MXPA00001443A - SELECTIVE FACTOR Xa INHIBITORS - Google Patents

Abstract

Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders and have formula (I).

Description

SELECTIVE INHIBITORS OF THE FACTOR Xa FIELD OF THE INVENTION This invention relates to a new class of bicyclic aryl azepinone compounds, which are highly potent and selective inhibitors of factor Xa or factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other coagulation proteases (e.g. thrombin, fVIIa, flXa) or fibrinolytic cascades (e.g., plasminogen activators, plasmin).

BACKGROUND OF THE INVENTION Blood coagulation protects mammalian species when the integrity of the blood vessel wall is damaged and uncontrolled loss of blood threatens survival. Coagulation, which results in the formation of blood clots, is an important component of the ostasis. Under normal haemostatic circumstances, an acute balance of the WF .: 32754 clot formation and clot elimination (fibrinolysis). The blood coagulation cascade involves the conversion of a variety of inactive enzymes (zymogens) into active enzymes, which ultimately convert the soluble plasma protein fibrinogen into an insoluble matrix of highly cross-linked fibrin. (See Davie et al., "The Coagulation Cascade: Initiation, Maintenance and Regulation" Biochemistry 30: 10363-10370 (1991)). Blood platelets that attach to damaged blood vessels are activated and incorporated into the clot and thus play a major role in the initial formation and stabilization of haemostatic "plugs". In certain diseases of the cardiovascular system, deviations from normal hemostasis push the balance of clot formation and clot dissolution to the formation of life-threatening thrombi, when thrombi occlude the blood flow in the coronary spleens ( myocardial infarctions) or the limbic and pulmonary veins (venous thrombosis). Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are te * _l mainly responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition. A key enzyme in the coagulation cascade, as well as hemostasis, is thrombin. Thrombin is intimately involved in the process of thrombus formation, but under normal circumstances it may also play an anticoagulant role in hemostasis through its ability to convert protein C to activated protein C, in a manner dependent on thrombomodulin. Thrombin plays a central role in thrombosis through its ability to catalyze the penultimate conversion of fibrinogen to fibrin, and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5: 411-436 (1994). The main classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (for example heparins, low molecular weight heparins and coumarins). Thrombin is generated in the convergence of the intrinsic and extrinsic coagulation pathways by the prothrombinase complex. The protokinase complex is formed when the activated Factor X (factor Xa) and its nonenzymatic cofactor, the Va factor, is assembled on the phospholipid surfaces in a Ca + 2 dependent manner as reviewed by Mann et al., "Surface- Dependent Reactions of the Vitamin K-Dependent Enzymes ", Blood 76: 1-16 (1990). The prothrombinase complex converts the zymogen proton bina to the active procoagulant thrombin. The localization of the prothrombinase complex in the convergence of the intrinsic and extrinsic coagulation pathways, and the significant amplification of thrombin generation (393,000 times over factor Xa not formed in complex) mediated by the complex to a limited number of target catalytic units present in vascular injury sites, suggests that the inhibition of generation of Thrombin is an ideal method to block uncontrolled procoagulant activity. Contrary to In the case of thrombin, which acts on a variety of protein substrates as well as on a specific receptor, factor Xa seems to have a unique physiological substrate, namely, the prothrombin. Plasma contains an endogenous inhibitor of the tissue factor Vlla-factor (TF) complex and factor Xa called tissue factor pathway inhibitor (TFPI). TFPI is a Kunitz-type protease inhibitor with three Kunitz tandem domains. TFPI inhibits the TF / fVIIa complex in a two-step mechanism which includes the initial interaction of the second Kunitz domain of TFPI with the active site of factor Xa, thereby inhibiting the proteolytic activity of factor Xa. The second step involves the inhibition of the TF / fVIIa complex by the formation of a TF / fVIIa / TFPI / fXa quaternary complex as described by Girard et al., "Functional Significance of the Kunitz-type Inhibitory Domains of Lipoprotein-associated Coagulation Inhibitor" , Nature 338: 518-520 (1989). Polypeptides derived from hematophagous organisms have been reported, which are highly potent and specific inhibitors of factor Xa. U.S. Patent No. 4,588,587 * -? a * B * # s awarded to Gasic, describes the anticoagulant activity in the saliva of the Mexican leech, Ha emen t eri a offi cinal i s. A major component of this saliva is shown to be the polypeptide inhibitor of factor Xa, antistasin, by Nutt et al., "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveáis to Repeated Infernal Structure", J. Biol. Chem. 263: 10162-10167 (1988). Another powerful and highly specific inhibitor of factor Xa, the tick anticoagulant peptide, has been isolated from the whole-body extract of the soft tick Omi thi doros mo uba ta, as reported by axman et al., "Tic Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa ", Science 248: 593-596 (1990). Other polypeptide-like inhibitors of factor Xa have been reported, including the following citations by: Condra et al., "Isolation and Structural Characterization of a Potent Inhibitor of Coagulation Factor Xa from the Leech Ha emen t eri a ghi l i ani i", Thromb. Haemost. 61: 437-441 (1989); Blankenship et al., "Amino Acid Sequence of Ghilanten: Anti-coagulant-antimetastatic Principle of the South American Leech, Haementeria ghilianii", Biochem. Biophys. Res. Commun. 166: 1384-1389 (1990); Brankamp, et al., "Ghilantens: Ancoagulants, Antimetastatic Proteins from the South American Leech Haementeria ghilianii", J. Lab. Clin. Med. 115: 89-97 (1990); Jacobs et al., "Isolation and Characterization of a Coagulation Factor Xa Inhibitor from Black Fly Salivary Glands", Thromb. Haemost. 64: 235-238 (1990); Rigbi et al., "Bovine Factor Xa Inhibiting Factor and Pharmaceutical Compositions Containing the Same", European Patent Application 352,903 (1990); Cox, "Coagulation Factor X Inhibitor From the Hundred-pace Snake Deinagki strodon acutus venom", Toxicon 31: 1445-1457 (1993); Cappello et al., "Ancylostoma Factor Xa Inhibitor: Partial Purification and its Identification as a Major Hookworm-derived Anticoagulant In Vitro", J ^ _ Infect. Dis. 167: 1474-1477 (1993); Seymour et al., "Ecotin is a Potent Anticoagulant and Reversible Tight-binding Inhibitor of Factor Xa", Biochemistry 33: 3949-3958 (1994). Factor Xa inhibitory compounds which are not large polypeptide type inhibitors have also been reported including: Tidwell et al., "Strategies for Anticoagulation With Synthetic Protease Inhibitors, Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res. 19: 339-349 (1980); Turner et al., "P-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry 25: 4929-4935 (1986); Hitomi et al., "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System", Haemostasis 15: 164-168 (1985); Sturzebecher et al., "Synthetic Inhibitors of Bovine Factor Xa and Thrombin, Comparison of Their Anticoagulant Efficiency", Thromb. Res. 54: 245-252 (1989); Kam et al., "Mechanism Based Isocoumarin Ihibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants", Biochemistry 27: 2547-2557 (1988); Hauptmann et al., "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost. 63: 220-223 (1990); Miyadera et al., Application for Japanese Patent JP-6327488 (1994); Nagahara et al, "Dibasic (Amidinoaryl) propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors ", J. Med. Chem. 37: 1200-1207 (1994); Vlasuk et al., "Inhibitors of Thrombosis", W093 / 15756; and Brunck et al., "Novel Inhibitors of Factor Xa", WO 94/13693. Al-obeidi et al., "Factor Xa Inhibitors", WO 95/29189, describes the pentapeptide derivatives X1-Y-I-R-X2 as factor Xa inhibitors. Said compounds are useful for inhibiting blood coagulation in the treatment of thrombosis, stroke and myocardial infarction.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to novel mimetic analogs, peptides, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives. In yet another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. These compositions are useful as potent and specific inhibitors of blood coagulation in mammals. In still another aspect, the invention relates to methods for using these > ? í * _T- > inhibitors as therapeutic agents for disease states in mammals which have coagulation disorders such as in the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic apoplexy, embolic stroke, disseminated intravascular coagulation including the treatment of septic shock, deep vein thrombosis in the prevention of pulmonary embolism or the treatment of the occlusion or restenosis of the reperfused coronary arteries. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. In other aspects of the invention there are provided compounds that are useful as diagnostic reagents. In preferred embodiments, the present invention provides the compounds of the general formula I: wherein: R1 and R2 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkylaryl of 1 to 3 carbon atoms, (alkyl of 1 to 3 atoms carbon) - (cycloalkyl of 3 to 8 carbon atoms) and aryl; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, or R2 and R3 are taken together to form a carbocyclic ring; q is an integer from 0 to 2 r is an integer from 0 to 4 s is an integer from 0 to 1, t is an integer from 0 to 4 A is selected from the group consisting of R8, -NR8R9, where RB, Ry, R 1 ± 0u and R, 1x1 ± are independently selected from the group consisting of ^ aa ^^ ^ a_A ._ »_ to hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R12 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R11 to form a ring of 5 to 6 members; D is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkenylaryl of 1 to 6 carbon atoms, aryl and a halocyclic ring system of five to ten members containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; E is selected from the group consisting of a direct bond, -CO-, -S02-, -O-CO-, -NR1 -S02- and -NR14-C0-, wherein R14 is selected from the group consisting of H, - OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; G is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, aryl and a five to ten member heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; J is selected from the group consisting of R15, -NR15R16, wherein R15, R16, R17 and R18 are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R19 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R17 or R18 to form a ring of 5 to 6 members; and R20 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R18 to form a ring of 5 to 6 members; with the proviso that when J is R15, then G must contain at least one nitrogen atom. K ', K' ', K' '', K '' '' are independently selected from the group consisting of -CH-, -CR4-, -CR5- and -N-; with the proviso that no more than one of K ', K ", K'", and K "'' be -CR4- and not more than one of K ', K' ', K' '' and K '' '' is -CR5-; R4 and R5 are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, - N02, -NR6R7, -NR6C0R7, -OR6, -OCOR6, COOR6, -CONR6R7, -CN, -CF3, -S02NR6R7 and (alkyl of 1 to 6 carbon atoms) -OR6, wherein R6 and R7 are independently selected from the group which consists of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; Q is selected from the group consisting of hydrogen, J_, wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and aryl; and T is selected from the group consisting of hydrogen, -COOR23, -CONR23R24, -CF3, -CF2CF3 and a group having the formula: wherein R23 and R24 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-; with the proviso that at least one of U 'or U "is -N-, or -NH-; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkylaryl of 0 to 6 carbon atoms, -! ____ __r ___-_ & ____ "* alkenylaryl of 2 to 6 carbon atoms, alkylheterocycle of 0 to 6 carbon atoms, alkenylheterocycle of 2 to 6 carbon atoms, -CF3 and -CF2CF3; V is selected from the group consisting of -S- -SO- -so2- -0- -NR or- wherein R, 26 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; and W is selected from the group consisting of: a heterocyclic ring system of 6 to 10 carbon atoms substituted with R29 and R30 and containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen; where: a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, -COOR31, -CONR31R32, -CN and -CF3; R29 and R30 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, > 4r & > to halogen, -N02-, -NR31R32, -NR31COR32, -OR31, -OCOR31, -COOR31, -C0NR3iR, -CN, -CF3, -S02NRJ1R ^ and (C 1-6 alkyl) -OR31; wherein R31 and R32 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; and all pharmaceutically acceptable salts and optical isomers thereof.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless stated otherwise. The term "alkyl" refers to saturated aliphatic groups that include straight chain, branched chain cyclic groups, and combinations thereof, which have the number of carbon atoms specified, or if the number is not specified, which they have up to 12 carbon atoms. The term "cycloalkyl" refers to a mono-, bi- or tricyclic aliphatic ring having 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms. The term "alkenyl" refers to the 5 unsaturated aliphatic groups that include straight-chain, branched-chain or cyclic groups, and combinations thereof, which have at least one double bond and which have the number of carbon atoms specified . The term "aryl" refers to one or more unsubstituted or substituted aromatic rings, substituted with one, two or three substituents such as, by way of example and not limitation, alkoxy of 1 to 6 carbon atoms, from 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, hydroxyl, halogen, cyano (- CN), mercapto, nitro (-N02), thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy, carboxamide, -NR'R ' ', -NR'COR' ', -OR, -OCOR, -COOR, -CONR'R' ', 0 -CF3 -S02NR'R' 'and (alkyl of 1 to 6 carbon atoms) -OR; aryl, alkylaryl of 1 to 6 carbon atoms (where the R groups can be hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl), including but not limited to the carbocyclic aryl groups aril fe ^ v /.^^ t & -i *? mi? ml? *? &?, ezz! -z ..... ...... a-, 3 heterocyclic, biaryl, and triaryl, and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, alkylphenyl of 1 to 6 carbon atoms, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and aromatic heterocycles or heteroaryls, the last of these being an aryl group containing one to four heteroatoms selected from the group It consists of nitrogen, oxygen and sulfur. The aryl groups preferably have 5 to 14 carbon atoms constituting the ring structure (s), while the heteroaryls preferably have 1 to 4 heteroatoms, with the remaining 4 to 10 atoms being carbon atoms. The terms "heterocycle" and "heterocyclic ring system" as used herein refer to any saturated or unsaturated mono- or bicyclic ring system, containing 1 to 4 heteroatoms, selected from the group consisting of nitrogen, oxygen and sulfur. A typical heterocyclic ring system will have 5 to 10 members, 1 to 4 of which are heteroatoms. Typical examples of monocyclic ring systems include piperidinyl, pyrrolidinyl, pyridinyl, piperidonyl, pyrrolidonyl and thiazolyl, while examples of bicyclic ring systems include benzimidazolyl, benzothiazolyl and benzoxazolyl, all of which may be substituted. The term "carbocyclic ring" as used herein refers to any saturated or unsaturated ring containing from three to six carbon atoms. The terms "alkylaryl" and "alkenylaryl" as used herein refer to an alkyl group or an alkenyl group, respectively, having the designated carbon atom number, attached to one, two or three aryl groups. The term "benzyl" as used herein refers to -CH2-C6H5. The term "alkyloxy" as used herein refers to an alkyl group linked to an oxygen atom, such as methoxy, ethoxy, and so forth. The term "halogen" as used herein refers to the chloro, bromo, fluoro or iodo substituents. The term "direct link" as used herein refers to a link that directly links the substituents on each side of the * f * r < ^ H »_ $ - direct link. When two adjacent substituents are each defined as a "direct link", it is considered that this is a simple link. Two substituents are "taken together to form a 5 to 6 membered ring" which means that an ethylene or propylene bridge is respectively formed between the two substituents. The term "pharmaceutically acceptable salts" includes the salts of the compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in the free base and salt form. In practice, the use of the salt form represents the use of the base form; salts by addition of acid and base are within the scope of the present invention. "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids -__ ___ a_fe_f -_? _ & ....._ Ji - "YES such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulonic acid, salicylic acid and the like The "pharmaceutically acceptable base addition salts" include those derivatives of inorganic bases such as bases of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. The Salts derived from the non-toxic, pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, substituted amines including substituted amines of natural origin, cyclic amines and exchange resins Basic ionic resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine. "Biological property" for purposes of the present means an effector or antigenic activity or activity in vi ve, which is directly or indirectly performed by a compound of this invention. Effector functions include binding to the receptor or ligand, any enzymatic activity or enzyme-modulating activity, any binding activity to the carrier, any hormonal activity, any activity that promotes or inhibits adhesion of cells to an extracellular matrix or to molecules of the cell surface, or any structural paper. Antigenic functions include the possession of an epitope or antigenic site that is capable of reacting with antibodies produced against it. The biological properties of the compounds of the present invention can be easily characterized by the methods described in * ^ ?? --4 -... z * s-r ^.

