ANTITHROMBOTIC AGENTS

Abstract: This invention relates to L-arginine aldehyde derivatives having formula (I) where R<1>, X and Y have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors and thromboembolic disorder agents.

Description: ANTITHROMBOTIC AGENTS This invention relates to thrombin inhibitors which are useful anticoagulants in mammals. In particular it relates to L-arginine aldehyde derivatives having high anticoagulant activity, and antithrombotic activity. The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin. Thrombin proteolytically removes activation peptides from the Aα-chains and the Bβ-chains of fibrinogen, which is soluble in blood plasma, initiating insoluble fibrin formation. Anticoagulation is currently achieved by the administration of heparins and coumarins. Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins. Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin) . Because antithrombin III levels vary in plasma and because ' surface-bound thrombin seems resistant to this indirect mechanism, heparins can be an ineffective treatment. Because coagulation assays are believed to be associated with efficacy and safety, heparin levels must be monitored with coagulation assays (particularly the activated partial thromboplastin time (APTT) assay) . Coumarins impede the generation of thrombin by blocking the posttranslational gamma- carboxylation in the synthesis of prothrombin and other proteins of this type. Because of their mechanism of action, the effect of coumarins can only develop slowly, 6-24 hours after administration. Further, they are not selective anticoagulants. Coumarins also require monitoring with coagulation assays (particularly the prothrombin time (PT) assay) . Recently, interest in small synthetic peptides that are recognized by proteolytic enzymes in a manner similar to that of natural substrates has grown. Tripeptide aldehydes such as D-Phe-Pro-Arg-H, Boc-D-Phe-Pro-Arg-H, and D-MePhe-Pro-Arg-H, Bajusz et al., J. Med. Chem.. 33. 1729-1735 (1990) demonstrate potent direct inhibition of thrombin. Many investigators have synthesized analogs in an effort to develop pharmaceutical agents, for example Shuman et al., J. Med. Chem. , 2 > 314-319 (1993), as well as European patent applications, publication 5. numbers 479489, 542525 and 530167. Although the heparins and coumarins are effective anticoagulants, and no drug has yet emerged from the known tripeptide aldehydes, and despite the continuing promise for this class of compounds, there exists a need for anticoagulants 0 that act selectively on thrombin, and independent of antithrombin III, exert inhibitory action shortly after administration, and do not interfere with lysis of blood clots, as required to maintain hemostasis. The present invention is directed to the discovery 5 that the compounds of the present invention, as defined below, are potent thrombin inhibitors. Accordingly, it is a primary object of the present invention to provide novel L-arginine aldehyde derivatives that are potent thrombin inhibitors useful as anticoagulants. 0 Other objects features and advantages will be apparent to those skilled in the art from the following description and claims. The present invention provides a thrombin inhibiting compound having the formula 5 H I H NH Y-C-X-N CH 2 ) 3 -N-C-NH, where R 1 is hydrogen; 0 X is prolinyl or azetidinyl-2-carbonyl; Y is a group where R is benzyl, phenyl, cyclopentyl, cyclohexyl, cyclopentyl-CH 2 - or cyclohexyl-CH2-; Z is -C (C=0 ) - , -S(0) n - or a bond; R 2 is C 1 -C6 alkyl, C 1 -C2 perfluoroalkyl, -(CH2) g -COOH, Cι_C 6 alkoxy, (C 1 -C 4 alkoxy)Cι-C 4 alkyl, cyclopentyl, cyclohexyl, (C 5 -C6 cycloalkyl)CH 2 -, amino, mono (C 1 -C 4 )alkylamino, di(Cι_C 4 )alkylamino, unsubstituted or substituted aryl, where aryl is phenyl or naphthyl, unsubstituted or substituted benzyl, a 5 or 6 membered unsubstituted or substituted heterocyclic ring, having one or two heteroatoms, one of which is nitrogen and the second heteroato is selected from sulfur, oxygen and nitrogen, or methylene substituted with a 5 or 6 membered unsubstituted or substituted heterocyclic ring having one nitrogen atom or two hetero atoms one of which is nitrogen and the second heteroatom is selected from sulfur, oxygen and nitrogen; or a 9 or 10 membered unsubstituted or substituted fused bicyclic heterocyclic ring; g is 1, 2 or 3; and n is 1 or 2; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of said compound or salt thereof; provided that when R is benzyl, phenyl, cyclopentyl or cyclohexyl and Z is -C(C=0)- or a bond, R 2 is other than C 1 -C 6 alkyl, C 1 -C 2 perfluoroalkyl or Ci-Cβ alkoxy. A particular subgroup of compounds of formula I of the invention consists of those compounds of formula I where R 1 is hydrogen; X is prolinyl or azetidinyl-2-carbonyl; Y is a group R 2 — Z NH H C I R where R is benzyl, phenyl, cyclopentyl, cyclohexyl, cyclopentyl-CH2- or cyclohexyl-CH2-; Z is -C(C=0)-, -S(0) n - or a bond; R 2 is Ci-Cβ alkyl, C 1 -C 2 perfluoroalkyl, C 1 -C6 alkoxy, (C 1 -C 4 alkoxy)Cι-C 4 alkyl, cyclopentyl, cyclohexyl, (C5-C 6 cycloalkyl)CH 2 -, amino, mono (Cχ-C 4 )alkylamino, di(Cι-C 4 )alkylamino, unsubstituted or substituted aryl, where aryl is phenyl or naphthyl, unsubstituted or substituted benzyl, a 5 or 6 membered unsubstituted or substituted heterocyclic ring, having one or two heteroatoms, one of which is nitrogen and the second heteroatom is selected from sulfur, oxygen and nitrogen, or methylene substituted with a 5 or 6 membered unsubstituted or substituted heterocyclic ring having one nitrogen atom or two hetero atoms one of which is nitrogen and the second heteroatom is selected from sulfur, oxygen and nitrogen; or a 9 or 10 membered unsubstituted or substituted fused bicyclic heterocyclic ring; and n is 1 or 2; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of said compound or salt thereof; provided that when R is benzyl, phenyl, cyclopentyl or cyclohexyl and Z is -C(C=0)- or a bond, R 2 is other than Cχ-C 6 alkyl, C 1 -C 2 perfluoroalkyl or Ci-Cδ alkoxy. In addition to the compounds of formula I, the present invention provides pharmaceutical formulations comprising a compound of formula I in association with a pharmaceutically acceptable carrier, diluent or excipient. The present invention also provides a method of inhibiting coagulation in mammals comprising administering to a mam al in need of treatment, a coagulation inhibiting dose of a compound of formula I. The present invention further provides a method of inhibiting thrombin comprising administering to a mammal in need of treatment, a thrombin inhibiting dose of a compound of formula I. Further, the present invention provides a method of treating thromboembolic disorders comprising administering to a mammal requiring treatment, an effective dose of a compound of formula I. This invention relates to new inhibitors of thrombin, pharmaceutical compositions containing the compounds as active ingredients, and the use of the compounds as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, yocardial infarction and cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflaminatory process. The term "alkyl" by itself or as part of another substituent means a straight or branched chain alkyl radical having the stated number of carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and sec-butyl. The term "alkoxy" means a straight or branched chain alkyl radical having the stated number of carbon atoms bonded to the parent moiety by an oxygen atom. The term "halo" means chloro, fluoro, bromo or iodo. The term "di(Cχ-C 4 alkyl)amino" means a group — (Cχ_C 4 alkyl) 2 where each alkyl group, independently, has the stated number of carbon atoms. The term "perfluoroalkyl" means a straight or branched chain alkyl radical having the stated number of carbon atoms with all available valences substituted with fluoro atoms such as trifluoromethyl and pentafluoroethyl. The term "5 or 6 membered heterocyclic ring" means any 5 or 6 membered ring that will afford a stable structure containing one nitrogen atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; or two nitrogen atoms. Heterocyclics include pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl and oxazinyl. The term "9 or 10 membered fused bicyclic heterocyclic ring" means any bicyclic group in which any of the above 5 or 6 membered rings is fused to a benzene ring or a cyclohexane ring that will afford a stable structure. These heterocyclics include indolyl, benzoxazolyl, benziosoxazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzothiazolyl. The above heterocycles may exist in tautomeric forms. All such forms are included within the scope of the invention. The groups - are referred to ' as prolinyl and azetidine-2-carbonyl, respectively, and are respectively abbreviated Pro and Azt. The carbonyl functionality of X is attached to the amino group drawn in formula I All of the above heterocycles, phenyl and the aromatic ring of benzyl are unsubstituted or substituted with one or two substituents that will afford a stable structure independently selected from halo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, carboxy, amino (-NH 2 ) , mono (C 1 -C 4 alkyDamino, di(Cχ-C 4 alkyDamino, -N(Cχ-C 4 alkyl) , mercapto, Cχ-C alkylthio (-S(0) p Cχ-C 4 alkyl); -NHS(0) p (Cχ-C alkyl), -NHC(0)C -C alkyl, -S(0) p NH 2 , -S (0) p H(Cχ-C 4 alkyl), and -S (0) p N(Cχ-C 4 alkyl) 2 , where p is 1 or 2. The asterisks in formula I and substituent X denote a chiral center that is (L) . In addition, diastereomers exist at the Y substituent and, depending on substitutions on said Y substituent, further diastereomers may exist. The compounds of the present invention include mixtures of two or more diastereomers as well as each individual isomer. Preferred compounds of the present invention include those compounds of formula I where R 2 is Cχ-C 6 alkyl, amino, mono(Cχ-C 4 alkyDamino, di(Cχ-C 4 alkyDamino, or a 9 or 10 membered unsubstituted or monosubstituted fused bicyclic heterocyclic ring; and where X, R, R 1 and Z are as defined above for formula I and pharmaceutically acceptable salts and solvates thereof; provided that when R is benzyl, phenyl, cyclopentyl or cyclohexyl and Z is -C(C=0)- or a bond, R 2 is other than Cχ-C δ alkyl. A first group of particularly preferred compounds of the present invention are those compounds of formula I where R 1 is hydrogen; X is prolinyl or azetidinyl-2-carbonyl; R is benzyl or cyclohexyl-CH 2 -; Z is -C(C=0)-; R 2 is a 9 or 10 membered unsubstituted or monosubstituted fused bicyclic heterocyclic ring containing one nitrogen atom and where the substituent is selected from Cχ-C 4 alkyl, amino, mono(Cχ-C 4 alkyDamino, di(Cχ-C 4 alkyDamino, and - HS0 2 (Cχ-C alkyl); and pharmaceutically acceptable salts and solvates thereof. A second group of particularly preferred compounds of the present invention are those compounds of formula I where R 1 is hydrogen; X is prolinyl or azetidinyl-2-carbonyl; Z is -SO 2 -; R 2 is Cχ-C6 alkyl, amino, mono(Cχ-C4 alkyDamino or di(Cχ-C4 alkyl) amino; and R is as defined above for formula I; and pharmaceutically acceptable salts and solvates thereof. A third group of particularly preferred compounds of the present invention consists of those compounds of formula I where R 1 is hydrogen; X is prolinyl or azetidinyl-2-carbonyl; Z is a bond; R 2 is -(CH 2 ) g -COOH; g is 1, 2 or 3 (and, more particularly, g is 1); and R is as defined above for formula I; and pharmaceutically acceptable salts and solvates thereof. These compounds have unexpectedly improved oral bioavailability and increased inhibition of factor Xa compared to the corresponding compounds lacking the carboxy group. As mentioned above, the invention includes pharmaceutically acceptable salts of the compounds defined by the above formula I. A particular compound of this invention can possess one or more sufficiently basic functional groups, and accordingly react with any of a number of nontoxic inorganic and organic acids, to form a pharmaceutically acceptable salt. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic ' acids such as p_-toluenesulfonic, methanesulfonic acid, oxalic acid, rj-bromophenylsulfonic acid, .carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid. As stated above, the present invention includes solvates of the compounds of formula I and the pharmaceutically acceptable salts thereof. A particular compound of the present invention or a pharmaceutically acceptable salt thereof may form solvates with water or common organic solvents. Such solvates are included within the scope of compounds of the present invention. A compound of formula I is prepared by removing simultaneously or sequentially the protecting group (s) P of a corresponding compound of formula II » ? * H NH PY-C-X-N-CIH-(CH 2 ) 3 - —"- HP C=0 R 1 II wherein P on the guanidino group represents an amino protecting group and PY represents a radical Y which may bear an independently selected amino protecting group P for a compound of formula I in which Y includes a basic NH moiety and may bear an independently selected carboxy protecting group P for a compound of formula I in which Y includes a carboxy residue; whereafter, when a salt of the compound of formula I is required, forming the salt with a pharmaceutically acceptable acid. For example, a compound of formula II in which the amino protecting group (s) is (are) benzyloxycarbonyl and the acid protecting group, if present, is benzyl, may be converted into the hydrochloride of the corresponding compound of formula I by hydrogenolysis at atmospheric pressure over palladium on carbon catalyst in dilute ethanolic hydrochloric acid. A compound of formula II also is represented by the formula PY(C=0) -X-Arg(P) -H in which X is Pro (prolinyl) or Azt (azetidinyl-2-carbonyl) . The compounds of formula I are prepared by known methods of peptide coupling. According to one such method the acid PY-COOH, where Y has the same meanings as defined for formula I, and P is an amino protecting group, is coupled with a carboxy protected proline (or azetidine-2-carboxy ester) to form the dipeptide. For a compound of formula I in which Y includes a carboxy group, P also denotes a carboxy protecting group, which may be in addition to an amino protecting group. The carboxy protecting ester group of the proline moiety is then removed (deblocked or deesterified) and the free acid form of the dipeptide is coupled with the lactam form of arginine. The above reaction sequence is illustrated by the following Scheme 1: PY-COOH + prolme (a, deesterify. PY _ (c=0 ) -Pro-OH (b) wherein P represents an amino protecting group. The coupled Arg(P) lactam product (c) is reacted with a hydride reducing agent, preferably lithium aluminum hydride or lithium tritert-butoxyaluminohydride, in an inert solvent or mixture of solvents to reduce the lactam ring and provide the tripeptide in the arginine aldehyde form represented by the formula PY(C=0) -Pro-Arg (P)-H. The protecting groups are removed by procedures known to those skilled in the art such as hydrogenation over a metal catalyst. The lactam form of arginine is obtained by intramolecular coupling of amino protected arginine [Arg-OH] . For example, Boc-Arg (Cbz)OH represented by the formula Boc-NH-CH- (CH 2 ) 3 -NH-C ( =NH ) -NHCbz COOH where Boc is t-butyloxycarbonyl and Cbz is benzyloxycarbonyl is first converted to an active ester form, such as an active mixed anhydride, with a chloroformate ester, e.g. ethyl chloroformate to isobutyl chloroformate. The ester formation is carried out in the presence of a tertiary amine such as N-methylmorpholine. Addition of further or another tertiary amine base, such as triethylamine or diisopropylethylamine, effects the internal acylation to provide the lactam form of the di-amino protected arginine as shown below Prior to use in the coupling with the PY(C=0)-Pro-OH as shown in the above scheme, the Boc or other amine protecting group is selectively removed with trifluoroacetic acid or HCl to provide the requisite free amino group. The coupling of an PYCOOH compound with a proline ester, when Y is as defined above for formula I, is carried out by first protecting the amino group of the amino acid. Conventional amino protecting groups commonly used for temporary protection or blocking of the amino group are employed. The amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such an amino-protecting group (P) include the for yl group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, t-butoxycarbonyl 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbony1, 4-chlorobenzyloxycarbony1, 3-chlorobenzyloxycarbony1, 2-chlorobenzyloxycarbony1, 2, 4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbony1, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbony1, 4-cyanobenzyloxycarbony1, 2- (4-xenyl) isopropoxycarbonyl, 1, 1-diphenyleth-l-yloxycarbonyl, 1, 1-diphenylprop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbony1, 2- (p-toluyl)prop-2-yloxycarbony1, cyclopentanyloxycarbonyl, 1-methyleyclopentanyloxycarbony1, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4-toluylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) ethoxycarbonyl, 9-fluoroenylmethoxycarbonyl ( "FMOC" ) , 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2, 2-trichlorethoxycarbonyl, 2-ethynyl-2-propoxycarbony1, cyclopropylmethoxycarbony1, 4- (decyloxy)benzyloxycarbony1, isobornyloxycarbonyl, 1-piperidyloxycarbony1 and the like; the benzoylmethylsulfonyl group, the 2- (nitro)phenylsulfenyl group, the diphenylphosphine oxide group, and the like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Preferred amino- protecting groups are the benzyloxycarbonyl, allyloxycarbonyl, t-butoxycarbonyl, and trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. . Barton, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7. The related term "protected amino" defines an amino group substituted with an amino- protecting group discussed above. In carrying out the coupling reaction, an ester protecting group for proline is employed which is removable by conditions under which the amino protecting group remains intact. The amino protecting group of the acylating acid PYCOOH thus remains in place for protection of the amino group during the subsequent coupling with the arginine lactam compound to form (c) . The carboxy protecting ester group as used in the specification refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include Cχ-C 4 alkyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3 , 4-dimethoxybenzyl, 2, 4-dimethoxybenzyl, 2,4, 6-trimethoxybenzyl, 2, 4, 6-trimethylbenzyl, pentamethylbenzyl, 3 , 4-methylenedioxybenzyl, benzhydryl, 4, 4 ' -dimethoxybenzhydryl, 2,2 ' , 4, 4 ' -tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytri y1, 4,4' -dimethoxytrityl, 4, 4 ' , 4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2, 2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (di (n-butyl)methylsilyl) ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) -prop-l-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups discussed below) . Preferred carboxy protecting groups are Cχ-C3 alkyl and benzyl. Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y. , 1981, Chapeer 5. The compounds of formula I where X is azetidinyl (or prolinyl) are prepared in an analogous manner by known methods of peptide coupling. According to one such method, the cyclic lactam form of arginine (e) is prepared and coupled with an amino protected azetidine-2-carboxylic acid (d) as shown below to afford the dipeptide (f) where P represents an amino protecting group such as the benzyloxycarbonyl (Cbz) group, t-butoxycarbonyl (Boc) , p-toluenesulfonyl, and the like. Preferably the amino protecting group used is removable by hydrogenation or treatment with mild acid (e.g. trifluoroacetic acid) or a strong acid (e.g. HCl) . Examples of other suitable amino protecting groups are provided in "Protective Groups in Organic Synthesis", Second Edition, by T. W. Greene and P. G. M. Wuts, Chapter 7, page 309- 405 (1991) , John Wiley & Sons, Inc., publishers. The Boc, or other suitable protecting group, is removed from the azetidine ring nitrogen which is then acylated with the desired amino acid acyl group to afford the tripeptide shown below. Although illustrated and described for those compounds of the present invention where X is azetidinyl-2-carbonyl, one skilled in the art will appreciate these procedures can also be used to afford those compounds of the present invention where X is prolinyl. The coupled Arg(P) lactam product (g) is reduced with a hydride reducing agent, preferably lithium aluminum hydride or lithium tri-tert-butoxyaluminohydride in an inert solvent or mixture of solvents to reduce the lactam and provide the tripeptide in the arginine aldehyde form represented by the formula PY(C=0) -Azt-Arg(P) -H wherein P represents an amino protecting group. The protecting groups are removed by procedures known to those skilled in the art such as hydrogenation over a metal catalyst. The protecting groups may be removed from the Y-group and from the arginal group simultaneously or sequentially, ' depending upon the protecting groups utilized. Alternatively, the compounds of the invention are prepared by coupling the PYCOOH acid with carboxy protected 2-azetidine-carboxylic acid. The carboxy is deprotected as the dipeptide which is then coupled with the amino protected arginine in the lactam form prepared as described above. The tripeptide is then reduced to provide the amino protected arginal tripeptide as described above. The coupling of an PYCOOH compound is carried out by first protecting the amino group (and any other functionality which requires protection) of the amino acid. Conventional amino protecting groups commonly used for temporary protection or blocking of the amino group are employed. Examples of such protecting groups are described above. The coupling reactions described above are carried out in the cold preferably at a temperature between about -20 °C and about 15 °C. The coupling reactions are carried out in an inert organic solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, chloroform, and like common solvents or a mixture of such solvents. Generally anhydrous conditions are used when, m the coupling reaction, an active ester of the acylating acid is used. The compounds of the invention are isolated best in the form of acid addition salts. Salts of the compounds of formula I formed with acids such as those mentioned above are useful as pharmaceutically acceptable salts for administration of the antithrombotic agents and for preparation of formulations of these agents. Other acid addition salts may be prepared and used in the isolation and purification of the peptides. For example, the salts formed with the sulfonic acids such as methanesulfonic acid, n-butanesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid may be so used. The preferred method for purifying the compounds of formula I, While at the same time preparing a desired stable salt form, is that described in U.S. Patent 5,250,660. According to the method, stable sulfates or hydrochlorides are provided by preparative purification over C 8 reversed-phase chromatography in which the aqueous component comprises sulfuric acid or hydrochloric acid at pH 2.5 and acetonitrile is the organic component. The pH of the acidic eluant is adjusted to between about pH 4 and about 6 with a basic anion exchange resin in the hydroxyl form e.g. Bio-Rad AG-1X8. After adjustment of the pH, the solution of tripeptide sulfate or hydrochloride salt is lyophilized to provide the pure salt in dry powder form. In an example of the process, crude N-ethylsulfonyl-D-phenylalanyl- L-Pro- -Arg-H hydrochloride is dissolved in water and the solution is loaded on a Vydac C 8 RPHPLC 5 cm X 50 cm column. A gradient of 2-20% B (A = 0.05% HCl; B = acetonitrile) over 10 hours is used. Multiple fractions are collected and those containing product as determined by analytical RPHPLC are pooled. The pH of the pooled fractions is adjusted to pH 4.0 - 4.5 with AG-1X8 resin in hydroxide form (Bio-Rad, 3300 Ragatta Blvd., Richmond, CA 94804). The solution is filtered and the filtrate is lyophilized to provide the pure D-,L-,L-tripeptide aldehyde in the form of the hydrochloride salt. The optically active isomers of the diastereomers of the Y substituent are also considered part of this invention. Such optically active isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by standard methods affords substantially optically pure isomers of the compounds of the present invention or their precursors. Further details regarding resoluti s can be obtained in Jacques, et al., Enantiomers. Racemateε, and Resolutions, John Wiley & Sons, 1981. The compounds employed as initial starting materials in the synthesis of the compounds of this invention are well known and, to the extent not commercially available, are readily synthesized by standard procedures commonly employed by those of ordinary skill in the art. The following Examples are provided to further describe the invention and are not to be construed as limitations thereof. The analytical HPLC methods used in the examples were as follows: Method 1. Waters 600E using a Vydac Cχ 8 reversed-phase column of 0.46 cm x 10 cm. The chromatogram was monitored on an LDC at 214 nM using a gradient of A = water containing 0.1% (v:v) TFA and B = acetonitrile containing 0.1% (v:v) TFA. Method 2. Pharmacia FPLC using a Vydac Cχ 8 reversed- phase column measuring 0.46 cm x 10.0 cm. Monitoring was done on a Pharmacia UV-M at 214 nM using a gradient of either A = water containing 0.1% (v:v) TFA or B = acetonitrile containing 0.1% (v:v) TFA. The abbreviations used in this specification have the following meanings. Amino acids: Arg = arginine, Pro = proline, Phe = phenylalanine, Azt = azetidine-2-carboxylic acid Ac = acetyl Boc = t-butyloxycarbony1 (t-butoxycarbonyl) Bzl or Bn = benzyl Cbz = benzyloxycarbonyl