ANTI-AGGREGATORY PEPTIDES CONTAINING A MERCAPTAN OR SULFIDE MOIETY

Abstract: This invention relates to compounds of the formula: X-(V-A-B-Gly-Asp-Q)n-(V'-A'-B'-Gly-Asp, Q')-P, wherein: V and V' are absent, Asn, Gln, Ala or Abu; A and A' are absent or a D- or L- amino acid chosen from Arg, HArg, NArg, (Me2)Arg, (Et2)Arg, Abu, Ala, Gly, His, Lys, or an alpha -R' substituted derivative thereof, Dtc, Tpr or Pro; B and B' are Arg, HArg, NArg, (Me2)Arg, (Et2)Arg, Orn, Lys, HLys or an alpha -R' substituted derivative thereof; Q and Q' are a D- or L- amino acid chosen from Tyr, (Alk)Tyr, Phe, (4'W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, Cys, (Alk)Cys, Pen, (Alk)Pen, Pcs, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal; R' is Alk or PhCH2; (a), (b), (c) or (d); W is halogen or Alk; X is R4R5N or H; Y is H, CONR1R2 or CO2R2; R1 and R2 are H, Alk or (CH2)pAr; R4 is H or Alk; R5 is R11, R11CO, R11OCO, R11OCH(R11')CO, R11NHCH(R11')CO, R11SCH(R11')CO, R11SO2 or R11SO; R7 is H, Alk, OAlk, halogen or Y; R8 and R8' are H, Alk, (CH2)pPh, (CH2)pNph or taken together are -(CH2)4- or -(CH2)5-; R11 and R11' are H, C1-5alkyl, C3-7cycloalkyl, Ar, Ar-C1-5alkyl, Ar-C3-7cycloalkyl; Ar is phenyl or phenyl substituted by one or two C1-5alkyl, trifluoromethyl, hydroxy, C1-5alkoxy or halogen groups; n is 0 or 1; p is 0, 1, 2, or 3; and q is 1 or 2; or a pharmaceutically acceptable salt thereof; which are effective for inhibiting platelet aggregation, pharmaceutical compositions for effecting such activity, a method for inhibiting platelet aggregation and clot formation in a mammal, and a method for inhibiting reocclusion of a blood vessel following fibrinolytic therapy.

Description: ANTI-AGGREGATORY PEPTIDES CONTAINING A MERCAPTAN OR SULFIDE MOIETY Field of the Invention This invention relates to novel peptides which inhibit platelet aggregation, pharmaceutical compositions containing the peptides and methods of using the peptides. In particular, a method of using the peptides of this invention in combination with fibrinolytic agents is disclosed. Background of the Invention A thrombus is the result of processes which initiate the coagulation cascade. It is composed of an aggregation of platelets enmeshed in a polymeric network of fibrin. This process is normally initiated as a consequence of tissue injury and has the effect of slowing or preventing blood flow in a vessel. Etiological factors which are not directly related to tissue injury, such as atherosclerotic plaque, inflammation of the blood vessels (phlebitis) and septicemia, may also initiate thrombus formation. In some instances, the inappropriate formation of a thrombus, and subsequent decrease in blood flow, may have pathological consequences, such as stroke, pulmonary embolism and heart disease. Platelets play a major role in thrombus formation. Current antithrombotic therapy employs agents that modify the platelet/endothelial cell arachidonate-prostaglandin system, such as prostacyclin analogues, cyclooxygenase inhibitors, thromboxane synthesis inhibitors and thromboxane receptor antagonists; and anti-coagulants, such as heparin. These agents inhibit one or both of two discernible phases of platelet aggregation. The primary phase, which is a response to chemical stimuli, such as ADP (adenosine diphosphate) , collagen, epinephrine or thrombin, causes initial activation of the platelets. This is followed by a secondary phase, which is initiated by the platelets themselves, and is characterized by thromboxane A2 (T A2) synthesis and the release of additional ADP from platelet storage granules, which further activates platelets. Prostacyclin, also called prostaglandin I2 (PGI2) , and stable PGI2 analogues inhibit both the primary and secondary phases of platelet aggregation. However, use of such analogues has been associated with undesirable changes in blood pressure. See Aiken, et al.. Prosta landins, 19, 629- 43 (1980) . Cyclooxygenase inhibitors and thromboxane synthetase inhibitors act to block the production of TX 2. TxA2 antagonists block the effects of TxA2 by binding the x 2 receptor. These therapies act only upon the secondary stage of platelet activation. Use of cyclooxygenase inhibitors has been associated with ulcerogenesis and an adverse effect upon prostacyclin synthesis. Heparin prevents the activation of fibrinogen by thrombin and thereby prevents the activation of the GPIIb- Illa receptor by thrombin. This inhibits only the primary phase of platelet aggregation and has little effect upon activation of platelets by other means, such as collagen, ADP and epinephrine. Cyclooxygenase inhibitors, prostaglandin analogues and heparin all inhibit platelet aggregation indirectly by inhibiting the primary or secondary phase of platelet/fibrinogen activation. There is therefore a need for selective therapeutic products which block platelet aggregation directly, whether it arises from the primary or secondary phase of platelet activation. Platelet aggregation is believed to be mediated primarily through the GPIIb-IIIa platelet receptor complex. Von illebrand factor, a plasma protein, and fibrinogen are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets. Fibronectin, vitronectin and thrombospondin are proteins which have also been demonstrated to bind to GPIIb-IIIa. Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls. The importance of the GPIIb-IIIa receptor to platelet aggregation has been demonstrated by methods which mask the receptor. Thus, Coller _______!__ (Blood. 66, 1456-9 (1985)) have shown that antibodies to this complex inhibit platelet aggregation induced by ADP in dogs. Peptides which contain an RGD (single letter amino acid code for Arg-Gly-Asp) sequence have been reported to inhibit platelet aggregation. Peptide fragments of human plasma fibronectin and synthetic-peptides containing the RGD sequence which promote cell attachment and enhance phagocytosis are disclosed in U.S. Patent 4,517,686, U.S. Patent 4,589,881, U.S. Patent 4,661,111 and U.S. Patent 4,614,517. Pierschbacher e _ai., J. Biol. Chem.. 262, 17294 (1987) disclose heptapeptides which contain an RGD sequence which inhibit the binding of rat kidney fibroblasts to a fibronectin substrate. Nievelstein et al. (Thromb. and Hemostasis. 