Examples 13 and 14, and by other methods such as are known in the art. In addition, the following abbreviations are used in the application: "Bn" refers to benzyl. "Boc" refers to t-butoxycarbonyl. "BOP" refers to benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate. "Bu" refers to butyl. "Cbz" refers to carbobenzyloxy. "DCM" refers to dichloromethane, "DIEA" refers to diisoprylethylamine, "DMF" refers to N, N-dimethyl formamide, "EDC" refers to l- (3-di-ethylaminopropyl) -3-ethylcarbodiimide hydrochloride; "Et" refers to ethyl, "Et20" refers to diethyl ether, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol, "HF" refers to hydrogen fluoride, "Me" refers to to methyl, "MeOH" refers to methanol, "NHS" refers to N-hydroxysuccinimide, "Ph" refers to phenyl, "p-TsOH" refers to p-toluensul phonic acid monohydrate, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "Cough" refers to p-toluenesulfonyl. In the compounds of this invention, the carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds can exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, enantiomers or diastereoisomers as starting materials or intermediates. The diastereoisomeric products resulting from such syntheses can be separated by chromatographic or crystallization methods by other methods known in the art. Similarly, mixtures of enantiomeric product can be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, can be in one of two configurations (R or S) and both are within the scope of the present invention. In the processes described above, the final products may, in some cases, contain a small amount of diastereomeric or enantiomeric products; however, these products do not affect their therapeutic or diagnostic application. In all peptides of the invention, one or more amide bonds (-CO-NH-) may be optionally replaced with another linkage which is an isostere such as -CH2NH-, -CH2S-, -CH20-, -CH2CH2-, - CH = CH- (cis and trans), -COCH2-, -CH (OH) CH2-, -CH2SO-, and -CH2S02-. This replacement can be done by methods known in the art. The following references describe the preparation of peptide analogs, which include these alternative link portions: Spatola, "Peptide Backbone Modifications" (general revision) Vega Data, Vol. 1, Section 3 (March 1983); Spatola, "Chemistry and Biochemistry of Amino Acids, Peptides and Proteins", (general review) B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Morley, Trends Pharm. Sci. (General review) pp. 463-468 (1980); Hudson et al. Int. J. Pept. Prot. Res. 14: 177-185 (1979) (-CH2NH-. -CH2CH2-); Spatola et al., Life Sci. 38: 1243-1249 (1986) (-CH2-S); Hann, J. Chem. Soc. Perkin , _-.___ Trans. I pp. 307-314 (1982) (-CH = CH-, cis and trans); Almquist et al., J. Med. Chem. 23: 1392-1398 (1980) (-COCH2-); Jennings-White and colloquators, Tetrahedron Lett. 23: 2533 (-COCH;-) (1982); Szelke et al., European Application EP-45665; CA: 97: 39405 (1982) (-CH (OH) CH2-); Holladay et al., Tetrahedron Lett 24: 4401-4404 (1983) (-CH (OH) CH :-); and Hruby, Life Sci. 31: 189-199 (1982) (-CH2-S-).

