SMALL CYCLIC PLATELET AGGREGATION INHIBITORS

Abstract: A platelet aggregation inhibitor useful as an antithrombotic is provided which consists of a synthetic cyclic pentapeptide containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. A preferred platelet aggregation inhibitor is represented by formula (I), where R1 and R9 are OH; R2, R4, R5, R6, R7, R8 and R14 are hydrogen; R3 and R4 are joined to form a pyrrolidine ring; X is sulfur; m is 1 and n is 3.

Description: SMALL CYCLIC PLATELET AGGREGATION INHIBITORS Held of the Invention The present invention relates to inhibitors of platelet aggregation. Specifically, the invention is directed to antagonists of the final common pathway of platelet aggregation and that as potent antithrombotics. The invention further relates to therapeutic applications of these inhibitors in diseases for which blocking of platelet aggregation and intracellular adhesion is indicated. Background of the Invention Platelets are particles found in whole blood which participate in the process of thrombus formation and blood coagulation. A membrane bound giycoprotein, commonly known as GP libllla, is present on the exterior surface of platelets. Giycoprotein libllla is a non-covalent, calcium ion dependent heterodimer complex composed of alpha and beta subunits (Jennings, et al., J. Biol. Chem. (1982) 257, 10458). These glycoproteins contribute to normal platelet function through interactions with proteins containing the amino acid sequence Arg-Gly-Asp, such as fibrinogen. The interaction of GP libllla with fibrinogen is stimulated by certain factors released or exposed when a blood vessel is injured. Multiple factors, including a variety of physiologic stimuli and soluble mediators, initiate platelet activation via several pathways. These pathways have a common final step which is the activation of the GP libllla receptor on the platelet surface and its subsequent binding to fibrinogen followed by aggregation and thrombus formation. By virtue of these interactions GP libllla is a component of the platelet aggregation system (Pytela et al., Science (1986) 231, 1559). Thus, inhibition of the interaction of GP libllla with Arg-Gly-Asp containing ligands such as fibrinogen is a useful means of modulating thrombus formation. An inhibitor which prevents this binding interaction would antagonize platelet activation by any stimulus and therefore would have important antithrombotic properties. Many common human disorders are characteristically associated with a hyperthrombotic state leading to intravascular thrombi and emboii. These are a major cause of medical morbidity, leading to infarction, stroke and phlebitis and of mortality from stroke and pulmonary and cardiac emboii. Patients with atherosclerosis are predisposed to arterial thromboembolic phenomena for a variety of reasons. Atherosclerotic plaques form niduses for platelet plugs and thrombi! that lead to vascular narrowing and occlusion, resulting in myocardiai and cerebral ischemic disease. This may happen spontaneously or following procedures such as angiopiasty or endarteroectomy. Thrombii that break off and are released into the circulation cause infarction of different organs, especially the brain, extremities, heart and kidneys. In addition to being involved in arterial thrombosis, platelets may also play a role in venous thrombosis. A large percentage of such patients have no antecedent risk factors and develop venous thrombophlebitis and subsequent pulmonary emboii without a known cause. Other patients who form venous thrombi have underlying diseases known to predispose to these syndromes. Some of these patients may have genetic or acquired deficiencies of factors that normally prevent hypercoaguiability, such as an.ithrom--.n-3. Others have mechanical obstructions to venous flow, such as tumor masses, that lead to low flow states and thrombosis. Patients with malignancy have a high incidence of thrombotk. phenomena for unclear reasons. Antithrombotic therapy in this situation with currently available agents is dangerous and often ineffective. Patients whose blood flows over artificial surfaces, such as prosthetic synthetic cardiac valves or through extracorporeal perfusion devices, are also at risk for the development of platelet plugs, thrombii and emboii. It is standard practice that patients with artificial cardiac valves be chronically anti-coagulated. However, in all instances, platelet activation and emboii formation may still occur despite adequate anticoagulation treatment. Thus, a large category of patients, including those with atherosclerosis, coronary artery disease, artificial heart valves, cancer, and a history of stroke, phlebitis, or pulmonary emboii, are candidates for limited or chronic antithrombotic therapy. The number of available therapeutic agents is limited and these, for the most part, act by inhibiting or reducing levels of circulating clotting factors. These agents are frequently not effective against the patienfs underlying hematologic problem, which often concerns an increased propensity for platelet aggregation and adhesion. They also cause the patient to be susceptible to abnormal bleeding. Available antiplatelet agents, such as aspirin, inhibit only part of the platelet activation process and are therefore often inadequate for therapy. An agent which effectively inhibits the final common pathway of platelet activation, namely fibrinogen binding to the GP libllla receptor, should accordingly be useful in a large group of disorders characterized by a hyperthrombotic state as described above. The present invention contemplates such an agent which is a new composition, namely a cyclic polypeptide consisting in part of natural a ino acids and in part of unnatural amino acids. This new composition interferes with the interaction of Arg-Gly-Asp containing peptides, particularly fibrinogen, with the GP libllla complex thereby preventing platelet aggregation. Platelet aggregation has been identified as an early step in the formation of platelet plugs, emboii and thrombii in the circulatory system which in turn have been shown to play an active role in cardiovascular complications and disease. Inhibition of fibrinogen bindng to the GP libllla complex has been shown to be an effective antithrombotic treatment in animals (H. K. GoW, et al., Circulation (1988) 77, 670-677; T. Yasuda, et al., J. Clin. Invest (1988) 81, 1284-1291; B. S. Coller, et al., Blood (1986) 68, 783-786.) Other proteins such as fitxonectin contain the Arg-Gly-Asp sequence of amino acids. Large polypeptide fragments of fibronectin have been shown to have activity for cell attachment to various surfaces which has been disclosed in U.S. Patents 4,517,686; 4,589,881; and 4,661,111. These large polypeptides contain the amino acid sequence Arg-Gly-Asp-Ser in the interior portion of the polypeptide chain. Short peptides derived from the large polypeptides were also found to promote cell attachment to various substrates when bound on the substrate. Alternatively, the same short peptides were found to inhibit cell attachment to the same substrates when dissolved or suspended in the medium surrounding the substrate. This activity has been disclosed in U.S. Patents 4,578,079, 4,614,517 and 4,792,525. The short peptides were defined as Q-Arg-Gly-Asp-AA1-B where Q is hydrogen or an amino acid; AA1 is serine, threonine, or cysteine; and B is hydroxy or an amino acid. No discussion of cy izing these short peptides is presented. A number of synthetic peptides, including cyclic disulfides, have been disclosed as inhibitors of fibrinogen binding to platelets all of which contain the Arg-Gly-Asp sequence. See U.S. Patent 4,683,291 ; WO89/05150; EPO 0319 506 A2; EPO 0 341 915 A2; Plow et al., Proc. Nat Acad. Sci. USA (1985) 82, 8057- 8061; Ruggeri et al., Proc. Natl. Acad. <Scl. USA (1986) 83, 5708-5712; Haverstick et al., Blood (1985) 66, 946- 952; Plow et al., β/σod(1987) 70, 110-115; F. El F. All, et al., Proc. Eleventh Airier: Peptide Symp. (1990) 94-96; M. Pierschbacherand E. Ruoslahti, J. Biol. Chem. (1987) 262, 17294-17298; and references cited in the above publications. Several synthetic cyclic peptides containing the thioether linkage have been synthesized. Gero et al., Btøctiem. Biophys. Res. Comm. (1984) 120, 840-845 describe a pseudohexapeptide analog of somatostatin where the group [CH2-S] is substituted for a peptide bond. Similarly, Edwards et al., Bbchem. Biophys. Res. Comm. (1986) 136, 730-736 compare the biological activity of linear and cyclic enkephalin pseudopeptide analogs containing the thiomethytene ether linkage. Other enkephalin related pseudopeptides and macrocycles containing the [CH2-S] substitution for peptides have been described, Spatola et al., Biopoly ers (1986) 25, 229-244 and Spatola et al., Tetrahedron (1988) 44, 821-833. None of these references disclose a small cyclic peptide containing a stable ring structure having high . platelet aggregation inhibition activity. Accordingly, it is an object of this invention to produce a small cyclic peptide having high platelet aggregation inhibition activity, it is a further object to produce such small cyclic peptides that are stable to ring opening. It is still a further object of this invention to provide a platelet aggregation inhibitor having a long in vivo lifetime. These and other objects of this invention will be apparent from consideration of the invention as a whole. Summary of the Invention The objects of this invention are accomplished by providing a small cyclic peptide containing the tripeptide sequence Arg-Gly-Asp and containing a thioether, sulfoxide or sidechain amide bond within the cycle. Preferably, the cyclic peptide has about 5 amino acids forming the ring of the cycle. More preferably, the ring of the cyclic peptide contains from about 17 to about 18 atoms, most preferably 18 atoms. Also preferably, the ring will contain a D amino acid most preferably linked to the Arg of the tripeptide sequence. The preferred and most preferred compounds of the instant invention are represented by Formulae I and la below. The invention in its broad aspects relates to peptide derivatives which are useful as inhibitors platelet function mediated by the GP libllla receptor and for the prevention of thrombus formation. Preferred compounds of this invention are represented by Formula I: Formula I wherein Ri and Rg are the same or different and are selected from hydroxy. Cι-Cβ alkoxy, C3-Ci2alkenoxy, Cβ-C^ aryloxy, di-Ci-Cg alkyiamino-Cι-C8-aIkoxy, acyiamino-Ci-Cs-alkoxy selected from the group acetylaminoethoxy, nicotinoylaminoethoxy, and sucαnamfcfoethoxy, pivaloy-oxyetnoxy, Cρ-Ci 2 aryl-Ci -Cs-alkoxy where the aryl group is unsubstituted or substituted with one or more of the groups nitro, halo (F, Cl, Br, I), Cι-C4-alkoxy, and amino, hydroxy-C2-C8-alkoxy, dihydroxy-C3-C8-alkoxy, and NR10R11 wherein R10 and Ri 1 are the same or different and are hydrogen, C-j-Cβ-alkyi, C3-C8-alkenyl, C6-Ci2-aryl where the aryl group is unsubstituted or substituted with one or more of the groups nitro, halo (F, Cl, Br, I), Cι-C4-alkoxy, and amino, C6-Ci2-aryl-Ci-C8-alkyl where the aryl group is unsubstituted or substituted by one or more of the groups nitro, halo (F, Cl, Br, I), Cι-C4-alkoxy, and amino; R2, R3, R5, Rg, R7, Rg are the same or different and are selected from hydrogen, C6-C12 aryl where the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo (F, Cl, Br, I), Ci-Cβ alkyl, halo-Ci-Cβ alkyl, Ci-Cs-alkoxy, amino, phenyloxy, phenyl, acetamkJo, benzamido, di-Ci-Cβ alkylamino, Ci-Cβ alkylamino, C6-C12 aroyi, Ci-Cβ alkanoyl, and hydroxy-Ci-Cβ alkyl. 