Cha = cyclohexylalanyl Chg = cyclohexylglycinyl DCC = dicyclohexylcarbodiimide DMF = dimethylformamide DMSO = dimethylsulfoxide EtOAc = ethyl acetate Et 2 θ = diethyl ether EtOH = ethanol FAB-MS = fast atom bombardment mass spectrum FD-MS = field desorption mass spectrum HOBT = 1-hydroxybenzotriazole hydrate HPLC = High Performance Liquid Chromatography MOC = methoxycarbonyl NMI = N-methylindolyl-2-carbonyl Ph = phenyl Phg = phenylglycinyl IR = Infrared spectrum LAH = Lithium aluminum hydride NMR = Nuclear Magnetic Resonance RPHPLC = Reversed Phase High Performance Liquid Chromatography TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography Unless otherwise stated, pH adjustments and work up are with aqueous acid or base solutions. RPHPLC is carried out using 0.1% aqueous (v:v) HCl (designated "A" in the Examples) and acetonitrile (designated "B" in the Examples) . Mixtures of A and B are v:v. Where ^-H-NMR is shown, the product afforded by the reaction was characterized by proton NMR to confirm the described compound was obtained. Example 1 Preparation of N- ( l-Methylindolyl-2-carbonvD -D-ohenylalanyl-L- prolinγl-L-arσinine Aldehyde Hydrochloride A) Boc-D-Phe-Pro-OBzl Tp a solution of Boc-D-Phe-OH (89.1 g, 336 mmol), Pro- OBzl.HCl (81.2g, 336 mmol), HOBT (50 g, 370 mmol) and N,N- diisopropylethyla ine (176 mL, 1,008 mmol) at 0 °C in dichloromethane (600 mL) was added 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide»HCl (71 g, 370 mmol) . After stirring for 18 h, the mixture was diluted with diethyl ether (1 L) and washed three times with 1 N citric acid (250 mL) , once with water (250 mL) , three times with sat'd aqueous NaHCθ 3 (250 mL) and once with sat'd aqueous NaCl (250 mL) . The organic phase was dried ( a 2 Sθ 4 ), filtered, and concentrated in vacuo to yield 140 g (92.5%) of a pale yellow foam. FD-MS m/e 452 (M + ) 1H NMR B) TFA* D-Phe-Pro-OBzl To a stirring solution of Boc-D-Phe-Pro-OBzl (68 g, 150 mmol) in dichloromethane (50 mL) at 0 °C, was added anisole (20 mL) followed by trifluoroacetic acid (400 mL) . After stirring for 3 h, the solvents were evaporated in vacua and the thick oily residue was dissolved in diethyl ether (1.5 L) and refrigerated (72 h) . The white precipitate was filtered, washed with diethyl ether (300 mL) and dried to yield 59.4 g (85%) of white powder. X H NMR C) NMI-D-Phe-Pro-OBzl To a solution of N-methylindole-2-carboxylic acid (2.6 g, 14.9 mmol) in dry tetrahydrofuran (45 mL) was added pentafluorophenol (3 g, 16.5 mmol), followed by l-(3- dimethylaminopropyl) -3-ethylcarbodiimide (3.2 g, 16.5 mmol). The mixture was allowed to stir at reflux for 3.5 h and then cooled to room temperature. Then, to this mixture was added a solution of TFA* D-Phe-Pro-OBzl (7 g, 14.9 mmol) and N,N- diisopropylethyl amine (4 g, 30 mmol) in tetrahydrofuran (25 mL) . After stirring for an additional 2 h, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate (500 mL) , then washed three times with 0.1 N aqueous NaHS0 4 (250 mL) and three times with 1 N aqueous K 2 CO 3 (250 mL) . The organic phase was dried ( a 2 Sθ 4 ) , filtered, and concentrated in vacuo to give 6.5 g of amorphous solid (a mixture of the desired product, contaminated with pentafluorophenol) . 1 H NMR FD-MS m/e 509 (M + ) D) NMI-D-Phe-Pro-OH To a stirring solution of NMI-D-Phe-Pro-OBzl (8.8 g, 17.3 mmol) in p-dioxane (150 mL) was added a solution of LiOH»H 2 θ (3.6 g, 86.3 mmol) in water (75 mL) . After stirring for 4 h, the volume of the solution was reduced to about 50 mL in vacuo, and the solution was diluted with 1 N NaOH (10 mL) . The aqueous phase was washed three times with diethyl ether and then acidified to pH 2 with 5 N HCl, and then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with sat'd aqueous NaCl (200 mL) , dried (MgS0 4 ) , filtered and concentrated to give 5.4 g (75%) of white solid. X H NMR FD-MS m/e 419 (M + ) E) Boc-Arg(Cbz) -OH Boc-Arg(HCl) -OH (82.1 g, 250 mmol) was dissolved in 5 N NaOH (240 mL) in a 3 necked flask. The reaction mixture was chilled to -5 °C and the pH was maintained at 13.2-13.5 using 5 N NaOH (250 mL) while adding benzyl chloroformate (143 mL, 1.0 mol) dropwise (55 min) . The reaction mixture was stirred for an additional 1 hour at -5 °C and diluted with water (100 mL) and diethyl ether (500 mL) . The aqueous layer was separated and extracted twice with diethyl ether (500 mL) . The aqueous layer was then acidified to pH 3.0 with 3 N H 2 SO 4 (560 mL) and extracted with ethyl acetate (550 mL) . The aqueous layer was separated and extracted once with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (MgS0 4 > and concentrated in vacuo to give 66.1 g (65%) of a white solid. 1 H NMR FD-MS 408 (M + ) F) Boc-Arg(Cbz) -Lactam Boc-Arg(Cbz) -OH (66.0 g, 0.162 mol) was dissolved in tetrahydrofuran (230 mL) and cooled to -10 °C. To this solution was added N-methylmorpholine (18.7 mL, 0.17 mol) followed by isobutyl chloroformate (22.5 mL, 0.17 mol) . After stirring 5 minutes at -10 °C, triethylamine (23.5 mL, 0.17 mol) was added. After an additional 1 hour at -10 °C, the mixture was allowed to warm to room temperature and stirring continued for 1 h at room temperature. The reaction mixture was then poured into 1 L of ice-water and the resulting precipitate was filtered, washed with cold water, and dried in vacuo . The product was crystallized from ethyl acetate to give 38 g (60% ) of a white solid. 1 H NMR FD-MS 391 (MH + ) G) 2HCl-Arg(Cbz) -Lactam A solution of HCl(g) saturated ethyl acetate (7.2 L) was added dropwise over 30 minutes to a solution of Boc- Arg(Cbz)-Lactam (641 g, 1.64 mol) dissolved in dichloromethane (3 D at -10 °C. After 1 h at -10 °C the cold bath was removed and the solution was allowed to warm to room temperature over 3 h. Diethyl ether (12 L) was added and the resulting precipitate was filtered, washed with diethyl ether, and dried in vacuo to give 580 g (97%) . FD-MS 291 (MH + ) H) NMI-D-Phe-Pro-Arg(Cbz)lactam In flask 1 ,- NMI-D-Phe-Pro-OH (5.3 g, 12.5 mmol) was dissolved in dimethylformamide (60 mL) , cooled to -15 °C and N- methylmorpholine (1.3 g, 12.5 mmol) was added, followed by isobutyl chloroformate (1.7 g, 12.5 mmol). The reaction mixture was allowed to stir at -15 °C for 10 min. In flask 2, 2HC1-Arg(Cbz) -Lactam (4.5 g, 12.5 mmol) was dissolved in dimethylformamide (60 mL) , cooled to 0 °C, and N,N-diisopropylethylamine (3.2 g, 25 mmol) was added. The contents of flask 2 were added to flask 1 in one portion and then the cold bath was left unattended and the reaction mixture was allowed to slowly warm to room temperature (24 h) . Then saturated aqueous NaHC0 3 (100 mL) was added and the solvent was removed in vacuo . The residue was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed twice with 0.01 N HCl, twice with saturated NaHC0 3 , and once with brine. The organic layer was dried (Na 2 Sθ 4 ), and the filtrate was concentrated in vacuo . The residue was chromatographed over silica gel, eluting with 95:5 ethyl acetate:acetonitrile and then the product containing fractions (as judged by TLC) were combined and concentrated to give 5 g (58%) of a light yellow foam. X H NMR FD-MS m/e 691 (M + ) Analysis calculated for C 38 H 4X N7O 6: C 65.98, H 5.97, N 14.17; Found: C 66.28, H 6.11, N 13.94. I) NMI-D-Phe-Pro-Arg-H.HCl To a stirring solution of NMI-D-Phe-Pro-Arg(Cbz)lactam (4.8 g, 6.9 mmol) in tetrahydrofuran (60 mL) at -78 °C, was slowly added a solution of 1 N lithium aluminum hydride (4.8 mL, 4.8 mmol) in tetrahydrofuran. After 30 min, the reaction mixture was poured into a stirring solution of cold 1 N HCl (10 mL) and tetrahydrofuran (25 mL) . The solution was then diluted with sat'd aqueous NaCl (50 mL) and extracted twice with ethyl acetate (100 ' mL) . The combined ethyl acetate extracts were dried (MgS04), filtered and concentrated to give 5.4 g of a yellow foam. The foam was then dissolved in ethanol (75 mL) and water (25 mL) and this solution was added to a stirring solution of ethanol (75 mL) , water (25 mL) and 1 N HCl (10 mL) . To this stirring solution was then added 5% Pd on carbon (2.4 g) . H 2 was then bubbled through the solution for 1.5 h, and then the reaction was flushed with N 2 and filtered over a pad of diatomaceous earth. The ethanol was removed in vacuo at 35 °C and then the residue was redissolved in water (25 mL) . The pH of the aqueous solution was adjusted to 4.1 with Bio Rad AG-1X8 ion exchange resin (basic form) , filtered and lyophilized to give 3.4 g of a fluffy pale yellow solid. The product was then purified by RPHPLC (80/20 (A/B), 80 min; ramping up to 65/35 (A/B), 320 min; hold to 380 min, up to 0/100 (A/B) 440 min, hold to 500 min) to give 1.97 g (73%) of pure NMI-D-Phe-Pro-Arg-H«HCl hydrate. 1 H NMR FAB-MS m/e 560 (MH + ) Analysis calculated for C3oH37 7θ4«H2θ»l .2 HCl: C 57.98, H 6.52, N 15.78; Found: C 58.25, H 6.61, N 15.33. Example 2 Preparation of N- (lsoσuinolinyl-2-carbonvP -D- p henylalanyl-L- prolinyl-L-arσinine Aldehyde Hydrochloride N- (isoquinoline-2-carbonyl) -D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 1-C, 1-D, 1-H and 1-1, 2.2 g of N-(isoquinoline-2-carbonyl) -D-Phe-Pro-Arg-H»HCl was prepared using isoquinoline-2-carboxylic acid in place of N-methylindole-2-carboxylic acid. N-(Isoquinoline-2-carbonyl) -D-Phe-Pro-Arg-H»HCl was purified by RPHPLC (90/10 (A/B), 90 min; ramp to 70/30 (A/B), 390 min; ramp to 0/100 (A/B) , 450 min; hold to 510 min) . 1 H NMR FAB-MS m/e 558 (MH + ) Analysis calculated for C3oH3sN7θ4»l .1 HCl • 0.5 H2O: C 59.39, H 6.16, N 16.16, Cl 6.43; Found: C 59.62, H 5.98, N 16.11, Cl 6.38. Example 3 Preparation of N- (NicotinovD -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride N-Nicotinoyl-D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Example 1-C, 1-D, 1-H and l-I, 2.8 g of N-nicotinoyl-D-Phe- Pro-Arg-H»HCl hydrate was prepared using nicotinic acid in place of N-methylindole-2-carboxylic acid. X H NMR FAB-MS m/e 508 (MH + ) Analysis calculated for C 26 H 33 7 θ 4 «l.3 HCPH 2 O: C 54.50, H 6.39, N 17.11; Found: C 54.85, H 6.14, N 16.74. Example 4 Preparation of N- (3-PyridylacetvD -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Dihydrochloride N- ( α- ( 3 -pyridyl ) acetyl ) -D-Phe-Pro -Arg-H» 2HCl By methods substantially equivalent to those described in Example 1-C, 1-D, 1-H and l-I, 2.2 g of N- (α- (3-pyridyl) - acetyl) -D-Phe-Pro-Arg-H»HCl hydrate was prepared using α-(3- pyridyl) acetic acid in place of N-methylindole-2-carboxylic acid. Also, ' the reduction of the tripeptide arginine lactam was performe using LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. 2 H NMR FAB-MS m/e 523 (MH+) Analysis calculated for C 27 H 35 7 θ 4 »2.4 HCl*3.5 H 2 0: C 48.25, H 6.66, N 14.59, Cl 12.66; Found: C 48.60, H 6.34, N 14.32, Cl 12.86. Example 5 Preparation of N- (l-Methylindolyl-2-carbonγD -D- cvclohexylalanyl-L-prolinyl-L-arαinine Aldehyde Hydrochloride NMI-D-Cha-Pro-Arg-H.HCl By methods substantially equivalent to those described in Example 1-A, 1-B, 1-C, 1-D, 1-H and l-I, 2.14 g of NMI-D-Cha- Pro-Arg-H»HCl hydrate was prepared using Boc-D-Cha-OH in place of Boc-D-Phe-OH. Also, the tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. λ H NMR FAB-MS m/e 566 (MH + ) Analysis calculated for C 3 oH 43 N 7 θ 4 »1.2 HCl: C 59.12, H 7.31, N 16.09, Cl 6.98; Found: C 59.17, H 7.04, N 15.88, Cl 6.95. Examole 6 Preparation of N- ( lsoσuinolinvl - 2 -carbonvl. ) -D-cvclohexvlalanvl - L-prolinyl -L-arσinine Aldehyde Hydrochloride N- (isoquinolinyl-2-carbonyl) -D-Cha-Pro-Arg-H»HCl By methods substantially equivalent to those described in example 1, 3.2 g of N- (isoquinoline-2-carbonyl) -D-Cha-Pro- Arg-H»HC1 hydrate was prepared using Boc-D-Cha-OH in place of Boc-D-Phe-OH, and using isoquinoline-2-carboxylic acid in place of N-methyli.ndole-2-carboxylic acid. Also, the tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. X H NMR FAB-MS m/e 565 ( H+) Analysis calculated for C 3 rjH 4 χN 7 θ 4 »l.3 HCl•1.1 H 2 O: C 57.11, H 7.11, N 15.54, Cl 7.31; Found: C 57.04, H 6.74, N 15.36, Cl 6.93. Example 7 Preparation of N- (Methylsulfonyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride M A) MeSθ 2 -D-Phe-Pro-OBzl To a stirring solution of TFA»D-Phe-Pro-OBzl (10 g, 21.4 mmol) in tetrahydrofuran (100 mL) at 0 °C, was added N,N-diisopropylethylamine (15 mL, 85 mmol) , followed by methanesulfonyl chloride (2 mL, 24 mmol) . The cold bath was left unattended and the reaction was allowed to warm slowly to room temperature. After stirring for 24 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (200 mL) . The ethyl acetate solution was washed twice with 1 N citric acid (100 mL) , once with water (100 mL) , twice with saturated aqueous NaHC0 3 (100 mL) and once with brine (100 mL) . The organic solution was then dried with MgSθ 4 , filtered and concentrated. The resulting foam was purified by chromatography over silica gel, eluting with 1:1 hexanes/ethyl acetate. The product containing fractions as judged by TLC were combined and concentrated to give 7.2 g (79%) of an off white foam. X H NMR FD-MS m/e 430 (M + ) Analysis calculated for C 22 H 26 N 2 O 5 S: C 61.38, H 6.09, N 6.51; Found: C 61.61, H 6.01, N 6.44. B ) MeS0 2 -D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 1-D, 1-H and l-I, 310 mg of MeSθ 2 -D-Phe-Pro-Arg-H»HCl hydrate was prepared from MeSθ 2 ~D-Phe-Pro-OBzl. MeS0 2 ~D-Phe- Pro-Arg-H.HCl was purified by RPHPLC (98/2 (A/B), ramp to 60/40 (A/B! , 360 min) . 