor is important in platelet attachment to and spreading on subendothelial matrices.
  • the binding sites for fibrinogen, fibronectin and von Willebrand factor have been located on the platelet membrane protein complex known as glycoprotein llb/llla. Adhesive glycoproteins, like fibrinogen, do not bind with normal resting platelets.
  • thrombogenic diseases such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.
  • U.S. Patent No. 4,992,463 (Tjoeng, et al.), issued February 12, 1991 , discloses generically that a series of aryl and aralkyl guanidinoalkyl peptide mimetic compounds exhibit platelet aggregation inhibiting activity and discloses specifically a series of mono- and dimethoxy phenyl peptide mimetic compounds and a biphenylalkyl peptide mimetic compound.
  • 4,857,508 (Adams, et al.), issued August 15, 1989, discloses generically that a series of guandinoalkyl peptide derivatives containing terminal aralkyl substituents exhibit platelet aggregation inhibiting activity and discloses specifically a series of O-methyl tyrosine, biphenyl, and naphthyl derivatives containing a terminal amide functionality.
  • Cyclic peptide analogues containing the moiety Gly-Asp are reported to be fibrinogen receptor antagonists in U.S. Patent No. 5,023,233.
  • the present invention relates to novel peptides and pseudopeptides which inhibit platelet aggregation and subsequent thrombus formation.
  • B may also be 5-tetrazol-1-yl, ;
  • Z is -OR a , nitrogen-containing heterocyclyl, a D- or -isomer of an ⁇ - amino acid bonded at the ⁇ -nitrogen, a dipeptide bonded at the N-terminal ⁇ - or -CH2-S-;
  • R e and Rf are independently H, alkyl, cycloalkyl, cycloalky I methyl, or
  • Ra Rg.
  • Rq, and R s are independently H, alkyl, cycloalkyl, cycloalkylmethyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
  • Rt is -H, -COOH, -COORk, carbamoyl, N-containing heterocyclyl or o II C— NR k R m;
  • R n is R ⁇ o or Y ⁇ ;
  • x, x', x", x"' and x M are independently 0 or 1 ; mi and m 2 are independently 0 to 9; hi, h 2 , and k are independently 0 or 1 ; n is 1 to 3; q is 1 to 5; and p and s are independently 0 to 6; provided that when A is guanidino, and B and D are -C(0)NH-, then Z is other than aralkylamino or substituted aralkylamino; and
  • Rf is R f and Rt is -C(0)NH2 and R e is hydrogen, then Rf is other than benzyl, substituted benzyl, naphthylmethyl or substituted napthylmethyl;
  • Z is other than a naturally occurring amino acid or a dipeptide composed of two naturally occurring amino acids
  • this invention relates to pharmaceutical compositions comprising such compounds, and to methods of treatment of abnormal thrombus formation in mammals comprising the administration of such compounds and pharmaceutical compositions
  • Neitrogen-containing heterocyclyl means about a 4- to about a 15- membered nitrogen-containing monocyclic or multicyclic ring system in which one or more of the other atoms in the ring or rings may be an element other than carbon, for example nitrogen, oxygen or sulfur and further that the heterocycle is bound at the nitrogen atom.
  • Preferred nitrogen-containing heterocyclyl groups include pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, 1 ,2,3,4-tetrahydroisoquinolin-2-yl, piperazin-1-yl.
  • the nitrogen at the 4-position preferably may be substituted by alkyl, cycloalkyl, cycloalkylmethyl, aryl, substituted aryl, aralkyl or substituted arakyl.
  • ⁇ -amino acid means a synthetic or naturally occurring amino acid.
  • Preferred ⁇ -amino acids are the naturally occurring amino acids, i.e, glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, praline, hydroxyproline, aspartic acid, aspargine, glutamine, glutamic acid, histidine, arginine, omithine, and lysine.
  • Dipeptide means ⁇ -aminoacyl- ⁇ -aminoacid.
  • Carboxy means a -COOH group.
  • Carbamoyl means a — c — NH z group.
  • Alkyl means a saturated aliphatic hydrocarbon group which may be straight or branched and having about 1 to about 20 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain. Preferred straight or branched alkyl groups are the "lower alkyl” groups which are those alkyl groups having from 1 to about 6 carbons.
  • Cycloalkyl means a saturated carbocyclic group having about 3 to about 8 carbon atoms.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Aryl means a phenyl or naphthyl group.
  • Substituted aryl means a phenyl or naphthyl group substituted by one or more aryl group substituents which may be the same or different, where "aryl group substituent” includes alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, hydroxyalkyl, acyl, formyl, carboxy, alkenoyl, aroyl, halo, nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, alkylsutfonyl, alkylsulfinyl, arylsulfonyl
  • Substituted- phenyl , naphth-1-yl, naphth-2-yl 1 ,1-diphenylmethyl, 1 ,1- di(substituted phenyl)methyl, indol-2-yl, indol-3-yl, quinolin-2-yl, quinolin-3-yl, quinoIin-4-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, and imidazol-1-yl means that these groups are substituted by an aryl group substituent.