PREFERRED MODALITIES This invention relates to a new class of bicyclic aryl-azepinone compounds, selected from those of the general formula I, which are potent and specific Xa inhibitors, the pharmaceutically acceptable compositions thereof, and the methods for using them as agents Therapeutics for mammalian disease states, characterized by abnormal thrombosis: wherein: R1 and R2 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkylaryl of 1 to 3 carbon atoms, (alkyl of 1 to 3 atoms carbon) - (cycloalkyl of 3 to 8 carbon atoms) and aryl; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, or R2 and R3 are taken together to form a carbocyclic ring; q is an integer from 0 to 2 r is an integer from 0 to 4 s is an integer from 0 to 1 t is an integer from 0 to 4 A is selected from the group consisting of R, -NR ° R% where RB, Rs, R, 1i0u and R 1 1i are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R12 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R11 to form a ring of 5 to 6 members; D is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkenylaryl of 1 to 6 carbon atoms, aryl and a halocyclic ring system of five to ten members containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; E is selected from the group consisting of a direct bond, -CO-, -S02-, -O-CO-, -NR1 -S02- and -NR1 -CO-, where R14 is selected from the group consisting of H, - OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; G is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, aryl and a five to ten member heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; J is selected from the group consisting of R15, -NR15R16, Wherein R15, R16, R17 and R18 are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R19 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R17 or R18 to form a ring of 5 to 6 members; and R20 is selected from group consisting of hydrogen, alkyl of 1 to 6 - "T- carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or can be taken together with R18 to form a 5- to 6-membered ring; with the proviso that when J is R15, then G must contain at least one nitrogen atom. K ', K' ', K' '', K '' '' are independently selected from the group consisting of -CH-, -CR4-, -CR5- and -N-; with the proviso that no more than one of K ', K' ', K' '', and K '' '' is -CR4- and not more than one of K ', K' ', K' '' and K '' '' be -CR5-; R4 and R5 are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, -N02, -NR6R7, -NR6COR7 , -OR6, -OCOR6, COOR6, -CONR6R7, -CN, -CF3 / -S02NR6R7 and (alkyl of 1 to 6 carbon atoms) -OR6; wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; Q is selected from the group consisting of hydrogen, wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and aryl; and T is selected from the group consisting of hydrogen, -COOR23, -CONR23R24, -CF3, -CF2CF3 and a group having the formula: wherein R23 and R24 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-; with the proviso that at least one of U 'or U "is -N-, or -NH-; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkylaryl of 0 to 6 carbon atoms, _____ «&__. £ ___ K_ £ _ &_ * _ &____ = __ £ alkenylaryl of 2 to 6 carbon atoms, alkylheterocycle of 0 to 6 carbon atoms, alkenylheterocycle of 2 to 6 carbon atoms, -CF3 and -CF2CF3; V is selected from the group consisting of -S-, -SO-, -S02-, -0- and -NR26-, wherein R26 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; and W is selected from the group consisting of: a heterocyclic ring system of 6 to 10 carbon atoms substituted with R29 and R30 and containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen; where: a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, -COOR31, -C0NR31R32, -CN and -CF3; R29 and R30 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, -N02-, -NR31R32 , -NR31C0R32, -OR31, -OCOR31, -COOR31, -CONR31R32, -CN, -CF3, -S02NR31R32 and (alkyl of 1 to 6 carbon atoms) -OR31; wherein R31 and R32 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; and all pharmaceutically acceptable salts and optical isomers thereof. A preferred embodiment of the compounds of the general structural formula I has the following stereochemistry: The substituents R1 and R2 are hydrogen and alkyl of 1 to 6 carbon atoms; more preferably hydrogen and methyl; more preferably hydrogen, R3 is preferably hydrogen. The integer "r" is preferably 3.

The integer "s" is preferably 3. The integer "t" is preferably O to 1 In the various substituents "A" it is preferred that R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; and are more preferably independently selected from the group consisting of hydrogen and methyl. It is also intended that R12 is hydrogen, alkyl of 1 to 6 carbon atoms or taken together with R10 or R11 to form a 5- to 6-membered ring; and is more preferably hydrogen or methyl. It is also preferred that R 13 is hydrogen, alkyl of 1 to 6 carbon atoms or taken together with R 10 to form a 5- to 6-membered ring; and is more preferably hydrogen or methyl. D is preferably selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, aryl and a five to ten membered heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

E is preferably a direct bond, CO- or -S02-. G is preferably a direct link. In substituent "J", it is preferred that R15, R16, R17, R18, R19 and R20 are independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, more preferably hydrogen and methyl. Preferably at least three of K ', K ", K"' and K "'" are -CH-; more preferably K ', K' ', K' '' and K '' '' are all -CH-. When one of the K's is -CR4- or -CR5-, then R4 or R5 is preferably halogen. Q is preferably: PR21 or - °? .R2 At where R is preferably hydrogen and R22 is preferably hydrogen. T is preferably hydrogen, -COOR23, -CONR23R24 or a group having the formula: ## STR2 ## R is preferably hydrogen, R24 is preferably alkylaryl of 1 to 4 carbon atoms. V is preferably -S-, -0- or -NR26-, wherein R26 is preferably hydrogen or methyl, more preferably hydrogen. W is preferably selected from the group consisting of: W is more preferably R29 and R30 are preferably independently selected from the group consisting of hydrogen, -O-R31, -COOR31, -C0NR, 311tR_ 32 -CF 3, more preferably hydrogen.