1-C12 alkyl either substituted or unsubstituted, branched or straight chain where the substituents are selected from halo (F, Cl, Br, I), Cι-Cs alkoxy, C6-C12 aryloxy where the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo (F, Cl, Br, I), Ci-Cβ alkyl, Ci -Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci -Cs alkylamino, C1 -C~ alkylamino, C6-C12 aroyi, and C1 -Cβ alkanoyl, isoth-oureido, C3-C7 cycloalkyl, ureido, amiro, Ci-Cβ alkylamino, di-Ci-Cβ alkylamino, hydroxy, amino-C2-Cβ alkyithio, amirx)-C2-C8 alkoxy, acetamido, benzamido wherein the phenyl ring is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo (F, Cl, Br, I), C1-C8 alkyl, C1 -Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci -Cs alkylamino, Ci-Cβ alkylamino, C6-C12 aroyi, and Ci -Cs alkanoyl, C -C12 aryiamino wherein the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo, Ci-Cβ alkyl, Ci -Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci-Cβ alkylamino, Cι-Cs alkylamino, C6-C12 aroyi, and C1-C8 alkanoyl, guanidino, phtnalimido, mercapto, C1-C8 alkyithio, C6-Ci2 arylthio, carboxy, carboxamide, carbo-Ci-Cβ alkoxy, C6-C12 aryl wherein the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo, Ci-Cs alkyl, Ci-Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci-Cβ alkylamino, Ci-Cβ alkylamino, hydroxy-Ci-Cs alkyl, C6-C12 aroyi, and Ci -Cβ alkanoyl, and aromatic heterocycle wherein the heterocydic groups have 5-10 ring atoms and contain up to two 0, N, or S heteroatoms; R2 and R3, R5 and Re, or R7 and Rs may optionally and independently be joined together to form a carbocyclk; or heterocydic ring of from four to seven atoms where the heteroatoms are selected from 0, S or NR12 where R12 is selected from hydrogen, Ci-Cs-alkyl, C3-Cs-alkenyl, C6-Ci2-aryl, C6-Ci2-aryI-Ci-C8-alkyl, Ci-Cs alkanoyl, and C6-C12 aroyi; R4 is selected from hydrogen, Ci-Cβ alkyl, . C3-C10 cydoalkyt, C6-C12 aryl, and C6-C12 aryl-Cι-C8-aIkyl; R2 or R3 may be optionally joined with R4 to form a piperidine, pyrrolidine or thiazolidine ring; R14 is selected from hydrogen, Ci-Cs-alkyl, C3-Cs-alkenyl, C6-Ci2-aryi, and C6-C12 aryl-Ci-Cs-alkyl; X is selected from an 0 or S atom, an S atom bearing one or two 0 atoms, NR13 wherein R13 is hydrogen, Ci-Cβ-alkyl, C3-Cs-alkenyl, C6-Ci2-aryl, C6-Ci2-aryl-Cι-Cs-alkyl, Ct-Cβ alkanoyl, and C6-C12 aroyi, and C6-Ci2 aryl, Ci-Cs alkanoyl, (CH2)k where k is an integer from 0 to 5; π is an integer from 1 to 6; m is an integer from 0 to 4; and pharmaceutically acceptable salts thereof. As used herein and unless spedfied otherwise: alkyl, alkenyi and alkynyl denote straight and branched hydrocarbon chains having single, double and triple bonds, respectively; C6-C12 aryl groups denote unsubstituted aromatic ring or fused rings such as, for example, phenyl or πaphthyl; hetero denotes the heteroatoms 0, N, or S; aromatic heterocydic groups have 5-10 ring atoms and contain up to four heteroatoms; hatogen or halo denote F, Cl Br, or I atoms; alkoxy denotes an alkyl group attached to 0. [Examples of Ci-Cs alkyl or C2-C8 alkenyi groups indude methyl, ethyl, propyl, isopropyi, butyl, t-butyl, pentyl, iεopentyi, hexyl, vinyl, allyl, butenyl and the like; examples of C3-Cιo-cydoalkyl groups indude cydopropyl, cydopentyi, cyciohexyl, and the like; aromatic heterocydic groups include but are not limited to pyridyl, thienyi, furyi, indolyi, benzthienvi, imidazolyl, thiazolyl, quinolinyi and isoquindinyl. Most preferred compounds of the instant invention are represented by Formula la: Formula la wherein Ri and Rg are the same or different and are hydroxy, NH2, C1-C4 alkoxy or benzyloxy; R2 is hydrogen R3 is selected from hydrogen, Ci-Cβ alkyl branched or unbranched, unsubstituted or substituted with substituents selected from amino, hydroxy, mercapto. methylthio, carboxy, carboxamide, guanidino, phenyl, 4- hydroxyphenyl, 4-methoxyphenyl, 3-indolyl, and 4-imidazolyl, phenyl either unsubstituted or substituted with one to three substituents that may be independently nitro, hydroxy, halo (F, Cl, Br, I), Ci -C4 alkyl, Ci -C4-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Cι-C4 alkylamino, C1-C4 alkylamino, halo-Cι-C4 alkyl, C6-C12 aroyi, and Ci -C4 alkanoyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; R5 and R6 are independently selected from hydrogen, Ci-Ce alkyl, either branched or unbranched, unsubstituted or substituted with substituents selected from amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl or4-hydroxyphenyi, 4-methoxyphenyl, 3-indolyI, and 4-imidazolyl, phenyl, either unsubstituted or substituted with one to three substituents that may be independently selected from nitro, hydroxy, halo (F, Cl, Br, I), Ci -C4 alkyl, Ci -C4-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Cι-C4 alkylamino, C1-C4 alkylamino, halo-Cι-C4 alkyl, CQ- C12 aroyi, and C1-C4 alkanoyl, 1-naphthyl, 2-naphthyi, 2-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; R7 or Rs are the same or different and are selected from hydrogen, C1-C4 alkyl, phenyl either unsubstituted or substituted with from one to three substituents independently selected from hydroxy, halo (F, Cl, Br, I), C1-C4 alkyl, and Cι-C4-alkoxy; R4 is hydrogen or may be joined with R3 to form a heterocydic ring selected from piperidine, pyrrolidine or thiazolidine; R14 is hydrogen or methyl; X is selected from an 0 or S atom, an S atom bearing one or two 0 atoms, NR13 where R13 is selected from hydrogen, C1-C4 alkyl, benzyl, phenyl, C1-C4 alkanoyl, benzoyiand (CH2)k, where kis 0 to 5; n is 3 or 4; mis1;and pharmaceutically acceptable salts thereof. The present invention indudes a method of making the compounds of Formulae I and la. The present invention also indudes a method for reducing platelet aggregation in a mammal. This method involves admiπiste'πg a therapeuticaliy effective amount of the compounds of the present invention alone or in combination with a pharmacologically acceptable carrier. This general method may also be applied to treat a mammal having an increased propensity for thrombus formation. Additionally, the present invention is directed to compositions of matter for redudng platelet aggregation in a mammal; treating a mammal having an increased propensity for thrombus formation; or inhibiting binding of a igand to GP libllla in a mammal; wherein each of these compositions contains as an active ingredient one or more of the cydic peptides defined in Formula I. Detailed Description of the Invention The products of Formula I and the preferred substituents can be made by using one of the methods depicted below or by other methods known in the art (see e.g., Spatola et al., Tetrahedron (1988) 44, 821-833, and references dted therein). The definitions of the substituent groups are the same as for Formula I except where noted. Method A 1. Cleave 2. Cyclize IV A peptide derivative bound to a polymer support, depicted by intermediate II, may be prepared by sequential coupling of individual amino add derivatives by standard techniques. (Meπifield, R. B., J. Am. Chem. Soc. (1963) 85, 2149-2154; Stewart, J. M. and Young, J. D., Solid Phase Peptide Synthesis (1984), Pierce Chemical Co., Rockford, IL and additional references dted in the above publications). When the tetrapeptide derivative II is obtained, the terminal amino group is acylated with a suitable carboxylic acid derivative III. The acylation to yield IV may be accomplished using a number of standard methods which require activation of the carboxylic acid group of III. For example, activation may be obtained by the addition of an equimolar amount of dicydohexylcarbodiimide or related carbodiimide reagent If desired an additive such as 1 -hydroxybenztriazole or N-hydroxysucdnimide may be incorporated. Alternatively, the carboxyl group may be activated by conversion to a halo derivative. For example, the chloride may be obtained by treatment of the acid with thionyl chloride or oxalyi chloride in a compatible solvent such as dichioromethane, toluene, or ethylene dichloride if desired. The substituent W is chosen such that it is readily displaceable by the group X. Suitable substituents W are, for example, halo atoms such as bromine or iodine or activated oxygen functions such as methaπesuffonyloxy or p-toluensulfonyloxy and related sulfonic add esters. Cydization to the resin bound intermediate V may be accomplished by selectively exposing the nudeophilic group X by removal of Rrø and allowing X to react such that it displaces group W with formation of a new chemical bond. For example, if X is a sulfur or oxygen atom and R-Q is a triphenylmethyl group, then R-Q may be selectively deaved from X using a very dilute solution of a strong add such as trifluoroacetic acid in a solvent compatible with the polymer resin. -Examples of resin compatible solvents are dimethylacetamide, dimethylformamide or dichioromethane and the like. The end result of the deavage process is replacement of the Ri6 group with a hydrogen atom. After deavage of Ri6, the resin bound peptide derivative V (R -Q = H) is allowed to react in a suitable solvent such as dimethylacetamide until cydization is complete. If desired, a base such as N-methylmoφholine may be incorporated into the reaction. Other protecting groups in the peptide molecule IV must be stable to the reaction conditions chosen to form V. For example, Rg may be a group which affords an ester such as methoxy, ethoxy, benzyloxy, t- butyioxy and the like or an amide or substituted amide. R15 may be an arylsulfonyl group such as 2,2,5,7,8- pentamethy.chroman-6-sulfonyl (PMC) or p-tolvenesulfonyl. Final deavage of the cydized peptide product from the polymer resin may be accomplished in a variety of ways dependent upon the type of resin used and the chemical linkage between the cydized peptide and the resin. If, for example, the resin is derived from a polymerized p- alkoxybenzyi alcohol derivative, then deavage of the peptide-resin linkage may be carried out using a strong acid such as trifluoroacetic add. If desired, additives such as phenol, anisole and ethanedithiol may be added to the reaction. The groups Rg and R15 may be chosen, if desired, to also be cleavable concurrently with deavage of the cydized peptide from the polymer resin. (Examples of such chemical groups are Rg - t-butytoxy, deavage of which yields Rg « OH and R15 = 2,2,5,7,8-pentamethylchroman-6-suifonyl, cleavage of which affords R15 « H. The crude product thus obtained may be further purified using chromatographic or other methods of chemical purification to obtain I. Further derivatization of I may be carried out if desired. For