MXPA97009386A - Derivatives of the arilsulfonilaminobenceno and the use of them as factor inhibitors - Google Patents

Abstract

The present invention relates to inhibitors of non-peptidic factor Xa, which are useful for the treatment of thrombotic occlusive disorders of the vein and the artery. Factor Xa inhibitors provide structure compounds (I) or pharmaceutically acceptable salts thereof, wherein R 1 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, R 2 is one hydrogen, alkyl, cycloalkyl or aryl, R3 is one of hydrogen, hydroxy, or alkoxy, R4 is one of -NH2, phenyl or pyridyl, wherein said phenyl and said pyridyl are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino , monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoacyl and / or dialkylaminoalkyl; X is one of -CH2- or -C (O) _; and n is from zero to 11, since when R4 is -NH2, then R3 is hydrogen and n is another that zero, and also given that when R3 is hydroxy or alkoxy then R4 is other than -NH2-, an n is other than

Description

DERIVATIVES OF ARILSULFONILAMINOBENCENO THE USE OF THEM AS INHIBITORS OF THE FACTOR Xa Field of the Invention The present invention relates to compounds which are inhibitors of thrombin production via inhibition of factor Xa, its pharmaceutically acceptable salts, and the pharmaceutically acceptable compositions thereof. The compounds and compositions are useful in the treatment of thrombotic disorders of the vein and art, in inflammation and cancer.

BACKGROUND OF THE INVENTION Thrombin from the serine protease plays a central role in heraostasis and in-thrombosis CTapparelli et al., Trends in Pharmaco logical Sciences 14: 366-376 (1Q93); Lefkovits and Topol, Circulation 90 (3): 1522-1536 (1 > Q4); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1): S47-S5 > (1QQ4)) The activation of the coagulation cascade through either the intrinsic pathway (activation of con-tact) or the extrinsic pathway activation by expo- Ref. 026156 plasma to a non-endothelial surface, d? The formation of tissue in the vessel, or release of tissue factor, leads to a series of biochemical events that converge in thrombin. Thrombin divides the fibrinogen, finally leads to a hemostatic plug (clot formation), potentially activates the platelets through a single-proteolytic partition of the cell surface thrombin receptor (Coughlin, Seminars in Hematology 31 (4): 270-277 (1994)), and amplifies this own production through a feedback mechanism-cidn.

As a multifactorial protein, thrombin induces a number of effects on platelets - on endothelial cells, on smooth muscle cells, on leukocytes, on the heart, and on neurons (Tapparelli et al., Trends in Pharmacologica Sciences 14: 366-376 (1993), Church and Hoffman, Trends in Cardiovascular Medicine 4 (3): 140-146 (1993)). Platelet activation leads to a change of form and aggregation, as well as the synthesis, release and secretion of vasoactive substances and lysosomal enzymes. Activation of the endothelial cell results in the secretion of simulatory agents that lead to increased vascular permeability and adhesion by mononuclear cells, a consequence of which is extravasation of leukocytes to the site of thrombin generation. Thrombin induces the fibroblast and - smooth muscle cell proliferation suggests that thrombin plays a key role in the development of the lesion following vascular damage. Increased automaticity and prolongation of repolarization has been observed in cardiac myocytes - showing sensitivity to thrombin. Normal neuronal development has also been shown to be influenced by thrombin. Therefore, inhibitors of thrombin function have therapeutic potential in a base of cardiovascular and non-cardiovascular diseases, including: myocardial in -fartation; unstable angina; the attack; restenosis; thrombosis of the deep vein; Disseminated intravascular coagulation caused by trauma, metastasis of sepsis or tumor; the hemo-dialisis; surgery for cardiopulmonary bypass; the adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; the induration; the metastasis; hypercoagulability during chemotherapy; Alzheimer's disease; and Down's syndrome, To date only 3 classes of compounds (heparins, low molecular weight heparins and coumarins, such as warfarin) have been used in anticoagulant therapy. Each class has severe limitations and drawbacks (Eitz and Hirsh, Journal of Laboratory Clinical Medicine 122: 364-373 (1993); Raj et al., The American Journal of the Medical Sciences 307 (2): 128 (1994)). All 3 classes indirectly inhibit thrombin. Heparin and low molecular weight heparins increase antithrombin III inhibition and / or heparin cofactor II of thrombin, whereas coumarins inhibit vitamin-dependent post-translational modifications. The adjusted control and trituration of the therapeutic dose is required when these agents are used due to the variability of the patient. Hemorrhagic complications due to bleeding are a side effect found. In fact, bleeding is the most common side effect of long-term oral anticoagulant therapy. The lack of activity in artery thrombosis in the case of heparin is due to this inability to inhibit thrombin bound to the clot. The level of oral activity in the case of heparins and low molecular weight heparins prevents their use by chronic administration.

The direct thrombin inhibitors of several structural classes have been recently identified (Tapparelli et al., Trends in Pharmacological Sciences 14: 366-376 (1993); Claeson, Blood Coagulation and Fibrinolysis 5: 411-436 (1994); -vits and Topol, Circulation 90 (3): 1522-1536 (1994)). Representative compounds that act by inhibition of the active site of thrombin include D-phenyllalanyl-L-propyl-L-arginyl-chloromethyl ketone of α-fa-chloroketone (PPACK), boroarginine DUP714, α-G-peptide arginine. 114766, the cycloteonamides A and B of the cyclic peptides, the benzamidine NAPAP, and the arganesulfonylarginine orgatroban. The hirudon of the thrombin peptides and the hirulogs additionally comprise between the active and the thrombin exosite domains. The perennial hirugen > Tido and braided DNA aptamers alone inhibit thrombin through the occupation of exosite. These classes of antithrombotic agents still suffer from one or more of the following drawbacks: (1) poor oral bioavailability due to the peptide or oligonucleotide nature of these agents, or high molecular weight or charged nature of the agents; (2) complications of excessive bleeding; - (3) poor selectivity towards thrombin against other serine proteases (which can lead to severe and sometimes fatal hypertension and respiratory depression in animal models); (4) toxicity of the liver; or (5) cost effectiveness.