When W is: ..- '"-' 'Ssft 527 (CH2) 8, 28 then R27 is preferably hydrogen and R28 is preferably hydrogen. When T is: then U 'is preferably oxygen, U' 'is preferably nitrogen and R25 is preferably -CF3 O -CF2CF3. In a preferred embodiment of the invention, s is 0; R2 and R3 are hydrogen; K ', K' ', K' '' and K '' '' are -CH-; and Q is -C (0) -T. This is also illustrated as a preferred group of compounds defined by general structural formula II as: ** ®¡f ~ *.? Jg 'j A preferred embodiment of compounds of general structural formula II has the following stereochemistry: In another preferred embodiment of the invention, s is 0; r is 3; R1, R2 and R3 are hydrogen; K ', K' ', K "' and K '' '' are -CH-; G is a bond; J is: NR "NR, 5R1ß> 17 wherein R15, R17, R18 and R19 are all hydrogen; and Q is -C (0) -T. This is also illustrated as a preferred group of compounds defined by general structural formula III as: A preferred embodiment of the compounds of the general structural formula III have the following stereochemistry: This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates and solvates of the compounds of formulas I, II and III. In addition, the compounds of the formulas I, II and III can exist in various isomeric and tautomeric forms, and it is understood that all such forms are included in the invention, together with the pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers . The compounds of this invention can be isolated as the free acid or base or converted to the salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the isolation and purification processes. A number of methods are useful for the preparation of the salts described above, and are known to those skilled in the art. For example, the free acid or free base of a compound of one of the above formulas can be reacted with one or more molar equivalents of the desired acid or base in a solvent or mixture of solvent in which the salt is insoluble, or in a solvent such as water, after which the solvent is removed by evaporation, distillation or lyophilization. Alternatively, the acid or free base of the product can be passed over an ion exchange resin to form the desired salt or a salt form of the product that can be converted into another using the same general process. This invention also encompasses the prodrug derivatives of the compounds contained herein. The term "prodrug" refers to a pharmacologically inactive derivative of a drug molecule that requires biotransformation parent, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have cleavable groups under metabolic conditions. The prodrugs become the compounds of the invention that are pharmaceutically active i n vi, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. The prodrug compounds of this invention may be referred to as single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functional groups present in a precursor type form. Pro-drug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, California, 1992). Prodrugs commonly known in the art include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by the reaction of the parent acid compound with an amine, or basic groups that are reacted to form an acylated base derivative. In addition, the prodrug derivatives of this invention can be combined with other portions shown herein to increase bioavailability.

The following structures are illustrative of the compounds of the present invention and are not intended to be limiting in any way. It should be noted that in the compounds of the invention, certain substituents are present among two other substituents. For example, D is placed between A- and - (CH2) t-E. Accordingly, substituents such as D are illustrated below having two "overhanging" bonds, the link on the left side represents a direct link to the substituent A- and the link on the right hand side represents a direct link to - (CH2) tE -, Therefore, the general formula AD- (CH2) tE- where D is phenyl can be written as: D, a phenyl group, could be written as follows in the following tables: Other substituents in the following table can also be presented having one or two similar "overhanging" links. It is understood that these represent direct links to or adjacent substituents. It is also understood that the compounds illustrated below may exist as other isomers, and the isomeric form illustrated herein is not intended to be limiting in any way. The invention encompasses the compounds of the general structural formula IV, wherein R1, R2 and R3 are hydrogen; r is 3; s is 0; G is a direct link; J is -NH-C- (NH) NH2; K ', K' ', K' '' and K '' '' are -CH-; Y Q is V) "_? S__ t wv n? Tív r ___ S? H -¡__rt ____ Í__., I-_. ^^ _ ^ _ ^ qg_-afeg ^^^ ftg ^ Sa ^^ a ^ fe. ^ A_i The invention encompasses the compounds of general structural formula V, wherein R1, R2 and R3 are lüi ífi __ & ___ i__ hydrogen; q is 2, t is 1; A is hydrogen; D is phenyl; E is -S02-; K ', K' ', K "' and K '' '' are -CH-, and Q is V) The invention encompasses the compounds of the general structural formula VI, wherein q is 1; r is 3; s is 0; t is 1; A is hydrogen; D is phenyl; E is -S02-; G is a direct link; J is -NH-C (NH) NH2; K 'K' K 'and K' are -CH-; and Q is v > The invention encompasses the compounds of the general structural formula VII, wherein R1, R2 and R3 are hydrogen; q is 0; r is 3; t is 1; A is hydrogen; D is phenyl; E is -S02-; G is a direct link; J is -NH-C (NH) NH2; K ', K' ', K' '' and K '' '' are -CH-: The invention encompasses the compounds of the general structural formula VIII, wherein R1, R2 and R3 are hydrogen; q and t are 1; r is 3; s is 0; A is hydrogen; D is phenyl; E is -S02-; G is a link direct; J is -NH-C (NH) NH2; and Q is * 0.

As mentioned above, the compounds of this invention find utility as therapeutic agents for disease states in mammals having coagulation disorders such as in the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, apoplexy thrombotic, embolic stroke, disseminated intravascular coagulation including the treatment of septic shock, deep vein thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of the reperfused coronary arteries. In addition, these compounds are useful for the treatment or prophylaxis of those diseases that involve the prevention and / or action of the factor Xa / prothrombin complex. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated, which include but are not limited to deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery and peripheral arterial occlusion. Accordingly, a method for preventing or treating a condition in a mammal, characterized by unwanted thrombosis, comprises administering to the mammal a therapeutically effective amount of a compound of this invention. In addition to the disease states noted above, other diseases treatable or preventable by administering the compounds of this invention include, without limitation, formation of occlusive coronary thrombi that result either from thrombolytic therapy or percutaneous transluminal coronary angioplasty, the formation of thrombi in the venous vasculature, disseminated intravascular coagulopathy, a condition where there is rapid consumption of the factors of the coagulation, and systemic coagulation that results in the formation of thrombi that threaten life, occurring throughout the microvasculature, leading to disseminated organ failure; hemorrhagic stroke, renal dialysis, blood oxygenation and cardiac catheterization.

The compounds of the invention also find utility in a method for inhibiting coagulation in biological samples, which comprises the administration of a compound of the invention. The compounds of the present invention can also be used in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this invention may be co-administered together with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulants, thrombolytic agents, or other antithrombotics, including inhibitors of platelet aggregation, activators of tissue plasminogen, urokinase, prourokinase, streptokinase, heparin, aspirin or warfarin. The compounds of the present invention can act in a synergistic manner to prevent reocclusion after successful thrombolytic therapy and / or reduce the time for reperfusion. These compounds may also allow reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side effects. The v * * - *** j * 3 * 'compounds of this invention may be used in vi, ordinarily mammals such as primates, (eg humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice , oin vi tro. The biological properties of the compounds of the present invention can be easily characterized by methods that are well known in the art, for example by in vitro protease activity assays and in vitro studies to evaluate antithrombotic efficacy, and the effects on haemostasis and haematological parameters, as illustrated in the examples. Diagnostic applications of the compounds of this invention will typically use formulations in the form of solutions or suspensions. In the management of thrombotic disorders the compounds of this invention can be used in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated within shaped articles. Subjects in need of treatment (typically mammals) using the compounds of this invention can be administered with doses that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and will be dependent on factors such as the type of mammal being treated, its sex, weight, diet, concurrent medication, general clinical condition, the particular compounds employed, the specific use for which are used these compounds, and other factors that will be recognized by those of experience in medical techniques. Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound, having a desired degree of purity, with physiologically acceptable carriers, excipients, stabilizers, etc., and can be provided in release formulations. sustained or controlled release. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. , (A.R. Gennaro, 1985). Such materials are non-toxic to patients at the doses and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight peptides (less than about ten residues) such as polyarginine, proteins, such as serum albumin, gelatin or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counter ions such as sodium and / or nonionic surfactants such as Tween, Pluronics or polyethylene glycol. The dosage formulations of the compounds of this invention that are to be used for therapeutic administration must be sterile. Sterility is easily achieved by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. The formulations will typically be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention will typically be from 3 to 11, more preferably from 5 to 9 and still more preferably from 7 to 8. It will be understood that the use of some of the above excipients, carriers or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as orally, intravenously (bolus and / or infusion), subcutaneously, intramuscularly, colonic, rectally, nasally, transdermally or intraperitoneally, employing a variety of dosage forms such as suppositories, implant pellets or small cylinders, aerosols, icroencapsulation, oral dose formulations and topical formulations such as ointments, drops and skin patches. The compounds of this invention are desirably incorporated into shaped articles such as implants that can employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other commercially available polymers.

The compounds of the invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, laminae esteari or phosphatidylcholines. The compounds of this invention can also be administered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting portions, to which the molecules of the compound are coupled. The compounds of this invention can also be coupled with suitable polymers such as steerable drug carriers. Such polymers may include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene-polylysine oxide substituted with palmitoyl residues. In addition, the compounds of the invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or antipathetic block copolymers of hydrogels. Polymers and semipermeable polymer matrices can be formed into shaped articles, such as valves, stents, pipes, prostheses and the like. Liquid formulations of the therapeutic compound are generally placed within a container containing a sterile access port, for example, an intravenous solution bag or bottle having a plug pierceable by hypodermic injection needle. The therapeutically effective doses can be determined either by means of a vi vi or i n vi ve methods. For each particular compound of the present invention, individual determinations can be made to determine the optimum dose required. The therapeutically effective dose range will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection with a hypodermic needle, it can be assumed that the dose is distributed within the bodily fluids. For other routes of administration, the absorption efficiency must be individually determined for each of the compounds by methods well known in pharmacology. Consequently, it may be necessary for the therapist, the holder to dose and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dose levels, i.e., the dose levels necessary to achieve the desired result, will be readily determined by one of skill in the art. Typically, the applications of the compounds are started at lower dose levels, with the dose levels being increased until the desired effect is achieved. The compounds of the invention can be administered orally or parenterally in an effective amount within the dose range of from about 0.1 to 100 mg / kg, preferably from about 0.5 to 50 mg / kg and more preferably from about 1 to 20 mg / kg in a regimen in a single dose or in divided doses of 2 to 4 times daily, and / or continuous infusion.