  • Preferred aryl group substitutents for these groups are hydrogen, halo, nitro, trihalomethyl, phenyl, alkyl, nitrogen-containing heterocyclyl carbonyl, nitrogen-containing heterocyclyl carbonylalkyl, amidino, guanidino, -NR q R S)
  • R_ wner ⁇ Rq and Rs are independently H, alkyl, cycloalkyl, cycloalkylmethyl, aryl, substituted aryl, aralkyl or substituted aralkyl.
  • Alkyl means an alkyl group substituted by an aryl radical. Preferred aralkyl groups include benzyl and phenethyl.
  • Substituted aralkyl means an aralkyl group substituted on the aryl portion by one or more aryl group substituents.
  • R z is nitrogen-containing heterocyclylcarbonyl, -COOR n , -OR n , -
  • Z is -ORa, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1 -yl, morpholin-4- yl, piperazin-1-yl, a D- or L-isomer of an ⁇ -amino acid bonded at the ⁇ - nitrogen, a dipeptide bonded at the N-terminal ⁇ -amino acid, or -NR a R x where
  • Z is phenethylamino or ,2,3,4-tetrahydroisoquinolin -2-yl.
  • Wt and W2 are independently hydrogen, halo, nitro, trihalomethyl, phenyl, alkyl, nitrogen-containing heterocyclyl carbonyl, nitrogen-containing heterocyclyl carbonylalkyi, amidino, guanidino, -NR q R s ,
  • Rn, Rq and Rs are independently H, alkyl, cycloalkyl, cycloalkylmethyl, aryl, substituted aryl, aralkyl or substituted aralkyl.
  • Rn, Rq and Rs are independently H, alkyl, cycloalkyl, cycloalkylmethyl, aryl, substituted aryl, aralkyl or substituted aralkyl.
  • A is guanidino or ;
  • 1712 is 0 or 1 ;
  • a still more preferred class of compounds of the present invention is described by the more preferred class of compounds wherein A is guanidino.
  • a most preferred class of compounds of the present invention is described by the still more preferred class of compounds wherein Z is a D- or L-isomer of an ⁇ -amino acid bonded at the ⁇ -nitrogen, or Z is a dipeptide bonded at the N-terminal ⁇ -amino acid.
  • Another most preferred class of compounds of the present invention is described by the still more preferred class of compounds wherein Z is a D- or L-isomer of an ⁇ -amino acid bonded at the ⁇ -nitrogen.
  • a particularly preferred special embodiment of the present invention is described by the still more preferred class of compounds wherein Z is a D- or L-isomer of an ⁇ -amino acid bonded at the ⁇ -nitrogen, said ⁇ -amino acid being selected from the group consisting of giycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, praline, hydroxyproline, aspartic acid, aspargine, glutamine, glutamic acid, histidine, arginine, ornithine, and lysine.
  • a most preferred special embodiment of the present invention is described by the still more preferred class of compounds wherein Z is a D- or L-isomer of an ⁇ -amino acid bonded at the ⁇ -nitrogen, said ⁇ -amino acid being selected from the group consisting of valine, leucine, isoleucine, and arginine.
  • Representative compounds of the present invention include:
  • Compounds of the present invention contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration.
  • the present invention comprises the individual stereoisomers and mixtures thereof.
  • the compounds of the present invention may be useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
  • acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non- toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial antithrombotic properties inherent in the free base are not vitiated by side effects ascribable to the anions.
  • Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
  • mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid
  • organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, quinic
  • the corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, malonate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that .is, salts whose cations are non- toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial antithrombotic properties inherent in the free acid are not vitiated by side effects ascribable to the cations.
  • the scope of the invention are those derived from the following bases: sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, N.N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, and the like.
  • Metal salts of compounds of the present invention may be obtained by contacting a hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous solvent with the free acid form of the compound.
  • the aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.
  • Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
  • Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous solvent with the free acid form of the compound.
  • Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
  • Compounds of this invention may be prepared in accordance with the reaction sequences described below, or can be prepared by methods known in the art.
  • the starting materials used in the preparation of compounds of this invention are known or are commercially available, or can be prepared by known methods or by specific reaction schemes described herein.
  • the compounds of the present invention may be readily prepared by standard solid phase or solution phase peptide synthesis using starting materials and/or readily available intermediates from chemical supply companies such as Aldrich or Sigma, (H. Paulsen, G. Merz, V. Weichart, "Solid- Phase Synthesis of O-Glycopeptide Sequences", Angew. Chem. Int. Ed. EngI. ZL (1988); H. Mergler, R. Tanner, J. Gosteli, and P. Grogg, "Peptide Synthesis by a Combination of Solid-Phase and Solution Methods I: A New Very Acid- Labile Anchor Group for the Solid-Phase Synthesis of Fully Protected Fragments.