An alternative approach to inhibit thrombin function is to inhibit factor Xa, Factor Xa is associated with factor Va and calcium in a phospholipid membrane thereby forming a prothrombinase complex. This pro-thrombinase complex then converts prothrombin to thrombin (Claeson, Blood Coagulation and Fibrinolysis 5: 411-436 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1): S47-S58 (1994)). Factor Xa inhibitors are considered to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still allow the generation of significant new thrombin (Lefkovits and Topol, Circulation 90 (3): 1522 -1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1): S47-S58 (1994)). Actually, the continuous generation of new thrombin rather than the re-exposure of coagulated thrombin does seem to be responsible in part for the reocclusion phenomenon since markers of thrombin generation have been found to increase during and after thrombolytic treatment for myocardial infarction. Therefore, it is now believed that the increased thrombin activity associated with thrombosis is at least partly due to the generation of new thrombin.

Factor Xa inhibitors of the specific pro tein, such as the suction cup derived, the amino acid protein of antistasin, and the soft-derived protein TAP (anticoagulant peptide of cuti), accelerate clot lysis and prevent reocclusion when they occur. as adjuncts to thrombolysis (Mellott et al., Circulation Research 70: 1152-1160 (1992); Sitko et al., Circulation 85: 805-815 (1992)). U.S. Patent No. 5,385,885, issued January 31, 1995, describes the inhibitory activity of smooth muscle cell proliferation-of both TAP and antlstasin. Additionally, TAP and antistasin have been shown to reduce experimental -restenosis. These results suggest that factor Xa may play a role in the process of restenosis through this effect in thrombus formation or through this mitogenic potential (Ragosta et al., Circulation 89: 1262-1271 (1994)). The ecotope of the peptide is another selective, reversible, herbal binding inhibitor of factor Xa that exhibits potent anticoagulant activity (Seymour et al., Biochemistry 33: 3949-3959 (1994); PCT Published Application WO 94/20535, publi every September 14, 1994). Ixodidae, -argasine, and ancilostomatin are other representative peptide factor Xa inhibitors isolated from animals that feed on blood (Mark-wardt, Thrombosis and Hemostasis 72: 477-479 (1994)).

Non-peptide diamidino derivatives, such as the pentahydrate of (+) - (2S) -2- [4- [L (3S) -l-acetimidoyl-3-pyrrolidinilloxy] phenyl] -3- [] hydrochloride 7-amidino-2-naphthyl] propanoic (DX-9065a), exhi-ant anticoagulant activity (Tid ell et al., Thrombosis Research 19: 339-349 (1980); Yamazaki et al., Thrombosis and Hemostasis 72: 393- 395 (1994); Hara et al., Thrombosis and Hemostasis 71: 314-319 (1994), Nagahara et al., Journal of Medicinal Chemistry 37: 1200-1207 (1994)). The synthetic amidino derivatives of phenylalanine and cycloheptanone have also shown potent inhibition of factor Xa (Sturzebecher et al., Thrombosis Research 54: 245-252 (1989)).

PCT Published Application WO 94/13693, published June 23, 1994, describes peptide analogs containing an aldehyde group. The application discloses that the analogs have substantial potency and specificity as mammalian factor Xa inhibitors.

The PCT Published Requests-WO 93/15756, published August 19, 1993, and WO 94/17817, published August 18, 1994, describe the peptidylarginine aldehydes which exhibit the inhibitory activity of factor Xa and / or thrombin.

PCT Published Application WO 94/20526, published September 15, 1994, discloses peptide derivatives having a C-terminal boronic acid group. The application discloses that these peptide derivatives possess activity that inhibits the protein and are potent inhibitors of thrombin.

PCT Published Application WO 94/20468, published September 15, 1994, discloses 4-aminopyridine derivatives which are shown to be useful as antithrombotic agents.

Chemical Abstracts 96: 181160 (1981) describes the N- (4-pyridylmethyl) benzamides and methods for the industrial production thereof. In particular, the compound 4 - [(phenylsulfonyl) amino] -N- (4-pyridylmethyl) benzamide is disclosed.

Chemical Abstracts 122: 9661 (1994) describes the derivatives of the sulfonylaminobenzylamine and the use thereof as inhibitors of the ulcer. In particular, the compound N-2 - [[[(4-chlorophenyl) methyl] methyl lamino] methyl-1-pheny1-5-quinolinesulfone-mide is disclosed.

HCUE LK-UUI LN IE IA pNENCKN The present invention is directed to novel arylsulfonylaminobenzamide or arylsulphonylaminobenzamine derivatives of Formula I (below). There is also a process for preparing the compounds of Formula I. The new compounds of the present invention exhibit antithrombotic activity via inhibition of factor Xa. A method of treating thrombosis, ischemia, attack, restenosis, or inflammation in a mammalia in need of such treatment, comprising administering to said mammal, is also provided with an effective amount of a compound of Formula I. A pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable carriers or diluents is also given.

DETAILED DESCRIPTION OF THE MODALITIES THAT ARE PREFER A first embodiment of the present invention is directed to a method of treating thrombosis, ischemia, stroke, restenosis or inflammation comprising administering to a mammal in need of said treatment a therapeutically effective amount or profi lactically of a compound of Formula I: or pharmaceutically acceptable salts thereof; wherein P is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; is one of hydrogen, alkyl, cycloalkyl, aryl or aralkyl; R is one of hydrogen, hydroxy alkoxy; is one of -NH 2 'phenyl, heterocycle C,. "having one or two nitrogen atoms, wherein said phenyl and said C3_10 heterocycle are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy , amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, and / or dialkylaminoalkyl; X is one of -CH2 ~ or -C (0) -; n is from zero to 11; and wherein X is attached to the benzene ring in an ortho-, meta- or para- position to the sulfo-nylamino group; 4 3 since when R is -NH ~ "then R is hydraulic and n is other than zero; and also given that cuají 3 4 of R is hydroxy or alkoxy, then R is other than -NH2, and n is other than zero.