58, 2133(1987)) have reported that -RGDS- peptides inhibit thrombin induced aggregation and adhesion of platelets to fibronectin, and may interact through the GPIIb-IIIa complex. U.S. Patent 4,683,291 discloses peptides containing Arg and Lys and an -RGD- sequence which inhibit binding of fibrinogen to platelets and inhibit platelet aggregation. Tetrapeptides which contain the sequence X-Gly-Asp-, wherein X is a guanidine-containing aliphatic carboxylic acid or amino acid residue, are disclosed in EP-A 0 319 506 as inhibitors of platelet aggregation. EP-A 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation. Other peptides and polypeptides which contain an RGD sequence and inhibit fibrinogen binding are disclosed by Plow et al.. Blood. 70, 110 (1987), Ginsberg et al. , J. Biol . Chem., 260, 3931 (1985), Ruggeri ±_al__, Proc. Natl. Acad. Sπi.. 83, 5708 (1986) and Haverstick et al.. Blood. 66, 946 (1985) . Linear and cyclic peptides, the disclosure of which are incorporated herein by reference, are reported in copending application U.S. Ser. No. 07/335,306. The instant invention provides linear peptides in which the peptide contains an α-amino- substituted arginine residue adjacent to -Gly-Asp and a sulfur-containing residue, the sulfur-containing residue being one residue removed from the Gly-Asp- sequence. This invention also provides peptides in which the sequence containing -Gly-Asp- is repeated within the peptide prior to the sulfur-containing residue. The instant peptides are surprisingly more active in inhibiting platelet aggregation and the formation of thrombi than prior art peptides . Recent advances for treatment of occluded arteries and deep vein thrombosis employ fibrinolytic agents to lyse thrombi or emboli in order to reestablish or improve blood flow. Fibrinolytic agents, such as anistreplase, tissue plasminogen activator (tPA) , urokinase (UK) , pro- Urokinase (pUK) , and streptokinase (SK) , and mutants and derivatives thereof, are proteolytic enzymes which cause fibrin to be hydrolyzed at specific sites and thereby fragment the fibrin network. Their action ia vivo is to proteolytically activate plasminogen in the blood to form plasmin, which causes lysis of the fibrin clot. Lysis of fibrin into smaller peptides has the effect of solubilizing the thrombus or embolus. A recurrent problem with such therapy, however, is the reocclusion of the blood vessel due to formation of a secondary thrombus. Fibrinolytic therapy is most commonly used for re¬ establishing flow in a thrombosed blood vessel. However, fibrinolytic therapy does not reverse the factors responsible for the initiation of the thrombus. For this reason, anticoagulants such as heparin are often used to prevent reocclusion. In fact, patients which have a high degree of stenosis in an artery are at extremely high risk of rethrombosis after reperfusion, even in the presence of high doses of heparin. See Gold et al.. Circ.. 73, 347-52 (1986) . In addition, use of SK and tPA has been associated with platelet hyperaggregability. See Ohlstein, et al.. Throm . Res. , 4, 575-85 (1987) . Treatment with higher doses of tPA can be associated with systemic bleeding and is not recommended for preventing reocclusion. There is, therefore, a need for a method for preventing rethrombosis after fibrinolytic therapy. U.S. Patent Application Serial No. 917,122 discloses TxA2 antagonists for use in a method for inhibiting reocclusion following reperfusion and for lowering the dose of tPA required for fibrinolysis. Yasuda et al . (Clin . Res . , 34, 2 (1986)) have demonstrated that reocclusion by fibrin rich platelet thrombi, after thrombolysis with tPA, may be inhibited by a murine monoclonal antibody to GPIIb-IIIa in dogs. This invention discloses a new method for inhibiting reocclusion of a blood vessel by administering peptides which directly inhibit platelet aggregation. Summary of the Invention In one aspect this invention is a compound of the formula (I) : X- (V-A-B-Gly-Asp-Q) n - (V- '-B'-Gly-Asp-Q' ) -P (I) wherein: V and V are absent, Asn, Gin, Ala or Abu; A and A' are absent or a D- or L- amino acid chosen from Arg, HArg, NArg, (Me2)Arg, (Et2) rg, Abu, Ala, Gly, His, Lys, or an α-R' substituted derivative thereof, Dtc, Tpr or Pro; B and B 1 are Arg, HArg, NArg, (Me2>Arg, (Et2)Arg, Orn, Lys, HLys or an α-R' substituted derivative thereof; Q and Q' are a D- or L- amino acid chosen from Tyr, (Alk)Tyr, Phe, (4'W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, Cys, (Alk)Cys, Pen, (Alk)Pen, Pcs, Ala, Val, Nva, Met, Leu, lie, Nle or Nal; is halogen or Alk; X is R4R5N or H; Y is H, CONR R 2 or CO2R2 Rl and R2 are H, Alk or (CH2)p r; R is H or Alk; R 5 is R 11 , R 11 CO, R 11 OCO, RnOCH(R n •) CO, RnNHCH(Rn. ) CO, R ll SCH(Rn') CO, R 11 SO 2 or RnSO; R7 is H, Alk, OAlk, halogen or Y; R8 and R Q t are H, Alk, (CH2) p P , (CH2)pNph or taken together are -(CH2)4~ or -(CH2)5~; Rn and Rιχι are H, Ci-salkyl, C3_ 7 cycloalkyl, Ar, Ar-Ci-salkyl, Ar-C3_ 7 cycloalkyl; Ar is phenyl or phenyl substituted by one or two Ci-salkyl, trifluoromethyl, hydroxy, Ci-salkoxy or halogen groups; n is 0 or 1; p is 0, 1, 2 or 3; and q is 1 or 2; or a pharmaceutically acceptable salt thereof; provided that: when n is 0, V is absent, A' is Gly and Q' is Ser, P is not Cys. This invention is also a pharmaceutical composition for inhibiting platelet aggregation and clot formation, which comprises, a compound of formula (I) and a pharmaceutically acceptable carrier. This invention is further a method for inhibiting platelet aggregation in a mammal in need thereof, which comprises internally administering an effective amount of a compound of formula (I) . In another aspect, this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following thrombolysis, which comprises internally administering an effective amount of a fibrinolytic agent and a compound of formula (I) . In combination with known fibrinolytics, such as anistreplase, streptokinase (SK) , urokinase (UK) , pro-urokinase (pUK) and tissue plasminogen activator (tPA) and variants or mutants thereof, these compounds are useful for inhibiting rethrombosis. This invention is also a pharmaceutical composition for effecting thrombolysis and reperfusion, and inhibiting reocclusion in an artery or vein in a mammal, which comprises a fibrinolytic and a compound of formula (I) in a pharmaceutical carrier. Finally, this invention is a kit for use in a method for effecting thrombolytic therapy, which comprises, in a container, a fibrinolytic and, a compound of formula (I) . Detailed Description of the Invention This invention provides linear peptides in which the peptide contains an α-amino-substituted arginine residue and a sulfur-containing residue, the sulfur-containing residue being one residue removed from