Typically, about 5 to 500 mg of a compound or mixture of compounds of this invention, such as the free acid or free base form or as a pharmaceutically acceptable salt, are composed of a carrier, carrier, excipient, binder, preservative, stabilizer. , coloring, flavoring, etc., physiologically acceptable, as required by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dose is obtained in the indicated range. Typical adjuvants that can be incorporated into tablets, capsules and the like are binders such as acacia, corn starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents such as corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavors. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline or a fatty acid. Other materials of various types can be used as coatings or as modifiers of the form . * • __? ______? __, __.._ • Zt. ™ M physics of the dose unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, the dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty acid vehicle such as ethyl oleate, or in a liposome may be desired. The buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.

Preparation of the Described Compounds The compounds of the present invention can be synthesized either by the solid phase or liquid phase methods described and referenced in standard textbooks, or by a combination of both methods. These methods are well known in the art. See, Bodanszky, "The Principles of Peptide Synthesis", Hafner et al., Eds., Springer-Verlag, Berlin, 1984. The initial materials used in any of these methods are commercially available from sellers of chemical products such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or can be easily synthesized by known procedures. The reactions are carried out in standard laboratory glassware and in reaction vessels under standard temperature and pressure reaction conditions, except where otherwise indicated. The reaction products are isolated and purified by conventional methods, typically by solvent extraction in a compatible solvent. The products can also be purified by column chromatography or other appropriate methods. Most compounds are purified by reverse phase HPLC and characterized by ion spray mass spectrometry. During the synthesis of these compounds, the functional gr of the amino acid derivatives used in these methods are protected by blocking gr to prevent collateral reactions during the cing procedure. Examples of suitable blocking gr and their use are described in "The Peptides; Analysis, Synthesis, Biology", Academic Press, Vol. 3 (Gross et al., Eds., 1981) and Vol. 9 (1987), the descriptions of which are incorporated by reference herein. The compounds of this invention can be preferably prepared by cing the carboxylic acid of the formula (a) to the amine of the formula (b) by standard amide bond formation strategies: fifteen The compounds of the formula (b) wherein Q is H can be prepared by the methods described in WO96 / 01338; WO96 / 24609; Feng and 20 co-workers, WO96 / 31504; and WO96 / 32110, the descriptions of which are incorporated by reference herein. The compounds of the formula (b), wherein Q is a boron-containing compound, can be prepared by the methods described in J. Org. __! Chem. 60: 3717-3722 (1995) and Nanteuil et al., European Patent EP-688,788, the descriptions of which are incorporated by reference herein. The compounds of the formula (b) wherein Q is -C (0) -T, where T is hydrogen, can be prepared by the methods described in W093 / 15756, supra; Vlasuk et al., W094 / 17817; Abelman et al., W094 / 21673; Webb et al, WO94 / 0891; Veber et al. WO94 / 25051; Levy et al., W095 / 35312; Semple et al., W095 / 35313; Abelman et al, WO95 / 28420; and Abelman et al., W096 / 19493, the descriptions of which are incorporated by reference herein. The compounds of the formula (b) wherein Q is -C (0) -T, where T is -COOR23 or -CONR23R24, can be prepared by the methods described WO94 / 25051, s upra, WO94 / 08941, s upra and W094 / 21673, the descriptions of which are incorporated by reference herein. The compounds of the formula (b) wherein Q is -C (0) -T, where T is -CF3 or -CF2CF3, can be prepared by the methods described in Schacht et al., British Patent GB-2287027, the description of which is incorporated by reference herein. The compounds of the formula (b) wherein Q is -C (0) -T, where T is: and V is -S-, -SO- or -S02- can be easily synthesized by the methods described in Costanzo et al., US Patent No. 5,523,308; Di Maio et al, W096 / 19483; U.S. Patent No. 5,164,371; J. Am. Chem. Soc. 114: 1854-1863 (1992); J. Med. Chem. 38: 76-85 (1995); and J. Med. Chem. 37: 3492-3502 (1994). At the end, the fragments where V is -NR21-, where R21 is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl, can be synthesized by techniques illustrated in J. Med. Chem. 37: 3492-3502 (1994). All of these references are incorporated herein by reference. The compounds of the formula (b) wherein Q is -C (0) -T, where T is: * _.-, 'fi.'Jt ~ t and U 'and U "are the various substituents (-0-, -S-, -N-, -NH-) can be prepared by the methods described in J. Med. Chem. 38: 1355-1371 (1995) and J. Med. Chem. 37: 2421-2436 (1994), the descriptions of which are incorporated by reference in the present. The starting compound of formula (a) is either a known compound or can be produced by known methods (Heitsch et al., Canadian Patent No. 2,071,744; Sugihara et al. contributors, Canadian Patent No. 2,126,026; Baker et al., European Patent EP-365,992; U.S. Patent No. 4,251,438; Carr et al., U.S. Patent No. 4,341,698; Goldman et al., Patent North American No. 5,120,718; Biswanath et al., US Patent No. 5,164,388; Duggan et al., US Patent No. 5,281,585; Sugihara et al., US Patent No. 5,294,713; Bovy and collaborators, WO95 / 06038; WO95 / 35308; J. Chem. Soc. Perkin Trans.

I 1687-1689 (1989); and Int. J. Peptide Protein Res. 37: 468-475 (1991)) or can be prepared by the methods shown in the following reaction formulas. The following reaction schemes are more specific illustrations of the above reaction formulas. The chemical reactions described in each scheme can be easily modified and combined with other techniques that are well known in the art to produce other compounds within the scope of the invention.

Reaction Scheme The reagent used in the eighth step of Reaction scheme can be synthesized as follows: Without further elaboration, it is believed that a person skilled in the art can use the present invention to its fullest extent. Therefore, the following specific and preferred embodiments have to be considered as merely illustrative and do not limit the rest of the description in any way.

Example 1 Preparation of To a suspension of Boc-Arg (Tos) -OH (2 g, 4. 7 mmol) in DMF (20 ml) at 0 ° C was added MeNHOMe »HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0 ° C for 10 hours. The DMF was evaporated in vacuo. The oily residue was dissolved in ethyl acetate (200 ml) and in 20 ml of * __.,. -*******"*."***"* Water. The organic layer was washed with saturated aqueous NaHCO 3 solution, 20 ml of water, 10 ml of 1M HCl and 2 portions of 20 ml of saturated NaCl. The organic layer was dried over magnesium sulfate, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold ethyl acetate (10 ml) and dried to give Boc-Arg (Tos) -N (Me) OMe, shown above (1.5 g, 70% yield). FAB-MS (M + H) + = 472 Example 2 Preparation of To a solution of thiazole (2.5 g, 29 mmol) in 25 ml of tetrahydrofuran at -78 ° C was added n-BuLi (1.6 M in hexane, 19 ml) dropwise. The mixture was stirred for 30 minutes. Then a solution \ tmmÉiñ \ i? M úá? of Boc-Arg (Cough) -N (Me) OMe, from Example 1 (1.7 g, 3.6 mmol) in 50 ml of tetrahydrofuran was added to the lithium thiazole mixture at -78 ° C. The solution was stirred for 2 hours. 30 ml of 1M HCl was added to the reaction mixture, and warmed to room temperature. The mixture was extracted with 100 ml ethyl acetate. The organic layer was washed with 30 ml of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The crude oily residue was purified by flash column chromatography on SiO2 (50% ethyl acetate in methylene chloride), to give the Boc-Arg (Tos) -thiazole, shown above, (1.5 g, yield 84%) as a powder DCI-MS (M + H) + = 496 Example 3 Preparation of To a solution of Boc-Arg (Tos) -thiazole from Example 2, (300 mg, 0.6 mmol) in 10 ml of methylene chloride at 0 ° C, 10 ml of TFA was added. The solution was stirred at 0 ° C for 2 hours. The solvent and excess TFA were evaporated to give an oily residue which was then used without further purification.