A second aspect of the present invention is directed to novel compounds, and pharmaceutical compositions thereof, having the Formula I (below), or pharmaceutically acceptable salts thereof; wherein R is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; 2 R is one of hydrogen, alkyl, cycloalkyl, aryl or aralkyl; 3 R is one of hydrogen, hydroxy or alkoxy; is one of -NH, phenyl, or heterocycle Co - | Q having one, or two nitrogen atoms, wherein said phenyl and said heterocycle C _? N are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl , monoalkylaminoalkyl, and / or dialkylaminoalkyl; X is one of -CH2 ~ or -C (0) -; and n is from zero to 11; and wherein X is attached to the benzene ring in an ortho-, meta- or para- position to gruoo sul-onylamine; since when R 4 is ~ NH2, then R3 is hydrogen and n is other than zero; and also given that when R 3 is hydroxy or alkoxy, then R 4 is -other than -NH.-, and n is other than zero; 2 further given that when R is hydrogen or methyl, while R 3 * is hydrogen, R 4 is pyridyl, X is -C (0) -, and n is zero or one, then R is other than unsubstituted phenyl. When R is heteroaryl or substituted heteroaryl, preferred heteroaryl groups include pyridyl, thienyl, chromenyl, benzoxazolyl, quinazolinyl, quinolinyl, and tetrahydroquinolinyl. Preferred groups when R is substituted heteroaryl include those heteroaryl groups mentioned as being preferred, having one or more substituents selected from halogen, alkyl, alkyl, alkoxy, carboxy, amino, alkylamino, and / or di. (C, fi) alkylamine.

When R is heterocycle C ~ ", preferred values of R include quinuclidinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, and imidazole.

The preferred values of R include -NH ?, phenyl, 2-pyridyl, 4-pyridyl, 3-quinuclidyl, piperidinyl and aminomethylphenyl.

It is understood that Formula I allows the arylsulfonylamino part to be attached at any of the ortho-, meta- or para- positions relative to -group X, with meta- being preferred.

The preferred compounds of the present invention are those of Formula I wherein R is aryl C, "optionally substituted, more preferably aryl C, _1f .; R is one of hydrogen, alkyl C, _R, cycloalkyl C q aryl Cfi _.?; R ^ is c 4 J one of hydrogen, hydroxy or C, R alkoxy; R is one of -NH2, phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with one or two of halogen, hydroxy, C, R, amino, mono (C,,) alkylamino, di (C. .,) alkylamino, or amino (Cj_.) alkyl; X is -C (0) -; and n is zero to eight.

More preferred are compounds of Formula I where R 1 is phenyl, aminophenyl or naphtyl; R2 3 is hydrogen or C, _, alkyl; R is hydrogen, 4-hydroxy or C-alkoxy,; R is one of ~ ^^ 2 'phenyl, pyridyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-dimethylamino-phenyl and 3-aminomethylphenyl. When R is -NH ", the most preferred values of n include 31 3, -4 on 4 and 7. When R is optionally substituted phenyl or optionally substituted pyridyl, the most preferred values of n include zero and one .

Therefore, the following compounds are the most preferred: 3-r (2-naphthalenylsulfonyl) aminol-Nr? -hydroxy-2- (3'-hydroxypheniDetyl Ibenzamide; 3-T (-naphthalenylsulfonyl) aminol-Nf 2-hydroxy-2- (4 '-hydroxyphenyl) -Dethyl-1-benzamide; 3- [(2-naphthalenylsulfonyl) amino] -N- 4' - [(N *, '-dimethylamino) -phenyl-U-methyl-benzamide; 3- (2-naphthalene-sulfonyl-D-amino) 1-N- [4- (amidinoamino) butyl benzamide; 3- [(phenylsulfonyl) amino] -N - [. (4-hydroxy-3-methoxy-phenyl-methyl-benzamide; 3- [(phenylsulfonyl) amino] -N- [2-hydroxy-2 (3'-hydroxyphenyl) ethyl] benzamide, 3 - [(phenylsulfonyl) amino] -N- [2-hydroxy-2- (4'-hydroxy-3'-methoxyphenyl) ethyl-1-benzamide, 3 - [(phenylsulfonyl) aminole-N- [ 2- (3-hydroxy-4'-methoxyphenyl) -ethyl-benzamide; 3 - [(phenylsulfonyl) amino] -N- [(3'-BOC-amino-methylphenyl) metip-benzamide; the hydrochloride salt of 3-r ( phenylsulfonyl) amino] -N - [(3'-aminomethylphenyl) methyl] benzamide; 3 - [. (2-naphthalenylsulfonyl) amino] -N - [(2'-pyridyl) metillbenzamide; 3- [(2-naphthalenylsulfonyl ) aminol-N - [(3'-aminomethylphenyl) methyl lbenzaraide, 3-T (phenylsulfonyl) amino] -N- (4-aminobutyl) benzamide, 3 - [(3'-aminophenylsulfonylDaminoJ-N- [4'- [(N ', N' -dimethylamino) -phenyl] methyl] benzamide; 3 - [(2-naphthalenylsulphonamino-N- (5-aminopentyl) benzamide; and 3- [(2-naphthalenylsulfonyl) amino] -N- (8-aminooctyl) benzamide.

The term "alkyl" as used herein includes both straight and branched chain radicals of up to 12 carbons, preferably 1-R carbons, such as methyl, ethyl, propyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl-pentyl, octyl, 2, 2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the various isomers of branched chain of them.

The term "substituted alkyl" used herein includes the alkyl groups defined above having one, two or three halo substituents, or an aryl C 6 -thi "C 1, C 1, 0 aryl, halo (C 6_ 10) aryl, C2-8'alkyl'-C1-6 ^ 3-8 ^ cycloalkyl, C2_2alkenyl, alkynyl CoS * hydroxy and / or carboxy.

The term "cycloalkyl" used herein includes saturated cyclic hydrocarbon groups containing from 3 to 12 carbons, preferably from 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cylcocyl decyl and cyclododecyl, any of said groups can be substituted with substituents such as halogen, lower alkyl, group, aj-coxy and / or hydroxy.

The term "aryl" used herein by itself as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably from 6 to 10 carbons in the portion of the ring. , such as phenyl, naphthyl or tetra-hydronaphthyl.

The term "aralkyl" as used herein refers to aryl groups defined above that bind to a C,, alkyl group.