example, if X is S, treatment of I with a stoichiometric amount of an oxidizing agent such as 3-chloroperoxybenzoic add or similar agent will produce the sultoxide derivative where X is SO. Use of an excess amount of oxidant will afford the sulfone derivative where X is S02- Method B VI Alternatively, the linear peptide derivative IV, prepared as described above in Method A, may be deaved from the resin prior to cydization to yield VI. For example, if IV is synthesized on a polystyrene resin the cleavage can be accomplished using liquid hydrogen flouride. The groups Rg, R15 and R16 may, if desired, be cleaved concurrently under these conditions. If concurrent deavage is desired, then examples of suitable substituents Rg are t-butyloxy, benzytoxy or cydohexyloxy, R15 is p-toluenesulfonyl or 2,2,5,7,8-pentamethylchroman-6-suIfonyl and R16 is triphenylmethyt or p-methyibenzyl if X is either 0 or S, or t-butoxycarbonyl if X is NR13. Cleavage of these groups would result in Rg being OH and R15 and R16 being hydrogen. The peptide derivative VI may then be cydized in solution in the presence of a weak base such as ammonium hydroxide. The group W is as described in Method A. The resulting crude I may then be purified as described above in Method A. The purified I may be further transformed as described in Method A. Additionally and if desired, when X is NR13 and R13 is hydrogen, I may be acyiated with, for example, acetyl chloride, acetic anhydride or benzoyl chloride, methanesuifonyi chloride or p-toluenesulfonyl chloride and the like. Method C ' Intermediate VI may be prepared by the sequential coupling of amino add derivatives in solution without the use of polymer resin or ottier solid supports. The methods useful for solution phase peptide synthesis are well documented in the chemical literature and are known to those skilled in the art (Houben-Weyl, Methoden der Organischen Chemie, 4th Edα, Vol. 15, Georg Thieme Vertag, Stuttgart 1974). The attached substituents Ri, Rg, Ri 5 and Ri 6 may be chosen such that they are transformable concurrently or sequentially as described in Methods A and B above. Cydization of of VI wherein R16 is H under conditions described above in Method B will provide compounds of Formula I. The starting materials required for the processes described herein are known in the literature or can be prepared using known methods and known starting materials. -someric Products In products of Formula I carbon atoms bonded to four non-dentical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described above may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art Each of the asymmetric carbon atoms, when present in compounds of Formula I, may be in one of two configurations (R or S) and both are within the scope of the present invention. The carbon atoms bearing the (CH2)n sidechain and the (CH2)m sidechain are generally preferred to have the S configuration. The carbon atom bearing the substituents R2 and R3 is generally preferred to have a configuration corresponding to that of a D amino acid. The configuration may be assigned R or S depending on the chemical composition of R2 and R 3 . The compounds described in this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic adds and bases. Such salts are within the scope of this invention. -Examples of such salts indude ammonium, metal salts like sodium, potassium, caidum and magnesium; salts with organic bases like dfcyefohexylamine, N-methyi-D-glucamine and the like; and salts with ammo acids like arginine or iysine. Salts with inorganic and organic adds may be likewise prepared, for example, using hydrochloric, hydrobromic, suifuric, phosphoric, trifluoroacetic, methanesulfbn-c, malic, aleic, fumaric and the like. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification. A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free add or free base form of a compound of Formula I with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble; or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process. The compounds described in the present invention inhibit the binding of fibrinogen to its receptor on platelets, GP libllla, and thus prevent the aggregation of platelets and the formation of platelet plugs, emboii and thrombii in the circulatory system in mammals. Thromboembolic disorders have been shown to be directly related to the susceptibility of blood platelets to aggregate. Mammals exposed to medical procedures such as angiopiasty and thrombolytic therapy are particularly susceptible to thrombus formation. The compounds of the present invention can be used to inhibit thrombus formation following angiopiasty. They may also be used in combination with thrombolytic agents such as tissue plasminogen activator and its derivatives (US patents 4,752,603; 4,766,075; 4,777,043; EP 199,574; EP 0238,304; EP 228,862; EP 297,860; PCT WO89/04368; PCT WO89/00197), streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial reocdusion following thrombolytic therapy. When used in combination with the above thrombolytic agents, the compounds of the present invention may be administered prior to, simultaneously with, or subsequent to the antithrombolytic agent Mammals exposed to renal dialysis, blood oxygenation, cardiac catheterization and similar medical procedures as well as mammals fitted with certain prosthetic devices are also susceptible to thromboembolic disorders. Physidogic conditions, with or without known cause may also lead to thromboembolic dsorders. Thus, the compounds described herein are useful in treating thromboembolic disorders in mammals. The compounds described herein may also be used as adjuncts to anticoagulant therapy, for example in combination with aspirin, heparin or warfarin and other anticoagulant agents. The application of the compounds described herein for these and related disorders will be apparent to those skilled in the art. Platelet Inhibition Assays The evaluation of inhibitors of the fibrinogen-platelet interaction is guided by in vitro receptor binding assays and in vitro platelet aggregation inhibition assays. In-vitro biological activity of the compounds of Formula I was monitored using a modified fibrinogen-GP libllla ELISA based on the method of Nachman and Leung (J. Clin. Invest (1982) 69, 263-269) which measures the inhibition of fibrinogen binding to purified human platelet GP libllla receptor. Human fibrinogen was prepared by the method of Lipinska, et al. (J. Lab. Clin. Med. (1974) 84, 509-516). Platelet GP libllla was prepared by the method of Fitzgerald, et al. (Anal. Biochem. (1985) 151 , 169-177. Microtiter plates are coated with fibrinogen (10 μg ml) and then blocked with TACTS buffer containing 0.5% bovine serum albumin (BSA). (TACTS buffer contains 20mM Tris.HCI, pH 7.5, 0.02% sodium azide, 2 mM calcium chloride, 0.05% Tween 20, 150 mM sodium chloride.) The plate is washed with phosphate buffered saline (PBS) containing 0.01% Tween 20 and the sample to be determined added, followed by addition of solubilized GP libllla receptor (40 μg/ml) in TACTS, 0.5% BSA. After incubation, the plate is washed and 1 μg/ml of murine anti-platelet monoclonal antibody AP3 (P. J. Newman et al. Blood (1985) 65, 227-232) is added. After another wash a goat anti-mouse kjG conjugated to horseradish peroxidase is added. A final wash is performed and developing reagent buffer (10 mg o-phenylenediamine dihydrochloride, 0.0212% hydrogen peroxide, 0.22 mM dtrate, 50 mM phosphate, pH 5.0) is added and then incubated until color develops. The reaction is stopped with 1 N sulfuric acid and the absorbance at 492 πm is recorded. In addition to the GP libllla ELISA assay, platelet aggregation assays may be performed in human platelet rich plasma (PRP). Fifty milliliters of whole human blood (9 parts) is drawn on 3.6% sodium dtrate (1 part) from a donor who has not taken aspirin or related medications for at least two weeks. The blood is centrifuged at 160 x g for 10 min at 22° C and then allowed to stand for 5 min after which the PRP is decanted. Platelet poor plasma (PPP) is isolated from the remaining blood after centrifugation at 2000 x g for 25 min. The platelet count of the PRP was adjusted to ca. 300,000 per microliter with PPP. A 225 μL aliquot of PRP plus 25 μL of either a dilution of the test sample or a control (PBS) is incubated for 5 min in a Chrono-log Whole Blood Aggregometer at 25 * C. An aggregating agent (collagen, 1 mg/ml; U46619, 100 ng/ml; or ADP, 8 μM) is added and the platelet aggregation recorded. In the management of thromboembolic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or eiixers for oral administration; suppositories for rectal administration; sterile solutions or suspensions for injectable administration, and the like. Animals in need of treatment using compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from animal to animal and be dependent upon such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. Dosage Rxm-iations Dosage formulations of the cydic polypeptides of the present invention are prepared for storage or administration by mixing the the cydic polypeptide having the desired degree of purity with physiologically acceptable carriers, exdpients, or stabilizers. Such materials are non-toxic to the redpients at the dosages and concentrations employed, and indude buffers such as phosphate, dtrate, acetate and other organic add salts; antiox Jants such as ascorbic add; low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as pdyvinyipyrrolidinone; amino acids such as glydne, glutamic add, aspartic add, or arginine; monosaccharides, disaccharides, and other carbohydrates induding cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as marmitol or sobitol; counterions such as sodium and/or nonionic surfactants such as Tween, Piuronics or pdyethylenegtycd. Dosage formulations of the cyclic polypeptides of the present invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes such as 0.2 microne membranes. Cydic polypeptide formulations ordinarily will be stored in lyophilized form or as an aqueous solution. The pH of the cydic polypeptide preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing exdpients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by hypodermic injection needle, other methods of administration are also antidpated such as suppositories, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. Therapeutic cydic polypeptide formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle. Therapeuticaliy effective dosages may be determined by either in vitro or in vivo methods. One method of evaluating therapeuticaliy effective dosages is illustrated in Example 23 where the cydic polypeptide cyclo-S- acetyl-Gly-Arg-Gly-Asp-Cys-OH was determined to have a 50% inhibitory concentration (IC50) of 5 nM when inhibiting fibrinogen binding to the GP libllla platelet receptor. Similarly, in a platelet aggregation assay in [Example 24 using the same cydic peptide, the IC50 was found to be 8.5 μM. Based upon such in vitro assay techniques, a therapeuticaliy effective dosage range may be determined. For each particular cydic polypeptide of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeuticaliy effective dosages will naturally be influenced by the route of administration. For injection by hypodermic needle it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption effidency must be individually determined for each cydic polypeptide by methods well known in pharmacology. The range of therapeutic dosages is from about 0.001 nM to 1.0 mM, more preferably from 0.1 nM to 100 μM, and most preferably from 1.0 nM to 50 μM. Typical formulation of compounds of Formula I as pharmaceutical compositions are discussed below. About 0.5 to 500 mg of a compound or mixture of compounds of Formula I, as the free acid or base form or as a pharmaceutically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, exdpient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained. Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acada, com starch or gelatin; an exdpient such as microcrystaliine cellulose; a disintegrating agent like corn starch or aiginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavoring agent such as peppermint, wintergreen or cherry. When the dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit A syrup or elixer may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent and a flavoring agent such as cherry. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehide such as water or naturally occurring vegetable oil like sesame, peanut or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antbxidants and the like can be incorporated according to accepted pharmaceutical practice. EXAMPLES In the following -Examples, common α-amino acids may be described by the standard three letter amino acid code when referring to tntermediates and final products. By common α-amino acids is meant those amino adds incorporated into proteins under mRNA direction. Standard abbreviations are listed in The Merck index, 10th Edition, pp Misc-2 - Misc-3. Unless otherwise designated the common α-amino acids have the natural or "L"- configuration at the alpha carbon atom. If the code is preceded by a "D" this signifies the opposite enantiomer of the common α-amino add. Modified or unusual α-amino adds such as πorieudne (Nle) and ornithine (Orn) are designated as described in U.S. Patent and Trademark Office Official Gazette 1114TMOG, May 15, 1990. If the product or intermediate name is preceded by "cydo * this shall be taken to mean that the peptide has been cydized, e.g. compounds of Formula I or V. Example 1 Bromoacetyl-Gly-Arg-Gly-Asp-Cys-OH The titie compound is prepared in protected form by standard solid phase peptide synthesis on 2% cross-linked polystyrene resin (Merrifield resin). Treatment of the resin bound intermediate with liquid hydrogen fluoride induces concomitant cleavage of the protecting groups from the title compound as well as cleavage of the peptide from the resin. The crude peptide is purified by reverse phase high performance liquid chromatography (HPLC) using a 4.6 mm x 250 mm cdumn containing 10 micron, 300 Angstrom pore size C-18 packing. The elution of the column is with an acetontrile 0.1% aqueous trifluoroacetic add gradient going from 0% • 40% acetonitrile linearly over 80 minutes. The title compound elutes at 14 minutes. FAB mass spectrum: calc.627; obs.628 (M+1). Example2 Cyclo-S-acetyl-Gly-Arg-Gly-Asp-Cys-OH The compound prepared in [Example 1 is dissolved in deionized water (1 mg/ml) and the pH of the solution is adjusted to 7.0-8.5 with ammonium hydroxide. After stirring for 4 hr at ambient temperature the reaction solution is acidified to pH 3.0 - 3.5 with trifluoroacetic add and then lyophilized. The resulting crude product is purified by HPLC using the conditions described in Example 1. The desired title compound elutes after 11 minutes. FAB mass spectrum: calc.546; obs.547 (M+1). Amino acid analysis: carboxymethyl-cys, 0.96; Asp, 1.04; Gly, 2.12; Arg, 0.94.1H NMR(300 MHz, D∑O, pH 7): 4.75, m; 4.34.4, m; 4.15, d; 4.0, ab q; 3.9, d; 3.4, ab q; 3.2, t; 2.95-3.15, m; 2.7, dq; 1.75-2.05, m; 1.55-1.7,m. Example 3 Cyclo-S-acetyl-Gly-Arg-Gly-Asp-Cys-OH Bromoacetyl-Gly-Arg(g-2,2,5,7,8-pentamethylchroman-6-sulfonyl)-Gly-Asp(beta-t-butyl)-Cys(S- triphenylmethyl)-0-(polymer resin) is prepared using standard solid phase peptide synthesis utilizing fluorenylmetnoxycarbonyl (FMOC) protecting group chemistry on a p-alkoxybenzyl alcohol resin. Repeated treatment of the resin bound peptide with a 1% solution of trifluoroacetic add in dichioromethane results in deavage of the S-triphenylmethyl group as evidenced by the bright yellow of the solution. Treatment is continued - until dissipation of the yellow color (ca. 1.5 L of the deavage solution is required per gram of resin bound peptide.) After complete deavage of the S-triphenylmethyl group, the resin bound peptide is washed several times with a 5% solution of N-methytmorpholine in N,N-dimethyiacetamide and then shaken in pure N . N-dimethytacetamide for 12 hr to complete the cydization. Treatment of the cydized resin bound peptide with trifluoroacetic add containing (v/v) 1% phenol, 1% anisole and 1% ethanedithiol effects concomitant cleavage of the remaining protective groups and deavage of the desired product from the resin. Purification of the crude product as described in (Example 2 affords the title compound identical to that described above. Example 4 Synthesis of Compounds of Formula VI Using the methods described in .Examples 1 and 2, the compounds listed in Table I may be prepared. The compounds are depicted by Formula VII wherein m = 1 and n = 3, Ri and Rg are OH, R14 is hydrogen and X is S. Crude products are purified using HPLC as described in Example 2. The following amino acid derivatives may be used in place of Boc-Gly for coupling to the alpha-amine group of Arg to obtain the substituents R2 and R3 shown in Table I. When Boc-Glydne is used, R2 and R3 are both hydrogen (H). Amino Add Derivative R2 R3 Boc-L-Ala methyl H Boc-D-Ala H methyl Boc-L-Val 2-propyl H Boc-D-Val H 2-propyl Boc-D-Thr H 1 -hydroxy-1 -ethyl Boc-L-Thr 1 -hydroxy-1 -ethyl H Boc-D-Asn H carboxamidomethyl Boc-L-Asn carboxamktomethyl H Boc-D-Gln H 2-carboxamidoethyl Boc-L-Gln 2-carboxamidoethyl H Boc-D-(0-2-bromobenzyloxy- H 4-hydroxybenzyl carbonyl)Tyr Boc-L-(0-2-bromobenzyloxy- 4-hydroxybenzyl H carbonylVTyr benzyl H 2-methyl-1-propyl H 2-methylthioethyl H 1 -butyl H 2-butyl H carboxymethyl H 2-carboxyethyl H hydroxymethyl H 4-imidazolylmethyl H 3-indolylmethyl H 4-amino-1 -butyl H 3-amino-1-propyl H 1-hydoxy-1 -ethyl H Boc-L-Pro gives R2 + R4 = CH2CH2CH2 Boc-D-Pro gi es R3 + R4 = CH2CH2CH2 The substituted bromoacetic acids listed below may be used in place of bromoacetic add in -Example 1 and in combination with the amino acid derivatives listed above to provide the compounds shown in Table 1 with variable substituents at R5, Rg. When bromoacetic acid is used in combination with the amino acid derivatives listed above R5 and β are hydrogen (H). 1-naphthyl-α-bromoacetic acid 2-naphthyi-α-bromoacetic acid phenyi-α-bromoacetic add 2-trifluromethylphenyl-α-bromoacetic acid 3-trifluromethylphenyl-α-bromoacetic acid 4-trifluromethylphenyl-α-bromoacetic acid 4-biphenyl-α-bromoacetic acid 2-bromopropionic add 2-bromobutyric acid 2-bromopentanoic add L-Pennidllamine may be substituted for L-cysteine in Example 1 to produce compounds in Table 1 where R7 and Re are methyl. VII TABLE 1 Selected compounds of Formula VII H H H H, 4- H H 698.4 699.0 50 biphenyl H H 652.2 653.2 20 H H 622.2 623.1 1 8 H 3 CH3 574.2 574.9 14 H H 588.2 588.9 1 8 H H 560.2 560.9 1 0 H H 603.2 604.1 1 1 H H 690.3 691.0 38 H H H, H H H 626.2 627.0 8 imidazolyl- methyl H 2-methyl- H H, H H H 602.3 602.9 23 1 -propyl H 4-hydroxy¬ H H, phenyl H H 728.2 729.0 38 benzyl H H H H, 4- H H 698.4 699.0 52 biphenyl H H H H, 1- H H 672.3 673.0 44 naphthyl H 2-methyl- H H. H H H 620.2 621.0 1 8 thioethyl H hydroxy¬ H H. H H H 576.2 577.0 8 methyl H 3-indolyl- H H. H H H 675.3 676.1 28 methyl H carboxamido H H. H H H 617.2 617.9 9 ethyl H H H H, 4-tri- H H 690.3 691.0 44 fluoromethyl phenyl H H H H, 2- H H 672.2 673.0 39 naphthyl H H H H, propyl H H 588.2 589.0 24 H H H H, 2-tri- H H 690.3 691.0 36 fluoromethyl phenyl H H, H H H 604.2 605.1 1 2 H H, H H H 620.2 620.8 20 H H. H H H 675.3 676.0 32 H H. H H H 603.2 604.2 5 H H, H H H 603.2 603.9 9 H H 2-carboxy¬ H ethyl carboxy¬ H H H. H H H 604.2 604.8 10 methyl Notes (1) Calculated molecular weight of the peptide. (2) Observed molecular weight for M+1 , where M is the molecular ion, determined by FAB mass spedrometry. (3) Observed chromatographic retention time of the peptide in minutes determined using the conditions given in Example 2. (4)R3+R4=CH2CH2CH2. (5) R2+R4=CH2CH2CH2. Example 5 N-(r+-t-Butoxycarbonyl(Nfl-p-toluenesulfonyl)arginyl) glydne N-t-Butoxycarbonyl-N9-p-toluenesulfonylarginine (10 mmoles), benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 10 mmoles), ethyl glydnate hydrochloride (13 mmoles) and N-methylmorpboline (50 mmoles) are stirred in a mixture of dichioromethane and N,N- dimethylacetamide (1:1, 50 ml) for 2 hr at room temperature. At the end of the reaction time the mixture is acidified with acetic add, concentrated in vacuo, and the residue taken up in ethyl acetate. The resulting solution is washed with 10% citric add (3 times), water (2 times), saturated sodium bicarbonate (3 times), water (2 times) and brine (2 times). The organic solution is dried over magnesium sulfate, filtered, dried and concentrated to afford the crude ethyl ester of the title compound. Crystalline material can be obtained from ethyl acetate- hexane mixtures. The dipeptide ethyl ester (10 mmoles) is treated with 10.5 mmoles of sodium hydroxide in ethaπol and water (4:1, 50 ml) for 1 hr. at room temperature. Water (100 ml) is added and the mixture concentrated to ca 50 mi, acidified with dtric acid, and extracted with ethyl acetate. After drying the extract over magnesium sulfate, concentration affords the desired title compound, it may be recrystallized from ethyl acetate-hexane mixtures. Example 6 N-(N-t-butoxycarbonyi(beta-cyclohexyl ester)aspartyl) cysteine (S-4-methylbenzyl) benzyl ester N-t-Butoxycarbonyl(beta-cydohexyl ester)aspartic acid (10 mmole), BOP reagent (10 mmole), and N- methyimoφholine (15 mmole) are stirred in N,N-dimethylacetamide (50 ml) at room temperature for 10 min. To the resulting solution is added a solution of cysteine(S-4-methyibenzyl) benzyl ester trifluoroacetate (10 mmole) and N-meihylmorpholine (15 mmoie) in N.N-dimethylacetamide (15 ml). The resulting reaction mixture is stirred overnight at room temperature. The solvent is then removed in vacuo and the reaction residue worked up as described in -Example 5 to afford the desired title compound. Example 7 N-(^(hKN-t-Butoxycar-»nyl(Nfl-p-toluenesulfonyl)aι^inyl)g-yclnyl)a^ ester))cystelne(S-4-methylbenzyl) benzyl ester N-(N-t-butoxycarbonyl(beta-cyclohexyl ester)aspartyl) cysteine (S-4-methyibenzyl) benzyl ester from Example 6 (10 mmole) is treated with trifluoroacetic acid in dichioromethane (1:1, 200 ml) for 40 min at room temperature and then