the Gly-Asp- sequence. The instant peptides are potent and effective in inhibiting platelet aggregation and the formation of thrombi. This invention discloses peptides of formula (I) as hereinbefore .described. Suitably, Q or Q' is Ser, (Me)Ser, Thr, Tyr, Phe, Nal or Val. Suitably, P is Cys or Pen. Suitably, B or B 1 is MeArg. Suitably, Q or Q' is Ser. Suitably, A and A' are absent. Suitably, V and V are absent. Preferably, one of B and B' is Arg, or an α-R' substituted derivative thereof. Preferably, B is MeArg. Preferably, Q and Q' are Ser. The meaning of X in the formulae herein depicted is intended to denote the terminal amino group of the peptide or, when X is H, a desamino terminus. In like manner, Y refers to the carboxy terminal group of the peptide or, when Y is H, a descarboxy terminus . It will be understood that P may have one or two chiral centers, depending upon the identity of 8, 8 * anci γ - For example P may be D- or L- Pen, Cys, or β-phenylcysteine. This invention encompasses each unique nonracemic compound which may be synthesized and resolved by conventional techniques. This invention also includes compounds in which any of the peptide linkages, -CONH-, is replaced by an isosteric linkage. Examples of peptide isosteres are -CH=CH-, -CH2CH2-, -COCH2-, -COO-, -CHOHCH2-, -CH2NR4-, -NHCO- and -CH2S-. Specific compounds of this invention are: Ac-MeArgGlyAspSerPen-NH2, Ac-MeArgGlyAspSer(SMe) en-NH2, and Ac-MeArgGlyAspSerArgGlyAspSerPen-NH2. The nomenclature commonly used in the art is used herein to describe the peptides. 3 Amino Acid letter : code Asparagine or Aspartic Acid Asx Glutamine or Glutamic Acid Glx In accordance with conventional representation, the amino terminus is on the left and the carboxy terminus is on the right. Unless specified otherwise, all chiral amino acids (AA) are assumed to be of the L-absolute configuration. Pen refers to L-penicillamine or β,β dimethyl cysteine, APmp refers to 2-amino-3,3-cyclopentamethylene-3-mercaptopropionic acid, Man refers to 2-mercapto-aniline, Pcs refers to 3- phenyl cysteine, HArg refers to homoarginine, NArg refers to norarginine, (Me2)Arg refers to N', N"-dimethyl arginine, (Et2) rg refers to N', N"-diethyl arginine, HLys refers to homolysine, Orn refers to ornithine, Dtc refers to 5,5- dimethylthiazolidine-4-carboxylic acid, Tpr refers to thiazolidine-4-carboxylic acid, Nva refers to norvaline, Nle refers to norleucine, α-MeAsp refers to N α -methyl aspartic acid, Nal refers to beta-2-napthyl alanine, Phg refers to phenyl glycine, HPhe refers to homophenylalanine, Abu refers to 2-amino butyric acid, (Alk)Tyr refers to 0-Cι_4alkyl- tyrosine, (Alk)Ser refers to 0-Cι_4alkyl-serine, (Alk)Thr refers to 0-Cι_4alkyl-threonine, (Alk)Cys refers to S-C^- 4alkyl-cysteine, (Alk)Pen refers to S-C]__4alkyl- penicillamine, (4'W)Phe refers to phenylalanine substituted in the 4 position of the phenyl ring by W, t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the carbobenzyloxy radical, BrZ refers to the o-bromobenzyloxycarbonyl radical, C1Z refers to the o-chlorobenzyloxycarbonyl radical, Bzl refers to the benyzl radical, 4-MBzl refers to the 4-methyl benzyl radical, Ac refers to acetyl, Alk refers to C]__ alkyl, Ph refers to phenyl, Nph refers to 1- or 2-naρhthyl, cHex refers to cyclohexyl, DCC refers to dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, EDC refers to N-ethyl- N 1 (dimethylaminopropyl) carbodiimide, HOBT refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DMF refers to dimethyl formamide, DIEA refers to diisopropyl- ethylamine, HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid. C ] __ alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. α-R 1 substituted derivatives of the amino acids of this invention, which may be denoted as (α-R')AA, indicate amino acids which are mono-substituted on the α-amino group by R 1 , wherein R' is Alk or benzyl. R 1 is preferably methyl. N α -methyl arginine and N α -methyl glycine, which are (α-Me) rg and (α-Me) Gly respectively, are also denoted herein as MeArg and Sar (sarcosine) in accordance with past conventional notation. All other N-α-substituted amino acids will carry the designation α- in their representation. - Thus, amino acids which may be alkylated upon a mercaptan, guanidino or hydroxyl group, such as Tyr, Ser, Thr, Cys or Pen, are distinguished by an absence of this designation. Thus, (α- Me)Ser is N α -methyl serine, (Me) Ser is O-methyl serine, (α- Me,Et)Ser is N α -methyl, O-ethyl serine and (α-Me,Et2) rg is N α -methyl-N',N"-diethyl arginine. The peptides are prepared preferably by the solid phase technique of Merrifield (J. Am. Chem. Soc, 85, 2149 (1964)), although solution methods known to the art may be successfully employed. A combination of solid phase and solution synthesis may be used, as in a convergent synthesis in which di-, tri-, tetra-, or penta-peptide fragments may be prepared by solid phase synthesis and either coupled or further modified by solution synthesis. The methods of peptide synthesis generally set forth by Ali et al. in J. Med. Chem.. 29, 984 (1986) and J. Med. Chem.. 30, 2291 (1987) were generally employed to produce the peptides of this invention and are incorporated herein by reference. The reactive functional groups of each amino acid or peptide are suitably protected as known in the peptide art . For example, the Boc, Cbz or Fmoc group may be used for protection of an amino group, especially an α-amino group. The Boc group is generally preferred for protection of the α-amino group. A carboxyl group is protected as an ester, such as a cyclohexyl or benzyl ester. A benzyl group or suitably substituted benzyl group is used to protect the mercapto group of cysteine, or other thiol containing residues; or the hydroxyl of serine or threonine. The tosyl group may be used for protection of the imidazolyl group of His, and tosyl or nitro group for protection of the guanidino nitrogen of Arg. A suitably substituted carbobenzyloxy group or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or the ε-amino group of lysine. The phthalamido group may also be used for the protection of the ε-amino group of lysine. Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group. Cysteine and other sulfur-containing amino acids may also be protected by formation of a disulfide with a thioalkyl or thioaryl group. Except for the Boc group, the protective groups are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment, as known in the art. If solid phase methods are used, the linear peptide is built up sequentially starting from the carboxy terminus and working toward the amino terminus of the peptide. Solid phase synthesis is begun by covalently attaching the C terminus of a protected amino acid to a suitable resin, such as a benzhydrylamine resin (BHA) , methylbenzhydrylamine resin (MBHA) , hydroxymethyl resin (HMR) or chloromethyl resin (CMR) , as is generally set forth in U.S. Patent No. 4,244,946. A BHA or MBHA support resin is used if the carboxy terminus of the product peptide is to be a carboxamide. A CMR or HMR support is generally used if the carboxy terminus of the product peptide is to be a carboxyl group, although this may also be used to produce a carboxamide or ester. Once the first protected amino acid (AA) has been coupled to the desired resin, the amino group is hydrolyzed by mild acid treatment, and the free carboxyl of the second protected AA is coupled to this amino group. This process is carried out sequentially, without isolation of the intermediate, until the desired peptide has been formed. The completed peptide may then be deblocked and/or split from the carrying resin in any order. Treatment of a CMR supported peptide with alkali in aqueous alcohol splits the peptide from the resin and produces the carboxy terminal amino acid as a carboxylic acid. Treatment of a CMR supported peptide with ammonia or alkyl amines in an alcoholic solvent provides a carboxamide or alkyl carboxamide at the carboxy terminus. If an ester is desired, the CMR resin may be treated with an appropriate alcohol, such as methyl, ethyl, propyl, butyl or benzyl alcohol, in the presence of triethylamine to cleave the peptide from the resin and produce the ester directly. Esters of the peptides of this invention may also be prepared by conventional methods from the carboxylic acid precursor. Typically, the carboxylic acid is treated with an alcohol in the presence of an acid catalyst . Alternatively, the carboxylic acid may be converted to an activated acyl intermediate, such as an acid halide, and treated with an alcohol, preferably in the presence of a ' base. Methods of producing C-terminal esters of the peptides without esterification of the side chain carboxyl group of aspartic acid are slightly more elaborate, but are well known to those skilled in the art of peptide synthesis. For example, the synthesis is begun with an ester of the C terminal amino acid, or of a dipeptide, and coupled via solution phase synthesis to an appropriately side-chain- protected aspartic acid residue. The side chain carboxyl group is then selectively deprotected and coupled to a chloromethyl resin (CMR) . The amino group is liberated and solid phase peptide synthesis is employed. Subsequent cleavage from the resin, using HF, produces the desired side chain carboxylic acid, whilst the carboxy terminus of the peptide remains as an ester. In a similar manner, if one begins the synthetic sequence with the alkyl amide of an appropriately protected amino acid or dipeptide, one obtains the corresponding C-terminal alkyl amide of the peptide. For producing esters and substituted amides in such a process, suitable protecting groups for the 4-carboxyl group of aspartic acid are benzyl esters and halogen- or alkyl- substituted benzyl esters. When the amino group is protected by the Boc group, the benzyl ester protecting group may be selectively removed by hydrogenation and coupled to a CMR support . If P possesses no carboxylic acid moeity, for instance, when P is a substituted mercapto-aniline; mercapto- cyclohexodamine or mercapto-naphthylamine, or the dipeptide Q'-P is to be coupled to the aspartic acid prior to attachment of the peptide to the resin, a t-butyl ester or other acid labile group is suitable for protecting the side- chain carboxyl of the aspartic acid. In this case the amino group of the aspartic acid is protected by a base labile group, such as the fluorenylmethoxycarbonyl moiety (Fmoc) . After solution phase coupling of the aspartic acid to the dipeptide, Q'-P, selective deprotection of the t-butyl ester is accomplished by mild acid hydrolysis and the side chain carboxyl is coupled to the resin by conventional methods . The fluorenylmethoxycarbonyl group is then removed by mild base for subsequent solid phase peptide synthesis. The preferred method for cleaving a peptide from the support resin is to treat the resin supported peptide with anhydrous HF in the presence of a suitable cation scavenger, such as anisole or dimethoxy benzene. This method simultaneously removes all protecting groups, except a thioalkyl group protecting sulfur, and splits the peptide from the resin. Peptides hydrolyzed in this way from the CMR are carboxylic acids, those split from the BHA resin are obtained as carboxamides . Modification of the terminal amino group of the peptide is accomplished by alkylation, acylation, or sulfonylation as is generally known in the art . These modifications may be carried out upon the amino acid prior to incorporation into the peptide, or upon the peptide after it has been synthesized and the terminal amino group liberated, but before the protecting groups have been removed. Typically, acylation is carried out upon the free amino group using the acyl halide, or anhydride, of the corresponding alkyl or aryl acid, in the presence of a tertiary amine. Sulfonylation is typically carried out with an appropriate sulfonyl halide. Mono-alkylation is carried out most conveniently by reductive alkylation of the amino group with an appropriate aliphatic aldehyde or ketone in the presence of a mild reducing agent, such as lithium or sodium cyanoborohydride. Dialkylation may be carried out by treating the amino group with an excess of an alkyl halide in the presence of a base. Solution synthesis of peptides is accomplished using conventional methods used to form amide bonds. Typically, a protected Boc-amino acid which has a free carboxyl group is coupled to a protected amino acid which has a free amino group using a suitable carbodiimide coupling agent, such as N, N' dicyclohexyl carbodiimide (DCC) , optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP) . Other methods, such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a protected Boc-amino acid, and subsequent reaction with the free amine of a protected amino acid, optionally in the presence of a base, are also suitable. For example, a protected Boc-amino acid or peptide is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran(THF) , in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or peptide. The peptide formed by these methods may be deprotected selectively, using conventional techniques, at the amino or carboxy terminus and coupled to other peptides or amino acids using similar techniques. 