The term "heterocyclic group" or "heterocycle" used herein refers to groups having from 3 to 10 carbon atoms and having one or more saturated or unsaturated ring of 4, 5, 6, or 7 members containing 1, 2 , or 3 heteroatoms of oxygen, nitrogen or sulfur (where the examples of heterocyclic radicals are: tetrahydrofuran, 1,4-dioxane, 1, 3, 5-trioxane, pyrrolidine, piperidine, piperazine, imadazoline, isoindoline, chroman, isochroman, pyrazolidine, quinuclidine, pyridine, pyrrole, oxazole, indole, purine, pyrimidine, 1,3-dithiane, azetidine, tetrahydropyran, imidazole , triazole, isoxazole, pyrazole, quinoline, cytosine, thymine, uracil, adenine, guanine, pyrazine, 1-ethyl-l, 4-dihydronicotine, picolinic acid, picoline, furoic acid, furfural, furfuryl alcohol, carbazole, isoquinoline, 3-pyrroline, thiophene, furan, hexamet ilenimine, £, -caprolactone, E -caprolactam, omega-thiocapro-loactam, and morpholine).

The term "heteroaryl" as used herein refers to groups having from 3 to 14 atoms in the ring; of 6, 10, or 14 1Y electrons distributed in a cyclic order; and containing carbon atoms and 1, 2 or 3 heteroatoms of oxygen, nitrogen or sulfur (where the examples of heteroaryl groups are: thienyl groups, benzof b] thienyl, naphtho (2,3-thienyl thienyl, thiantrenyl, furyl , pyridyl, isobenzofuranyl, • > benzoxazolyl, chromenyl, xanthenyl, phenoxythinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H- quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cynolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl).

The terms "substituted aryl" and "substituted heteroaryl" as used herein include aryl groups and heteroaryl groups, defined above, which include one or two substituents on the aromatic ring (s) such as C, C, C, C, C, C alkyl. C, _-C (C-D-cycloalkyl, C C-C al-alkenyl, C2_R alkynyl, cyano, amino, C, di, di (C,,) alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo (C, Dalcoxy, trifluoromethyl, halogen, alkoxy C, phthalyl C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C,. -10 * The terms "alkoxy" or "aralkoxy" include any of the above alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" used herein by itself, or as part of another group, refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred.

The term "monoalkylamino" used herein refers to the group -NH2, wherein a hydrogen has been replaced by an alkyl group, defined above.

The term "dialkylamino" used herein refers to the group ~ NH2, wherein both hydrogens have been replaced by alkyl groups, defined above.

The term "aminoalkyl" as used herein refers to any of the above alkyl groups substituted by -NH2.

The term "hydroxyalkyl" as used herein refers to any of the above alkyl groups substituted by one or more hydroxyl portions.

The term "BOP" as used herein refers to benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.

The term "BOC" excited herein refers to the group 'protective-amine t-butoxycarbonyl.

The compounds of the present invention can be prepared by standard techniques as summarized in Scheme I.

Scheme I wherein R1, R2, R3, R4 and n are defined above. Additionally, R 4 groups having more than one amino group may have one or more amino-protecting groups attached to amino groups that are not reacted with the carboxylic acid.

Useful protective amino groups include benzyloxycarbonyl (CBZ) or t-butyloxycarbonyl (BOC) An ester of the aminobenzoic acid (which is optionally N-substituted) 2 is treated with an appropriate sulfonyl chloride under standard conditions to give an N-sulfonylated derivative 3. The solvents useful for this step include methylene chloride, tetrahydrofuran, acetonitrile and dimethylformamide. The reaction proceeds at room temperature using a weak base, such as N-methylmorpholine, tritylamine or luditin. Hydrolysis of 3 with the aqueous hydroxide, preferably at elevated temperature for a short time, followed by acidification with aqueous acid, such as 2N HCl, gives the corresponding carboxylic acid 4. The final product is formed by the acid binding carboxylic acid 4 with an appropriate amine (or diamine from which an amino group is protected) using well-known peptide-binding methods. Reagents for the binding step include, Castro's reagent (BOP) / diisopropylethylamine, or alternatively, hydroxybenzotriazole (HOBT), hydroxysuccinimide, 1,3-dicyclocardoxy-imide (DCC), carbonyldiimidazole (CDI), isobutylchloroformate / NEt io diphenylphosphorylazide (DPPA) / NEt3.

The compounds of the present invention where x is -CH2 ~ are synthesized by reductive amination of the appropriate benzaldehyde derivative using an appropriate amine 5.

Compounds having the aryl-sulfonylamino part in the ortho- or para-position can be formed by the use of anthranilic acid methylester or commercially available methyl p-aminobenzoate in place of methyl 3-aminobenzoate, The compounds of the present invention are distinguished by their ability to preferentially inhibit factor Xa in comparison to thrombin and / or plasmin. As inhibitors of factor Xa, the compounds of the present invention inhibit the production of thrombin. Therefore, the compounds are useful for the treatment or prophylaxis of conditions characterized by thrombosis of the vein or the abnormal artery that involves either the production or action of thrombin. These conditions-include, but are not limited to: deep vein thrombosis, disseminated intravascular coagulopathy that occurs during septic shock, viral infections, and cancer; myocardial-diallet infarction; the attack; the derivation of the coronary artery; the replacement of the hip; and thrombus formation resulting from either thrombo-lithic therapy or percutaneous transluminal coronary angioplasty (PCTA). The compounds of the present invention can also be used as an anticoagulant in extracorporeal blood circuits. Under the effects of both factor Xa and thrombin on a base of cell types, such as smooth muscle cells, endothelial cells and neutrofiles, the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome.; inflammatory responses, such as edema; the reperfusion damage; atherosclerosis; and restenosis following damage such as balloon angioplasty, atherectomy, and artery-thrust placement.

The compounds of the present invention may be useful in the treatment of neoplasia and metastasis, as well as in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

The compounds of the present invention can be used in combination with thrombolytic agents, such as tissue plasminogen activator, streptokinase, and urokinase. Additionally, the compounds of the present invention can be used in combination with other anticoagulant or antithrombotic drugs such as, but not limited to, fibrinogen antagonists and thromboxane receptor antagonists.