concentrated. The resulting solid is washed with ether and dried. The above solid (10 mmole), BOP reagent (10 mmole), N-methyimorpholine (40 mmole) and N-(N-t- Butoxycarbonyl(N9-p-toluenesulfonyl)arginyl)glydne from -Example 22 (10 mmole) are stirred in N,N- dimethylacetamide (50 ml) for 4 hr. After the reaction the solution is concentrated and the residue taken up in ethyl acetate and worked up as described in Example 5. The crude product thus obtained is crystallized from chloroform-hexane. Example 8 N-(N-(N-(N-(N-t-Butoxycarbonyl(0-benzyl)-D-threonyl)(N9-p-toluenesuIfonyl)arginyl) glydnyI)aspartyl(beta-cyclohexyl ester))cysteine(S-4-methylbenzyl) benzyl ester The t-butoxycarbonyl group is removed from N-(N-(N-(N-t-butoxycarbonyl(N9-p- toluenesulfonyl)arginyl) glycinyl)aspartyl(beta-cydohexyl ester))cysteine(S-4-methyibenzyl) benzyl ester using the procedure described in Example 7 to afford the trifiuoroacetate salt of the tetrapeptide. The above salt is coupled with N-t-butoxycarbonyl(0-benzyl)-D-threonine using the procedure described in Example 7. The desired title compound is isolated after workup as described above. Example 9 Cyclo-S-acetyl-(D-Thr)-Arg-Gly-Asp-Cys-OH The t-butoxycarbonyl group is removed from N-(N-(N-(N-(N-t-Butoxycarbonyl(0-benzyl)-D- threonyl)(N9-p-toluenesulfonyl)arginyl) glycinyl)aspartyl(beta-cyclohexyi ester))cysteine(S-4-methylbenzyl) benzyl ester using the procedure described in -Example 7 to afford the trifluoroacetate salt of the pentapeptide. Bromoacetic acid (4 mmole) and dicydohexytoarbodiimide (2 mmole) are stirred together in 5 ml of dichioromethane for 10 min. The solution is filtered and added to the pentapeptide trifluoroacetate prepared above (1 mmole) and N-methyimorpholine (3 mmole) in N,N-dimethylacetamide (5 ml). After stirring for 1 hr at room temperature the reaction is concentrated in vacuo and the residue taken up in ethyl acetate and worked up as described in Example 5. The residue isolated from the ethyl acetate solution is treated directly with a mixture of hydrogen fluoride, anisole and methylethyl sulfide (905:5) at 0 C for 1 hr. After removal of the hydrogen fluoride the crude material is dissolved in 10% acetic acid and lyophilized. The isolated powder is then dissolved in water at a concentration of 1 mg/ml and the pH adjusted to 7.3 with ammonium hydroxide. After stirring at ambient temperature for 4 hr the reaction solution is loaded onto a DEEAE 52 cellulose column equilibrated in 5 M ammonium acetate at pH 7.3. The desired title compound is eluted with 45 mM ammonium acetate at pH 7.3. The fractions containing the desired cydized peptide are desalted immediately by acidification to pH 4 with acetic add and chromatography over a C-18 reverse phase column. The loaded column is first washed with 0.1% aqueous trifluoroacetic add followed by linear gradient with 0.1% trifluoroacetic add in acetonitrile. The purified peptide, after lyophilization, is identical with the product described in Example 7. Example 10 Method for Preparation of Other Compounds of Formula VII Using the methods described in Examples 5-9, the replacement amino adds shown below may be used in place of D-threonine in Example 8 and the replacement bromo adds listed below may be used in place of bromoacetic acid in Example 9 to produce the compounds listed in Table 2. In this example, Riand Rg are OH, R1 is hydrogen, and X is S. The benzyl ester of S-(4-methylbenzyl)-L-pennidllamine may be used in place of the corresponding cysteine derivative in -Example 5 to produce compounds in which R7 and Rs are methyl. 4-amino-1 -butyl H 3-amino-1-propyl H 1-hydoxy-1 -ethyl H Replacement bromo acids 1-naphthyl-α-bromoacetic acid 2-naphthyl-α-bromoacetic acid phenyl-α-bromoacetic add 2-trifluromethylphenyl-α-bromoacetic acid 3-trifiuromethylphenyl-α-bromoacetic acid 4-trifiuromethylphenyl-α-bromoacetic acid 4-biphenyl-α-bromoacetic acid 2-bromopropionic add 2-bromobutyric acid 2-bromopentanoic add When bromoacetic add is used in combination with the amino add derivatives listed above R5 and Re are hydrogen (H). Table 2 Other Selected Compounds of Formula VII H carboxamido H H,H H H 603.2 604.1 11 methyl H 4- H H.H H H 626.2 627.0 8 imidazolyl- methyl H 2-methyl- H H.H H H 602.3 602.9 23 1-propyl H 2-methyl¬ H H,H H H 620.2 621.0 18 thioethyl H hydroxy¬ H H,H H H 576.2 577.0 8 methyl H 3-indolyl¬ H H,H H H 675.3 676.1 28 methyl H carboxamido H H,H H H 617.2 617.9 9 ethyl H H H H,H H H 546.2 547.0 10 H 3-amino-l- H H.H H H 603.2 603.9 6 propyl H 2-butyl H H.H H H 602.3 603.0 22 4- H H H.H H H 626.2 627.1 14 imidazolyl- methyl benzyl H H H,H H H 636.2 637.0 25 H 4-hydroxy¬ H H.H CH 3 CH 3 680.2 681.0 21 benzyl H 4-amino-l- H H.H H H 617.3 618.0 8 butyl CH 3 H H H,H H H 560.2 561.0 13 (5) H (5) H.H H H 586.2 587.0 17 1-hydroxy- H H H,H H H 590.2 591.0 12 1-ethyl H 2-carboxy- H H.H H H 618.2 619.0 11 1 -ethyl 1 -butyl H H H,H H H 602.2 2-propyl H H H.H H H 588.2 589.0 19 2-butyl H H H,H H H 602.3 602.8 24 Notes (1) Calculated molecular weight of the peptide. (2) Observed molecular weight for M+1 , where M is the molecular ion, based on FAB mass spectrometry. (3) Observed chromatographic retention time of the peptide in minutes determined using the conditions given in -Example--. (4) R3+R =CH2CH2CH2. (5) R2+R4=CH2CH2CH2. (6) isomer 1- first to elute from the chromatography column. (7) Isomer 2- second to elute from the chromatography column. Example 11 Cyclo-S-acetyl-(D-Tyr)-Arg-Gly-Asp-Cys-OC2H5 Using the procedures described in Examples 5-9 and repladng cysteine(S-4-methylbenzyl) benzyl ester trifluoroacetate with the corresponding ethyl ester the title compound shown above is obtained. HPLC retention time: 30 min. Molecular weight (calc): 680.2. Found (FAB): 681.0 (M+1 ). Example 12 Cyclo-S-acetyl-(D-Tyr)-Arg-Gly-Asp(OC2H5)-Cys-OH Using the procedures described in -Examples 5-9 and repladng N-t-butoxycarbonyl(beta-cyclohexyl ester)aspartic add with the corresponding beta-ethyl ester the title compound shown above is obtained. HPLC retention time: 26 min. Molecular weight (calc): 680.2. Found (FAB): 681.2 (M+1). Example 13 Cyclo-S-acetyl-(D-Tyr)-Arg-Gly-Asp(QC2H5)-Cys-OC2H5 Using the procedures described in -Examples 5-9 and repladng cysteine(S-4-methylbenzyl) benzyl ester trifluoroacetate with the corresponding ethyl ester and N-t-butoxycarbonyl(beta-cydohexyl esterjaspartic acid with the corresponding beta-ethyl ester the title compound shown above is obtained. HPLC retention time: 40 min. Molecular weight (calc): 709.2. Found (FAB): 710.1 (M+1). Example 14 Preparation of cydic thioether peptide esters Using the methods described in -Examples 11-13 above, the following cydized peptide esters are analogously prepared. Cyclo-S-acetyl-Gly-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyl-Gly-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-Gly'-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 Cyclo-S-acetyl-(D-Ala)-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyl-(D-Ala)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-(D-Ala)-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 Cyclo-S-acetyl-(D-Val)-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyl-(D-Val)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-(D-Val)-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 Cyclo-S-acetyl-(D-Leu)-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyl-(D-Leu)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-(D-Leu)-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 CycIo-S-acetyl-(D-lle)-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyl-(D-lle)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-(D-lle)-Arg-GIy-Asp(OC2H5)-Cys-OC2H5 Cyclo-S-acetyl-(D-Phe)-Arg-Gly-Asp-Cys-OC2H5 CycIo-S-acetyl-(D-Phe)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-(D-Phe)-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 Cyclo-S-acetyI-(D-Thr)-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyI-(D-Thr)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyl-(D-Thr)-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 Cyclo-S-acetyI-(D-Pro)-Arg-Gly-Asp-Cys-OC2H5 Cyclo-S-acetyl-(D-Pro)-Arg-Gly-Asp(OC2H5)-Cys-OH Cyclo-S-acetyI-(D-Pro)-Arg-Gly-Asp(OC2H5)-Cys-OC2H5 Example 15 Cyclo-S-acetyl-(D-Tyr)-Arg-GIy-Asp-Cys-NH2 Synthesis of the title compound was accomplished using standard Boc-synthetic protocols on a 4- me-hylbenzyttiydrylamine resin to obtain first a linear peptide as described in -Example 1. Cleavage of tt e linear peptide from the resin with hydrogen fluoride followed by cydization as described in Example 2 affords the title compound after HPLC purification. HPLC retention time: 18 minutes. Molecular weight Calc: 651-2. Obs. (FAB mass spectrum): 652.2 (M+1). Using this procedure the following compounds are analogously obtained. Cyclo-S-acetyl-(D-Ala)-Arg-Gly-Asp-Cys-NH2 Cyclo-S-acetyl-(D-Val)-Arg-Gly-Asp-Cys-NH2 Cyclo-S-acetyl-(D-Leu)-Arg-Gly-Asp-Cys-NH2 Cyclo-S-acetyl-(D-lle)-Arg-Gly-Asp-Cys-NH2 Cyclo-S-acetyl-(D-Phe)-Arg-Gly-Asp-Cys-NH2 Cyclo-S-acetyl-(D-Pro)-Arg-Gly-Asp-Cys-NH2 Cyclo-S-acetyl-Gly-Arg-Gly-Asp-Cys-NH2 Example 16 Cyclo-S-acetyl-Gly-Arg-Gly-Asp-Cys-OH sultoxide The purified product from -Example 2 was dissolved in water at a concentration of 10 mg per mL The pH of the solution was adjusted to 7. A 50% solution of hydrogen peroxide was added to make a final concentration of 3% hydrogen peroxide and the resulting reaction mixture was stirred overnight at room temperature. The solution was loaded directly onto an octadecyisilyl reverse phase chromatography column. The sultoxide isomers formed in the reaction were eluted with a linear gradient of acetonitrile in 1% trifluoroacetic acid in water. Isomer 1 eluted at 3.5 minutes. Isomer 2 eluted at 4 minutes. For both isomers: Molecular weight (calc.) 562.2. Found (FAB mass spectrum): isomer 1 : 563.3; isomer 2: 563.3 (M+1). Example 17 Preparation of cydic thioether suffo-ddes Application of the procedure of Example 16 to thioether peptides prepared in -Example 4 and shown in Table 1 and in to peptides prepared by the procedure in Example 15 affords the sultoxide stereoisomers of Formula VIII listed in Table 3 where R14 is hydrogen, Rg is OH, and X is SO. VIII Table 3 SuHb-ddes of Formula VM RI R2 R3 R4 R5, R6 R7 R8 MW 1 MW 2 R (calc) (obs) H H 606.2 607.1 5 H H 606.2 607.1 7 CH3 CH3 680.2 681.1 1 CH 3 CH 3 680.2 681.1 2 Notes (1) Calculated molecular weight of the peptide. (2) Observed molecular weight for M+1, where M is the molecular ion, based on FAB mass spectrometry. (3) Observed chromatographic retention time of the peptide in minutes determined using the conditions given in Example 2. (4) R3 + R4 = CH2CH2CH2. Example 18 Synthesis of the compound of Formula IX IX α-FMOC-am ' moadipic add δ-allylester was coupled to Wang resin with diisopropyicarbodiimide and a catalytic amount of 4-dimethy-aminopyridine in dichioromethane solvent The FMOC-group was then removed with 20% piperidine in N,N-dimethylacetamide. Standard FMOC synthesis chemistry was then used to add the Asp, Gly, Arg, and D-Val residues. After the coupling of the D-Val residue, treatment of the resin-bound peptide with 0.3 equivalents of tetrakis(triphenyiphosphine)palladium(0) in N,N-dimethyiacetamide containing 20% piperkline resulted in removal of the allyl and FMOC groups. The resin-bound peptide was then washed 5 times with 5% N- methylmorpholine in N,N-dimethyiacetamide. The peptide was then cydized with 2 equivalents of BOP reagent. Cleavage of the peptide from the resin was accomplished by treatment with trifluoroacetic acid : triethylsilane (98-2). The peptide was purified by HPLC as described in Example 2. HPLC retention time: 14 minutes. Molecular weight calc: 556.3. obs.