5 Accordingly, the invention is also a process for preparing compounds of the formula (I) , as hereinbefore defined, which comprises : a) coupling protected amino acids to form a suitably protected compound of the formula: X- (V-A-B-Gly-Asp-Q) n - (V • - '-B'-Gly-Asp-Q • ) -P-Y' wherein X, V, A, B, Q, V, A', B', Q', P, R', RT . , R 2 , R4r R5 r *7r *8 R 8 ' ■ RII A R-ll' Ar, n, p, q, W and X are as defined for 15 formula (I) with any reactive groups protected; Y is H, CONR1R2, CO2R2 or CO-T"; and T" is a chloromethyl, hydroxymethyl, benzhydrylamine or methylbenzhydryl amine resin; b) removing any protecting groups and, if necessary, 20 cleaving the peptide from the resin; and c) optionally forming a pharmaceutically acceptable salt thereof. The α-R' substituted derivatives of the amino acids of this invention, which includes derivatives of Arg, HArg, 25 (Me2)Arg, (Et2)Arg, Ala, Gly, His, Abu, Tyr, (Alk)Tyr, Phe, (4'W)Phe, HPhe, Phg, Trp, His, Ser, (Alk) Ser, Thr, (Alk) Thr, Cys, (Alk) Cys, Pen, (Alk)Pen, Ala, Val, Nva, Met, Leu, lie, Nle and Nal, are prepared by methods common to the chemical art. The R' sustituent may be Alk, as hereinbefore defined, 30 or benzyl. Representative methods for preparing these derivatives are disclosed in U.S. Patent No. 4,687,758; Cheung ≤£ al .. Can. J. Chem.. 55, 906 (1977) ; Freidinger et al.. J. Qrσ. Chem.. 48, 77, (1982) ; and Shuman ≤£. al .. Pep ides; Proceedings of the 7th American Peptide Symposium, 35 Rich, D., Gross, E., Eds, Pierce Chemical Co., Rockford, 111. ,617 (1981), which are incorporated herein by reference. Typically, a solution of the Cbz- or Boc-amino acid in DMF/THF is condensed with an appropriate alkyl halide, such as methyl or ethyl iodide, in the presence of a base, such as sodium hydride or potassium hydride. Optionally, a crown ether, such as 18-crown-6 with potassium hydride, may be added to facilitate the reaction. Generally, in this process and those that follow, if the amino acid bears a functional group such as a hydroxyl, mercaptan, amino, guanidino, indolyl or imidazolyl group, these groups are protected as hereinbefore described. Thus, Boc-Tyr(Bzl) is treated with sodium hydride and methyl iodide in THF/DMF solution at 0°C and stirred at room temperature for 24 h to yield Boc- (α-Me)Tyr(Bzl) . Alternately, the free amine of the amino acid is reacted with an appropriate aldehyde, such as acetaldehyde or benzaldehyde, in the presence of a reducing agent, such as sodium cyanoborohydride, to effect mono-alkylation. This process is especially useful for preparing α-benzyl amino acids . α-Benzylated amino acids may also be used as intermediates to prepare α-methyl amino acids. For example, α-methyl arginine is prepared in three steps by 1.) reacting Arg(Tos) with benzaldehyde and sodium cyanoborohydride in a methanol solution to yield (α-Bzl)Arg(Tos) ; 2.) reducing the benzylated product with formaldehyde/formic acid solution to yield (α-Bzl, α-Me)Arg(Tos) ; and 3.) liberating the benzyl group by catalytic hydrogenation (5% Pd/C in glacial acetic acid/HCl) to yield MeArg(Tos) . α-R' substituted derivatives of amino acids may also be prepared by reduction of oxazolidinones prepared from the Fmoc- or Cbz-amino acids . Typically, an Fmoc- or Cbz-amino acid is heated with an appropriate aldehyde such as acetaldehyde or benzaldehyde, in the presence of toluenesulfonic acid, in toluene solution to produce a 2- substituted 5-oxo-oxazolidine. Reduction of this oxazolidinone with triethylsilane and TFA in chloroform solution affords the Cbz- or Fmoc-α substituted amino acid directly. It will be appreciated by those skilled in the art that when formaldehyde is used, the oxazolidinone is unsubstituted in the 2-position and α-methyl amino acids are produced. Acid addition salts of the peptides are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts . This invention provides a pharmaceutical composition which comprises a peptide according to formula (I) and a pharmaceutically acceptable carrier. Pharmaceutical compositions of the peptides prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, these peptides may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. For rectal administration, the peptides of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. This invention also provides a method of inhibiting platelet aggregation and clot formation in a mammal, especially a human, in need thereof, which comprises the internal administration of an effective amount of the peptide and a pharmaceutically acceptable carrier. Indications for such therapy include myocardial infarction, deep vein thrombosis, pulmonary embolism, dissecting anurysm, stroke and other infarct-related disorders . Chronic or acute states of hyper-aggregability, such as disseminated intravascular coagulation (DIC) , septicemia, surgical or infectious shock, post-operative and post-partum trauma, cardiopulmonary bypass surgery, incompatible blood transfusion, abruptio placenta, thrombotic thrombocytopenic purpura (TTP) , snake venom and immune diseases, are likely to be responsive to such treatment. In addition, the peptides of this invention may be used in a method for the prevention of metastatic conditions. The peptide is administered either orally or parenterally to the patient, in a manner such that the concentration of drug in the plasma is sufficient to inhibit platelet aggregation. Typically, the pharmaceutical composition containing.the peptide is administered at a dose between about .2 to about 50 mg/kg in a manner consistent with the condition of the patient. For acute therapy, parenteral administration is preferred. For persistant states of hyperaggregability, an intravenous infusion of the peptide in 5% dextrose in water or normal saline is most effective, although an intramuscular bolus injection may be sufficient. For chronic, but noncritical, states of platelet aggregability, oral administration of a capsule or tablet, or a bolus intramuscular injection is suitable. The peptide is administered one to four times daily at a level of about . to about 50 mg/kg to achieve a total daily dose of about . to about 200 mg/kg/day. This invention further provides a method for inhibiting the reocclusion or an artery or vein following fibrinolytic therapy, which