For medical use, pharmaceutically acceptable acid addition salts are preferred, those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the organic cation. The acid addition salts are obtained either by reaction of an organic base of Fmululaq I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any skilled physician. -in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, palmolic acid, cyclamic acid, pivalic acid and the like. Useful inorganic acids are hydrohalide acids, such as HCl, HBr, Hl, sulfuric acid, phosphoric acid and the like.

The compounds of the present invention can be administered in an effective amount within the dosage range of from about 0.1 ha.to about 500 mg / kg, preferably between 0.1 to 10 mg / kg body weight, over a regimen in single or individual daily doses. 2-4 divided.

The pharmaceutical compositions of the invention can be administered to any animal which can undergo the beneficial effects of the compounds of the invention. First among such animals are humans, although the invention is not intended to be limited in this way The pharmaceutical compositions of the present invention can be administered by any means that achieves its intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular route. Alternatively, or concurrently, the administration may be by oral route. The dosage administered will depend on the age, health, and weight of the recipient, type of treatment, if any, frequency of treatment, and the nature of the desired effect.

In addition to the pharmacologically active compounds, the new pharmaceutical preparations may contain acceptable pharmaceutically acceptable carriers comprising excipients and excipients that facilitate the processing of the active compounds into preparations that can be used pharmaceutically. The pharmaceutical preparations of the present invention are manufactured in a manner that is, per se, well known, for example, by conventional mixing, granulating, candy-making, digesting or lyophilizing processes. Therefore, pharmaceutical preparations for oral use can be obtained by combining the active compounds with the solid excipients, optionally by grinding the resulting mixture and processing the mixture of granules, after adding the appropriate additional ones, if desired or necessary, to get tablets or candy cores.

Suitable excipients are, in particular, fillers such as saccharides. for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example, tricalcium phosphate or calcium acid phosphate, as well as binders such as starch paste, using, for example, corn starch, tri-starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also the carboxymethyl starch, the intermolecular polyvinyl pyrrolidone, the agar, or the alginic acid or a salt thereof, such as the sodium alginate. The additional ones are, all the above, the agents that regulate the flow and the lubricants, for example, the silica, the talc, the stearic acid or the salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Candy cores are given with appropriate coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talcum, polyvinyl pyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solutions and solvents or mixtures. of appropriate organic solvents. In order to produce the gastric juice resistant coatings, suitable cellulose preparation solutions are used, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dry ingredients or pigments can be added to the tablets or caramel coatings, for example, by identification or in order to the characteristic combinations of the doses of the active compound.

Other pharmaceutical preparations that can be used orally include the capsules of apt-impulse made of gelatin, as well as the sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Suitable impulse capsules may contain the active compounds in the form of granules which can be mixed with fillers such as lacto sa, binders such as starches, and / or lubricants such as. talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.

Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. Especially the alkaline salts which are preferred are the ammonium salts prepared, for example, with tris, chlorine hydroxide, bis-Tris propane, N-methylglucamine or arginine. In addition, suspensions of the active compounds such as the appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (compounds are soluble in PEG -400). Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limited, of the method and compositions of the present invention. Other modifications and adaptations of the variety of conditions and parameters -normally found and obvious for these -experts in the art are within the spirit and scope of the invention.

Example 1 Preparation of methyl 3-aminobenzoate (11) A mixture of methyl 3-nitrobenzoate (18.1 g, 0.10 mmol) in ethanol / tetrahydrofuran (THF) (9: 1), and 1.3 g of 10% Pd / C are hydrogenated at atmospheric pressure and at room temperature for 24 hours. The reaction mixture is filtered through Celite (Celite is a registered trademark of the Johns-Manville Product Corporation for diatomaceous earth) and washed with ethanol. The solvent is removed in vacuo to give the title compound as a pale yellow solid (14.7 g, yield 97) which is used without further purification in the next reaction. H-NMR (200 MHz; CDC13) delta 7.43 (d, 1H, J = 7.6 Hz), 7.35 (t, 1H, J = 2.3 Hz), 7.25 (d, 1H, J = 2.3 Hz), 7.19 (d, 1H, J = 7.7 Hz), 3.89 (s, 3H), 3.7 ppm (bs, 2H).

Example 2 3- ((2-Naphthalenyl) sulfonyl) aminobenzoate methyl (12) To 5.0 g (33 mmol) of methyl 3-aminobenzoate (11) prepared in Example 1 in 70 ml of methylene chloride containing 4.0 ml (36 mmoles) of N-methylmorpholine is added 7.49 g (33 mmoles) of chloride of '2-naphthalenesulfonyl. after stirring at room temperature overnight, the reaction mixture is quenched with IN HCl (100 ml). The suspension is dissolved in 250 ml of THF ca. and sufficient ether is added to induce phase separation. The organic extract is washed with a saturated sodium chloride solution (2x). The organic phase is dried (MgSO,), and concentrated to give 11.0 g (yield 97) of the title compound as a pale yellow solid: H-NMR (200 MHz; DMS-d6) delta 8.46 ( s, 1H), 8.13 (t, 2H), 7.99 (d, 1H), 7.55-7.75 (m, 5H), 7.43 (dd, 21H), 7.38 (d, 1H), 3.79 ppm (s, 3H).

Example 3 Preparation of 3- ((2-naphthalenyl) sulfonyl) aminobenzoic acid (13) A solution of 10.8 g (31.7 mmoles) of 3- ((2-naphthalenyl) sulfonyl) aminobenzoate and methyl (12) prepared in Example 2 in 100 ml of IN NaOH is stirred at 50 ° C for 20 minutes. The reaction mixture is quenched with excess 2N HCl, diluted with tetrahydrofuran to dissolve the suspension. Ether is added to induce phase separation. The organic extract is dried (MgSO,) and the solvent is removed in vacuo. Trituration with ether / tetrahydrofuran / hexane gives 10.0 g of the title compound; H-NMR (200 MHz, DMS0-d6) delta 8.45 (s, 1H), 8.13 (t, 2H), 7.99 (d, 1H), 7.54-7.81 (m, 5H), and 7.77-7.43 ppm (m, 2H). The mass spectrum (MALDI-T0F) calculated for the C ^ H ^ NO ^ S: 328.1 (M + H) and 350.0 (M + Na). Found: 328.7 (M + H), 349.8 (M + Na).