  • a preferred method of preparing compounds of the present invention is by the solid phase method schematically represented as follows:
  • the solid support may be, but is not limited to, p-alkoxy benzyl resin, Xn-N— P r i and P R is a protected amino acid.
  • the amino acid derivatives are added one at a time to the insoluble resin until the total sequence has been built up on the resin.
  • the functional groups of the amino acid derivatives are protected by blocking groups to prevent cross reaction during the coupling procedure.
  • blocking groups include N- ⁇ -tertiary butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), benzyl, t-butyl, 9-fluor- enylmethyloxycarbonyl (FMOC), 2-(trimethylsilyl)ethyl, and 4-methoxy-2,3,6- trimethylbenzenesulfonyl.
  • a functional group is deprotected by standard methods to give an active a-amino function which, in turn, is reacted with a protected amino acid derivative having a free carboxyl function thereon. This procedure is repeated until the desired peptide or pseudopeptide is formed. The compound is then deprotected and removed from the solid support by standard procedures to obtain the final product.
  • the compounds of the present invention may be prepared in solution, i.e., without using a solid support.
  • the protected amino acid derivatives or analogs are coupled by using standard procedures, then deprotected to yield the desired final compound.
  • substituents may be protected by standard blocking groups which may subsequently be removed or retained, as required, by known methods to afford the desired products or intermediates (see, for example, Green, "Protective Groups in Organic Synthesis", Wiley, New York, 1981 ). Selective protection or deprotection may also be necessary or desirable to allow conversion or removal of existing substituents, or to allow subsequent reaction to afford the final desired product.
  • the deprotected resin is treated with 0.92g of N-FMOC-L-aspartic acid-B-t-butyl ester in 15 ml of dimethylformamide in the presence of 0.43g 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 0.31 ml triethylamine, and 0.30g 1 -hydroxybenzotriazole (HOBT), for 1 1/2 hours.
  • EDC 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBT 0.30g 1 -hydroxybenzotriazole
  • the resulting resin derivative is then treated as above with 1.36g N- ⁇ -FMOC- N-c_-(4-methoxy-2,3,6-trimethylbenzenesulfonyI)-L-arginine in the presence of triethylamine, EDC, and HOBT.
  • the FMOC group is removed as above.
  • the peptide is removed from the resin by treating with 20 ml of 95% trifluoroacetic acid for two hours.
  • the arginine residue is deprotected by overnight treatment with concentrated trifluoroacetic acid.
  • Example 2A The amide obtained in Example 2A is dissolved in 20% (v/v) piperidine in methylene chloride and stirred at room temperature for 2 hours. The solution is evaporated in vacuo and the residue dissolved in ethyl acetate and this solution is washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to give 1.7g L-aspartic acid- ⁇ -isobutyl amide- ⁇ -t-butyl ester.
  • Example 2B 0.67g N- ⁇ -FMOC glycine and 0.55g of the amide obtained in 2B are treated under the conditions of Example 2A to give N- ⁇ -(FMOC)-glycyl-L- aspartic acid isobutyl amide- ⁇ -butyl ester.
  • Example 2C The product obtained in Example 2C is treated as in Example 2B to remove the FMOC protecting group to give glycyl-L-aspartic acid isobutyl amide- ⁇ -butyl ester.
  • Example 2D E. 0.40g of the product of Example 2D and 0.78g N- ⁇ -t-BOC-N- ⁇ -(4- methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine are treated as in Example 2A with 0.29g EDC, 0.17g HOBT and 0.18 ml triethylamine to give N- ⁇ -BOC-N- (4-co-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginylglycyl-L-aspartic acid isobutyl amide- ⁇ -butyl ester.
  • Example 2E 0.35g of the product obtained in Example 2E is treated with concentrated trifluoroacetic acid in the presence of two drops of ethanedithiol overnight. The solution is diluted with 0.5% acetic acid and washed with 4x100 ml of ethyl acetate. The aqueous solution was lyophilized to 0.19g of a white solid, L-arginylglycyl-L-aspartyl- ⁇ -isobutylamide as the ditrifluoroacetate salt; m.p. 90-95°C.
  • Example 2A 1.27g L-valine t-butyl ester and 2.5g N- ⁇ -FMOC-L-aspartic acid fi ⁇ t-butyl ester are treated as in Example 2A in the presence of 1.16g EDC, 0.93g triethylamine and 0.82g hydroxybenzotriazole. The resulting product is then deprotected as in Example 2B to give L-aspartyl- ⁇ -t-butyl ester-L-valine- ⁇ -t- butyl ester.
  • Example 3A 1.1 g of the product obtained from Example 3A is treated with N- ⁇ - FMOC-glycine in the presence of 0.60g EDC, and 0.43g of triethylamine in methylene chloride as in Example 2A and the resulting product deprotected in 20% piperidine in methylene chloride as in Example 2B to give 0.65g glycyl-L- aspartyl- ⁇ -t-butyl ester-L-valine- ⁇ -t-butyl ester.