Example 4 Preparation of (S) -N- [2- (1,3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) -l-oxo-3-phenylpropyl] glycine: The title compound was prepared as described in Biopolymers (38) 1-12 (1996) with minor modifications. A mixture of N-phthaloyl-L-phenylalanine (10.0 g, 33.9 mmol), EDC (15.9 g, 83.0 mmol), and NHS (8.77 g, 76.2 mmol) in DCM (100 mL) was stirred at room temperature under an argon atmosphere overnight. The reaction mixture was then concentrated to give a residue which was taken up in 100 ml of dioxane. To this mixture was added a solution of glycine (6.35 g, 84.7 mmol) and 5 g of sodium bicarbonate in 100 ml of water, and the reaction was stirred overnight. Most of the solvent was removed by concentration, and the remainder was acidified with IN HCl to give an opaque, white mixture. This was extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts were washed several times with IN HCl and water, in an alternate manner. The organic extracts were dried over magnesium sulfate and concentrated to give a white solid, which was triturated several times with less amounts of Et20 using filtration to recover the desired crude product as a white solid (9.78 g).

Example 5 Preparation of (S) -3- [2- (1,3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) -l-oxo-3-phenylpropyl) -5-oxazolidinone: ^ MH ^ HH ^ The title compound was prepared as described in Biopolymers (38) 1-12 (1996) with minor modifications. A mixture of the dipeptide of Example 4 (9.62 g, 27.3 mmol), paraformaldehyde (20.5 g, 25 equivalents), and p-TsOH (550 mg, 0.1 equivalent) in 555 ml of toluene was heated to reflux using a water separator Dean-Stark In the course of 4 hours, three more aliquots of paraformaldehyde (4 g, 5 equivents) at intervals of one hour. After this time, all the initial dipeptide material had been consumed by TLC analysis. The residue was digested with 500 mL of EtOAc and 250 mL of saturated aqueous solution of sodium bicarbonate, and the solids were removed by decanting. The layers were separated, and the organic materials were washed with saturated sodium bicarbonate and saturated aqueous sodium chloride, then dried over sodium sulfate. magnesium. Filtration and concentration gave the desired product as an off-white solid (6.77 g). This material was used in the next step without further purification. ** '* ** - "-s Example 6 Preparation of (S) -4- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,3,4,5,5-tetrahydro-3-oxo-2H-benzazepin acid -2-acetic: The title compound was prepared as described in Biopolymers (38) 1-12 (1996). A solution of oxazolidinone from Example 5 (924 mg, 2.54 mmol) in anhydrous DCM (6 mL) was treated at room temperature with 5 g of trifluoromethanesulfonic acid. The reaction mixture turned dark brown, and was stirred overnight at room temperature. 50 ml of DCM was added, the mixture was cooled in an ice-water bath, and about 10 g of ice were added. The organic layer was washed with 2 portions of 30 ml of water and with 50 ml of saturated aqueous sodium chloride, and then extracted with 6% aqueous sodium bicarbonate (3 x 50 ml). The organic layer was acidified to pH 2 with concentrated HCl, and extracted with 3 50 ml portions of DCM. The organic materials were dried over magnesium sulfate and concentrated to give a slightly sticky yellow solid. When treated with DCM, the product was able to be isolated as a light yellow powdery solid (799 mg).

Example 7 Preparation of (S) -4-amino-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic acid: The title compound was prepared as described in Biopolymers (38) 1-12 (1996). A solution of the phthalimido acid and of Example 6 (720 mg, 1.98 mmol) and hydrazine monohydrate (593 mg, 12 mmol) in 25 ml of absolute ethanol was heated to gentle reflux for 2 hours, then cooled and concentrated. The residue was dissolved in 20 ml of water and the solution was acidified to pH 5 with glacial acetic acid. This mixture was stirred for 1 hour, then filtered to give 180 mg of a white solid, which was determined by HPLC analysis as a mixture of the desired product and the phthaloyl hydrazide. This solid was stirred for 10 minutes with IN acetic acid, filtered, and the filtrate was concentrated to give 461 mg of a white solid, which was determined by HPLC to be 90% the desired product and 10% phthaloyl hydrazide. This mixture was used in the next reaction without further purification.

Example 8 Preparation of (S) -amino-1,4,4,5-tetrahydro-3-oxo-2H-2-benzazepin-2-acetic acid methyl ester: ml of MeOH was cooled with an ice-acetone bath, and 60 μl of thionyl chloride was added. This solution was stirred for 1 minute, and then the amino acid of Example 7 (163 mg, 0.70 mmol) was added all at once. After removing the cooling bath, the reaction was stirred while warming to room temperature, over a period of 1 hour, then heated to 40 ° C for another 1.5 hour. When the reaction mixture was concentrated to dryness, HPLC analysis of the residue indicated that the reaction was incomplete, so that the above reaction sequence was repeated, this time the heating of the reaction was 0.5 hour until completion. The reaction mixture was heated to dryness, giving the product as a light yellow solid (168 mg, 97%).

Example 9 Preparation of A solution of the aminomethylester of Example 8 (168 mg, 0.70 mmol) in 5 ml of dichloromethane was cooled to -78 ° C, and 410 ml of DIEA (3.5 eq.) And a-toluenesulfonyl chloride (143 mg) were added. 0.75 mmol). The reaction was then allowed to warm to room temperature over a period of 3 hours. The reaction was incomplete so that the reaction was again cooled to -78 ° C, and additional a-toluenesulfonyl chloride (52 mg, 0.27 mmol) was added. The reaction was then allowed to stir while warming to room temperature overnight. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate in hexane, followed by 50% ethyl acetate in hexane) to give the desired product ( 182 mg, 67%) as a white solid.

Example 10 Preparation of A mixture of the sulfonamide methyl ester of Example 9 (58 mg, 0.14 mmol), 10 ml of IN HCl, and 3 ml of methanol were heated at 70 ° C for 24 hours, following the progress of the reaction by HPLC. When the reaction was complete, the mixture was lyophilized to give a gum-like residue. This material was lyophilized again from 5 ml of water to give the desired product in the crude form as a solid (85 mg). This material was used in the next step without further purification.

Example 11 Preparation of To a solution of Boc-Arg (Cough) -thiazole of Example 2 (89 mg, 0.18 mmol) in 2 ml of DCM was ., _..__ .. ^^ ^ ^^ g ^ - «- added 2 ml of TFA, and the reaction was stirred at room temperature for 40 minutes. The concentration gave a residue which was again taken up in 5 ml of DCM and reconcentrated to give the free amine as the TFA salt. This material was dissolved in 1 ml of DMF and a solution of the crude acid of Example 10 in 10 ml of DMF was added. The pH of the solution was raised to 9 with 200 μL of DIEA, and the reaction mixture was placed in an ice-water bath. BOP reagent was added (80 mg, 0.18 mmol), the reaction mixture was checked with pH paper to ensure continuous alkalinity, and allowed to stir while heating at room temperature overnight. The solution was then divided between 50 mL of ethyl acetate and 25 L of 0.1 N HCl, and the organic materials were washed with saturated aqueous sodium bicarbonate (2 x 25 mL), saturated aqueous sodium chloride (25 mL) and finally dried over anhydrous sodium sulfate. Filtration and concentration gave 105 mg of the crude product as an orange solid, which was used in the next reaction without further purification. APCI-MS (M + H +) = 766.

Example 12 Preparation of Compound VI (4 A mixture of the crude product of Example 11, 1 ml of anisole, and 250 ml of ethylmethyl sulfide and 500 mg of Merrifield resin was cooled with liquid nitrogen and treated with 5 ml of HF. The reaction was allowed to stir for 1 hour in an ice-water bath, then the HF was removed in vacuo. The residue was washed with ether (2 x 50 mL), and the dried resin was extracted twice with 2M aqueous acetic acid (25 mL, then 5 mL). The aqueous solution was lyophilized to give the crude product as a solid, which was purified by reverse phase HPLC to give the desired product as a white solid (12 mg). APCI-MS (M + H +) = 612 Example 11 (Determination of IC50) The compounds of the present invention are first dissolved in a buffer to give solutions containing concentrations such that the test concentrations are in the range of 0 to 100 μM. In the trials for thrombin, Prothrombinase and factor Xa, a synthetic chromogenic substrate could be added to a solution containing a test compound, and the enzyme of interest and the residual catalytic activity of that enzyme could then be determined spectrophotometrically. The IC50 of a compound is determined from the conversion of the substrate. The IC50 is the concentration of the test compound that gives 50% inhibition of substrate conversion. The Preferred compounds of the invention desirably have an IC 50 of less than 500 nM in the factor Xa assay, preferably less than 200 nM, and more preferably less than 100 nM. The preferred compounds of the invention desirably have a IC50 less than 4.0 μM in the prothrombinase assay, - .z .. ^ ¡and * preferably less than 200 nM, and more preferably less than 10 nM. Preferred compounds of the invention desirably have an IC50 greater than 1.0 μM in the thrombin assay, preferably greater than 10.0 μM, and more preferably greater than 100.0 μM.