Example 4 Preparation of 3- [(2-naphthalenylsulfonyl) amino] -N- [2-hydroxy-2- (3'-hydroxyphenyl) -eti-11-benzamide (14) To 160 mg (0.469 mmoles) of 3 - ((2-naphthalenyl) sulfonyl) aminobenzoic acid (13) prepared in Example 3 in 2 ml of N, N-diraethylformamide is added sequentially 221 mg (0.50 mmoles) of the Castro's Reagent ( benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) and 500 μL (2.87 mmoles) of N, N-diisopropylethylamine. 94.8 mg (0.50 mmoles) of + -norepinephrine HCl are added. After stirring for 20 min, the reaction mixture is quenched with 2N HCl (5 mL) and then extracted with ethyl acetate (2 x 4 mL). The organic phase is washed with saturated NaHCO ~, dried (Na "S0.) And concentrated to give 150 mg of the title compound as a foam. NMR (DMSO-do ,; 300 MHz) delta 10.56 (s, 1H), 9.31 (s, 1H), 8.45 (m, 2H), 8.11 (t, 2H), 8.00 (d, 1H), 7.77 (dd, 1H, Jl.8, 8.7 Hz), 7.59- 7.72 (m, 3H), 7.42-7.47 (m, 1H), 7.22-7.30 (m, 2H), 7.08 (t, 1H), 6.77 (s, 1H), 6.72 (d, lfl, J = 7.6 Hz) , 6.62 (dd, 1H "Jl.8, 7.7 Hz), 5.40 (d, 1H, J-4.2 Hz), 4.63 (penteto, 1H), and 3.14-3.23 ppra (m, 1H). The mass spectrum (MALDI-TOF) calculated for C25H22N2 ° 5S: 485-l (M + Na). Found: 484.9.

Example 5 Preparation of 3 - [(2-naphthalenylsul onyl) amine] -N- 2-hydroxy-2- (4'-hydroxy phenyl) ethyl-1-benzamide (15) The title compound is prepared in an identical manner to Example 4 using 94.8 mg (0.5 mmol) of + -octopamine HCl. Purification is achieved by passing the crude reaction product through 15 ml of silica gel using elutions of methylene chloride / ethyl acetate (2: 1 to 1: 1) to give 122 mg of the title compound C or a foam NMR (DMS0-d &; 300 MHz) delta 10.56 (s, 1H), 9.26 (s, 1H), 8.44 (s, 1H), 8.36 (t, 1H, J = 5 Hz), 8.10 (t, 2H) , J = 9 Hz), 8.00 (d, 8Hz), 7.78 (dd, 1H, J = 1.7 Hz, 8 Hz), 7.61-7.72 (m, 3H), 7.39-7.44 (m, 1H), 7.24-7.29 (m, 2H), 7.12 (d, 2H, J = 7 Hz), 6.69 (d, 2H, J = 7 Hz), 5.28 (d, 1H, J- 5Hz, 4.60), 4.03 (q, 1H, J = 7 Hz), 3.16-2.52 ppm (m, 1H).

Example 6 Preparation of 3- (2-naphthalenylsulfoni.l) amino] -N-L4 '[(N', N'-dimethylamino) phenylethyl] benzamide (16) To a solution of 160 mg (0.469 mmol) of 3- ((2-naphthalenyl) sulfonyl) aminobenzoic acid (13) prepared in Example 3 in 1 ml of N, N-dimethylformamide is added 1 ml of 0.5 M ( 0.5 mmole) of the Castro's reagent (benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) in N, N-dimethylformamide and then 500 uL of N, -diisopropyl-ethylamine. After 5 minutes, the solution is transferred dropwise to a solution of 104 mg (0.47 mmoles) of 4- (dimethylamino) benzylamine hydrochloride salt in N, N-dimethylformamide. After 30 minutes, the reaction mixture is rapidly cooled. With 10 ml of saturated NaHC0, and extracted with ethyl acetate (3 ml). The organic phase is washed with sat. NaHCO4 (4 x 5 .mi), concentrated in vacuo, and crystallized with ethyl acetate / methylene chloride / ether to give 90 mg of the title compound: NMR (DMS0 -d &; 300 MHz) delta 10.55 (s, 1H), 8.82 (t, 1H, J = 6 Hz), 8.44 (d, 1H, J = l Hz), 8.0-9 (t, 2H), 7.99 ( d, 1H, J = 7 Hz), 7.77 (dd, 1H, J = 1.8 Hz), 7.61-7.72 (m, 3H), 7.44-7.48 (m, 1H), 7.22-7.29 (m, 2H) , 7.09 (d, 2H, J = 9 Hz), 6.65 (d, 2H, J-9 Hz), 4.27 (d, 2H, J = 6 Hz), 2.84 ppm (s, 6H).

Example 7 Preparation of 3- [(2-naphthalenylsulfonyl) aminoJ-N- [(4-amidinoamino) butyl] benzamide (17) To a 50 ml dry-bottom round flask equipped with a magnetic stir bar is added agmatine sulfate ((4-aminobutyl) guanidine sulfate), commercially available from Aldrich Chem. Co.) (173.4 mg, 0.76 mmol) suspended of anhydrous methylene chloride (5 ml) under a nitrogen atmosphere. Chlorotrimetíj is added. silane (0.44 mL, 2.66 mmol) to the reaction vessel followed by N, N-diisopropylethylamine (3.8 mL, 22.8 mmol). The reaction mixture is stirred -magnetically at room temperature for 2 hours after which the agmatine sulfate disappears from the solution.

A 3- ((naphthalenyl) sulfonyl) amino benzoic acid (13) (250 mg, 0.76 mmol) is added to a separate dry 25 ml round bottom flask equipped with a magnetic stir bar and a reflux condenser. and thionyl chloride (2 ml) under an atmosphere of dry nitrogen. The mixture is heated to 50 ° C for one hour. The excess of thionyl chloride is then removed in vacuo. The remaining residue is dissolved in anhydrous methylene chloride (2 ml) and transferred to the reaction vessel containing the agmatine. The reaction is stirred at room temperature for an additional hour after which the mixture is dissolved in a cold saturated aqueous sodium bicarbonate solution (25 ml). The aqueous layer is brought with ethyl acetate (10 x 20 ml). The organic layer is dried over sodium sulfate, then evaporated to yield the title product: H-NMR (300 MHz, DMS0-d6) delta 8.45-7.12 (13H; m), 3.25-2.72 (2H; m ), 1.53-1.46 (2H; m), 1.26-1.01 (4H; m). The mass spectrum (MALDI-T0F, si-napinic acid matrix) calculated for C22H25 5 ° 3: 44 ° (M +) • Found: 440 (M + H).