  • Example 3D E. 0.23g of the product obtained in Example 3D is dissolved in 5 ml trifluoroacetic acid with 3 drops of ethanedithiol added. The solution is stirred for 7 hours, evaporated, and the residue partitioned between ethyl acetate and 0.5M acetic acid. The aqueous portion was separated and lyophilized and the resulting solid purified by HPLC to give L-omithyl-glycyl-L-aspartyl-L-valine as the ditrifluoroacetate salt; m.p. 122-25°C.
  • N- ⁇ -FMOC-sarcosine is substituted for N- ⁇ -FMOC-glycine and the resulting product is treated with piperidine in methylene chloride as in Example 1 to remove the FMOC group. The corresponding product is obtained.
  • Treating this product with the arginine derivative of Example 1 cleaving the resulting peptide from the resin and deprotecting as in Example 1 gave L- arginylsarcosyl-L-aspartyl-L-valine as the ditrifluoroacetate salt; m.p. 145°C (dec).
  • L-aspartic acid, glycine and L-arginine are coupled and deprotected, sequentially, as in the previous examples and the peptide removed from the resin to give L-arginylglycyl-L-aspartyl-L-(N-methyl)vaiine as the ditrifluoroacetate salt which decomposes at 153°C.
  • L-arginylglycyl-L-aspartyl glycine is obtained as the ditrifluoroacetate salt; m.p. 85-90°C.
  • Example 7C 1.64g sodium acetate, 1.23g sodium cyanoborohydride and 1g of 3 Angstrom molecular sieves are stirred together in 100 ml methanol for 3 days. The solution is filtered and 5 ml of 5% hydrochloric acid is added. The solution is diluted with water and adjusted to pH 9 with 10% sodium carbonate, then extracted with water, and dried over sodium sulfate. The solution is evaporated and the residue purified by flash chromatography in ethyl acetate/hexane, 1 :1 , to give 1.1g N-CBZ-aminoethyl-L-aspartyl- ⁇ -t-butyl ester- L-valine-t-butyl ester.
  • Example 3D to give N-aminoethyl-L-aspartyl-t-butyl ester-L-valine-t-butyl ester.
  • Example 7E The product from Example 7E is coupled with N- ⁇ -t-BOC-N- ⁇ -(4- methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine as in Example 2D and the resulting product deprotected as in 2E to give N-(L-arginyl-2-aminoethyl)-L- aspartyl-L-valine as the tritrifluoroacetate salt; m.p. 91-5°C.
  • N-t-BOC-L-aspartic acid ⁇ -benzyl ester is treated with 0.366g of 2-(trimethylsilyl)ethanol in the presence of 0.592g EDC, 0.419g HOBT and 0.43 ml triethylamine in 20 ml of methylene chloride for 2 hours.
  • the product is isolated as in Example 2A to give N-t-BOC-L-aspartic acid ⁇ -benzyl ester- ⁇ -2- (trimethylsilyl)ethyl ester.
  • Example 8A The product of Example 8A is deprotected by treating with 10 ml of trifluoroacetic acid in 30 ml of methylene chloride for 2 hours at room temperature. The mixture is cooled to 0°C and 20 ml of saturated sodium carbonate solution is added dropwise. The layers are separated and the organic layer dried over magnesium sulfate, filtered, evaporated to give L- aspartic acid- ⁇ -benzyl ester- ⁇ -2-(trimethylsilyl)ethyl ester.
  • Example 8B The product of Example 8B and N-t-BOC glycine are coupled in a manner similar to that described in the previous examples to give BOC-glycyl-
  • Example 8C The BOC group is removed from the product of Example 8C as in Example 8B to give glycyl-L-aspartic acid- ⁇ -benzyl ester- ⁇ -2- (trimethyisilyl)ethyl ester.
  • Example 8D The product from Example 8D is coupled to N- ⁇ -BOC-N- ⁇ -(4- methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine as in 2D to give N- ⁇ -BOC- N-_ (4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-L-arginyl-glycylaspartic acid ⁇ -benzyl ester- ⁇ -2-(trimethylsilyl)ethyl ester.
  • Example 8E 0.30g of the product obtained in Example 8E is stirred with 5 ml of trifluoroacetic acid at room temperature for 24 hours. The reaction mixture is then stirred with 0.5 N acetic acid and washed with ethyl acetate. The aqueous layer is lyophilized to give L-arginylglycyl-L-aspartic acid ⁇ -benzyl ester ditrifluoroacetate; m.p. 85-7°C.
  • Example 9A The product from Example 9A is shaken with 0.92g of N- ⁇ -FMOC- L-aspartic acid ⁇ -t-butyl ester, 0.3 g of 1 -hydroxybenzotriazole (HOBT), 0.43 g of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 0.32 ml of triethylamine in 10 ml of dimethylformamide for 2 hours. The mixture is filtered and the resin washed with methylene chloride. The resin derivative is then deprotected as in Example 1 to give L-aspartyl- ⁇ -t-butyl ester-L-valine p-alkoxybenzyl resin ester.