Amidolitic assays to determine protease inhibition activity The factor Xa and thrombin assays are performed at room temperature, the buffer of 0.02 M Tris HCl, pH 7.5, containing 0.15 M sodium chloride. The proportions or rates of hydrolysis of the substrate of para-nitroanilide S-2765 (Chromogenix ) for factor Xa, and substrate Chromozym TH (Boehringer Mannheim) for thrombin after preincubation of the enzyme with the test compound for 5 minutes at room temperature, are determined using a Softmax 96-well plate reader (Molecular Devices), monitored at 405 nm to measure the p-nitroanilide occurrence, time-dependent. The prothrombinase inhibition assay is performed in a plasma-free system with modifications to the method as described by Sinha et al., Thromb. Res., 75: 427-436 (1994). The activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p-nitroanilide substrate Chromozym TH. The test consists of a pre-incubation of 5 minutes of the selected compounds to be tested, as inhibitors with the complex formed from factor Xa (0.5 nM), factor Va (2 nM), phosphatidyl-serine: phosphatidyl-choline ( 25:75, 20 μM) in 20 mM Tris HCl buffer, pH 7.5 containing 0.15 M NaCl, 5 mM CaCl 2, and 0.1% bovine serum albumin. Aliquots from the complex-compound test mixture are added to prothrombin (1 nM) and Chromozym TH (0.1 mM). The cleavage rate of the substrate is verified at 405 nm for two minutes. Various concentrations of a given test compound are tested in duplicate. A standard thrombin generation curve for an equivalent amount of the untreated complex is then used for the determination of percent inhibition. The compounds of the invention showed inhibitory activity in the Factor Xa assay described above. The preferred compounds of the invention have an IC 50 value of less than 100 nM.

Example 14 The antithrombotic efficacy of the compounds of this invention can be easily evaluated using a series of studies in rabbits, as described below. These studies are also useful in the evaluation of the effects of the compounds on hemostasis and its haematological parameters.

Ant Thrombotic Efficacy in a Rabbit Model of Venous Thrombosis A model of deep vein thrombosis in rabbit as described by Hollenbach et al., Thromb. Haemost. 71: 357-362 (1994), is used to determine the antithrombotic activity of the compounds of the present invention. Rabbits are anesthetized with intramuscular injections of a cocktail of Ketamine, Xylazine and Acepromazine.

A standardized protocol consists of the insertion of an apparatus of cotton thread and thrombogenic copper wire into the abdominal vena cava of the anesthetized rabbit. A non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus development is then used as a measure of the antithrombotic activity of the compound being evaluated. The test agents or control saline are administered through a catheter in the marginal vein of the ear. A femoral vein catheter is used for blood sampling before and during the infusion at rest of the compound being evaluated. The onset of thrombus formation will begin immediately after the advancement of the cotton thread apparatus into the central venous circulation. The compounds that are evaluated are administered from time = 30 minutes to time = 150 minutes, at which point the experiment is terminated. The rabbits are sacrificed and the thrombus is removed by surgical dissection and characterized by weight and histology. The blood samples are then analyzed for changes in the hematological and coagulation parameters. -3 * »f_í ' Although the insemination has been described with reference to the embodiments described, those skilled in the art will readily appreciate that the specific * detailed experiments are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (49)

Having described the invention as above, the content of the following claims is claimed as property:

1. A compound that has the formula: characterized in that: R1 and R2 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkylaryl of 1 to 3 carbon atoms, (alkyl of 1 to 3 atoms carbon) - (cycloalkyl of 3 to 8 carbon atoms) and aryl; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, or R2 and R3 are taken together to form a carbocyclic ring; * i ___ £ r ___ r.:r, q is an integer from 0 to 2; r is an integer from 0 to 4; s is an integer from 0 to 1; t is an integer from 0 to 4; A is selected from the group consisting of Re -NRHR and, where RB, R, Rlu and R J- are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R12 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms. | H carbon, or it can be taken together with R to form a ring of 5 to 6 members; D is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkenylaryl of 1 to 6 carbon atoms, aryl and a halocyclic ring system of five to ten members containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; E is selected from the group consisting of a direct bond, -CO-, -S02-, -O-CO-, -NR14-S02- and -NR14-CO-, wherein R14 is selected from the group consisting of H, - OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; G is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, aryl and a five to ten member heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; J is selected from the group consisting of R15, -NR15R16, _-__ .. ^ _________ Mflt < _ wherein R15, R16, R17 and R18 are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R19 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or may be taken in conjunction with R17 or R18 to form a 5-6 membered ring; and R20 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or can be taken together with R18 to form a ring of 5 to 6 members; with the proviso that when J is R15, then G must contain at least one nitrogen atom. K ', K' ', K' '', K '' '' are independently selected from the group consisting of -CH-, -CR4-, -CR5- and -N-; with the condition that no more 91 from one of K ', K' ', K' '', and K '' '' be -CR4- and not more than one of K ', K' ', K' '' and K '' '' be - CR5-; R4 and R5 are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, -N02. -NR6R7, -NR6COR7, -OR6, -OCOR6, COOR6, -CONR6R7, -CN, -CF3 -S02NR6R7 and (alkyl of 1 to 6 carbon atoms) -OR6; wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; Q is selected from the group consisting of hydrogen, wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and aryl; and T is selected from the group consisting of hydrogen, -COOR23, -CONR R, -CF3, -CF2CF3 and a group having the formula: wherein R23 and R24 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-; with the proviso that at least one of U 'or U "is -N-, or -NH-; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkylaryl of 0 to 6 carbon atoms, alkenylaryl of 2 to 6 carbon atoms, alkylheterocycle of 0 to 6 carbon atoms, alkenylheterocycle of 2 to 6 carbon atoms, -CF3 and -CF2CF3; V is selected from the group consisting of -S-, -SO-, -S02-, -O- and -NR26-, wherein R26 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; and W is selected from the group which consists of: u *., _., i_.s? _8 ____ ig ^ & m a heterocyclic ring system of 6 to 10 carbon atoms substituted with R29 and R30 and containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen; where: a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, -COOR31, -CONR31R32, -CN and -CF3; R29 and R30 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, -N02-, -NR31R32 , -NR31COR32, -OR31, -OCOR31, -COOR31, -CONR31R32, -CN, -CF3, -S02NR31R32 and (alkyl of 1 to 6 carbon atoms) -OR31; wherein R31 and R32 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; and all pharmaceutically acceptable salts and optical isomers thereof.

2. The compound according to claim 1, characterized in that R1 is selected from the group consisting of H and alkyl of 1 to 6 carbon atoms.

3. The compound according to claim 2, characterized in that it is selected from the group consisting of hydrogen and methyl.

4. The compound according to claim 3, characterized in that R1 is hydrogen.

5. The compound according to claim 1, characterized in that R2 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms.

6. The compound according to claim 5, characterized in that R2 is selected from the group consisting of hydrogen and methyl. _ £ _ * -.

7. The compound according to claim 6, characterized in that R ~ is hydrogen.

8. The compound according to claim 1, characterized in that R3 is hydrogen.

The compound according to claim 1, characterized in that R 'is halogen.

10. The compound according to claim 1, characterized in that R5 is halogen.

11. The compound according to claim 1, characterized in that the integer "r" is 3.

12. The compound according to claim 1, characterized in that the integer "s" is 0.

13. The compound according to claim 1, characterized in that the integer "t" is 0-1.

14. The compound according to claim 1, characterized in that R R9, R 10

R 11 are independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms. 15. The compound according to claim 14, characterized in that R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl.

16. The compound according to claim 1, characterized in that R is hydrogen, alkyl of 1 to 6 carbon atoms together with R10 or R11 form a ring of 5 to 6 20 members

17. The compound according to claim 16, characterized in that R 13 is hydrogen or methyl. 25 ^ _ ^ ______ S___ - &__ £? ßS

18. The compound according to claim 1, characterized in that R13 is hydrogen, alkyl of 1 to 6 carbon atoms or taken together R10 form a ring of 5 to 6 members .