comprises internal administration of a peptide of formula (I) and a fibrinolytic agent. It has been found that administration of a peptide in fibrinolytic therapy either prevents reocclusion completely or prolongs the time to reocclusion. When used in the context of this invention the term fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot. Plasminogen activators are a well known group of fibrinolytic agents . Useful plasminogen activators include, for example, anistreplase, urokinase (UK) , pro-urokinase (pUK) , streptokinase (SK) , tissue plasminogen activator (tPA) and mutants, or variants, thereof, which retain plasminogen activator activity, such as variants which have been chemically modified or in which one or more amino acids have been added, deleted or substituted or in which one or more functional domains have been added, deleted or altered such as by combining the active site of one plasminogen activator with the fibrin binding domain of another plasminogen activator or fibrin binding molecule. Other illustrative variants include tPA molecules in which one or more glycosylation sites have been altered. Preferred among plasminogen activators are variants of tPA in which the primary amino acid sequence has been altered in the growth factor domain so as to increase the serum half-life of the plasminogen activator. tPA Growth factor variants are disclosed, e.g., by Robinson et al. , EP-A 0 297 589 and Browne et al., EP-A 0 240 334 and in GB 8815135.2. Other variants include hybrid proteins, such as those disclosed in EP 0 028 489, EP 0 155 387 and EP 0 297 882, all of which are incorporated herein by reference. Anistreplase is a preferred hybrid protein for use in this invention. Fibrinolytic agents may be isolated from natural sources, but are commonly produced by traditional methods of genetic engineering. Useful formulations of tPA, SK, UK and pUK are disclosed, for example, in EP-A 0 211 592 (U.S. Ser. No. 890,432), German Patent Application No. 3032606, EP-A 0 092 182 and U.S. Patent 4,568,543, all of which are incorporated herein by reference. Typically the fibrinolytic agent may be formulated in an aqueous, buffered, isotonic solution, such as sodium or ammonium acetate or adipate buffered at pH 3.5 to 5.5. Additional excipients such as polyvinyl pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene, glycol, mannitol and sodium chloride may also be added. Such a composition can be lyophilized. The pharmaceutical composition may be formulated with both the peptide and fibrinolytic agent in the same container, but formulation in different containers is preferred. When both agents are provided in solution form they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement. Indications for such therapy include myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and other infarct-related disorders . The peptide is administered just prior to, at the same time as, or just after parenteral ad inistraton of tPA or other fibrinolytic agent . It may prove desirable to continue treatment with the peptide for a period of time well after reperfusion has been established to maximally inhibit post-therapy reocclusion. The effective dose of tPA, SK, UK or pUK may be from 0.1 to 5 mg/kg and the effective dose of the peptide may be from about 0.1 to 25 mg/kg. For convenient administration of the inhibitor and the fibrinolytic agent at the same or different times, a kit is prepared, comprising, in a single container, such as a box, carton or other container, individual bottles, bags, vials or other containers each having an effective amount of the inhibitor for parenteral administration, as described above, and an effective amount of tPA, or other fibrinolytic agent, for parenteral administration, as described above. Such kit can comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized plugs, and containers of solutions for reconstitution. A variation of this is to include the solution for reconstitution and the lyophilized plug in two chambers of a single container, which can be caused to admix prior to use. With such an arrangement, the fibrinolytic and peptide may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container. When both agents are provided in solution form, they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement. For example, the platelet aggregation inhibitor may be in an i.v. injectable form, or infusion bag linked in series, via tubing, to the fibrinolytic agent in a second infusion bag. Using such a system, a patient can receive an initial bolus-type injection or infusion, of the anti-fibrotic inhibitor followed by an infusion of the fibrinolytic agent. The pharmacological activity of the peptides was assessed by the following tests: In Vivo Inhibition of Platelet Aggregation In vivo inhibition of thrombus formation is demonstrated by recording the systemic and hemodynamic effects of infusion of the peptides into anesthetized dogs according to the methods described in Aiken et al . , Prostaglandins, 19, 629-43 (1980) . Inhibition of Platelet Aggregation Blood was collected (citrated to prevent coagulation) from, naive, adult mongrel dogs. Platelet rich plasma, PRP, was prepared by centrifugation at 150 x g for 10 min. at room temperature. Washed platelets were prepared by centrifuging PRP at 800 x g for 10 min. The cell pellet thus obtained was washed twice in Tyrode's buffer (pH 6.5) without Ca ++ and resuspended in Tyrode's buffer (pH 7.4) containing 1.8 mM Ca ++ at 3 x 10^ cells/ml. Peptides were added 3 min. prior to the agonist in all assays of platelet aggregation. Final agonist concentrations were 0.1 unit/ml thrombin and 2 mM ADP (Sigma) . Aggregation was monitored in a Chrono-Log Lumi- Aggregometer. Light transmittance 5 min. after addition of the agonist was used to calculate percent aggregation according to the formula % aggregation = [ (90-CR) ÷ (90-10)] x 100, where CR is the chart reading, 90 is the baseline, and 10 is the PRP blank reading. ICSQ'S were determined by plotting [% inhibition of aggregation] vs. [concentration of peptide] . Peptides were assayed at 200 mM and diluted sequentially by a factor of 2 to establish a suitable dose response curve. To assess the stability of the peptide to plasma proteases, the peptides were incubated for 3 h (rather than 3 min) in the PRP prior to addition of the agonist. Compounds of this invention showed the following IC50 for the aggregation of dog platelets stimulated by ADP. The IC50 of Ac-ArgGlyAspSer-NH2 is shown for comparison purposes . Inhibition of Platelet Aggregation Ac-ArgGlyAspSer-NH2 Ac-MeArgGlyAspSerPen-NH2 Ac-MeArgGlyAspSer(Me)Pen-NH2 Ac-MeArgGlyAspSerArgGlyAspSerPen-NH2 The examples which follow are intended to in no way limit the scope of this invention, but are provided to illustrate how to make and use the compounds of this invention. Many other embodiments will be readily apparent and available to those skilled in the art . EXAMPLES In the examples which follow all temperatures are in degrees centigrade. Amino acid analysis was performed upon a Dionex autoion 100. Analysis for peptide content is based upon amino acid analysis. Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment . EM silica gel thin layer (.25 mm) plates were used for thin layer chromatography. ODS refers to an octadecylsilyl silica gel chromatographic support. The abbreviations used to represent the eluent composition are B: butanol, A: acetic acid, W: water, E: ethyl acetate, IP: isopropanol, P: pyridine and CA: chloroacetic acid. HPLC was performed upon a Beckman 344 gradient chromatography system with a CRIB recording integrator in either an isocratic or continuous gradient mode. Solid phase peptide synthesis was performed using an automated Beckman 990 synthesizer. Where indicated, the purity of the peptide is based upon integration of the HPLC chromatogram. MeArg was prepared by the method disclosed by Ali et al., in U.S. Patent 4,687,758 (1987) . E m le 1 Preparation of Nα-acetyl-Ntt-methylarginvlglycYlaspartγlseryl penir.il Tamineamide r α-Ao-Nα-MeΑr GlyΑs .βrPenNH _l The protected peptide-resin intermediate, N α -Ac- • MeArg(Tos)-Gly-Asp ( (O-cHex)-Ser(Bzl)-Pen(4-MBzl)-MBHA, was synthesized by the solid-phase method on 4-methylbenzhydrylamine resin on 1.0 mmol scale. All the amino acids were protected as t-butyloxycarbonyl on the amino group, and were coupled sequentially using N,N- dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBt) in • the manner set forth by Ali ≤£. a_L in . Med. Chem. r 30 r 2291 (1987) and J. Med. h^m.. 29, 984 (1986) . After coupling of the last amino acid, the peptide is acetylated using acetic anhydride/diisopropylethylamine. The peptide was cleaved from the resin with deprotection of the side chain protecting groups using anhydrous HF (30 iαL) in the presence of anisole (3.0 mL) at 0°C for 60 min. After the evaporation of HF in vacuo, the residue was washed with anhydrous ether, and the crude peptide was extracted with 50% acetic acid and lyophilized to provide of the crude peptide (350 mg) . The peptide was purified by flash chromatography (ODS reversed phase column, 6% acetonitrile/H2θ-0.1% TFA) to yield the titled peptide. FAB : (M+H) + at 620 AAA: Asp(l.OO), Gly(l.Ol), Ser(0.18), Pen and MeArg (not quantitated) . Peptide content: 62.98% TLC: R f = 0.37, (B:A:W:E, 1:1:1:1) R f =0.43, (B:A:W"P, 15:5:10:10) HPLC: k'=4.6 (Altex Ultrasphere ODS column, 5 μ, 4.5 mm x 25 cm, det. at 220 nm, 6% acetonitrile/H2θ-0.1% TFA) Example 2 Preparation of N α -acetvl-Nα-me hvlarginvlglγc;γlaspartγl seryl-fS-methy] )pertioil larrπneamide rN«-Aπ-N«-MeAr7- GlγΑspSer(Me)Pen-NKA The protected peptide-resin intermediate N α -Ac- MeArg(Tos)-Gly-Asp(O-cHex)-Ser(Bzl) -(SMe)Pen-MBHA-resin was . synthesized, cleaved and isolated on 1.0 mmol scale as in Example 1 to yield a crude peptide (479 mg) . During the HF cleavage a few drops of ethane dithiol was added. Purification by flash chromatography (medium pressure ODS reversed-phase C-18 silica, 7% acetonitrile/H2θ-0.1% TFA) afforded the titled peptide (70 mg) . FAB: (M+H) + at 634.3, (M-H) " at 632.2 AAA: Asp(l.OO), Ser(1.10), Gly(1.19) TLC: Rf =0.61, (B:A:W:E, 1:1:1:1) Rf = 0.64, (B:A:W:P, 15:5:10:10) HPLC: k'= 5.4, (Altex Ultrasphere ODS column, 5 μ, 4.5mm x 25 cm, det. at 220 nm, 7% acetonitrile/H2θ-0.1%TFA k*= 7.0 (gradient :A: acetonitrile, B: H2θ-0.1% TFA, 1-50% during 20 min.) F.xample 3 Preparation of N α -acetγl . N«-me hγlπr inγlg1 γπyla sparfγl serylarginylglycylaspartylserylcysteineamide rN α -Ac-N α -MeAr g GlγAspSerAr g GlγAspSerCγs-NH2 The protected peptide-resin intermediate, N^-Ac- MeArg(Tos)-Gly-Asp(O-cHex)-Ser(Bzl)-Arg(Tos)-Gly-Asp (O-cHex)- Ser(Bzl) -Cys (4-MBzl)-MBHA, was prepared, cleaved and isolated on 1.0 mmol scale in the same manner as in Example 1. Flash chromatography (medium-pressure reversed-phase C-18 silica column, gradient 7% to 10% acetonitrile/H2θ-0.1% TFA) yielded a crude peptide (200 mg) . Final purification (Sephadex® G-15 gel filtration, 0.2M acetic acid) gave the titled peptide (13 mg) . FAB: (M+H) + at 1007.3 AAA: Asp(2.00), Ser(1.96), Gly(1.88), Arg(0.99) Peptide content: 89.13% TLC: R f =0.1, (B:A:W:E, 1:1:1:1) Rf =0.32, (B:A:W:P, 15:5:10:10) HPLC : k'=3.89, (Altex Ultrasphere ODS column, 5 μ, 4.5mm x 25 cm, det. at 220 nm, 10% acetonitrile/H O-0.1% TFA) k'= 4.83, (gradient :A: acetonitrile, B: H2θ-0.1% TFA. 0-50% A during 20 min.) Example Employing substantially the same procedure as described in Example 3, the following compounds are prepared: N α -Ac-N α -MeArgGlyAspSerMeArgGlyAspSerAPmp-NH2, N α -Ac-N α -MeArgGlyAspThrArgGlyAspSerAPmp-NH2, N -EtArgGlyAspValArgGlyAspTyrCys-NH , N α -Ac-N α -MeArgGlyAspCysArgGlyAspNal (Me) Cys-NH2, Ntt-Ac-Ntt-MeArgGlyAspCys (Et2)ArgGlyAspAla(Me)Pen-NH2, N α -Ac-N α -MeArgGlyAspPheArgGlyAsp(Me) SerCys-NH2, and N α -Ac-N α -AsnDtcMeArgGlyAspPheArgGlyAspPheCys-NH2, and Ntt-Bzl-ArgGlyAspPheArgGlyAsp(Me) SerCys-NH2. Example 5 Employing substantially the same procedure as described in Example 1, the following compounds are prepared: N α -Ac-N α -MeArgGlyAspIleCys-NH 2 , N α -Ac-N α -MeArgGlyAspMetCys-NH 2 , N α -Ac-N α -MeArgGlyAspTyrCys-NH 2 , N α -MeArgGlyAspHPheCys-NH2, N α -Ac-(α-Et)ArgGlyAsp(Me)PenCys-NH 2 , and N α_ Ac _( Me )HArgGlyAspTrpCys-NH , Example 6 Parenteral Dosage Unit Composition A preparation which contains 20 mg of the compound of Example 1 or 2 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions into a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system. Exam le Oral Dosage Unit Composition A capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 3 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule. Example 8 Oral Dosage Unit Composition A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 3 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet. The above description fully discloses how to make and use this invention. This invention', however, is not limited to the precise embodiments described herein, but encompasses all modifications within the scope of the claims which follow.