Example 8 Preparation of methyl 3- (phenylsulfonyl) aminobenzoate (18) To 4.6 g (3.03 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 30 ml of methylene chloride containing 4.0 ml (36 mmol) of N-methylmorpholine is added 4 ml (33 mmol) of benzenesulfonyl. After stirring at room temperature for one hour the reaction mixture is rapidly cooled with water (100 ml). The suspension is dissolved in the combination of ethyl acetate / ether. The organic phase is washed sequentially with 2N HCl and then with sodium bicarbonate. The organic phase is dried (MgSO,), and concentrated and triturated with ethyl acetate / hexane / ether to give 8.0 g (90%) of the title compound as a colorless solid: NMR (DMSO-d, 300 MHz ) delta 10.58 (s, 1H), 7.75-7.84 (ra, 3H), 7.52-7.72 (m, 4H), 7.35-7.45 (m, 2H), and 3.82 ppm (s, 3H).

Example 9 Preparation of 3- (phenylsulfonylDaminobenzoic acid (19)) To 8.0 g (27 mmol) of methyl 3-aminobenzoate is added 60 ml of 2N NaOH. After stirring for 30 minutes at room temperature, the reaction mixture is washed with ether and then acidified with 2.5 N HCl. The reaction mixture is extracted with ethyl acetate, dried (MgSO,), and concentrated to give 6.62 g (89%) after washing the solid thoroughly with the ether / hexane mixture: NMR (DMS0-dfi; 300 MHz ) delta 13.0 (bs, 1H), 10.53 (s, 1H), 7.75-7.84 (m, 2H), 7.69 (t, 1H), 7.52-7.66 (m, 4H), 7.28-7.42 opm (m, 2H) . The mass spectrum (MALDI-T0F) calculated for the C13 UN04S: 300 '° (M + Na). Found: 299.7.

Example 10 Preparation of 3- [phenylsulfonyl) amino] -N- [(4-hydroxy-3-methoxyphenyl) methyl-benzamide (20) To 139 mg (0.5 mmol) of the 3- (phenylsulfonyl) aminobenzoic acid prepared in Example 9 in 1 ml of, N-dimethylformamide is added sequentially 1 ral of 0.5 M (0.5 mmol) of the Castro's reactant (benzotriazole hexafluorophosphate). -1-iloxitris (dimethylaraine) phosphonium) in N, -dimethylformamide and then 500 uL of N, N-diisopropylethylamine. After 5 minutes, 95 mg (0.5 mmoles) of 4-hydroxy-3-ethoxybenzylamine HCl is added. After 30 minutes, the reaction mixture is quenched with 7 ml of 2N HCl, extracted with ethyl acetate (2 x 2 ml), washed with water (3 x 4 ml) and then with NaHCO3. sat (1 mi) The organic phase is passed through a Waters solid phase extraction column (5 g of silica gel) in which Na2SO is added, to act as a drying agent. Elution with ethyl acetate gives the title compound: NMR (DMS0-d6; 300 MHz) delta 10.46 (s, 1H), 8.88 (t, 1H), 8.84 (s, 1H), 7.74-7.81 (m, 3H ), 7.50-7.70 (m, 6H), 7.30 (t, 1H), 7.22 (d, 1H), 6.87 (s, 1H), 6.69 (t, 2H), 4.31 (d, 2H), 3.73 ppm (s) , 3H). The mass spectrum (MALDI-TOF; gentic acid matrix) calculated for C21H20N2 ° 5S: 435 «1 (M + Na). Found: 435.0. 11 Preparation of 3 - [(phenylsulfonyl) amino] N- 2-hydroxy-2- (3'-hydroxyphenyl) ethyl-1-benzamide (21) The title compound (115 mg) is prepared using the identical procedure described in Example 10 and + -norepinephrine (95 mg, 0.5 mmol) as the binding amine: NMR (DMSO-d, 300 MHz) delta 10.46 (s, 1H), 9.31 (s, 1H), 8.46 (t, 1H, J = 5 Hz), 7.70-7.8 (m, 2H), 7.41-7.7 (m, 5H), 7.30 (t, 1H), 7.22 (d, 1H), 7.10 (t, 1H), 6.79 (s, 1H), 6.74 (d, 1H), 6.63 (dd, 1H), 5.41 (d, 1H, J = 4 Hz), 4.64 (pente , 1H), 3.36-3.48 (m, 1H), and 3.15-3.28 ppm (m, 1H). The mass spectrum (MALDI-T0F; gentisic acid matrix) calculated for C ^ H ^ N ^ S: 435.1 (M + Na), 451.1 (M +). In contrado: 435.0, 451.2.

Example 12 Preparation of 3- [(phenylsulfonyl) amino] -N- [2-hydroxy-2- (4 '-hydroxy-3' -methoxyphenyl) ethyl-J-benzamide (22) The title compound is prepared using the identical procedure described in Example 10 and the + -numernatefriña (110 mg, 0.5 mmol) as the binding amine: NMR (DMSO-d, 300 MHz) delta 10.45 (s, 1H ), 8.81 (s, 1H), 8.37 (t, 1H), 7.71-7.8 (m, 2H), 7.45-7.68 (m, 5H), 7.29 (t, 1H), 7.21 (d, 1H), 6.88 ( s, 1H), 6.71 (s, 2H), 5.33 (d, 1H), 4.63 (penteto, 1H), 3.72 (s, 3H), and 3.2-3.4 ppm (m, 2H). The mass spectrum (MALDI-T0F; gentisic acid matrix) calculated for C22H22N2 ° 6S: 463-l (M + Na), 481.1 (M +). Found: 464.5, 480.5.