19. The compound according to claim 18, characterized in that R 13 is hydrogen or methyl. The compound according to claim 1, characterized in that D is selected from the group consisting of a direct bond, cycloalkyl of 3 to 6 carbon atoms,

Aryl and a 5- to 10-membered heterocyclic ring system containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

21. The compound according to claim 1, characterized in that E is a direct bond, -CO- or -S02-,

22. The compound according to claim 1, characterized in that G is a 25 direct link.

23. The compound according to claim 1, characterized in that R 15 R 16, R 17, RJ R 19 and R are independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms.

24. The compound according to claim 23, characterized in that R 15 R 16 R, 1x7 ', R a R19 and R 2o are independently selected from the group consisting of hydrogen and methyl

25. The compound according to claim 1, characterized in that at least three of K ', K ", K' '' and K" '' 'are -CH-.

26. The compound according to claim 25, characterized in that K ', K ", K' '' and K" "are all -CH-.

27. The compound according to claim 1, characterized in that Q is: .

The compound according to claim 27, characterized in that R 21 is hydrogen.

29. The compound according to claim 28, characterized in that R2 is hydrogen.

30. The compound according to claim 27, characterized in that T is hydrogen, -COOR23, -CONR23R24 or a group having the formula:

31. The compound according to claim 30, characterized in that R23 is hydrogen.

32. The compound according to claim 30, characterized in that R24 is alkylaryl of 1 to 4 carbon atoms.

33. The compound according to claim 30, characterized in that V is -S-, -O- or -NR26-.

The compound according to claim 33, characterized in that R 26 is hydrogen or methyl.

35. The compound according to claim 34, characterized in that R 26 is hydrogen.

36. The compound according to claim 30, characterized in that W is selected from the group consisting of: twenty

37. The compound according to claim 36, characterized in that W is: > __ ^ S¿? A ^^

38. The compound according to claim 36, characterized in that R29 and R30 are independently selected from the group consisting of hydrogen, -O-R31, -COOR31, -CONR31R32 or -CF3-.

39. The compound according to claim 38, characterized in that R29 is hydrogen.

40. The compound according to claim 1, characterized in that R30 is hydrogen.

41. The compound according to claim 1, characterized in that W is: and R, 27 is hydrogen . ,. ^^ a ****** * *. *

42. The compound according to claim 41, characterized in that R28 is hydrogen.

43. The compound according to claim 37, characterized in that T is: U 'is O, U' 'is N and R 2z5o is -CF3 or -CF2CF

44. A compound that has the formula characterized in that: R1 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, ? f * M "cycloalkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms, (alkyl of 1 to 3 carbon atoms) - (cycloalkyl of 3 to 8 carbon atoms) and aryl: q is a number integer of 0-2 r is an integer of 0-4 t is an integer of 0-4 A is selected from the group consisting of R8, -NR8R9, wherein R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R12 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R11 to form a ring of 5 to 6 members; 5 D is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkenylaryl of 1 to 6 carbon atoms, aryl and a five-to-five-ring halocyclic system ten 10 members containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; E is selected from the group consisting of a direct bond, -CO-, -S02-, -O-CO-, -NR14-S02- and fifteen - . -NR1 -CO-, wherein R14 is selected from the group consisting of H, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; G is selected from the group consisting of A direct bond, cycloalkyl of 3 to 8 carbon atoms, aryl and a five to ten membered heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; J is selected from the group consisting of R 1 5 -NR1 5R1 6, NR18 NR18 NT _ NR? 1_SR, 199. A ^ NR ^ R20, 17 wherein R15, R16, R17 and R18 are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R19 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R17 or R18 to form a ring of 5 to 6 members; and R20 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or can be taken together with R18 to form a ring of 5 to 6 members; with the proviso that when J is R15, then G must contain at least one nitrogen atom fffWl '^ »! ^ 1 T is selected from the group consisting of hydrogen, -COOR23, -CONR23R24, CF3, -CF2CF3 and a group having the formula ^ wherein R23 and R24 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-; with the proviso that at least one of U 'or U "is -N-, or -NH-; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkylaryl of 0 to 6 carbon atoms, alkenylaryl of 2 to 6 carbon atoms, alkylheterocycle of 0 to 6 carbon atoms, alkenylheterocycle of 2 to 6 carbon atoms, -CF3 and -CF2CF3; V is selected from the group consisting of -S-, -SO-, -S02-, -O- and -NR26-, wherein R26 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; and W is selected from the group consisting of: a heterocyclic ring system of 6 to 10 carbon atoms substituted with R29 and R30 and containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen; where: a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, -COOR, -CONR 3 -'1-'nR3'32, -CN and -CF3; R29 and R30 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, -N02-, -NR31R32 , -NR31C0R32, -OR31, -OCOR31, -COOR31, -CONR31R32, -CN, -CF3, -S02NR31R32 and (C 1 -C 6 alkyl) -OR; where R and R are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; and all pharmaceutically acceptable salts and optical isomers thereof.

45. A compound of the formula: characterized in that: q is an integer of 0-2; t is an integer of 0-4; A is selected from the group consisting of Rc -NRBR S, where R c R: R 10 R, 1 ± 1 J- are independently selected from the group consisting of hydrogen, -OH, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; R12 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms, or it may be taken together with R11 to form a ring of 5 to 6 members; D is selected from the group consisting of a direct bond, cycloalkyl of 3 to 8 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkenylaryl of 1 to 6 carbon atoms, aryl and a halocyclic ring system of five to ten members containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; E is selected from the group consisting of a direct bond, -CO-, -S02-, -O-CO-, -NR1 -S02- and -NR14-CO-, where R14 is selected from the group consisting of H, - OH, alkyl of 1 to 6 atoms TflHfl f * k¿ carbon, aryl and alkylaryl of 1 to 4 carbon atoms; T is selected from the group consisting of hydrogen, -COOR23, -CONR23R24, CF3, -CF2CF3 and a group having the formula: where R and R24 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl and alkylaryl of 1 to 4 carbon atoms; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-; with the proviso that at least one of U 'or U "is -N-, or -NH-; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkylaryl or of 0 to 6 carbon atoms, alkenylaryl of 2 to 6 carbon atoms, alkylheterocycle of 0 to 6 carbon atoms, alkenylheterocycle of 2 to 6 carbon atoms, -CF3 and -CF CF; V is selected from the group consisting of -S-, -SO-, -SO2-, -O- and -NR, 26D-, wherein R, 26 is selected from the group consisting of hydrogen, »*« alkyl of 1 to 6 carbon atoms and benzyl; and W is selected from the group consisting of: a heterocyclic ring system of 6 to 10 carbon atoms substituted with R29 and R30 and containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen; where: a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, -COOR31, -C0NR31R32, -CN and -CF3; R29 and R30 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkylaryl of 1 to 6 carbon atoms, alkyloxy of 1 to 4 carbon atoms, halogen, -N02-, -NR31R32 , -NR31COR32, -OR31, -OCOR31, -COOR31, -CONR31R32, -CN, -CF3, -S02NR31R32 and (alkyl of 1 to 6 carbon atoms) -OR31; wherein R31 and R32 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 3 carbon atoms and aryl; and all pharmaceutically acceptable salts and optical isomers thereof.

46. A pharmaceutical composition for preventing or treating a condition that includes unwanted thrombosis, in a mammal, characterized in that the composition comprises a pharmaceutically acceptable carrier and the compound according to claim 1.

47. A method for preventing or treating a condition including unwanted thrombosis, in a mammal, characterized in the method comprising administering to a mammal, a therapeutically effective amount of the compound according to claim 1.

48. The method according to claim 47, characterized in that the condition is selected from the group consisting of: the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic apoplexy, - ** T_ * _ * E embolic stroke, disseminated intravascular coagulation including the treatment of septic shock, deep vein thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries, deep vein thrombosis, pulmonary embolism, infarction of the myocardium, stroke, thromboembolic complications of surgery and peripheral arterial occlusion, formation of occlusive coronary thrombi resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty, formation of thrombi in the venous vasculature and disseminated intravascular coagulopathy.

49. A method for inhibiting the coagulation of biological samples, characterized in that it comprises the administration of a compound according to claim 1. The novel compounds, their salts and compositions related thereto which have activity against mammalian factor Xa are described. The compounds are useful in preventing or treating coagulation disorders and have the formula (I). j_i ___- ^ a ¿____ > ii = __ i