  • HOBT 1 -hydroxybenzotriazole
  • EDC 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride
  • triethylamine in 10 ml
  • Example 9B The product from Example 9B is shaken with 0.52g of N- ⁇ -BOC-6- aminohexanoic acid, 0.3 g of HOBT, 0.43g of EDC and 0.32 ml of triethylamine in 10 ml of dimethylformamide for 17 hours. The mixture is filtered and the resin derivative washed with methylene chloride. The peptide derivative is - deprotected and cleaved from the resin by treating with 10 ml of 95% trifluoroacetic acid for 2 hours. The resin is filtered off and the filtrate diluted with 50 ml of 0.5 N acetic acid.
  • 7-Guanidinoheptanoic acid is prepared essentially by the method of Miller, et al, Synthesis. 777 (1986), which is incorporated herein by reference. 0.50g of 7-aminoheptanoic acid is dissolved in a solution of 0.475g of potassium carbonate in 3.5 ml of water. 0.427g of aminoiminomethanesulfonic acid is added portionwise over 10 minutes and the mixture stirred at room temperature for 24 hours. The resulting solid is collected by filtration. The guanidine is dissolved in diluted hydrochloric acid and the solution evaporated in vacuo. Two portions of 2-propanol are evaporated from the residue to give 7-guanidinoheptanoic acid hydrochloride.
  • L-aspartyl- ⁇ -t-butyl ester-L-valine p-alkoxy-benzylalcoholester (prepared from 1 g of N-FMOC-L-valine p-alkoxybenzylalcohol ester resin as in Examples 9A and B) is treated with 0.50 of 7-guanidinoheptanoic acid hydrochloride, 0.3 g of HOBT, 0.43g of EDC and 0.32 ml of triethylamine in 10 ml of dimethylformamide in a manner similar to that in Example 1 D to give N- (7-guanidino-heptanoyl)-L-aspartyl-L-valine as the trifluoroacetate salt; m.p. 75-80°C.
  • 8-guanidinooctanoic acid hydrochloride is prepared from 8- aminooctanoic acid in a manner similar to the process used in Example 11 A.
  • N- ⁇ -BOC-8-aminooctanoic acid is substituted for N- ⁇ -BOC-6- aminohexanoic acid in Example 9D, N-(8-amino-octanoyl)-L-aspartyl-L-valine is prepared as the trifluoroacetate salt.
  • L-aspartyl- ⁇ -t-butylester-L-valine p-alkoxybenzyl resin ester (prepared from 0.6g of N-FMOC-valine p-alkoxybenzyl resin ester as in Examples 1A and B) is treated with 0.33g of 8-guanidino-2-octenoic acid hydrochloride in the presence of 0.184g of HOBT, 0.26g of EDC and 0.19 ml of triethylamine in 10 ml of dimethylformamide in a manner similar to that in Example 1 D to give 8-guanidinooct-2-enoyl-L-aspartyl -L-valine as the trifluoroacetate salt.
  • Example 11 A 6-guanidinohexanoic acid is prepared.
  • N-ethyl glycine hydrochloride is stirred in 35 ml of water. This is treated with 8.31 g of sodium carbonate and cooled to 0°C, followed by the dropwise addition of 6.77 g of 9-fluorenylmethyl chloroformate in 15 ml of tetrahydrofuran (THF). The reaction mixture is allowed to slowly warm to room temperature and stirred for 24 hours. The THF is removed in vacuo and the residue is diluted with water and extracted with ether. The aqueous fraction is acidified to pH ⁇ 2 with 1 N aqueous HCI and extracted with ethyl acetate.
  • N- ⁇ -FMOC-N- ⁇ -ethyl glycine is substituted for N- ⁇ -FMOC glycine and the resulting product is treated with piperidine in methylene chloride as in Example 1 to remove the FMOC groups.
  • N- ⁇ -Ethyl glycyl-L-aspartyl- ⁇ -t-butyl ester-L-valine-p-alkoxybenzyl alcohol resin ester is obtained.
  • the trifluoroacetate acid solution is diluted with 0.5% acetic acid, washed with 3 portions of ethyl acetate, then lyophilized to give 6-guanidinohexanoyl-N-ethyl glycyl-L- aspartyl-L-valine as a white powder.
  • 6-(imidazol-1-yl)-hexanoic acid methyl ester is treated with 1N aqueous HCI for 24 hours at reflux to provide, after concentration in vacuo. 6-(imidazol- 1-yl)-hexanoic acid hydrochloride.
  • the layers are separated and the aqueous phase is extracted with 250 ml of ethyl acetate
  • the combined organic layers are washed with 150 ml of 10% aqueous sodium carbonate, then with two 125 ml portions of saturated aqueous sodium chloride.
  • the organic phase is dried (MgSO- and concentrated in vacuo to give 7.39 g of a white solid. Recrystallization of the product from dichioromethane-hexane gives 6.22 g (96%) of the title compound as a fluffy solid.