1 H NMR FAB-MS m/e 481 (MH + ) Analysis calculated for C2χH 3 N 6 θ 5 S»HCl»H 2 θ: C 47.14, H 6.59, N 15.71; Found: C 47.33, H 6.49, N 15.66. Example 8 Preparation of N- (EthylsulfonvD -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride EtS0 2 -D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Example 7, 0.5 g of EtSθ 2 -D-Phe-Pro-Arg-H»HCl hydrate was prepared using EtSθ 2 Cl in place of MeS0 2 Cl. EtSθ 2 ~D-Phe-Pro- Arg-H-HCl was purified by RPHPLC (98/2 (A/B), 30 min; ramp to 80/20 (A/B) , 270 min) . !H NMR FAB-MS m/e 495 (MH+) Analysis calculated for C22H3 N6θ5S«2 HCl* 1.5 H2O: C 44.56, H 6.37, N 14.17; Found: C 44.73, H 6.41, N 14.08. Example 9 Preparation of N- (n-Propylsulfonyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride n-Pr-S02-D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, 0.47 g of n-Pr-S0 2 -D-Phe-Pro-Arg-H»HCl hydrate was prepared using n-Pr-S0 2 Cl in place of MeS0 2 Cl. n-Pr-S0 2 -D-Phe- Pro-Arg-H«HCl was purified by RPHPLC (98/2 (A/B) , ramp to 60/40 (A/B) , 240 min) . X H NMR FAB-MS m/e 509 (MH+) Analysis calculated for C 23 H 36 N 6 θ 5 S»HCl»1.5 H 2 O: C 48.29, H 7.05, N 14.69; Found: C 48.00 H 6.71 N 14.54. Example 10 Preparation of N- (n-Butylsulfonyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride n-Bu-S02-D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Example 7, 0.94 g of n-Bu-S0 2 -D-Phe-Pro-Arg-H»HCl was prepared using n-Bu-S0 2 Cl in place of MeSθ 2 Cl. n-Bu-S0 2 ~D-Phe- Pro-Arg-H»HCl was purified by RPHPLC (98/2 (A/B) , ramp to 60/40 (A/B) , 240 min) . λ H NMR FAB-MS m/e 523 (MH+) Analysis calculated for C 24 H 38 N 6 O 5 SΗCI: C 51.56, H 7.03, N 15.03; Found: C 51.65, H 7.22, N 14.79. Example 11 Preparation of N- (IsopropylsulfonvD -D-phenylalanyl-L-prolinyl- L-arσinine Aldehyde Hydrochloride i-Pr-S0 2 -D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, 1 g of i-Pr-S0 2 -D-Phe-Pro-Arg-H»HCl hydrate was prepared using i-Pr-S0 2 Cl in place of MeS0 2 Cl. i-Pr-S0 2 ~D-Phe- Pro-Arg-H.HCl was purified by RPHPLC (98/2 (A/B) , ramp to 60/40 (A/B) , 240 min) . λ E NMR FAB-MS m/e 509 (MH+) Analysis calculated for C 23 H 3 7 6 θ 5 S»HCl»1.25 H 2 O: C 48.67, H 7.01, N 14.80; Found: C 48.83, H 6.85, N 14.91. Examole 12 Preparation of N- (Dimethylaminosulfonyl) -D-phenylalanyl-L- prolinyl-L-arσinine Aldehyde Hydrochloride Me2NSθ2-D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, 1.1 g of Me2NSθ 2 -D-Phe-Pro-Arg-H«HCl hydrate was prepared using Me 2 NSθ 2 Cl in place of MeSθ 2 Cl. Also, the tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C . Me 2 NS0 2 -D-Phe-Pro-Arg-H.HCl was purified by RPHPLC (98/2 (A/B), ramp to 60/40 (A/B), 240 min) . X H NMR FAB-MS m/e 510 (MH+) Analysis calculated for C 2 2H 35 N 7 O 5 SΗCIΗ 2 O: C 44.27, H 6.57, N 16.08, Cl 11.28; Found: C 44.55, H 5.89, N 16.05, Cl 10.82. Example 13 Preparation of N- (PhenylsulfonvD -D-phenvlalanvl-L-prolinvl-L- arσinine Aldehyde Hydrochloride P PhS0 2 -D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Example 7, 2.3 g of PhS0 2 -D-Phe-Pro-Arg-H»HCl dihydrate was prepared using PI SO 2 CI in place of MeS0 2 Cl. Also, the tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. 1 H NMR FAB-MS m/e 543 (MH+) Analysis calculated for C 2 βH 34 N 6 θ 5 S«1.2 HCD2.1 H 2 O: C 50.01, H 6.39, N 13.46, Cl 6.81; Found: C 49.88, H 6.16, N 13.10, Cl 6.63. Example 14 Preparat ion of N- ( 2 , 4 -Dif luorophenylsul fonyD -D- p henylalanyl -L- prolinyl -L-arσinine Aldehyde Hydrochloride 2, 4-F-PhS0 2 -D-Phe-Pro-Arg-H.HCl By methods substantially equivalent to those described in Example 7, 0.94 g of 2, 4-difluorophenyl-S0 2 -D-Phe-Pro-Arg- H»HC1 hydrate was prepared using 2, 4-difluorophenyl-S0 2 Cl in place of MeS0 2 Cl. Also, the tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. 2,4-F-PhS0 -D-Phe-Pro-Arg-H«HCl was purified by RPHPLC (95/5 (A/B) , ramp to 70/30 (A/B), 240 min) . 1 H NMR FAB-MS m/e 579 (MH+) Exact Mass calculated for C 26 H 33 F 2 N 6 O 5 S: 579.220122; Found: 579.218900. Analysis calculated for C 26 H 32 F 2 N 6 θsS»l.5 HCDH 2 O: C 47.95, H 5.49, N 12.90; Found: C 47.92, H 5.19 , N 12.78. Example 15 Preparation of N- (2.5-Dimethoxyphenylsulfonyl) -D-phenylalanyl-L- prolinyl-L-arσinine Aldehyde Hydrochloride 2,5- (MeO) 2 -PhS0 -D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, 5 g of 2, 5-dimethoxyphenyl-Sθ 2 -D-Phe-Pro-Arg-H»HCl hydrate was prepared using 2, 5-dimethoxyphenyl-S0 2 Cl in place of MeS0 2 Cl. Also, the tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. 1 H NMR FAB-MS m/e 603 (MH+) Analysis calculated for C 28 H 3δ N 6 θ7S»1.5 HCDH 2 O: C 49.79, H 6.19, N 12.44; Found: C 50.32, H 6.17, N 12.05. Example 16 Preparation of N- ( 3 , 5 -Dimethyl - 4 - isoxazolylsul fonyl ) -D- p ' nenylalanyl -L-prolinyl -L-arσinine Aldehyde Hydrochloride 3 , 5-Me-4-isoxazolyl-Sθ 2 -D-Phe-Pro-ArgH»HCl By methods substantially equivalent to those described in Example 7, 0.43 g of 3 , 5-dimethyl-4-isoxazolyl-Sθ 2 -D-Phe-Pro- Arg-H«HC1 hydrate was prepared using 3 , 5-dimethyl-4-isoxazolyl- SO 2 CI in pla ' ce of MeSθ 2 Cl. 3 , 5-dimethyl-4-isoxazolyl-Sθ 2 -D-Phe- Pro-Arg-H«HCl was purified by RPHPLC (98/2 (A/B) , ramp to 65/35 (A/B) , 240 min) . *H NMR FAB-MS m/e 562 (MH+) Analysis calculated for C 2 5H 35 N 7 θgS«l.4 HCDH 2 O: C 47.61, H 6.14, N 15.55; Found: C 47.97, H 5.91, N 15.22. Example 17 Preparation of N- (8-Ouinolinylsulfonvl) -D-phenvlalanvl-L- prolinyl-L-arσinine Aldehyde Dihvdrochloride 8-Quinolyl-S0 -D-Phe-Pro-Arg-H»2HCl By methods substantially equivalent to those described in Example 7, 0.050 g of 8-quinolyl-Sθ2-D-Phe-Pro-Arg-H»2HCl was prepared using 8-quinolyl-Sθ 2 Cl in place of MeS0 2 Cl. 8-Quinolyl-S0 2 -D-Phe-Pro-Arg-H«HCl was purified by RPHPLC (95/5 (A/B), ramp -to 70/30 (A/B), 240 min) . λ E NMR FAB-MS m/e 594 (MH+) Exact Mass calculated for C 29 H 36 N 7 O 5 S: 594.2499; Found: 594.2505. Analysis calculated for C 9 H 35 N 7 θ 5 S«4 HCl*2 H 2 O: C 44.91, H 5.59, N 12.64; Found: C 44.97, H 5.09, N 10.32. Examole 18 Preparation of N- ( 4 -Carboxyphenyl sul f onyl ) -D-phenylalanyl-L- prol inyl -L-arσinine Aldehyde Hydrochloride A) 4 - (Bzlθ2θ -C 6 H S0 2 C1 To a solution of p-chlorosulfonylbenzoic acid (25 g, 113 mmol) in dichloromethane (500 mL) and dimethyl formamide (150 mL) , was added oxalyl chloride (12.3 mL, 141 mmol). After stirring for 2 h, the solvents were removed in vacuo . The residue was then mixed with benzyl alcohol (95 mL) at room temperature, which caused the development of heat. After the heat dissipated, the mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried with Na 2 Sθ 4 , filtered and then concentrated to about A 4 original volume, then refrigerated over night. The next morning, the precipitate was filtered and dried to give 2.8 g (8%) of the named product. 1 H NMR FD-MS m/e 310 (M + ) B) Cbz-D-Phe-Pro-O-t-Bu By a method substantially equivalent to that described in example 1-A, 29 g (90%) of Cbz-D-Phe-Pro-O-t-Bu was prepared, using Cbz-D-Phe-OH in place of Boc-D-Phe-OH and HCl»Pro-0-t-Bu in place of HCl»Pro-OBzl. l E NMR FD-MS m/e 452 (M + ) C) D-Phe-Pro-O-t-Bu To a solution of Cbz-D-Phe-Pro-O-t-Bu (29 g, 64 mmol) in ethanol (500 mL) was added 5% Pd/C (14.5 g) . The mixture was shaken on a hydrogenation apparatus for 16 h under H 2 at 4.1 bar (60 psi) . The solution was then filtered through a pad of diato aceous earth and concentrated in vacuo to give 17.5 g (86%) of thick oil. λ E NMR FD-MS m/e 319 (MH + ) Analysis calculated for C 18 H 26 N 2 O 3 . . C 67.90, H 8.23, N 8.80; Found: C 67.66, H 8.19, N 8.67. D) 4- (Bzl0 2 C) -C 6 H S0 2 -D-Phe-Pro-0-t-Bu By a method substantially equivalent to that described in Example 7-A, 11.3 g (50%) of 4- (Bzl0 2 C) -C 6 H S0 2 -D-Phe-Pro-0- t-Bu was prepared, using 4- (BZIO 2 O -C 6 H 4 SO 2 CI in place of MeSθ 2 Cl and D-Phe-Pro-O-t-Bu in place of TFA»D-Phe-Pro-OBzl. FD-MS m/e 592 (M + ) E) 4-(Bzlθ2C)-C 6 H 4 S0 2 -D-Phe-Pro-OH 4- (BZIO 2 C) -C 6 H Sθ 2 -D-Phe-Pro-0-t-Bu (11.3 g, 19 mmol) was dissolved in trifluoroacetic acid (100 mL) and anisole (5 mL) . After stirring for 2 h, the solvent was removed by rotary evaporation. The residue was partitioned between diethyl ether (300 mL) and saturated aqueous NaHC0 3 (300 mL) . The layers were separated and the aqueous phase was acidified to pH 2 with 5 N HCl, then extracted three times with ethyl acetate (200 mL) . The combined ethyl acetate extracts were dried (MgS0 4 ) , filtered and concentrated in vacuo to give 6.5 g (64%) of a thick, light brown oil. FD-MS m/e 538 (MH + ) F) 4-(H0 2 C) -C 6 H 4 S0 2 -D-Phe-Pro-Arg-H»HC1 By methods substantially equivalent to those described in Example 1-H and l-I, 0.8 g of 4- (H0 2 C) -C 6 H Sθ 2 -D-Phe-Pro-Arg- H»HC1 hydrate was prepared. The tripeptide arginine lactam was reduced with LiAl (O-t-Bu) 3 H at -23 °C rather than LAH at -78 °C. The product was contaminated with tripeptide arginine alcohol which could not be removed by RPHPLC. λ E NMR FAB-MS m/e 587 (MH + ) Analysis calculated for C 27 H 34 N 6 θ 7 S»1.3 HCDH 2 O: C 49.73, H 5.77, N 12.89;: Found: C 49.60, H 5.76, N 12.93. Example 19 Preparation of N- (2-ThiazolvlsulfonvD -D-phenvlalanvl-L- prolinyl-L-arσinine Aldehyde Hydrochloride A) 2-Thiazolyl-S0 2 Cl To a solution of thiazole (10 g, 118 mmol) in tetrahydrofuran (600 mL) at -78 °C was slowly added a solution of -butyl lithium, 1.6 M in hexanes (73 mL, 118 mmol) . After 1 h, SO 2 (g) was bubbled through the solution until an aliquot was acidic to moist pH paper. The cold bath was then removed and the solution was allowed to warm to room temperature. The solution was then poured into hexanes (1.5 L) and the resulting precipitate was filtered and dried to give 16.7 g of a light yellow solid. The solid (10 g) was then suspended in dichloromethane (60 mL) , cooled to 0 °C, and treated with N-chlorosuccinimide (8.6 g, 64.5 mmol) . After stirring for 2 h, the solution was filtered, and the filtrate was concentrated in vacuo to give 6.2 g of a yellow oil. The oil was then dissolved in diethyl ether, filtered and concentrated in vacuo to give 4.4 g (34%) of oil. FD-MS m/e 183 (M + ! B) 2-Thiazolyl-Sθ 2 -D-Phe-Pro-Arg(Cbz) lactam By methods substantially equivalent to those described in Example 7-A, 1-D, and 1-H, 7.7 g of 2-thiazolyl-S0 2 -D-Phe-Pro- Arg(Cbz) lactam was prepared using 2-thiazolyl-S0 2 Cl in place of MeS02Cl. 1 H NMR FD-MS m/e 682 (M + ) Analysis calculated for C 31 H 35 N7O7S: C 54.61, H 5.17, N 14.38; Found: C 54.38, H 5.27, N 14.09. C) 2-Thiazolyl-Sθ 2 -D-Phe-Pro-Arg-H»HCl 2-Thiazolyl-Sθ 2 -D-Phe-Pro-Arg(Cbz) lactam was reduced using LAH by a method substantially equivalent to that described in Example l-I. The Cbz protecting group was then removed by treatment with liquid HF (10 mL) and anisole (1.0 mL) in a perfluorocarbon apparatus at 0 °C for 1 hour to yield, after evaporation of HF and precipitation with E 2 θ, 1.1 g of crude 2-thiazolyl-Sθ 2 -D-Phe-Pro-Arg-H»HF. The crude product was then purified by RPHPLC (98/2 (A/B) , 40 min; ramp to 80/20 (A/B), 280 min) to yield 280 mg of pure 2-thiazolyl-Sθ 2 ~D-Phe-Pro-Arg- H»HC1. 1 H NMR FAB-MS m/e 550 (MH + ) Analysis calculated for C 23 H 3 iN 7 θ 5 S 2 »l.1 HC1»H 2 0: C 45.45, H 5.65, N 16.13, Cl 6.42; Found: C 45.29, H 5.35, N 15.86, Cl 6.72. Example 20 Preparation of N- (EthvlsulfonvD -D-nhenvlαlvcinvl-L-prolinvl-L- arσinine Aldehyde Hydrochloride EtS0 2 -D-Phg-Pro-Arg-H*HCl By methods substantially equivalent to those described in Examples 1-A, 1-B, 7-A, 1-D, 1-H and l-I, using Boc-D-Phg-OH in place of Boc-D-Phe-OH, EtSθ 2 Cl in place of MeSθ 2 Cl, and LiAl (O-t-Bu) 3 H at -23 °C in place of LAH at -78 °C, 450 mg of EtS0 2 -D-Phg-Pro-Arg-H»HCl hydrate was prepared. EtS0 2 -D-Phg- Pro-Arg-H»HCl was purified by RPHPLC (98/2 (A/B), ramp to 60/40 (A/B) , 240 min) . X H NMR FAB-MS m/e 481 (MH + ) Analysis calculated for C2iH3 2 N6θ5S»HCl«l.5 H 2 0: C 46.36, H 6.67, N 15.45; Found: C 46.66, H 6.35, N 15.31. Example 21 Preparation of N- (EthylsulfonvD -D-cvclohexylalanyl-L-prolinyl- L-arσinine Aldehyde Hydrochloride EtSθ2-D-Cha-Pro-Arg-H"HCl By methods substantially equivalent to those described in Example 1-A, 1-B, 7-A, 1-D, 1-H and l-I, using Boc-D-Cha-OH in place of Boc-D-Phe-OH, and EtS0 2 Cl in place of MeS0 2 Cl, 1.3 g of EtS02-D-Cha-Pro-Arg-H»HCl was prepared. EtS0 2 ~D-Cha-Pro-Arg- H.HC1 was purified by RPHPLC (98/2 (A/B), ramp to 60/40 (A/B), 240 min) . 