(FAB mass spectrum): 557.3. Example 19 The compounds of Formula VIII in which Ri and Rg are OH, R5, Rβ, R7, Rs, and R14 are hydrogen, the group X is (CH2) where k is 0 or 1 , m is 1 , and n is 3 are prepared using the procedure of Example 18. In Table 4 k=0meansglulamcacidandk= 1 nrøansaminoac-ipicacid. Table 4 Cycϋc Peptides Containing glutamlc or 2-aminoadipic acid Notes (1) Calculated molecular weight of the peptide. (2) Observed molecular weight for M+1 , where M is the molecular ion, based on FAB mass spectrometry. (3) Observed chromatographic retention time of the peptide in minutes determined using the conditions given in Example 2. (4) R 3 + R4 = CH2CH2CH2 (5) R2 + R4 = CH2CH2CH2. Example 20 L-2-RUIC<>Amlrx)-3-(.vM-butoxycarbOT acid Slow distillation of a solution of N-CBZ-D-serine methyl ester, dimethoxypropane (5 eq) and a catalytic amount of pyridinium p-toluenesulfonate (0.014 eq) in benzene resulted in the dean formation of the methyl 3- Cbz-2,2-dimethytoxazolidine-4- carboxylate. Reduction of the methyl ester with LJBH4 (3 eq) in 2:1 ethanol- THF gave 3- Cbz-2,2-dimethyioxazolidine-4- mettianol. Swern oxidation with (COCI)2 (2 eq), DMSO (4 eq) and Et3N (5 eq) in CH2CI2 gave the 3- Cbz-2,2-dimethyloxazolidine-4- carboxyaldehyde which was reductively aminated with glydne benzyl ester hydrochloride (5 eq) and NaBH3CN (1 eq) in mettianol to give 4- (N- benzytoxycarbonylmethyl)-aminomettiyl-3- Cbz-2,2-dimethyloxazoiϊdine. The resulting amine was protected as the Boc derivative using B0C2O (1.25 eq) and NaHCθ3 (1.4 eq) in 2:1 THF-H2O. Hydrogenation of a methanolic solution of 4- (N-t-butyloxycarbonyl-N-beπzyloxycarbonylmethyl)-aminomethyi-3- Cbz-2.2-dimethyloxazolidiπe, obtained in the previous step, at 50 psi in the presence of 10% Pd-C, the CBZ and benzyl ester groups were deaved and the oxazolidine ring hydrolyzed, giving L-2-amino-3-(N-t-butoxycarbonyl-N-carboxymethyl)amino-1- propanol. The FMOC group was appended to the 2-amino function using N-(9- fluorenyimethoxycarbonyloxy)sucdnimide (1.15 eq) and NaHCX.3 (2.5 eq) in 1:1 dioxane-H2θ. Ally! esterification of the ω-carboxyi group using allyl bromide (7 eq) and NaHCθ3 ( 2 - 5 e q) in DMF followed by Jones oxidation (3 eq) of the primary alcohol gave the desired title compound. Example 21 ^FlWXX}-altytoxycarbonylmethy_-L-seιine O-allylation of N-CBZ-L-serine in DMF solution was achieved by sequential treatment with NaH (2.2 eq) and allyl bromide (1.1 eq). The carboxylic acid was converted to the tert-butyi ester using isobutyiene and H2SO4 in methytene chloride to afford O-allyl-N-Cbz-L-serine t-butyl ester. Cleavage of the terminal olefiπ of the allyl group by ozonotysis in mettianol with a dimethylsulfide workup gave the aldehyde which, without isolation, was reduced to 0-(2-hydroxy-1 -ethyl)- N-Cbz-L-serine t-butyl ester with NaBϋj. (1 eq). The FMOC group was introduced by first reductively deaving the CBZ group at 50 psi H2 in mettianol over 10% Pd-C catalyst, then reprotecting the resulting free amine with fluorenyimethylchtoroformate (1.15 eq) and NaHCθ3 0-8 eq) in 2:1 THF-H2O. Jones oxidation (3 eq) of the alcohol on the hydroxyethyi group gave FMOC-0-carboxymethyl-L- serine-t-butyl ester, which was treated with allyl bromide (3 eq) and NaHC03 (1.5 eq) in DMF to give FMOC-O- allyloxycarbonyimethyi-L-serine-t-butyl ester. Finally, the t-butyl ester was removed with trifluoroacetic add giving the desired N-FMOC-O-allyloxycarbonyimethyl-L-serine. Example 22 Synthesis of cyclic peptides of Formula VIII derived from 0<arboxymethyt-L-serine and 3-(N-cartwxymethyl -_-3-d-am-rx_propton-cac-d The protected amino adds from Examples 20 and 21 were coupled to Wang resin using diisopropytearbodBm.de and catalytic 4-dime-hyIaminopyridine. Standard FMOC solid phase synthesis protocol was used to couple the Asp, Gly, Arg and selected D-amino acid residues. Thus, coupling steps were carried out using BOP and N-methyl morpholine in N,N-dimethylacetamide. Deprotections were performed with 20% piperidine in N,N-dimethyiacetamide. Cleavage of the allyl ester groups was effected with (Ph3P)4Pd in 20% pjperidine/N.N-dimethylacetamide. The peptide was cydized while still attached to the resin using diisopropyfcarbodiimide and a catalytic amount of N-hydroxybenztriazole in dichioromethane to effect cydization. The cydized peptides were deaved from the resin with trifluoroacetic acid and purified on reverse phase HPLC. The peptides prepared by this route are derivatives of Formula VIII wherein Ri and Rg are OH, R2, R4, R5, Re. R7, Re, and Ri 4 are hydrogen, n is 3 and m is 1 and the remaining substituents are as shown. R3 X MW(calc) 1 MW(obs) 2 RT 3 Notes (1) Calculated molecular weight of the peptide. (2) Observed molecular weight for M+1 , where M is the molecular ion, based on FAB mass spectrometry. (3) Observed chromatographic retention time of the peptide in minutes determined using the conditions given in Example 2. Example 23 Inhibition of fibrinogen binding to GP ItbOia Microtiter plates are coated with fibrinogen (10 μg/ml) and then blocked with TACTS buffer containing 0.5% BSA. (TACTS buffer contains 20mM Tris.HCI, pH 7.5, 0.02% sodium azide, 2 mM calcium chloride, 0.05% Tween 20, 150 mM sodium chloride.) The plate is washed with phosphate buffered saline containing 0.01% Tween 20 and a dilution of the sample to be determined added, followed by addition of solubilized libllla receptor (40 μg/ml) in TACTS, 0.5% BSA. After incubation, the plate is washed and murine monodonal anti-platelet antibody AP3 (1 μg/ml) added. After another wash goat and anti-mouse IgG conjugated to horseradish peroxidase is added. A final wash is performed and developing reagent buffer (10 mg 0- phenylenediamine dihydrochloride, 0.0212% hydrogen peroxide, 0.22 mM dtrate, 50 mM phosphate, pH 5.0) is added and then incubated until color developed. The reaction is stopped with 1 N sulfuric acid and the absorbance at 492 nm is recorded and the IC50 values determined. The results are recorded in Table 5. Table 5 inhiUtion of Fibrinogen Bittf^ Rl R2 R3 R4 5. R6 R7 R8 9 X FBI * OH H (2) (2) H, H H H OH S 0.95 H H OH 1.3 H H OH 1.4 (5) H H OH SO 1.4 (7) H H OH SO 1.5 (7) OH H H H OH S 1.7 (5) H H OH SO 1.8 (7) H H H, 4- H H OH 1.9 (5) biphenyl OH H OH H OH H 2-methyl- H H, H H H OH 3.0 1 -propyl OH H 4-hydroxy¬ H H, phenyl H H OH S 3.0 benzyl OH H H H H, 4- H H OH 3.5 (6) biphenyl OH H 4-hydroxy¬ H H, H H H OH CH2 3.5 benzyl OH H OH H OH H OH H OH H OH H H H H, ethyl H H OH S 6.0 (5) 2-butyl H H,H H H OH S 6.0 benzyl H H.H H H OH SO 6.6 (7) H H H.H H H OH S 6.8 H H H.H H H OH S 7.0 1 -hydroxy- H H, phenyl H H OH S 7.0 (6) 1 -ethyl OH H 4-hydroxy- H H.H CH 3 CH 3 OH S 7.0 benzyl (2) (2) H,H H H OH SO 7.0 (8) 4-amino-l- H H,H H H OH S 7.5 butyl 4-hydroxy¬ H H,H H H OH NH 8.0 benzyl hydroxy¬ H H.H H H OH SO 8.0 methyl H H H,H H H OH S 9.5 2-propyl H H,H H H OH O 9.7 1-hydroxy- H H,H H H OH SO 10 (8) 1 -ethyl H (3) H,H H H OH S 11.4 H H H, 2- H H OH S 11.5 (6) naphthyl OH 1- H H H.H H H OH S 11.6 hydroxy- 1-ethyl eth- H 4-hydroxy¬ H H,H H H OH S 12 oxy benzyl OH H 4-amino-l- H H.H H H OH SO 14 (8) butyl H H H, phenyl H H OH S 15 (6) 2-carboxy- H H.H H H OH S 15 1 -ethyl 4-hydroxy¬ H H.H CH 3 CH 3 OH SO 15 (8) benzyl H H OH S 38 H H OH S 39 H H OH SO 39 (8) H H OH O 42 nyl H H OH SO 43 (6) H H OH SO 50 (8) H H OH SO 50 (8) H H OH S 1 10 H H ethoxy S 158 H H OH 180 (6) fluoromethyl phenyl H H OH S 260 H H OH S 500 H H ethoxy S 500 H H OH (4) 1.05 H H OH (4) 2.9 H H OH (4) 3.0 H H OH (4) 4.0 H H OH (4) 5.0 H H OH (4) 6.0 H H OH (4) 8.0 OH H H H OH (4) 1 0 OH H H H OH (4) 1 1.2 OH H H H OH (4) 1 2 H H OH (4) 1 2 H H OH (4) 25 H H OH (4) 41.5 H H OH (4) 60 H H OH (4) 67 OH (3) (3) H H, H H H OH (4) 360 * Rbrinogen Binding Inhibition 1 IC50 (nM) Notes (1) Rbrinogen binding inhibition assay data is from Example 23. The IC50 values are in nanomolar units. (2) R3 + R4 = CH2CH2CH2 (3) R2 + R4 = CH2CH2CH2 (4) X = (CH2)k and k is 0. (5) IC50 for the more active isomer at R5/R6 (6) IC50 for the less active isomer at R5/R6. (7) IC50 for the more active sultoxide isomer (8) IC50 for the less active sultoxide isomer. -Example 24 Inhibition of platelet aggregation Fifty milliliters of whole human blood (9 parts) is drawn on 3.6% sodium citrate (1 part) from a donor who has not taken aspirin or related medications for at least two weeks. The blood is centrifuged at 160 x g for 10 min at 22° C and then allowed to stand for 5 min after which the PRP is decanted. Platelet poor plasma (PPP) is isolated from the remaining Wood after centrifugation at 2000 x g for 25 min. The platelet count of the PRP was diluted to ca. 300000 per microliter with PPP. A 225 μL aliquot of PRP plus 25 μL of either a dilution of the test sample or a control (PBS) is incubated for 5 min in a Chrono-log Whole Blood Aggregometer at 25° C. Adenosine diphosphate (ADP, 8 μM) is added and the platelet aggregation recorded. The results of this test are recorded in Table 6. Where the possibility of stereoisomers exists, the values in Table 6 are for the most active stereoisomers. Tableβ Inhibition of Platelet Aggregation by Compounds of Formula VIII Ri R2 R3 R4 R5. R6 R 7 R 8 R 9 PAI * Platelet Aggregation Inhibition 1 IC50 (μM) Notes (1) Platelet aggregation inhibition assay data is from Example 24. The IC50 values are in micromolar units. (2) R3 + R4 = CH2CH2CH2 (3) X = (CH2)κ and k is O. In view of the efficacy of these cyclic polypeptides as inhibitors of fibrinogen binding to GP libllla, and the feasibility as demonstrated herein of producing these cyclic polypeptides, the present invention may have application in the treatment of a large group of disorders associated with, or characterized by, a hyperthrombotic state. Representative of such disorders are genetic or acquired deficienα ' es of factors which normally prevent a hyperthrombotic state; medical procedures such as angiopiasty and thrombolytic therapy; mechanical obstructions to blood flow, such as tumor masses, prosthetic synthetic cardiac valves, and extracorporeal perfusion devices; atherosclerosis; and coronary artery disease. The present invention has of necessity been discussed herein by reference to certain specific methods and materials. It is to be understood that the discussion of these specific methods and materials in no way constitutes any limitation on the scope of the present invention, which extends to any and all alternative materials and methods suitable for accomplishing the objectives of the present invention.