  • the combined filtrate and washings are concentrated to dryness and the residue (1.98 g) is dissolved in 20 ml of 50% aqueous ethanol and 515 mg (16.1 mmol; 5000 ml) of 55% aqueous hydrazine is added. This solution is heated for 2.5 hours, cooled to room temperature and concentrated to dryness. The residue is stirred with 15 ml of 2 ⁇ aqueous hydrochloric acid for 13 hours, then the suspension is heated under reflux for 30 minutes. The cooled suspension is filtered and the precipitate is washed with 15 ml of water. The filtrate and washings are concentrated in vacuo to give 3.05 g of the crude amine hydrochloride as a colorless semisolid. Further solid impurities are removed by filtration of the ethanol-soluble material; this gives 1.93 g of a pale yellow oil.
  • the desired product is prepared by the procedure described for the preparation of [4-(4'-guanidinobutyl)tetrazol-1-yl]-acetyl-L-aspartyl-L-valine, by substituting N-phthalyl-6-aminohexanoic acid for N-phthalyl-6-aminopentanoic acid in Example 18A.
  • oxazolidinone (4.38g, 15.8 mmol) is dissolved in tetrahydofuran (THF) (40 ml) and the solution cooled to -78°C under a nitrogen atmosphere. A solution of 1 M sodium bis(trimethylsilyl)amide (23 ml) in THF is added and the mixture stirred at -78°C for 30 minutes.
  • THF tetrahydofuran
  • B. BOC-2,2-dibenzyl glycine (3.29g, 9.25 mmol) is dissolved in a solution of methanol (18 ml) and water (2 ml) and the pH adjusted to 8 with 20% cesium carbonate solution (11 ml).
  • the solution is concentrated in vacuo to dryness and the residue dissolved in dimethylformamide (DMF) (25 ml) and re-concentrated twice and dried under high vacuum.
  • the cesium salt is taken up into DMF (25 ml), benzyl bromide (1.74g, 10.2 mmol) is added and the mixture stirred at room temperature for 16 hours.
  • the mixture is concentrated in vacuo and the residue diluted with ether.
  • BOC-2,2-dibenzyl glycine benzyl ester is deprotected (trifluoroacetic acid) as in Example 8 and coupled (BOP-CI) to N-BOC-L- aspartic acid- ⁇ -benzyl ester essentially in the manner of Example 16.
  • the resulting dipeptide is, in turn, deprotected (TFA) and coupled (EDC) essentially in the manner of Example 2 to 9-nitroguanidinononanoic acid.
  • BOC-L-leucine is converted to racemic BOC-(2-isobutyl)-allyl glycine benzyl ester using essentially the procedures of Example 20, Steps A and B, substituting allyl bromide in the alkylation step.
  • the benzyl ester (2.07g, 5.73 mmol) is dissolved in THF (40 ml), under nitrogen, 0.5 M 9- borabicyclo[3.3.1]-nonane (9-BBN) in hexanes (46 ml, 23 mmol) is added and mixture stirred at room temperature for 16 hours.
  • the reaction mixture is quenched with water (1 ml) and a mixture of 1 N aqueous sodium hydroxide solution (51 ml) and 30% hydrogen peroxide solution (18 ml) is added dropwise.
  • the mixture is stirred for 1 hour at room temperature, saturated with solid sodium chloride, then extracted with ether.
  • the organic layer is washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo .
  • the crude product is purified by flash chromatography, eluting with 20% ethyl acetate/hexanes to give BOC-(2- isobutyl)-3-hydroxypropyl glycine benzyl ester.
  • the primary tosylate (0.23g, 0.43 mmol) is dissolved in DMF/water (10:1) (2 ml) and sodium azide (0.29g, 4.46 mmol) is added.
  • the mixture is heated at 90°C for four hours, cooled, diluted with ether and poured into brine.
  • the organic layer is washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo .
  • the crude product is purified by flash chromatography, eluting with 10% ethyl aceate in hexanes to give BOC-(2- isobutyl)-3-azidopropyl glycine benzyl ester.
  • BOC-2,2-diethyl glycine benzyl ester is prepared from BOC-2,2-diethylglycine.
  • BOC -2,2-diethyl glycine benzyl ester is coupled (EDC) to N-BOC-L-aspartic acid- ⁇ -benzyl ester, to N-BOC-N-ethyl glycine (BOP-CI), and finally to 6-nitro 35
  • guanidinohexa ⁇ oic acid to give, after hydrogenation and deprotection as described above, 6-guanidinohexanoyl-N-ethyl-glycyl-L-aspartyl-2,2- diethylglycine, which is isolated as the acetate salt.
  • Step E 9- guanidino-L-aspartyl-(S)- ⁇ -isobutylarginine methyl ester is prepared from (S)- BOC-(2-isobutyl)-nitroarginine methyl ester, and isolated as the ditrifluoroacetate salt, M.S., Cal'd: 557, Found: 557.