1 H NMR FAB-MS m/e 501 (MH + ) Analysis calculated for C 22 H 4 oNeθ 5 S»l.8 HCl: C 46.66, H 7.44, N 14.84; Found: C 47.05, H 7.05, N 14.65. Example 22 Preparation of N- (Ethylsulfonyl) -D-cyclohexylσlvcinyl-L- prolinyl-L-arσinine Aldehyde Hydrochloride A . HCDD-Chg-OMe HCl (g) was bubbled through a suspension of D-Chg- 0H»HC1 (37.8 g, 240 mmol) in methanol (750 mL) for about 20 min. During this time, all of the solid went into solution. The solution was allowed to stir for 48 h, and then diethyl ether (1.5 L) was added. The resulting precipitate was filtered and dried to give 32.1 g (64%) of a light brown solid. FD-MS m/e 172 (MH + ) B. EtSθ 2 -D-Chg-OMe By a method substantially equivalent to that described in Example 7-A, 14.2 g (75%) of EtSθ 2 -D-Chg-OMe was prepared from HCl»D-Chg-OMe, using EtS0 2 Cl in place of MeSθ 2 Cl. λ E NMR FD-MS m/e 263 (M + ) Analysis calculated for C 11 H 21 NO 4 S: C 50.17, H 8.04, N 5.32; Found: C 50.07, H 8.13, N 5.31. C. EtSθ 2 ~D-Chg-OH By a method substantially equivalent to that described in Example 1-D, 12.5 g (94%) of EtSθ 2 -D-Chg-OH was prepared from EtSθ 2 -D-Chg-OMe. 1 H NMR FD-MS m/e 250 (MH + ) Analysis calculated for C 10 H 19 NO 4 S: C 48.17, H 7.68, N 5.62; Found: C 48.40, H 7.93, N 5.23. D. EtS0 2 -D-Chg-Pro-Arg-H«HCl By methods substantially equivalent to those described in Examples 1-A, 1-D, 1-H and l-I, 0.25 g of EtSθ 2 ~D-Chg-Pro- Arg-H»HC1 hydrate was prepared using EtSθ 2 ~D-Chg-OH in place of Boc-D-Phe-OH. EtSθ 2 -D-Chg-Pro-Arg-H»HCl hydrate was purified by RPHPLC (98/2 (A/B) , 30 min; ramp to 75/25 (A/B), 270 min) . 1 H NMR FAB-MS m/e 487 (MH + ) Analysis calculated for C 2 iH 38 Ngθ 6 S«l.5 HCDH 2 O: C 45.09, H 7.48, N 15.02; Found: C 44.76, H 7.27, N 15.02. Examole 23 Preparation of N- (Acetvl) -D-phenvlalanvl-L-prolinvl-L-arσinine Aldehyde Hydrochloride Ac-D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, using acetyl chloride in place of MeSθ 2 Cl, 210 mg of Ac-D-Phe-Pro-Arg-H»HCl dihydrate was prepared. Ac-D-Phe-Pro- Arg-H»HC1 was purified by RPHPLC (95/5 (A/B), 80 min; ramp to 75/25 (A/B), 320 min; hold to 360 min). λ E NMR FAB-MS m/e 445 (MH + ) Analysis calculated for C 22 H 32 6 θ 4 »2 HCl*2 H 2 O: C 47.74, H 6.92, N 15.18; ■ Found: C 47.40, H 6.83, N 14.88. Examole 24 Preparation of N- (Methoxyacetyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride CH 3 OCH 2 CO-D-Phe-Pro-Arg-H»HC1 By methods substantially equivalent to those described in Example 7, using CH 3 OCH 2 (C0)C1 in place of MeSθ 2 Cl, 110 mg of CH 3 OCH 2 CO-D-Phe-Pro-ArgH»HCl was prepared. CH 3 OCH 2 CO-D-Phe-Pro- Arg-H»HC1 was purified by RPHPLC (95/5 (A/B), 80 min; ramp to 75/25 (A/B) ,.320 min; hold to 360 min) . 1 H NMR FAB-MS m/e 475 (MH + ) Analysis calculated for C 23 H 34 N 6 θ 5 »HCl: C 54.06, H 6.90, N 16.44, Cl 6.94; Found: C 54.33, H 6.69, N 16.54, Cl 6.94. Example 25 Preparation of N- (Trifluoroacetyl) -D-phenylalanyl- L-prolinyl-L- arσinine Aldehyde Hydrochloride 0 CF 3 CO-D-Phe-Pro-Arg-H»HC1 By methods substantially equivalent to those described in Example 7 , using trifluoroacetic anhydride in place of MeS0 2 Cl, 3.6 mg of CF 3 C0-D-Phe-Pro-Arg-H»HCl ethanolate was prepared. 1 H NMR FAB-MS m/e 499 (MH + ) Analysis calculated for C 2 2H 29 3 Neθ 4 «l.5 HCl«H 2 0»EtOH: C 46.62, H 6.44, N 13.59; Found: C 46.32, H 6.19, N 13.70. Eχξimple 26 Preparation of N- (Phenylacetyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride PhCH 2 CO-D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, using phenylacetyl chloride in place of MeS0 2 Cl, 3.5 g of PhCH 2 CO-D-Phe-Pro-Arg-H«HCl was prepared. X H NMR FAB-MS m/e 521 (MH + ) Analysis calculated for C 28 H 36 N 6 θ 4 »l.2 HCl^ 2 0*0.5 EtOH: C 57.53, H 7.03, N 13.88; Found: C 57.63, H 6.66, N 13.52. Example 27 Preparation of N- (CylohexanoyD -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride cyclohexyl-CO-D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Example 7 , using cyclohexanecarbonyl chloride in place of MeS0 2 Cl, 5.3 g of cyclohexyl-CO-D-Phe-Pro-Arg-H»HCl was prepared. i H NMR FAB-MS m/e 513 (MH + ) Analysis calculated for C 27 H 40 N 6 O 4 ΗCI: C 59.06, H 7.53, N 15.31; Found: C 59.00, H 7.34, N 15.07. Example 28 Preparation of N- (Acetyl) -D-cyclohexylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride Ac-D-Cha-Pro-Arg-H.HCl By methods substantially equivalent to those described in Examples 1-A, 1-B, 7-A, 1-D, 1-H and l-I, using Boc-D-Cha-OH in place of Boc-D-Phe-OH, and using acetyl chloride in place of MeSθ2Cl, 0.62 g of Ac-D-Cha-Pro-Arg-HΗCl was prepared. Ac-D- Cha-Pro-Arg τ H»HCl was purified by RPHPLC (95/5 (A/B) ramp to 70/30 (A/B) , 240 min) . l -H NMR FAB-MS m/e 451 (MH + ) Analysis calculated for C 22 H 38 N 6 θ 4 «2 HCl-0.5 H 2 O: C 49.62, H 7.76, N 15.78; Found: C 49.63, H 7.61, N 15.81. Example 29 Preparation of N- (4-Di-n-propylaminosulfonylbenzoyl) -D- phenylalanyl-L-prolinyl-L-arσinine Aldehyde Hydrochloride A. 4 - (n-Pr 2 NS0 2 ) -C 6 H C0-D-Phe-Pro-0Bzl To a solution of 4- (n-Pr 2 NS0 2 ) -C 6 H COOH (2.5 g, 8.8 mmol) in dichloromethane (100 mL) was added TFA»D-Phe-Pro-OBzl (4.1 g, 8.8 mmol), prepared substantially according to Example 1-B, N,N-diisopropylethylamine (8.0 mL, 44 mmol), and HOBT (1.2 g, 8.8 mmol), followed by 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide»HCl (1.9 g, 9.6 mmol). After stirring for 16 h, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed twice with 1 N citric acid, twice with saturated aqueous NaHC0 3 , twice with water and once with brine. The ethyl acetate was then removed in vacuo and the residue was chromatographed over silica gel, eluting with 1:1 ethyl acetate:hexanes. The product containing fractions as judged by TLC were combined and concentrated in vacuo to give 3.32 g (61%) of white foam. 1 H NMR FD-MS m/e 619 (M + ) Analysis calculated for C 34 H 41 N 3 O 6 S: C 65.89, H 6.67, N 6.78; Found: C 65.79, H 6.86, N 6.55. B . 4 - (n-Pr 2 NS0 2 ) -C 6 H CO-D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Examples 1-D, 1-H and l-I, 1.4 g of 4- (n-Pr 2 NS0 2 ) -C6H 4 CO-D- Phe-Pro-Arg-H.HCl was prepared from 4- (n-Pr2NS02) -Cg^CO-D-Phe- Pro-OBzl, using LiAl(O-t-Bu) 3 H at -23 °C in place of LAH at -78 °C. 4- (n-Pr 2 NS0 2 ) -C 6 H 4 CO-D-Phe-Pro-Arg-H»HC1 was purified by RPHPLC (95/5 (A/B) ramp to 60/40 (A/B), 240 min). λ E NMR FAB-MS m/e 670 (MH + ) Analysis calculated for C 33 H 4 7N7θ 6 S»HCl: C 56.12, H 6.85, N 13.88, Cl 5.02; Found: C 56.40, H 6.81, N 13.78, Cl 5.06. Example 30 Preparation of N- (Cvclohexylmethyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride A. cyclohexyl-CH 2 -D-Phe-Pro-0-t-Bu To a solution of Cbz-D-Phe-Pro-O-t-Bu (11.2 g, 24.7 mmol) and cyclohexanecarboxaldehyde (4.4 mL, 37.6 mmol) in ethanol (135 mL) was added 5% Pd/C (2 g) . The suspension was shaken under an atmosphere of H 2 (4.1 bar, 60 psi) overnight. The solution was then filtered and concentrated in vacuo . The residue was then dissolved in methanol, filtered through an acrodisc, and then concentrated in vacuo . The residue was then dissolved in diethyl ether, filtered and extracted three times with 1 N citric acid. The combined aqueous acid phase was adjusted to pH 10 with 2 N NaOH and extracted three times with chloroform. The combined chloroform extracts were dried over Na 2 Sθ , filtered and concentrated in vacuo to give 6.5 g (64%) of clear oil. i H-NMR FD-MS m/e 415 (MH + ) B. Cbz-N-cyclohexyl-CH 2 -D-Phe-Pro-OH To a solution of cyclohexyl-CH 2 -D-Phe-Pro-0-t-Bu (6.3 g, 15.2 mmol) in dichloromethane (100 mL) at 0 °C was added N,N-diisopropylethylamine (10.4 mL, 62.6 mmol). To this stirring solution was slowly added a solution of benzyl chloroformate (3.8 mL, 16.8 mmol) in dichloromethane (25 mL) . After 1.5 h, chloroform (100 mL) was added and the solution was washed three times with 1 N HCl and once with water. The organic phase was then dried over Na 2 ≤θ 4 , filtered and concentrated in vacuo . The residue was dissolved in a solution of anisole (5 mL) in trifluoroacetic acid (50 mL) at 0 °C and allowed to stir for 5 h. The solvents were then removed in vacuo and the residue was partitioned between diethyl ether and saturated aqueous NaHC0 3 . The diethyl ether phase was again extracted three times with saturated aqueous NaHC0 3 and three times with water. The combined aqueous extracts were acidified to pH 2 with 1 N HCl and extracted three times with chloroform. The combined chloroform extracts were dried (Na 2 Sθ 4 ) , filtered and concentrated in vacuo to give 6.3 g (84%) of a pale yellow foam. λ E NMR FD-MS m/e 493 (MH + ) Analysis calculated for C 29 H 36 2 θ 5 »0.15 CHCI 3 . C 68.58, H 7.14, N 5.48; Found: C 68.36, H 7.21, N 5.30. C . cyclohexyl-CH2-D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Examples 1-H and l-I, 3.4 g of cyclohexyl-CH2-D-Phe-Pro-Arg- H»HC1 dihydrate was prepared from Cbz-N-cyclohexyl-CH2-D-Phe- Pro-OH. FAB-MS m/e 499 (MH + ) Analysis calculated for C 27 H 42 N 6 O 3 -2.5 HCl*2 H 2 O: C 51.82, H 7.81, N 13.43; Found: C 51.94, H 7.50, N 13.25. Example 31 Preparation of N-Methyl-D-cyclohexylalanyl-L-prolinyl-L-arσinine Aldehyde Dihydrochloride A. Cbz-D-Cha-Pro-OH By a method substantially equivalent to that described in Example 18-E, 16.6 g (86%) of Cbz-D-Cha-Pro-OH was prepared from Cbz-D-Cha-Pro-O-t-Bu. FD-MS m/e 403 (MH + ) Analysis calculated for C22H30N2O5: C 65.65, H 7.51, N 6.96; Found: C 66.10, H 7.44, N 7.55. B . Cbz-N-Me-D-Cha-Pro-OH To a suspension of KH (19.3 g, 25% suspension in oil, 120 mmol) in tetrahydrofuran (100 mL) at 0 °C was slowly added (over 25 min) a solution of Cbz-D-Cha-Pro-OH (16.8 g, 41.7 mmol) 5. in tetrahydrofuran (50 mL) . During this addition period the internal temperature was monitored and maintained at less than 10 °C. To this solution was then slowly added a solution of methyl iodide (5 mL, 80 mmol) and 18-crown-6 (661 mg, 2.5 mmol), again maintaining the internal temperature below 10 °C. After 2 0 h acetic acid (10 mL) was added dropwise, followed by water (10 mL) . The solution was then poured into cold water and the pH was adjusted to 9 with 2 N NaOH. The aqueous base was washed twice with diethyl ether and then acidified to pH 2 with cone. HCl and extracted four times with chloroform. The chloroform 5 extracts were combined, dried over Na2S0 4 , filtered and concentrated ii vacuo to afford 15.7 g (90%) of a pale yellow solid. 1 H-NMR 0 FD-MS m/e 417 (MH + ) Analysis calculated for C 23 H 32 N 2 O 5 . C 66.33, H 7.74, N 6.73; Found: C 66.49, H 7.86, N 6.67. C. Me-D-Cha-Pro-Arg-H»2 HCl By methods substantially equivalent to those described 5 in Examples 1-H and l-I, using LiAl (O-t-Bu) 3H at -23 °C in place of LAH at -78 °C, 2.2 g of Me-D-Cha-Pro-Arg-H»2 HCl dihydrate was prepared from Cbz-N-Me-D-Cha-Pro-OH. λ E NMR 0 FAB-MS m/e 423 (MH + ) Analysis calculated for C 2 iH3 8 Ngθ 3 »2 HC1»2 H 2 O: C 47.45, H 8.34, N 15.81, Cl 13.34; Found: C 47.07, H 7.95, N 15.61, Cl 13.77. Example 32 Preparation of N- ( Ethylaminocarbonyl ) -D-phenylalanyl -L-prolinyl - L-arσinine Aldehyde Hydrochloride A. EtNHCO-D-Phe-Pro-OBzl To a solution of TFA»D-Phe-Pro-OBzl (10 g, 21.4 mmol) in dichloromethane (150 mL) was added N,N-diisopropylethylamine (3.73 mL, 21.4 mmol) followed by ethyl isocyanate (1.86 mL, 23.5 mmol) . After stirring for 16 h, the solution was washed three times with 1 N HCl, dried over Na 2 S0 4 , filtered and concentrated in vacuo to .give 9.7 g (107%) of white foam. FD-MS m/e 424 (MH + ) B. EtNHCO-D-Phe-Pro-Arg-H«HCl By methods substantially equivalent to those described in Example 1-D, 1-H and l-I, 1.2 g of EtNHCO-D-Phe-Pro-Arg-H«HCl hydrate was prepared from EtNHCO-D-Phe-Pro-OBzl. FAB-MS m/e 474 (MH+) Analysis calculated for 0 23 ^ 5 ^0 4 *2.1 HC1»H 2 0: C 48.62, H 6.94, N 17.26; Found: C 48.79, H 6.88, N 16.90. Example 33 Preparation of N- (Ethoxycarbonyl) -D-phenylalanyl-L-prolinyl-L- arσinine Aldehyde Hydrochloride EtOCO-D-Phe-Pro-Arg-H»HCl By methods substantially equivalent to those described in Example 7, using ethyl chloroformate in place of MeSθ 2 Cl, 2.5 g of EtOCO-D-Phe-Pro-Arg-H»HCl was prepared. λ E NMR FAB-MS m/e 475 (MH + ) Analysis calculated for C 23 H 34 N 6 θ 5 »l.7 HCl«H 2 O«0.6 EtOH: C 49.93, H 7.15, N 14.43; Found: C 50.04, H 6.76, N 14.14. Example 34 Preparation of N- (Ethoxycarbonyl) -D-cvclohexylalanyl-L-prolinyl- L-arσinine Aldehyde Hydrochloride EtOCO-D-Cha-Pro-Arg-H«HCl By methods substantially equivalent to those described in Examples 1-A, 1-B, 7-A, 1-D, 1-H and l-I, using ethyl chloroformate in place of MeSθ 2 Cl and using Boc-D-Cha-OH in 5 . place of Boc-D-Phe-OH, 0.6 g of EtOCO-D-Cha-Pro-Arg-H»HCl hydrate was prepared. EtOCO-D-Cha-Pro-Arg-H»HCl was purified by RPHPLC (95/5 (A/B) ramp to 60/40 (A/B) , 240 min) . λ E NMR 0 FAB-MS m/e 481 (MH + ) Analysis calculated for C 23 H 4 oNgθ 5 »2.8 HCDH 2 O: C 45.99, H 7.52, N 13.99; Found: C 45.86, H 7.15, N 13.70. Exam le 5 Preparation of N- (Carboxymethyl) -D-phenylalanyl-L-prolinyl-L- 5 arσinine Aldehyde Hydrochloride 0 A) Preparation of D-Phe-Pro-OBn-HCl. To a suspension of Boc-D-phenylalanine (42.4 g, 160 mmol) in methylene chloride was added proline benzyl ester hydrochloride (38.7 g, 160 mmol) , 1-hydroxybenzotriazole hydrate 5 (21.6 g, 160 mmol) and diisopropylethylamme (83 mL, 480 mmol) . Once the solution was homogeneous, 1- (3-dimethylaminopropyl) -3- ethyicarbodiimide hydrochloride (40 g, 200 mmol) was added. This mixture was allowed to stir at room temperature for 16 hrs and was then concentrated in vacuo . The residue was dissolved in ethyl acetate (500 mL) and this solution was washed twice with saturated aqueous ammonium chloride (400 mL) , twice with saturated aqueous bicarbonate (400 mL) , and twice with brine (400 mL) . The organic solution was dried (MgS0 4 ) , filtered and concentrated in vacuo to give 74.6 g (103%) of a straw colored syrup. This syrup was dissolved in p-dioxane (400 mL) and anhydrous HCl gas was bubbled through for 15 minutes and was allowed to stir for 3 hr at room temperature. The solution was concentrated in vacuo to give a yellow foam coating the sides of the flask. The foam was washed several times with diethyl ether and the solvent was decanted. The foam was dried under high vacuum to give 61 g (98%) . 