Claims: What is claimed is: 1. A compound of the formula: wherein Ri and Rg are the same or different and are selected from hydroxy, Ci-Cs alkoxy, C3-Ci2alkenoxy, C6-Ci2 aryloxy, di-Ci-Cβ alkyla ino-Ci-Cβ-alkoxy, acylamino-Cι -Cs-alkoxy selected from the group acetylaminoethoxy, nicotinoyiaminoethoxy, and succinamidoethoxy, pivaloyloxyethoxy, C6-C12 aryl-Ci-Cβ-alkoxy where the aryl group is unsubstituted or substituted with one or more of the groups nitro, halo (F, Cl, Br, I), Cι-C4-alkoxy, and amino, hydroxy-C2-C8-alkoxy, dihydroxy-C3-C8-alkoxy, and NRto ii wherein R10 and Rn are the same or different and are hydrogen, Ci-Cβ-alkyl, C3-C8-alkenyl, C6-Ci2-aryl where the aryl group is unsubstituted or substituted with one or more of the groups nitro, halo (F, Cl, Br, I), Ci-C-j-alkoxy, and amino, Cβ-Ci 2-aryl-Cι -Cβ-alkyl where the aryl group is unsubstituted or substituted by one or more of the groups nitro, halo (F, Cl, Br, I), Ci-C-j-alkoxy, and amino; R2. R3. R5. Rβ. R7. Ftø are the same or different and are selected from hydrogen, C6-C12 aryl where the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo (F, Cl, Br, I), C1-C8 alkyl, halo-Ci-Cβ alkyl, Ci-Cs-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Ci-Cβ alkylamino, Ci-Cs alkylamino, C6-C12 aroyi, Ci-Cs alkanoyl, and hydroxy-Ci-Cs alkyl, C1-C12 alkyl either substituted or unsubstituted, branched or straight chain where the substituents are selected from halo (F, Cl, Br, I), Ci-Cβ alkoxy, C6-C12 aryloxy where the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo (F, Cl, Br, I), Ci-Cβ alkyl, Ci-Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci -Cs alkylamino, Ci -Cs alkylamino, C6-C12 aroyi, and C1-C8 alkanoyl, isothioureido, C3-C7 cy oalkyl, ureido. amino, Ci-Cs alkylamino, di-Ci-Cs alkylamino, hydroxy, amino-C2-C8 alkyithio, amino-C2-C8 alkoxy, acetamido, benzamido wherein the phenyl ring is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo (F, Cl, Br, I), C1-C8 alkyl, Ci-Cβ-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci -Cs alkylamino, Ci-Cs alkylamino, C6-C12 aroyi, and Ci -Cs alkanoyl, C6-C 2 arytamino wherein the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo, Ci-Cs alkyl, Ci-Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci -Cs alkylamino, Ci-Cs alkylamino, C6-C 2 aroyi, and Ci-Cs alkanoyl, guanidino, phthalimido, mercapto, Ci-Cs alkyithio, C6-Ci2 arylthio, carboxy, carboxamide, carbo-Ci-Cβ alkoxy, Cg-C 2 aryl wherein the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo, C -Cs alkyl, Ci -Cs-alkoxy, amino, phenyloxy, acetamido, benzamido, di-Ci-Cs alkylamino, Ci-Cs alkylamino, hydroxy-Ci-Cs alkyl, C6-C12 aroyi, and Ci -Cs alkanoyl, and aromatic heterocyde wherein the heterocydic groups have 5-10 ring atoms and contain up to two 0, N, or S heteroatoms; R2 and R3, R5 and Rg, or R7 and Rs may optionally and independentiy be joined together to form a carbocyclic or heterocydic ring of from four to seven atoms where the heteroatoms are selected from 0, S or NR12 where R12 is selected from hydrogen, Ci-Cβ-alkyl, C3-C8-alkenyl. Cβ-Cι 2-aryl-Cι -Cβ-alkyi, C1-C8 alkanoyl, and C6-C12 aroyi, R4 is selected from hydrogen, Ci-Cβ alkyl, C3-C10 cycloal yl, C6-C12 aryl, and C6-C12 aryl-C-j-Cβ-alkyl; R2 or R3 may be optionally joined with R4 to form a piperidine, pyrrolidine or thiazolidine ring; R14 is selected from hydrogen, Ci-Cs-alkyl, C3-C8-alkenyi, C6-Ci2-aryl, and C6-C12 aryl-Cι -Cs-alkyi; X is selected from an 0 or S atom, an S atom bearing one or two 0 atoms, NR13 wherein R13 is hydrogen, Ci-Cs-alkyl, C3-Cs-alkenyl, C6-Ci2-aryl, Ce-Ci 2-aryl-Cι -Cβ-alkyl, Ci -Cs alkanoyl, and Cβ-Ci 2 aroyi, and C6-C12 aryl, Ci-Cs alkanoyl, (CH2)k where k is an integer from 0 to 5; n is an integer from 1 to 6; m is an integer from 0 to 4; and pharmaceutically acceptable salts thereof. A compound of the formula wherein Ri and Rg are the same or different and are hydroxy, N , C1-C4 alkoxy or benzytoxy; R2 is hydrogen R3 is selected from hydrogen, C1-C6 alkyl branched or unbranched, unsubstituted or substituted with substituents selected from amino, hydroxy, mercapto, methylthto, carboxy, carboxamide, guam ' dino, phenyl, 4- hydroxyphenyl, 4-methoxyphenyl, 3-indolyl, and 4-imidazolyi, phenyl either unsubstituted or substituted with one to three substituents that may be independently nitro, hydroxy, halo (F, Cl, Br, I), C1-C4 alkyl, Cι-C4-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Ci -C4 alkylamino, Ci -C4 alkylamino, halo-Ci -C4 alkyl, C6-C12 aroyi, and C1-C4 alkanoyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; R5 and Rε are independently selected from hydrogen, Ci-Cg alkyl either branched or unbranched, unsubstituted or substituted with substituents selected from amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl or 4-hydroxyphenyl, 4-methbxyphenyi, 3-indolyl, and 4-im Jazolyl, phenyl either unsubstituted or substituted with one to three substituents that may be independently selected from nitro, hydroxy, halo (F, Cl, Br, I), Ci -C4 alkyl, Ci -C4-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Cι-C4 alkylamino, C1-C4 alkylamino, halo-Cι-C4 alkyl, CQ- C12 aroyi, and Ci -C4 alkanoyl, 1-naphthyl, 2-naphthyl, 2-thienyI, 2-pyridyl, 3-pyridyl, and 4-pyridyl; R7 or Re are the same or different and are selected from hydrogen, C1-C4 alkyl, phenyl either unsubstituted or substituted with from one to three substituents independentiy selected from hydroxy, halo (F, Cl, Br, I), C1-C4 alkyl, and Cι-C4-aIkoxy; R4 is hydrogen or may be joined with R3 to form a heterocydic ring selected from piperidine, pyrrolidine or thiazolidne; R14 is hydrogen or methyl; X is selected from an 0 or S atom, an S atom bearing one or two 0 atoms, NR13 where R13 is selected from hydrogen, C1-C4 alkyl, benzyl, phenyl, C1-C4 alkanoyl, benzoyland (CH2)k,where kis0 to 5; n is3 or4; mis1;and pharmaceutically acceptable salts thereof. 3. A compound of the formula wherein Ri and Rg are the same or different and are hydroxy, NH2, Cι-C4 alkoxy or benzyloxy; R3 is hydrogen R2 is selected from hydrogen, Ci -Cg alkyl branched or unbranched, unsubstituted or substituted with substituents selected from amino, hydroxy, mercapto, methytthio, carboxy, carboxamide, guanidino, phenyl, 4- hydroxyphenyl, 4-methoxypbenyl, 3-indolyl, and 4-imidazolyl, phenyl either unsubstituted or substituted with one to three substituents that may be independently nitro, hydroxy, halo (F, Cl, Br, I), C1-C4 alkyl. Cι-C4-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Ci -C4 alkylamino, Ci -C4 alkylamino, halo-Cι -C4 alkyl, Cg-C 2 aroyi, and Ci -C4 alkanoyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; R5 and Rg are independently selected from hydrogen, Ci-Cg alkyl either branched or unbranched, unsubstituted or substituted with substituents selected from amino, hydroxy, mercapto, carboxy, carboxamide, guanidino, phenyl or 4-hydroxyphenyl, 4-methoxyphenyl, 3-indolyl, and 4-ιmidazolyl, phenyl either unsubstituted or substituted with one to three substituents that may be independently selected from nitro, hydroxy, halo (F, Cl, Br, I), Ci -C4 alkyl, Ci -C4-alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-Cι-C4 alkylamino, C1-C4 alkylamino, halo-Cι-C4 alkyl, Cg- C12 aroyi, and C1-C4 alkanoyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-pyridyl, 3-pyridyI, and 4-pyridyl; R7 or Rs are the same or different and are selected from hydrogen, C1-C4 alkyl, phenyl either unsubstituted or substituted with from one to three substituents independently selected from hydroxy, halo (F, Cl, Br, I), C1-C4 alkyl, and Cι-C4-alkoxy; R4 is hydrogen or may be joined with R3 to form a heterocydic ring selected from piperidine, pyrrolidine or thiazol fine; R14 is hydrogen or methyl; X is selected from an 0 or S atom, an S atom bearing one or two 0 atoms, NR13 where R13 is selected from hydrogen, Ci -C4 alkyl, benzyl, phenyl, C1-C4 alkanoyl, benzoyiand (CH2)k, where is0 to 5; n is3or4; mis 1;and pharmaceutically acceptable salts thereof. 4. The compound of claim 2 wherein Ri and RgareOH; R2, R4, R5, Rg, R7, Rs. and R14 are hydrogen; R3 is selected from hydrogen, 4-amino-1 -butyl, 3-amino-1-propyl, hydroxymethyl, 2-hydroxy-1-propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyi, 2-butyi, methylthioethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyi, and carboxamidoethyl; Xis S;and n is 3 or 4. 5. The compound of claim 2 wherein Ri and R areOH; R2, R4. 5, Rg, R7, Rs, and Ri 4 are hydrogen; R3 is selected from hydrogen, 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyl, 2-butyi, methylthioethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; X is SO; and n is 3 or 4. 6. The compound of claim 2 wherein Ri and Rgare OH; R2, R3, R4, R7, Re, and Ri 4 are hydrogen; R5 and Rg are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethyiphenyl, 1- naphthyl, 2-naphthyl, 4-biphenyi, and pentafluorophenyl; X is S;and n is 3 or 4. 7. The compound of claim 2 wherein Ri and Rgare OH; R2. R3. R4. R7. Rβ. and R14 are hydrogen; R5 and Rg are independently selected from hydrogen methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenyl, 2-trifiuoromethylphenyi, 3-trifluoromethylphenyl, 4-trifluoromethyiphenyl, 1- naphthyl, 2-naphthyl, 4-biphenyl, and pentafluorophenyl; X is SO; and n is 3 or 4. 8. The compound of claim 2 wherein Ri and R are OH; R2. R3, R4. R5. R6. and Ri 4 are hydrogen; R7 and Rβ are independently selected from hydrogen, methyl and phenyl; Xis S;and n is 3 or 4. 9. The compound of claim 2 wherein Ri and Rgare OH; R2, R3, R4, R5, Rε, and R14 are hydrogen; R7 and Rβ are independentiy selected from hydrogen, methyl and phenyl; X is SO; and n is3 or4. 10. The compound of claim 2 wherein Ri and RgareOH; R2. R4. R7. R8. and R14 are hydrogen; R3 is selected from 4-amino-1 -butyl, 3-amino-1-propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyl, 2-butyl, methytthioethyl, benzyl, 4- hydroxybenzyi, 4-methoxybenzyl, 3-indolyimethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxam-doethyl; R5 and Rg are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenyl, 2-trifiuoromethyiphenyl, 3-trifluoromethylpheπyl, 4- triftuoromethylphenyi, 1-naphthyl, 2-naphthyl, 4-biphenyl, and pentafluorophenyl; XisS;and n is3 or4. 