  • the mixture is extracted with ethyl acetate and the organic layer washed with satruated sodium bicarbonate solution, brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo .
  • the crude product was purifed by flash chromatography, eluting with 10% ethyl acetate in hexanes to give the corresponding BOC-L-leucine- ⁇ , ⁇ -unsaturated ethyl ester.
  • the ester (1.5 g, 5.26 mmol) is dissolved in ethanol (20 ml) and hydrogenated at atmospheric pressure over 10% palladium on carbon (0.16g) for 24 hours.
  • pseudotripeptide ethyl ester (0.16g, 0.25 mmol) is dissolved in methanol/water (2:1) (6 ml), cesium carbonate (0.33g, 1.01 mmol) is added, and the mixture stirred at room temperature for 18 hours. The solvent is removed in-vacuo and the residue dissolved in ethyl acetate. The ethyl acetate is stirred with 1 N HCI, then the organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo .
  • Step A (R)-BOC- 6-amino-6-sec-butylhexanoic acid ethyl ester is prepared from BOC-L- isoleucinal and triethyl-4-phosphonocro.onate.
  • Example 26 Using essentially the procedures of Example 26, the desired product is prepared from (R)-BOC-6-amino-6-sec-butylhexanoic acid ethyl ester, and isolated as the ditrifluoroacetate salt, M.S., Cal'd: 656, Found: 656.
  • Example 28 Using essentially the procedures of Example 28, the desired product is prepared from (R)-BOC-(6-amino-6-sec-butylhexyl)nitroarginine, and isolated as the ditrifluoroacetate salt, M.S., Cal'd: 527, Found: 527.
  • Compounds within the scope of the present invention inhibit platelet aggregation by inhibiting fibrinogen binding to activated platelets and other adhesive glycoproteins involved in platelet aggregation and blood clotting and are useful in the prevention and treatment of thrombosis associated with certain disease states, such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation in humans and other mammals.
  • the compounds of this invention can normally be administered orally or parenterally, in the treatment or prevention of thrombosis associated disease states.
  • compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine.
  • Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • compositions may be formulated in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions, or solutions, injectable solutions, elixirs, syrups and the like and may contain one or more agents selected from the group including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a pharmaceutically acceptable preparation.
  • the particular carrier and the ratio of platelet aggregation and thrombus inhibiting compound to carrier are determined by the solubility and chemical properties of the compounds, the particular mode of administration and standard pharmaceutical practice.
  • excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used in producing tablets.
  • lactose and high molecular weight polyethylene glycols are among the preferred pharmaceutically acceptable carriers.
  • the carrier can be emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerin and chloroform and their combinations can be employed as well as other materials.
  • solutions or suspensions of these compounds in sesame or peanut oil or aqueous propylene glycol solutions, as well as sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein can be employed.
  • Solutions of the salts of these compounds are especially suited for intramuscular and subcutaneous injection purposes.
  • the aqueous solutions, including those of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes, provided that their pH is properly adjusted, they are suitably buffered, they are made isotonic with sufficient saline or glucose and sterilized by heating or microfiltration.
  • the dosage regimen in carrying out the method of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief.
  • the oral dose may be between about 1 mg/kg and about 200 mg/kg, preferably between about 2 mg/kg to 100 mg/kg, and most preferably between about 10 mg/kg and 100 mg/kg, and the i.v. dose about 0.1 mg kg to about 20 mg/kg, preferably between about 0.5 mg/kg to 10 mg/kg, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, age, and other factors which may influence response to the drug.
  • the drug may be administered orally 1 to 4 times per day, preferably twice daily.
  • the following pharmacologic tests evaluate the inhibitory activity of compounds of the present invention on fibrinogen-mediated platelet aggregation and fibrinogen binding to thrombin-stimulated platelets, and results of these tests correlate to the in-vivo inhibitory properties of compounds of the present invention.
  • the Platelet Aggregation Assay is based on that described in Blood 66 (4), 946-952 (1985).
  • the Fibrinogen-Binding Assay is essentially that of Ruggeri, Z.M., et al., Pr ⁇ . Natl. Acad. Sci. USAB3, 5708-5712 (1986) and Plow, E.F., et al., Proc. Natl. Acad. Sci., USA 82, 8057-8061 (1985).
  • Platelets are isolated from human platelet concentrates using the gel- filtration technique as described by Marguerie, G.A., et al., J. Biol. Chem. 254, 5357-5363 (1979) and Ruggeri, Z.M., et al., J. Cli ⁇ . Invest. 72, 1-12 (1983).
  • the platelets are suspended at a concentration of 2 x 10 ⁇ cells/ml in a modified calcium-free Tyrode's buffer containing 127 mM sodium chloride, 2 mM magnesium chloride, 0.42 mM Na2HP04, 11.9 mM NaHC ⁇ 3, 2.9 mM KCI, 5.5 mM glucose, 10 mM HEPES, at a pH of 7.35 and 0.35% human serum albumin (HSA).