1 H NMR FD-MS m/e 353 (MH + ) Analysis for C 21 H 24 N 2 O 3 -HCl: Calc: C, 64.86; H, 6.44; N, 7.21; Found: C, 65.48; H, 6.75; N, 7.94. B) Preparation t-BuOOCCH 2 -D-Phe-Pro-OBn. To a solution of D-Phe-Pro-OBn-HCl (30 g, 77 mmol) in acetonitrile (400 mL) was added diisopropylethylamme (40 L, 231 mmol) and t-butyl bromoacetate (13.7 mL, 85 mmol). This solution was brought to reflux and maintained there for 3 h. After cooling to room temp, the solution was concentrated in vacuo . The residue was dissolved in ethyl acetate (300 L) and this solution was washed twice with saturated aqueous ammonium chloride (200 mL) , twice with saturated aqueous sodium bicarbonate (200 mL) , and twice with brine (200 mL) . The organic layer was dried (MgS0 4 ) , filtered, and concentrated in vacuo to give an orange oil which was purified by silica gel chromatography eluting with a gradient of hexanes to 1:1 hexanes/ethyl acetate. Fractions containing product (as judged by TLC) were combined and concentrated to give 23.6 g (66%) of a colorless oil. λ E NMR FD-MS m/e 466 (M + ) C) Preparation of Boc-t-BuOOCCH 2 -D-Phe-Pro-OBn. To a solution of t-BuOOCCH 2 -D-Phe-Pro-OBn (22.5 g, 48 mmol) in THF (200 mL) was added diisopropylethylamme (12.5 mL, 72 mmol) and di-t-butyl dicarbonate (11.6 g, 53 mmol) . This solution was brought to gentle reflux and maintained for 16 h. Heating was discontinued, and once cool, the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (400 mL) and washed twice with 1.0 M citric acid (200 mL) , twice with saturated aqueous sodium bicarbonate (200 mL) , and twice with brine (200 mL) . The organic solution was dried (MgS0 4 ) , filtered, and concentrated in vacuo to give a yellow oil which was purified by silica gel chromatography eluting with a gradient of hexanes to 2:1 hexanes/ethyl acetate. Fractions containing product (as judged by TLC) were combined and concentrated to give 23.7 g (87%) of a colorless oil. λ E NMR FD-MS m/e 566 (M + ) D) Preparation of Boc-t-BuOOCCH 2 -D-Phe-Pro-OH. To a solution of Boc-t-BuOOCCH 2 -D-Phe-Pro-OBn (23 g, 41 mmol) in ethyl acetate (250 mL) was added 5% Pd/C catalyst (5 g) . This solution was degassed in vacuo several times. A balloon filled with hydrogen was used to introduce the gas. The mixture was allowed to stir under a hydrogen atmosphere for 2 h with stirring. The balloon was removed, diatomaceous earth was added and the slurry was filtered over a pad of diatomaceous earth. The filtrate was concentrated in vacuo to give 18.7 g (96%) of a white foam. 1 H NMR FD-MS m/e 476 (M + ) E) Preparation of HOOCCH 2 -D-Phe-Pro-ArgH-HCl. By methods substantially equivalent to those described in Example 1-H and l-I, crude Boc-t-BuOOCCH 2 -D-Phe-Pro-ArgH-HCl was prepared from Boc-t-BuOOCCH 2 -D-Phe-Pro-OH. The crude residue was re-dissolved in 5% anisole/ trifluoroacetic acid at 0 °C. This was allowed to stir cold for 1 hour at which time the solvent was removed in vacuo . The residue was taken into 0.1 N HCl and washed twice with diethyl ether. The aqueous layer was concentrated to a volume of 30 mL and the product was then purified by RPHPLC Method A to give 550 mg (22%) of pure HOOCCH 2 -D-Phe-Pro-ArgH-HCl. X H NMR FAB-MS m/e 461.3 (MH + ) Analysis for C 22 H 32 N 6 O 5 •1.5 HCl: Calc: C, 51.29; H, 6.55; N, 16.31; Found: C, 51.40; H, 6.42; N, 16.15. Example 36 Preparation of N- (CarboxymethvP -D-cvclohexylalanyl-L-prolinyl- L-arσinine Aldehyde Hydrochloride Preparation of HOCCH 2 -D-Cha-Pro-ArgH-HCl. By methods substantially equivalent to those described in example 35, 453 mg of HOCCH 2 -D-Cha-Pro-ArgH-HCl were prepared from Boc-D-Cha. X H NMR FAB-MS m/e 467.3 (MH + ) Analysis for C 22 H 38 N 6 O 5 •1.5 HCl-0.5 H 2 O: Calc: C, 49.83; H, 7.70; N, 15.85; Found: C, 49.56; H, 7.36; N, 15.82. The compounds of the invention are believed to selectively inhibit thrombin over other proteinases and nonenzyme proteins involved in blood coagulation without appreciable interference with the body's natural clot lysing ability (the compounds have a low inhibitory effect on fibrinolysis) . Further, such selectivity is believed to permit use with thrombolytic agents without substantial interference with thrombolysis and fibrinolysis. The invention in one of its aspects provides a method of inhibiting thrombin in mammals comprising administering to a mammal in need of treatment an effective (thrombin inhibiting) dose of a compound of formula I. In another of its aspects, the invention provides a method of treating a thromboembolic disorder comprising administering to a mammal in need of treatment an effective (thromboembolic disorder therapeutic and/or prophylaetic amount) dose of a compound of formula I. The invention in another of its aspects provides a method of inhibiting coagulation in mammals comprising administering to a mammal in need of treatment, an effective (coagulation inhibiting) dose of a compound of formula I. The thrombin inhibition, coagulation inhibition and thromboembolic disorder treatment contemplated by the present method includes both medical therapeutic and/or prophylactic treatment as appropriate. In a further embodiment the invention relates to treatment, in a human or animal, of conditions where inhibition of thrombin is required. The compounds of the invention are expected to be useful in animals, including man, in treatment or prophylaxis ' of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility are in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility, in treatment and/or prophylaxis, include venous thrombosis and pulmonary embolism, arterial thrombosis, such as in myocardial ischemia, myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis. Further, the compounds have expected utility in the treatment or prophylaxis of atherosclerotic diseases such as coronary arterial disease, cerebral arterial disease and peripheral arterial disease. Further, the compounds are expected to be useful together with thrombolytics in myocardial infarction. Further, the compounds have expected utility in prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass operations. Further, the compounds have expected utility in prevention of rethrombosis after microsurgery. Further, the compounds are expected to be useful in anticoagulant treatment in connection with artificial organs and cardiac valves. Further, the compounds have expected utility in anticoagulant treatment in hemodialysis and disseminated intravascular coagulation. A further expected utility is in rinsing of catheters and mechanical devices used in patients in vivo , and as an anticoagulant for preservation of blood, plasma and other blood products in vi tro . Still further, the compounds have expected utility in other disorders (diseases) where blood coagulation could be a fundamental contributing process or a source of secondary pathology, such as cancer, including metastasis, inflammatory diseases, including arthritis, and diabetes. The anti-coagulant compound is administered orally or parenterally e.g. by intravenous infusion (iv) , intramuscular injection (im) or subcutaneously (sc) . The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the rate of administration, the route of administration, and the condition being treated. A typical daily dose for each of the above utilities is between about 0.01 mg/kg and about 1000 mg/kg. The dose regimen may vary e.g. for prophylactic use a single daily dose may be administered or multiple doses such as 3 or 5 times daily may be appropriate. In critical care situations a compound of the invention is administered by iv infusion at a rate between about 0.01 mg/kg/h and about 20 mg/kg/h and preferably between about 0.1 mg/kg/h and about 5 mg/kg/h. The method of this invention also is practiced in conjunction with a clot lysing agent e.g. tissue plasminogen activator (t-PA) , modified t-PA, streptokinase or urokinase. In cases when clot formation has occurred and an artery or vein is blocked, either partially or totally, a clot lysing agent is usually employed. A compound of the invention can be administered prior to or along with the lysing agent or subsequent to its use and preferably further is administered along with aspirin to prevent the reoccurrence of clot formation. The method of this invention is also practiced in conjunction with a platelet glycoprotein receptor (Ilb/IIIa) antagonist, that inhibits platelet aggregation. A compound of the invention can be administered prior to or along with the Ilb/IIIa antagonist or subsequent to its use to prevent the occurrence or reoccurrence of clot formation. The method of this invention is also practiced in conjunction with aspirin. A compound of the invention can be administered prior to or along with aspirin or subsequent to its use to prevent the occurrence or reoccurrence of clot formation. As stated above, preferably a compound of the present invention is administered in conjunction with a clot lysing agent and aspirin. This invention also provides pharmaceutical formulations for use in the above described therapeutic method. Pharmaceutical formulations of the invention comprise an effective thrombin inhibiting amount of a compound of formula I in association with a pharmaceutically acceptable carrier, excipient or diluent. For oral administration the antithrombotic compound is formulated in gelatin capsules or tablets which may contain excipients such as binders, lubricants, disintegration agents and the like. For parenteral administration the antithrombotic is formulated in a pharmaceutically acceptable diluent e.g. physiological saline (0.9%) , 5% dextrose, Ringer's solution and the like. The compound of the present invention can be formulated in unit dosage formulations comprising a dose between about 0.1 mg and about 1000 mg. Preferably the compound is in the form of a pharmaceutically acceptable salt such as for example the sulfate salt, acetate salt or a phosphate salt. An example of a unit dosage formulation comprises 5 mg of a compound of the present invention as a pharmaceutically acceptable salt in a 10 ml sterile glass ampoule. Another example of a unit dosage formulation comprises about 10 mg of a compound of the present invention as a pharmaceutically acceptable salt in 20 ml of isotonic saline contained in a sterile ampoule. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds of the present invention are preferably formulated prior to administration. Another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutically acceptable carrier, diluent or excipient therefor. The active ingredient in such formulations comprises from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. The compositions of this invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium) , soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient, " of course, means a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof. Formulation 1 Hard gelatin capsules are prepared using the following ingredients : Quantity (mσ/capsule) Active ingredient 250 Starch, dried 200 Magnesium stearate _U2 Total 460 mg Formulation 2 A tablet is prepared using the ingredients below: Quantity (mσ/caosule) Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg Formulation 3 An aerosol solution is prepared containing the following components: Weiσht Active ingredient 0. .25 Ethanol 25, .75 Propellant 22 (Chlorodifluoromethanel 70. ,00 Total 100. .00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 °C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. Formulation 4 Tablets, each containing 60 mg of active ingredient, are made as follows: Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium carboxymethyl starch 4 . . 5 mg Magnesium stearate 0 . . 