Claims: What is claimed is : 1. A compound of the formula: X- (V-A-B-Gly-Asp-Q) n - (V*- '-B'-Gly-Asp-Q' )-P (I) wherein: V and V are absent, Asn, Gin, Ala or Abu; A and A' are absent or a D- or L- amino acid chosen from Arg, HArg, NArg, (Mβ2)Arg, (Et2)Arg, Abu, Ala, Gly, His, Lys, or an α-R' substituted derivative thereof, Dtc, Tpr or Pro; B and B' are Arg, HArg, NArg, (Me2)Arg, (Et2) rg, Orn, Lys, HLys or an α-R' substituted derivative thereof; Q and Q' are a D- or L- amino acid chosen from Tyr, (Alk)Tyr, Phe, (4'W)Phe, HPhe, Phg, Trp, His, Ser, (Alk) Ser, Thr, (Alk) Thr, Cys, (Alk)Cys, Pen, (Alk)Pen, Pcs, Ala, Val, Nva, Met, Leu, lie, Nle or Nal; W is halogen or Alk; X is R4R5N or H; Y is H, CONR 1 R or CO2R2 R ] _ and R2 are H, Alk or (CH2)p r; R 4 is H or Alk; R5 is Rn , RnCO, RnOCO, RnOCH (Rn . ) CO, RιιNHCH (Rn . ) CO, RllSCH (Rn t ) CO, R11SO2 or RnSO; R7 is H, Alk, OAlk, halogen or Y; R8 and Rg' are H, Alk, (CH2)pP , (CH2)pNph or taken together are -(CH2)4~ or -(CH2)5~; Rn and Rn« are H, Ci-salkyl, C3_ 7 cycloalkyl, Ar, Ar-Cι-5alkyl, Ar-C3_ 7 cycloalkyl; Ar is phenyl or phenyl substituted by one or two Ci-salkyl, trifluoromethyl, hydroxy, Ci-salkoxy or halogen groups; n is 0 or 1; p is 0, 1, 2 or 3; and q is 1 or 2; or a pharmaceutically acceptable salt thereof; provided that: when n is 0, V is absent, A' is Gly and Q' is Ser, P is not Cys. 2. A compound according to claim 1 in which Q or Q' is Ser, (Me)Ser, Thr, Tyr, Phe, Nal or Val. 3. A compound according to claim 1 in which P is Cys or Pen. 4. A compound according to claim 1 in which B or B' is MeArg. 5. A compound according to claim 1 in which Q or Q' is Ser. 6. A compound according to claim 1 which is: Ac-MeArg-Gly-Asp-Ser-Pen-NH2; Ac-MeArg-Gly-Asp-Ser-(SMe)Pen-NH2; or Ac-MeArg-Gly-Asp-Ser-Arg-Gly-Asp-Ser-Pen-NH2. 7. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition which comprises a compound according to claim 6 and a pharmaceutically acceptable carrier. 9. A method for effecting inhibition of platelet aggrega¬ tion which comprises administering to a mammal in need thereof, an effective amount of a compound according to claim 1. 10. A method for effecting thrombolysis and inhibiting reocclusion of an artery or vein in a mammal which comprises internally a»dministering to a mammal in need thereof, an effective amount of a fibrinolytic agent and a compound according to claim 1. 11. A method according to claim 10 in which the fibrinolytic is anistreplase, streptokinase (SK) , urokinase (UK) , pro- urokinase (pUK) or tissue plasminogen activator (tPA) , or a mutant or derivative thereof. 12. A kit for use in a method for effecting thrombolysis and inhibiting reocclusion of an artery in a mammal which comprises, in separate containers, an effective amount of a fibrinolytic agent and a compound according to claim 1. 13. A kit according to claim 12 in which the fibrinolytic agent is anistreplase, streptokinase (SK) , urokinase (UK) , pro-urokinase (pUK) , tissue plasminogen activator (tPA) or a mutant or derivative thereof. 14. A process for preparing a compound of the formula: X- (V-A-B-Gly-Asp-Q) n - (V'-A'-B'-Gly-Asp-Q' )-P wherein X, V, A, B, Q, V, A', B', Q', P and n are as defined in claim 1, which comprises, a) coupling protected amino acids to form a suitably protected compound of the formula: X-(V-A-B-Gly-Asp-Q) n - (V'- '-B'-Gly-Asp-Q' )-P wherein X, V, A, B, Q, V, A', B', Q', P, R', Rl, R2, R , *5, *1 r *8r Rδ ' , Rll, ll*, Ar, n, p, q, W and X are as defined in claim 1 with any reactive groups protected; Y is H, CONR3 . R2, CO2R2 or CO-T"; and T" is a chloromethyl, hydroxymethyl, benzhydrylamme or methylbenzhydryl amine resin; b) removing any protecting groups and, if necessary, cleaving the peptide from the resin; and c) optionally forming a pharmaceutically acceptable salt thereof; provided that: when n is 0, V is absent, A' is Gly and Q' is Ser, P is not Cys.

Inventors: ALI FADIA EL-FEHAIL, SAMANEN JAMES, ALI, FADIA, EL-FEHAIL, SAMANEN, JAMES
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1990
Main classification: A61K37
IPC codes: A61K38, A61P7, C07K1, C07K7, C07K14