  • HSA human serum albumin
  • the fixed activated platelets are incubated with a selected dose of the compound to be tested for platelet aggregation inhibition for one minute and aggregation initiated by addition of human fibrinogen to a final concentration of 250 ⁇ g/ml.
  • a platelet aggregation profiler Model PAP-4 is used to record the platelet aggregation.
  • the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
  • IC50 i.e., the amount of inhibitor required to reduce the aggregation rate by 50%, is then calculated for each compound (see, for example, Plow, E.F., et al., Proc. Natl. Acad. Sci., USA 82, 8057-8061 (1985)).
  • Platelets are washed free of plasma constituents by the albumin density- gradient technique of Walsh, P.N., et al., Br. J. Haematol. 281-296 (1977), as modified by Trapani-Lombardo, V., et al., J. Cli ⁇ Invest.76, 1950-1958 (1985).
  • platelets in modified Tyrode's buffer (Ruggeri, Z.M., et al., J. Clin. Invest.72, 1-12 (1983)) are stimulated with human ⁇ - thrombin at 22-25°C for 10 minutes (3.125 x 10 11 platelets per liter and thrombin at 0.1 NIH units/ml).
  • Hirudin is then added at a 25-fold excess (unit/unit) for 5 minutes before addition of the 125 l-labeled fibrinogen and the compound to be tested. After these additions, the final platelet count in the mixture is 1 x 10 11 /liter. After incubation for an additional 30 minutes at 22- 25°C, bound and free ligand are separated by centrifuging 50 ⁇ l of the mixture through 300 ⁇ l of 20% sucrose at 12,000xg for 4 minutes. The platelet pellet is then separated from the rest of the mixture to determine platelet-bound radioactivity. Nonspecific binding is measured in mixtures containing an excess of unlabeled ligand.
  • N-(L-arginyl-2-aminoethyl)-L-aspartyl-L-valine >200 10 10 tritrifluoroacetate, m.p. 91-95°C, M.S., Cal'd: 432, Found: 432
  • N-(9-guanidinononanoyl-L-aspartyl)-(R)-4- 54 25 amino-4-isobutyl butyric acid ditrifluoroacetate, M.S., Cal'd: 472, Found: 472

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Abstract

Cette invention concerne de nouveaux peptides et pseudopeptides qui inhibent l'agrégation plaquettaire et la formation de caillots dans le sang d'un mammifère et qui sont par conséquent utiles pour prévenir et traiter la thrombose associée aux états pathologiques tels que l'infarctus du myocarde, l'attaque cardiaque, l'artérite oblitérante et la coagulation intravasculaire disséminée. Des compositions pharmaceutiques renfermant ces composés sont également décrites ainsi que leur utilisation permettant d'inhiber la formation de caillots et l'agrégation plaquettaire chez les mammifères.
EP92912095A 1991-03-28 1992-03-30 Peptides et pseudopeptides antithrombotiques. Withdrawn EP0577775A4 (fr)

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US5780303A (en) * 1990-04-06 1998-07-14 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US6521594B1 (en) 1990-04-06 2003-02-18 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US6017877A (en) * 1990-04-06 2000-01-25 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5672585A (en) * 1990-04-06 1997-09-30 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
EP0677043A1 (fr) * 1992-12-29 1995-10-18 Smithkline Beecham Corporation Composes inhibant l'aggregation des plaquettes
US5753659A (en) * 1993-03-29 1998-05-19 Zeneca Limited Heterocyclic compouds
JP3088016B2 (ja) * 1993-03-29 2000-09-18 ゼネカ・リミテッド 血小板凝集抑制剤としての複素環式化合物
US5750754A (en) * 1993-03-29 1998-05-12 Zeneca Limited Heterocyclic compounds
US5652242A (en) * 1993-03-29 1997-07-29 Zeneca Limited Heterocyclic derivatives
NZ262941A (en) * 1993-03-29 1997-07-27 Zeneca Ltd Pyridine derivatives and medicaments
US5516889A (en) * 1993-06-21 1996-05-14 University Technologies International, Inc. Synthetic thrombin receptor peptides
GB9313285D0 (en) * 1993-06-28 1993-08-11 Zeneca Ltd Acid derivatives
GB9313268D0 (en) * 1993-06-28 1993-08-11 Zeneca Ltd Chemical compounds
US5463011A (en) * 1993-06-28 1995-10-31 Zeneca Limited Acid derivatives
US5780590A (en) * 1993-10-15 1998-07-14 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
US5639765A (en) * 1995-01-17 1997-06-17 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting bone loss
US5602155A (en) * 1995-01-17 1997-02-11 G. D. Searle & Co. Platelet aggregation inhibitors
US5681820A (en) * 1995-05-16 1997-10-28 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
US20210395299A1 (en) * 2018-10-29 2021-12-23 Huahai Us Inc. Novel dipeptide compounds and uses thereof

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WO1991004746A1 (fr) * 1989-09-29 1991-04-18 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques

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