5 mg Talc 1 mσ Total ' 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinyl- pyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50 °C and passed through a No. 18 mesh U.S. Sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formuiation 5 Capsules, each containing 80 mg of active ingredient, are made as follows: Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mq Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities. Formulation 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: Active ingredient 225 mg Saturated fatty acid glycerides 2,000 mσ Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. Formulation 7 Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume. Formulation 8 An intravenous formulation may be prepared as follows: Active ingredient 100 mg Isotonic saline 1,000 ml The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute. The compounds provided by the invention (formula I) selectively inhibit the action of thrombin in mammals. The ability of the compounds of the present invention to be an effective thrombin inhibitor is evaluated in one or more of the following assays. The inhibition of thrombin is demonstrated by in vitro inhibition of the amidase activity of thrombin as measured in an assay in which thrombin hydrolyzes the chromogenic substrate, N-benzoyl-L-phenylalanyl-L-valyl-L-arginyl-p-nitroanilide, N-benzoyl-Phe-Val-Arg-p-nitroanilide. The assay is carried out by mixing 50 μl buffer (0.03M Tris, 0.15M NaCl, pH 7.4), 25 μl of human thrombin solution (purified human thrombin Enzyme Research Laboratories, South Bend, Indiana) at 8 NIH units/ml and 25 μl of test compound in a solvent (50% aqueous methanol (v:v) ) . Then 150 μl of an aqueous solution of the chromogenic substrate (at 0.25 mg/ml) are added and the rates of hydrolysis of the substrate are measured by monitoring the reactions at 405 nm for the release of p-nitroaniline. Standard curves are constructed by plotting free thrombin concentration against hydrolysis rate. The hydrolysis rates observed with test compounds are then converted to "free thrombin" values in the respective assays by use of the standard curves. The bound thrombin (bound to test compound) is calculated by subtracting the amount of free thrombin observed in each assay from the known initial amount of thrombin used in the assay. The amount of free inhibitor in each assay is calculated by subtracting the number of moles of bound thrombin from the number of moles of added inhibitor (test compound) . The Kass value is the hypothetical equilibrium constant for the reaction between thrombin and the test compound (I) . Thrombin + I *~Thrombin-I Kass= [Thrombin I] [(Thrombin) x (I)] Kass is calculated for a range of concentrations of test compounds and the mean value is reported in units of liter per mole. By substantially following the procedures described above for human thrombin, and using other human blood coagulation system serine proteases, and using fibrinolytic system serine proteases, with the appropriate chromogenic substrate, identified below, selectivity of the compounds of the present invention with respect to the coagulation factor serine proteases and to the fibrinolytic serine proteases are evaluated as well as their substantial lack of interference with human plasma clot fibrinolysis. Human factors X, Xa, IXa, XIa, and Xlla are purchased from Enzyme Research Laboratories, South Bend, Indiana; human urokinase from Leo Pharmaceuticals, Denmark; and recombinant activated Protein C (aPC) is prepared at Eli Lilly and Co. substantially according to U.S. Patent 4,981,952. Chromogenic substrates: N-Benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide (for factor Xa) ; N-Cbz-D-Arg-Gly-Arg-p- nitroanilide (for factor IXa assay as the factor Xa substrate) pyroglutamyl-Pro-Arg-p- nitroanilide (for factor XIa and for aPC) ; H-D-Pro-Phe-Arg-p- nitroanilide (for factor Xlla) ; and pyroglutamyl-Gly-Arg-p- nitroanilide (for urokinase) ; are purchased from KabiVitrum, Stockholm, Sweden, or from Midwest Biotech, Fishers, Indiana. Bovine trypsin is purchased from Worthington Biochemicals, Freehold, New Jersey, and human plasma kallikrein from Kabi Vitrum, Stockholm, Sweden. N-Benzoyl-Phe-Val-Arg-p- nitroanilide, the substrate for human thrombin and for trypsin, is synthesized according to procedures described above for the compounds of the present invention, using known methods of peptide coupling from commercially available reactantε, or was purchased from Midwest Biotech, Fishers, Indiana. Human plasmin is purchased from Boehringer Mannheim, Indianapolis, Indiana; nt-PA is purchased as single chain activity reference from American Diagnostics, Greenwich, Connecticut; modified-t-PA6 (mt-PA6) is prepared at Eli Lilly and Company by procedure known in the art. (See, Burck, et al., J. Biol. Chem.. 265. 5120-5177 (1990) .) Plasmin chromogenic substrate H-D-Val-Leu-Lys-p-nitroanilide and tissue plasminegen activator (t-PA) substrate H-D-Ile-Pro-Arg-p-nitroanilide are purchased from Kabi Vitrum, Stockholm, Sweden. In the chromogenic substrates described above the three-letter symbols lie, Glu, Gly, Pro, Arg, Phe, Val, Leu and Lys are used to indicate the corresponding amino acid group isoleucine, glutamic acid, glycine, proline, arginine, phenylalanine, valine, leucine and lysine, respectively. Table 1 which follows lists the Kass values obtained with the indicated compound represented by the formula 1. Table 1 Serine Protease Inhibition Enzyme Kass (L/mol x 10 6 ) Human Example Thrombin Xa Trvosin Plasmin 1 850. 0.51 120. 7.9 2 110. 0.16 22. 0.55 3 58. 0.080 12. 0.41 4 13. 0.067 5.2 0.27 5 320. 4.6 7.9 25. 6 200. 0.83 2.5 2.5 7 690. 2.4 220. 17. 8 450. 2.6 260. 31. 9 1,700. 13. 480. 29. 10 470. 8.3 230. 27. 11 460. 6.0 260. 25. 12 300. 3.9 160. 21. 13 270. 3.6 180. 19. 14 230. 11. 160. 25. 15 200. 8.8 150. 9.5 16 260. 11. 200. 18. 17 N.T. N.T. N.T. N.T. 18 70. 2.0 43. 7.0 19 68. 2.8 52. 3.4 20 510. 45. 160. 14. 21 550. 20. 200. 45. 22 260. 24. 260. 13. 23 3.4 0.066 14. 0.28 24 33. 0.29 57. 3.8 25 26. 0.033 15. 0.31 26 29. 0.10 14. 0.54 27 20. 0.064 5.9 0.24 28 26. 1.1 12. 0.61 29 43. 0.32 15. 0.86 30 480. 0.11 69. 0.49 31 590. 5.6 160. 7.7 32 25. 0.21 60. 2.0 33 170. 2.3 240. ■ 16. 34 360. 8.1 140. 26. 35 695. 3.3 194. 14.2 36 556. 40.5 334. 14.2 N.T. = Not Tested. Thrombin inhibitors preferably should spare fibrinolysis induced by urokinase, tissue plasminogen activator (t-PA) and steptokinase. This would be important to the therapeutic use of such agents as an adjunct to streptokinase, t-PA or urokinase thrombolytic therapy and to the use of such agents as an endogenous fibrinolysis-sparing (with respect to t- PA and urokinase) antithrombotic agent. In addition to the lack of interference with the amidase activity of the fibrinolytic proteases, such fibrinolytic system sparing can be studied by the use of human plasma clots, and their lysis by the respective fibrinolytic plasminogen activators. Materials Dog plasma is obtained from conscious mixed-breed hounds (either sex Hazelton-LRE, Kalamazoo, Michigan, U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from fresh dog plasma and human fibrinogen is prepared from in-date ACD human blood at the fraction 1-2 according to previous procedures and specifications. Smith, Biochem. J.. 185. 1-11 (1980) ; and Smith, et al., Biochemistry. 11. 2958-2967, (1972) . Human fibrinogen (98 percent pure/plasmin free) is from American Diagnostics, Greenwich, Connecticut. Radiolabeling of fibrinogen 1-2 preparations is performed as previously reported. Smith, et al., Biochemistry. 11. 2958-2967, (1972) . Urokinase is purchased form Leo Pharmaceuticals, Denmark, as 2200 Plough units/vial. Streptokinase is purchased from Hoechst-Rousεel Pharmaceuticals, Somerville, New Jersey. Methods - Effects on Lvsis of Human Plasma Clots by t-PA Human plasma clots are formed in micro test tubes by adding 50 ul thrombin (73 NIH unit/ml) to 100 ul human plasma which contained 0.0229 uCi 125-iodine labeled fibrinogen. Clot lysis is studied by overlaying the clots with 50 ul of urokinase or streptokinase (50, 100, or 1000 unit/ml) and incubating for 20 hours at room temperature. After incubation the tubes are centrifuged in a Beckman Microfuge. 25 ul of supernate is added into 1.0 ml volume of 0.03 M tris/0.15 M NaCl buffer for gamma counting. Counting controls 100 percent lysis are obtained by omitting thrombin (and substituting buffer) . The thrombin inhibitors are evaluated for possible interference with fibrinolysis by including the compounds in the overlay solutions at 1, 5, and 10 ug/ml concentrations. Rough approximations of IC50 values are estimated by linear extrapolations from data points to a value which would represent 50 percent of lysis for that particular concentration of fibrinolytic agent. " Table 2 Serine Protease Inhibition Enzyme Kass (L/mol x 10 6 ) Example No. t-PA 1 31. 2 0.32 3 0.17 4 0.22 5 1.1 6 0.088 7 13. 8 2.9 9 2.8 10 0.83 11 3.5 12 (100% inhib. at 13 μg/mL) 13 2.3 14 2.4 15 1.5 16 2.7 17 N.T. 18 1.1 19 0.31 20 0.34 21 0.73 22 0.11 23 0.11 24 0.30 25 0.17 26 0.37 27 0.26 28 0.035 29 0.62 30 0.046 31 0.037 32 0.54 33 2.5 34 0.75 35 0.202 36 0.167 N.T. = Not Tested Anticoagulant Activity Materials Dog plasma and rat plasma are obtained from conscious mixed- breed hounds (either sex, Hazelton-LRE, Kalamazoo, Michigan, U.S.A.) or from anesthetized male Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Indianapolis, Indiana, U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from in-date ACD human blood as the fraction 1-2 according to previous procedures and specifications. Smith, Biochem. J. , 185. 1-11 (1980); and Smith, et al., Biochemistry, H, 2958-2967 (1972) . Human fibrinogen is also purchased as 98 percent pure/plasmin free from American Diagnostics, Greenwich, Connecticut. Coagulation reagents ACTIN, Thromboplastin, and Human plasma are from Baxter Healthcare Corp., Dade Division, Miami, Florida. Bovine thrombin from Parke-Davis (Ann Arbor, Michigan) is used for coagulation assays in plasma. Methods Anticoaαulation Determinations Coagulation assay procedures are as previously described. Smith, et al., Thrombosis Research. 50. 163-174 (1988). A CoAScreener coagulation instrument (American LABor, Inc.) is used for all coagulation assay measurements. The prothrombin time (PT) is measured by adding 0.05 ml saline and 0.05 ml Thromboplastin-C reagent to 0.05 ml test plasma. The activated partial thromboplastin time (APTT) is measured by incubation of 0.05 ml test plasma with 0.05 ml Actin reagent for 120 seconds followed by 0.05 ml CaCl2 (0.02 M) . The thrombin time (TT) is measured by adding 0.05 ml saline and 0.05 ml thrombin (10 NIH units/ml) to 0.05 ml test plasma. The compounds of formula I are added to human or animal plasma over a wide range of concentrations to determine prolongation effects on the APTT, PT, and TT assays. Linear extrapolations are performed to estimate the concentrations required to double the clotting time for each assay. Table 3 Anticoaαulation Evaluations In Human Plasma 2 x Clotting time (ng/ML) Example No. TT APTT PT 1 43 440 870 3 47 1, ,300 1,700 4 150 2 , ,300 3,400 5 110 1, ,000 2,500 6 97 1, ,400 2,700 7 21 330 530 8 9 260 660 II- 9 6 220 510 10 18 300 700 11 13 270 510 12 46 360 480 13 14 450 930 14 21 350 940 15 92 550 2,000 16 33 430 1,300 17 N.T. N.T. N.T. 18 120 1,200 3,000 19 66 810 2,900 20 34 250 880 21 25 260 730 22 46 330 1,100 23 140 2,700 4,100 24 38 440 1,200 25 59 1,300 1,800 26 64 1,100 2,000 27 63 1,300 1,800 28 92 1,900 3,500 29 150 3,500 4,800 30 16 860 1,200 31 18 420 720 32 63 1,100 1,700 33 22 390 2,000 34 48 410 890 35 14 723 1129 36 9 284 695 N.T. = Not Tested Animals Male Sprague Dawley rats (350-425 gm, Harlan Sprague Dawley Inc., Indianapolis, IN) are anesthetized with xylazine (20 mg/kg, s.c.) and ketamine (120 mg/kg, s.c.) and maintained on a heated water blanket (37 °C) . The jugular vein(s) is cannulated to allow for infusions. Arterio-Venous shunt model The left jugular vein and right carotid artery are cannulated with 20 cm lengths of polyethylene PE 60 tubing. A 6 cm center section of larger tubing (PE 190) with a cotton thread (5 cm) in the lumen, is friction fitted between the longer sections to complete the arterio-venous shunt circuit. Blood is circulated through the shunt for 15 min before the thread is carefully removed and weighed. The weight of a wet thread is subtracted from the total weight of the thread and thrombus (see J.R. Smith, Br J Pharmacol. 