11. The compound of claim 2 wherein Ri and RgareOH; R2, R4, R7, Rs. and R are hydrogen; R3 is selected from 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; R5 and Rg are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenyl, 2-trifiuoromethylpnenyl, 3-trifluoromethylphenyl, 4- trifiuoromethylphenyl, 1-naphthyi, 2-naphthyl, 4-Wphenyi, and pentafluorophenyl; X is SO; and n is 3 or 4. 12. The compound of claim 2 wherein Ri and Rgare OH; R2. R4, R5, Rg, and Ri 4 are hydrogen; R3 is selected from 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyi, 2-butyi, methyithioethyl, benzyl, 4- hydroxybenzyi, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; R7 and Rs are independently selected from hydrogen, methyl and phenyl; X is S;and n is 3 or 4. 13. The compound of claim 2 wherein Ri and R are H; R2» R4. 5. Rg, and R14 are hydrogen; R3 is selected from 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; R7 and Rβ are independently selected from hydrogen, methyl and phenyl; X is SO; and n is 3 or 4. 14. The compound of claim 2 wherein Ri and Rgare OH; R2, R3, R4. and R14 are hydrogen; R5 and Rg are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4- trifiuoromethyiphenyi, 1-naphthyl, 2-naphthyl, 4-biphenyl, and pentafluorophenyl; R7 and Rβ are independently selected from hydrogen, methyl and phenyl; Xis S;and n is 3 or 4. 15. The compound of claim 2 wherein Ri and RgareOH; R2. R3. R4. and R14 are hydrogen; R5 and Rg are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, and pentafluorophenyl; R7 and Rβ are independently selected from hydrogen, methyl and phenyl; X is SO; and n is 3 or 4. 16. The compound of claim 2 wherein Ri and RgareOH; R2. R4. R5. R& R7. Rβ. and Ri 4 are hydrogen; R3 is selected from hydrogen, 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; XisO;and n is 3 or 4. 17. Thecompoundof aim 2wherein Ri and Rgare OH; R2. 4. R5. & R 7. Rβ. and R14 are hydrogen; R3 is selected from hydrogen, 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyi, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; X is NR13 where R13 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, benzoyl and benzyl; and n is3 or4. 18. The compound of daim 2 wherein Ri and RgareOH; R2. R4. R5. Rβ. R7. Rδ. and R14 are hydrogen; R3 is 4-hydroxybeπzyi; XisS;and nis3. 19. The compound of claim 2 wherein Ri andRgareOH; R2. R4. R5. δ. R7, Rδ. and R14 are hydrogen; R3 is 4-hydroxybeπzyl; X is SO; and nis3. 20. The compound of aim 2 wherein Ri andRgareOH; R2, R4. R5. R6. R7. R8. and R14 are hydrogen; R3 is isopropyl; XisS;and nis3. 21. The compound of claim 2 wherein Ri andRgareOH; R2. R4. R5. Rδ. R7. Rδ. and R14 are hydrogen; R3 is isopropyl; X is SO; and nis3. 22. The compound of claim 2 wherein Ri and RgareOH; R2. R4. R5. Rδ. R7. Rδ. and R14 are hydrogen; R3 is 2-butyi; XisS;and nis3. 23. The compound of claim 2 wherein Ri andRgareOH; R2. 4. R5, & 7. Rδ. and R14 are hydrogen; R3 is 2-butyi; X is SO; and nis3. 24. The compound of claim 2 wherein RiandRgareOH; R2, R5. Rδ. R7. Rβ. and Ri 4 are hydrogen; R3 and R4 are joined together to form a pyrrolidine ring; XisS;and nis3. 25. The compound of claim 2 wherein RiandRgareOH; R2. R5. Rδ. R7. Rδ. and R14 are hydrogen; R3 and R4 are joined together to form a pyrrolidine ring; X is SO; and n is 3. 26. The compound of claim 2 wherein RiandRgareOH; R 2. R4, 5. δ. and R14 are hydrogen; R3 is 4-hydroxybenzyi; R7 and Rβ are methyl; XisS;and nis3. 27. The compound of claim 2 wherein RiandRgareOH; R2. R4, 5. Rδ. and R14 are hydrogen; R3 is 4-hydroxybenzyl; R7 and Rβ are methyl; X is SO; and nis3. 28. The compound of claim 2 wherein Rian RgareOH; R 2. R4, R5. δ. and R14 are hydrogen; R3 is isopropyl; R7 and Rβ are methyl; XisS;and nis3. 29. The compound of claim 2 wherein RiandRgareOH; R2. R4, 5. Rδ. and R14 are hydrogen; R3 is isopropyl; R7 and Rδ are methyl; X is SO; and nis3. 30. The compound of claim 2 wherein Ri and RgareOH; R2. R3, R4, 5. Rδ» and R14 are hydrogen; R7and Rβ are methyi; XisS;and nis3. 31. The compound of claim 2 wherein Ri and RgareOH; R2. R3, R4, R5. Rδ. and R14 are hydrogen; R7 and Rδ are methyl; X is SO; and nis3. 32. The compound of claim 2 wherein R1 .S H2; RgisOH; 2. 4. R5. Rδ. 7. Rδ. and R14 are hydrogen; R3 is selected from hydrogen, 4-amino-1-butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyi, isobutyl, n-propyi, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indoly.methyi, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; XisS;and n is 3 or 4. 33. The compound of claim 2 wherein R1 .SNH2; RgisOH; R2. R4. R5. Rδ. 7. Rβ. and R14 are hydrogen; R3 is selected from hydrogen, 4-amino-1 -butyl, 3-amino-1-propyi, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyi, isobutyl, n-propyi, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; X is SO; and nis3or4. 34. The compound of claim 2 wherein Ri andRgareOH; R2. R4. Rδ. Rδ. 7. Rδ. and R14 are hydrogen; R3 is selected from hydrogen, 4-amino-1 -butyl, 3-amino-1 -propyl, hydroxymethyl, 2-hydroxy-1 -propyl, methyl, ethyl, 2-propyl, isobutyl, n-propyl, n-butyl, 2-butyl, methyithioethyl, benzyl, 4- hydroxybenzyl, 4-methoxybenzyl, 3-indolylmethyl, 4-imidazolylmethyl, phenyl, carboxymethyl, carboxyethyl, carboxamidomethyl, and carboxamidoethyl; Xis(CH2)k here is0,1or2;and n is 3 or 4. 35. The compound of claim 2 wherein RiandRgareOH; R2. R4. R5. Rδ. 7. Rδ. and R14 are hydrogen; R3 is 4-hydroxybenzyi; XisCH2;and nis3. 36. The compound of claim 2 wherein Rian RgareOH; R2, R4, R5, Re. R7. Rβ. and R14 are hydrogen; R3 is isopropyl; XisCH2;and nis3. 37. The compound of claim 2 wherein RiandRgareOH; R2. R4. R5. Rβ- 7. Rδ. and R14 are hydrogen; R3 is 2-butyl; XisCH2;and nis3. 38. The compound of daim 2 wherein Rian RgareOH; R2. 5. Rδ. R 7. Rβ. and R14 are hydrogen; R3 and R4 are joined together to form a pyrrolidine ring; XisCH2;and nis3. 39. A process for preparing the compound of daim 2 which comprises: (a) cydizing an intermediate of Formula IV wherein R -Rg, n and are as defined in claim 2, Wis Br, α,or l, Ri4 is selected from hydrogen, Ci-Cg alkyl, and Cg-C 2 aryl R15 is 2,2,5,7,8-pentamethylchroman-6-sulfonyi, R g is hydrogen, and Xis S; (b) deaving the desired product from the resin; (c ) deaving any protecting groups; and ( d ) purifying and isolating the more biologically active isomer. 40. A process for preparing the compound of daim 2 which comprises: ( a) cydizing an intermediate of Formula VI vι wherein Rl-Rg, n and are as defined in claim 2, Wis Br. α.or l, R14 is selected from hydrogen, Ci-Cg alkyl, and Cg-Ci2 aryl Ri5 is 2,2,5,7,8-pentamethyichroman-6-sulfonyl, Rl6isH,and Xis S; ( b ) deaving any protecting groups; and ( c ) purifying and isolating the more biologically active isomer. 41. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of Claim 1. 42. A method for inhibiting platelet aggregation which method comprises administering a platelet aggregation inhibiting amount of the compound of Claim 1. 43. A method for redudng platelet aggregation in a mammal, comprising administering a pharmaceutically effective amount of the composition of matter as defined by daim 1 to said mammal. 44. The method of daim 43, further comprising administering said composition of matter to said mammal in admixture with a pharmaceutically acceptable carrier. 45. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by claim 1 to said mammal. 46. A composition of matter for redudng platelet aggregation in a mammal, comprising the composition of matter as defined by claim 1. 47. A composition of matter for treating a mammal who has an increased propensity for thrombus formation, comprising the composition of matter as defined by daim 1. 48. A composition of matter for inhibiting fibrinogen binding to platelets in a mammal, comprising the composition of matter as defined by daim 1. 49. A composition of matter comprising the compositions of daim 1 wherein Ri is Ci -Cg alkoxy which indudes branched and unsaturated alkyl groups. 50. A composition of matter comprising the compositions of claim 1 wherein Rg is Ci -Cg alkoxy which indudes branched and unsaturated alkyl groups. 51. A composition of matter comprising the compositions of daim 1 wherein Ri and Rg are both Ci -Cg alkoxy which indudes branched and unsaturated alkyl groups. 52. A method of treating a mammal who has an increased propensity for thrombus formation which comprises administering to said mammal a therapeuticaliy effective amount of the composition of daim 51 , 52, or 53 wherein the Ri and Rg alkoxy groups are hydrolyzed following administration to said mammal. 53. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by daim 1 in combination with a thrombolytic agent. 54. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by daim 1 in combination with an anticoagulant 55. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by daim 1 following angiopiasty. 56. A cydic peptide containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. 57. The cydic peptide of daim 57 wherein the cydic peptide contains 5 amino adds in the cycle. 58. The cydic peptide of claim 57 wherein the cycle contains 17 or 18 atoms in a ring. 59. The cydic peptide of daim 58 wherein the cydic peptide contains at least one D-α-amiπo acid. 60. The cydic peptide of daim 59 wherein the D-amino acid is in any position in the cycle except the Arg- Gly-Asp sequence. 61. The cyclic peptide of claim 57 wherein the sulfur of the thioether linkage is bonded to at least one oxygen. 62. A cydic pentapeptide containing the tripeptide sequence Arg-Gly-Asp wherein the cyde comprises a peptide linkage through an amino add sidechain. 63. The cydic peptide of daim 62 wherein the peptide linkage is through the 6 carboxyl of 2-amino-1 ,6- hexanedtofcacid. 64. The cyclic pentapeptide of claim 63 wherein the cyde contains 17 or 18 atoms in a ring.

Inventors: BARKER PETER L, BURNIER JOHN P, GADEK THOMAS, THORSETT EUGENE D, BARKER, PETER, L., BURNIER, JOHN, P., GADEK, THOMAS, THORSETT, EUGENE, D.
Applicants: GENENTECH INC, GENENTECH, INC.
Application year: 1990
Main classification: C07K7
IPC codes: A61K38, C07K1, C07K7, C07K14