22:29,1982) . FeCD model of arterial iniurv The carotid arteries are isolated via a midline ventral cervical incision. A thermocouple is placed under each artery and vessel temperature is recorded continuously on a strip chart recorder. A cuff of tubing (0.058 ID x 0.077 OD x 4 mm, Baxter Med. Grade Silicone) , cut longitudinally, is placed around each carotid directly above the thermocouple. FeCl 3 hexahydrate is dissolved in water and' the concentration (20%) is expressed in terms of the actual weight of FeCl 3 only. To injure the artery and induce thrombosis, 2.85 ul is pipetted into the cuff to bathe the artery above the thermocouple probe. Arterial occlusion is indicated by a rapid drop in temperature. The time to occlusion is reported in minutes and represents the elapsed time between application of FeCD and the rapid drop in vessel temperature (see K.D. Kurz, Thromb. Res.. ££:269, 1990) . Spontaneous thrombolysis model In vi tro data suggests that peptide thrombin inhibitors inhibit thrombin and at higher concentrations may inhibit other serine proteases, such as plasmin and tissue plasminogen activator. To assess if the compounds inhibit fibrinolysis in vivo, the rate of spontaneous thrombolysis is determined by implanting a labeled whole blood clot into the pulmonary circulation. Rat blood (1 ml) is mixed rapidly with bovine thrombin (4 IU, Parke Davis) and 125 I human fibrogen (5 μCi, ICN) , immediately drawn into silastic tubing and incubated at 37 °C for 1 hr. The aged thrombus is expelled from the tubing, cut into 1 cm segments, washed 3X in normal saline and each segment is counted in a gamma counter. A segment with known counts is aspirated into a catheter that is subsequently implanted into the jugular vein. The catheter tip is advanced to the vicinity of the right atrium and the clot is expelled to float into the pulmonary circulation. One hour after implant, the heart and lungs are harvested and counted separately. Thrombolysis is expressed as a percentage where: %Thrombolysis = (injected com - lunα com) x 100 injected cpm The fibrinolytic dissolution of the implanted clot occurs time- dependently (see J.P. Clozel, Cardiovas. Pharmacol.. 12 :520. 1988) . Coagulation parameters Plasma thrombin time (TT) and activated partial thromboplastin time (APTT) are measured with a fibrometer. Blood is sampled from a jugular catheter and collected in syringe containing sodium citrate (3.8%, 1 part to 9 parts blood) . To measure TT, rat plasma (0.1 ml) is mixed with saline (0.1 ml) and bovine thrombin (0.1 ml, 30 U/ml in TRIS buffer; Parke Davis) at 37 °C. For APTT, plasma (0.1 ml) and APTT solution (0.1 ml, Organon Teknika) are incubated for 5 minutes (37 °C) and CaCl (0.01 ml, 0.025M) is added to start coagulation. Assays are done in duplicate and averaged. Index of Bioavailabilitv A measure of bioactivity, plasma thrombin time (TT) , serves as a substitute for the assay of parent compound on the assumption that increments in TT result from thrombin inhibition by parent only. The time course of the effect of the thrombin inhibitor upon TT is determined after i.v bolus administration to anesthetized rats and after oral treatment of fasted conscious rats. Due to limitations of blood volume and the number of points required to determine the time course from time of treatment to the time when the response returns to pretreatment values, two populations of rats are used. Each sample population represents alternating sequential time points. The average TT over the time course is used to calculate area under the curve (AUC) . The index of bioavailability is calculated by the formula shown below and is expressed as percent relative activity. The area under the curve (AUC) of the plasma TT time course is determined and adjusted for the dose. This index of bioavailability is termed "% Relative Activity" and is calculated as ^Relative Activity = AϋC po χ Dose iv χι 0 0 AϋC iv Dose po Compounds Compound solutions are prepared fresh daily in normal saline and are injected as a bolus or are infused starting 15 min before and continuing throughout the experimental perturbation which is 15 minutes in the arteriovenous shunt model and 60 minutes in the FeCD model of arterial injury and in the spontaneous thrombolysis model. Bolus injection volume is 1 ml/kg for i.v., and 5 ml/kg for p.o. and infusion volume is 3 ml/hr. Statistics Results are expressed as means +/- SEM. One-way analysis of variance is used to detect statistically significant differences and then Dunnett's test is applied to determine which means are different. Significance level for rejection of the null hypothesis of equal means is P<0.05. Table 4 Index of Bioavailab:ilitv Example Relat :ive Activity 1 2 2 ■ 1 3 3 4 N.T. 5 N.T. 6 N.T. 7 27 8 31 9 14 10 18 11 10 12 26 13 3 14 6 15 N.T. • 16 N.T. 17 N.T. 18 13 19 N.T. 20 N.T. 21 19 22 N.T. 23 N.T. 24 N.T. 25 N.T. 26 N.T. 27 N.T. 28 9 29 N.T. 30 1 31 13 32 N.T. 33 14 34 N.T. 35 50 36 30 N.T. = Not Tested. Animals Male dogs (Beagles; 18 months - 2 years; 12-13 kg, Marshall Farms, North Rose, New York 14516) are fasted overnight and fed Purina certified Prescription Diet (Purina Mills, St. Louis, Missouri) 240 minutes after dosing. Water is available ad libiπum. The room temperature is maintained between 66-74 °F; 45-50% relative humidity; and lighted from 0600-1800 hours. Pharmacokinetic model. Test compound is formulated immediately prior to dosing by dissolving in sterile 0.9% saline to a 5 mg/ml preparation. Dogs are given a single 2 mg/kg dose of test compound by oral gavage. Blood samples (4.5 ml) are taken from the cephalic vein at 0.25, 0.5, 0.75, 1,2,3,4 and 6 hours after dosing. Samples are collected in citrated Vacutainer tubes and kept on ice prior to reduction to plasma by centrifugation. Plasma samples are derivatized with dinitrophenylhydrazine and analyzed by HPLC (Zorbax SB-C8 column) eluting with methanol/500 mM sodium acetate adjusted to pH7 with phosphoric acid (60:40, v/v) . Plasma concentration of test compound is recorded and used to calculate the pharmacokinetic parameters: elimination rate constant, Ke; total clearance, Clt; volume of distribution, Vp; time of maximum plasma test compound concentration, Tmax; maximum concentration of test compound at Tmax, Cmax; plasma half-life, to.5; area under the curve, A.U.C.; and fraction of test compound absorbed, F. Canine Model of Coronary Artery Thrombosis Surgical preparation and instrumentation of the dogs are as described in Jackson, et al., Circulation, 82, 930-940 (1990) . Mixed-breed hounds (aged 6-7 months, either sex, Hazelton-LRE, Kalamazoo, MI, U.S.A.) are anesthetized with sodium pentobarbital (30 mg/kg intravenously, i.v.), intubated, and ventilated with room air. Tidal volume and respiratory rates are adjusted to maintain blood PO 2 , PCO 2 , and pH within normal limits. Subdermal needle electrodes are inserted for the recording of a lead II ECG. The left jugular vein and common carotid artery are isolated through a left mediolateral neck incision. Arterial blood pressure (ABP) is measured continuously with a precalibrated Millar transducer (model (MPC-500, Millar Instruments, Houston, TX, U.S.A.) inserted into the carotid artery. The jugular vein is cannulated for blood sampling during the experiment. In addition, the femoral veins of both hindlegs are cannulated for administration of test compound. A left thoracotomy is performed at the fifth intercostal space, and the heart is suspended in a pericardial cradle. A 1- to 2- cm segment of the left circumflex coronary artery (LCX) is isolated proximal to the first major diagonal ventricular branch. A 26-gauge needle-tipped wire anodal electrode (Teflon- coated, 30-gauge silverplated copper wire) 3-4 mm long is inserted into the LCX and placed in contact with the intimal surface of the artery (confirmed at the end of the experiment) . The stimulating circuit is completed by placing the cathode in a subcutaneous (s.c.) site. An adjustable plastic occluder is placed around the LCX, over the region of the electrode. A precalibrated electromagnetic flow probe (Carolina Medical Electronics, King, NC, U.S.A.) is placed around the LCX proximal to the anode for measurement of coronary blood flow (CBF) . The occluder is adjusted to produce a 40-50% inhibition of the hyperemic blood flow response observed after 10-s mechanical occlusion of the LCX. All hemodynamic and ECG measurements are recorded and analyzed with a data acquisition system (model M3000, Modular Instruments, Malvern, PA. U.S.A.) . Thrombus Formation and Compound Administration Reαimens Electrolytic injury of the inti a of the LCX is produced by applying 100-μA direct current (DC) to the anode. The current is maintained for 60 min and then discontinued whether the vessel has occluded or not. Thrombus formation proceeds spontaneously until the LCX is totally occluded (determined as zero CBF and an increase in the S-T segment) . Compound administration is started after the occluding thrombus is allowed to age for 1 h. A 2-h infusion of the compounds of the present invention at doses of 0.5 and 1 mg/kg/h is begun simultaneously with an infusion of thrombotic agent (e.g. tissue plasminogen activator, streptokinase, APSAC) . Reperfusion is followed for 3h after administration of test compound. Reocclusion of coronary arteries after successful thrombolysis is defined as zero CBF which persisted for > 30 min. Hematoloαv and template bleeding time determinations Whole blood cell counts, hemoglobin, and hematocrit values are determined on a 40-μl sample of citrated (3.8%) blood (1 part citrate:9 parts blood)' with a hematology analyzer (Cell-Dyn 900, Sequoia-Turner. Mount View, CA, U.S.A.). Gingival template bleeding times are determined with a Simplate II bleeding time device (Organon Teknika Durham, N.C., U.S.A.). The device is used to make 2 horizontal incisions in the gingiva of either the upper or lower left jaw of the dog. Each incision is 3 mm wide x 2 mm deep. The incisions are made, and a stopwatch is used to determine how long bleeding occurs. A cotton swab is used to soak up the blood as it oozes from the incision. Template bleeding time is the time from incision to stoppage of bleeding. Bleeding times are taken just before administration of test compound (0 min) , 60 min into infusion, at conclusion of administration of the test compound (120 min), and at the end of the experiment. All data are analyzed by one-way analysis of variance (ANOVA) followed by Student-Neuman-Kuels post hoc t test to determine the level of significance. Repeated-measures ANOVA are used to determine significant differences between time points during the experiments. Values are determined to be statistically different at least at the level of p<0.05. All values are mean ± SEM. All studies are conducted in accordance with the guiding principles of the American Physiological Society. Further details regarding the procedures are described in Jackson, et al., J. Cardiovasc. Pharmacol.. 21, 587-599 (1993) .

Claims: AMENDED CLAIMS [received by the International Bureau on 24 Ouly 1995 (24.07.95) ; original claim 1 amended; remaining claims unchanged ( 1 page)] nitrogen; or a 9 or 10 membered unsubstituted or substituted fused bicyclic heterocyclic ring ; g is 1 , 2 or 3 ; and n is 1 or 2 ; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of said compound or salt thereof; provided that when R is benzyl, phenyl, cyclopentyl o cyclohexyl and Z is -C(C=0)- or a bond, R 2 is other than C -C 6 alkyl, Cχ-C2 perfluoroalkyl, Cχ-Cg alkoxy or phenyl. 2. A compound or salt or solvate thereof as claimed in Claim 1 where R 2 is Cχ-C6 alkyl, Cχ-C2 perfluoroalkyl, Cχ-Cg alkoxy, (C -C 4 alkoxy)C -C 4 alkyl, cyclopentyl, cyclohexyl, (C5-C6 cycloalkyl)CH 2 -, amino, mono (Cχ-C.4)alkylamino, di (Cχ-C 4 ) alkylamino, unsubstituted or substituted aryl, where aryl is phenyl or naphthyl, unsubstituted or substituted benzyl, a 5 or 6 membered unsubstituted or substituted heterocyclic ring, having one or two heteroatoms, one of which is nitrogen and the second heteroatom is selected from sulfur, oxygen and nitrogen, or methylene substituted with a 5 or 6 membered unsubstituted or substituted heterocyclic ring having one nitrogen atom or two hetero atoms one of which is nitrogen and the second heteroatom is selected from sulfur, oxygen and nitrogen; or a 9 or 10 membered unsubstituted or substituted fused bicyclic heterocyclic ring; and n is 1 or 2. 3. A compound or salt or solvate therof as claimed in Claim 1 or 2 where alkyl by itself or as part of another substituent is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl or sec-butyl; halo is chloro, fluoro, bromo or iodo; perfluoroalkyl is trifluoromethyl or pentafluoroethyl 97 STATEMENT UNDER ARTICLE 19 The International Search Report for the captioned application was mailed 22 May 1995. In accordance with Article 19 of the Patent Cooperation Treaty, applicant submits herewith a replacement sheet for page 91 of the International Application as originally filed. The proviso of original claim 1, on page 91, lines 8-10 is amended to include phenyl, and thus exclude phenyl as an R 2 group substituent when R is benzyl, phenyl, cyclopentyl or cyclohexyl and Z is -C(C=0) - or a bond. Applicant notes that the proviso of claim 1 at page 91, lines 8-10, as amended, removes the species N-benzoyl-D-phenylalanyl-L-prolinyl-L-arginine aldehyde from the scope of claim 1. Accordingly the claimed invention does not include the compounds

Inventors: SCHACHT AARON LEIGH, SHUMAN ROBERT THEODORE, SMITH GERALD FLOYD, WIKEL JAMES HOWARD, WILEY MICHAEL ROBERT, SCHACHT, AARON, LEIGH, SHUMAN, ROBERT, THEODORE, SMITH, GERALD, FLOYD, WIKEL, JAMES, HOWARD, WILEY, MICHAEL, ROBERT
Applicants: LILLY CO ELI, ELI LILLY AND COMPANY
Application year: 1995
Main classification: C07K5
IPC codes: A61K31, A61K38, A61P7, C07D207, C07D401, C07D403, C07D413, C07D417, C07K5, C07K14