Example 13 Preparation of 3- [(phenylsulfonyl) amino] -N ~ t2- (3 'hydroxy-4' -methoxyphenyl) etl] benzamide (23) The title compound is prepared - using the identical procedure described in Example 10 and 4-0-metild? Damin (102 mg, 0.5 mmol) as the binding amine: NMR (DMSO-d, 300 MHz) delta 10.45 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.74-7.78 (m, 2H), 7.4-7.7 (m, 5H), 7.30 (t, 1H), 7.21 (d, 1H) ), 6.81 (d, 1H, J = 8 Hz), 6.65 (d, 1H, J = 2 Hz), 6.57 (dd, 1H), 3.71 (s, 3H), 3.26-3.47 (m, 2H), 2.64 ppm (t, 1H). The mass spectrum (MALDI-T0F; gentisic acid matrix) calculated for C22H22N205S: 449.1 (M + Na). Found: 448.9.

Example 14 Preparation of N-BOC-m-xylylenediamine (24) To 4.5 g (0.033 mole) of m-xylylenediamine in 100 ml of THF containing 6 ml (0.047 mmol) of, N-diisopropylethylamine is added 3.0 g of di-t-butyldicarbonate. The reaction mixture-stirring for 10 minutes, quenching rapidly-with 2N NaOH, is extracted with methylene chloride. -The organic phase is washed with water (5x), and then acidified with 10% citric acid. The aqueous phase is basified with 2N NaOH and then extracted with methylene chloride. The organic phase is dried (K2C0D) and concentrated to give 1.0 g of the title compound: NMR (CDC13, 300 MHz) delta 7.31 (d, 1H), 7.27 (d, 1H), 7.23 (s, 1H), 7.18 (t, 1H), 4.87 (bs, 1H), 4.32 (d, 2H), 3.86 (s, 2H), 1.45 ppm (s, 9H).

Example 15 Preparation of 3- [(phenylsulfonyl) amino] -N- [(3'-BOC-aminornetylphenyl) methyl] benzamide (25) The title compound (45 mg) is prepared using the identical procedure described in Example 10 using 118 mg of the amine (24) of Example 14 as the binding amine. Purification is achieved by chromatography through a 5 g Waters solid phase extraction column (silica gel) using ethyl acetate as elution: NMR (DMS0-d6; 300 MHz) delta 10.5 (bs, 1H), 9.0 (t, 1H), 7.0-7.8 (m, 13 H), 4.41 (d, 2H), 4.09 ppm (d, 2H). The mass spectrum (MALDI-TO ^, gentisic acid matrix) calculated for C26H29N3 ° 5S: 496-2 (M + fO.518.2 (M + Na), 534.1 (M + K). Found: 496.9, 517.9, 534.5.

Example 16 Preparation of the salt of 3 - [(phenyl-sulfonyl) amino] -N - [(3'-amino-phenylphenyl) methyl-J-benzamide hydrochloride salt (26) HCI The compound obtained in Example 15 (35 mg) is treated with 1 ml of 4N HCl in dioxane for 1 hour. Concentration and trituration with ether / methylene chloride / methanol gives 15 mg of the title compound: NMR (DMS-d, 300 MHz) delta 10.5 (bs, 1H), 9.07 (t, 1H), 8.22 (bs, 2H ), 7.0-7.8 (m, 3H), 4.44 (d, 2H), and 4.00 ppm (d, 2H). The mass spectrum (MALDI-TO ^; gentisic acid matrix) calculated for 2lH21N3 ° 3S: 39o-l (M + H) Found: 396.0.

Example 17 Preparation of 3 - [(2-na talenylsulfonyl) aminoJ-N - [(2'-pyridyl) methyl] benzamide (27) The 3 - ((2-naphthalenyl) sulfonyl) aminobenzoic prepared in Example 3 (164 mg, 0.5 mmol), the Castro's reagent (benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) (221 m, 0.5 mmol), 2- (2-aminoethyl) pyridine (7.3 mg, 0.6 mmol) and triethylamine (0.2 ml) are mixed in dry DMF (5 ml) and stirred at room temperature for 3 hours. The mixture is dissolved in ethyl acetate (100 ral) and washed with saturated NaHCO 3 (2 x 50 mL), brine (2 x 50 mL) and dried over Na 2 SO 4. Evaporation of the solvent gives the title compound (185 mg, 86%) as a white foam:! H-NMR (300 MHz, CDCD / CD30D): delta 3.15 (t, 2H), 3.72 (t, 2H), 7.27 ( t, 1H), 7.43 (m, 5H), 7.59 (m, 2H), 7.78 (dd, 1H), 7.87 (m, 4H), 8.37 (s, 1H), 8.47 (d, 1H). The mass spectrometer (MALDI-TOF) calculated for C24 21N3 ° 3S: 456.5 (M + Na). Found: 456.5.

Example 18 Preparation of 3- ((2-naphinatedlenylsulfonyl) amino] -N- [(3'-aranedomethylphenyl) methyl] benzamide (28) 3- ((2-Naphthalenyl) sulfonyl) aminobenzoic acid prepared in Example 3 (230 mg, 0.7 mmol), Castro's reagent (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) (310 mg, 0.7 mmol) ), m-xylylenediamine (680 mg, 5 mmol) and triethylamine (0.3 ml) are mixed in dry DMF (5 ml) and stirred at room temperature for 3 hours. The mixture is dissolved in ethyl acetate (100 ml) and washed with saturated NaHCO- (2 x 50 ml) and brine (2 x 50 ml). The organic phase is then washed with IN HCl (4 x 50 mL) and the acid solution neutralized to pH 8 and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate extracts are washed with brine (2 x 50 mL), dried over Na 2 SO 4, and evaporated to give the title compound (130 mg, 42%) as a white solid: 1 H-NMR (300 MHz, DMSO-dg): delta 3.82 (s, 2H), 4.40 (d, 2H), 7.27 (m, 5H), 7.42 (t, 1H), 7.65 (m, 3H), 7.78 (dd, 1H), 7.97 (d, 1H), 8.05 (d, 1H), 8.08 (d, 1H), 8.42 (s.lH), 8.42 (s, 1H), 8.95 (t, 1H). The mass spectrum (MALDI-T0F) calculated for C25H23N3 ° 3S: 468-5 (M + Na +). Found: 468.0.

Example 19 Preparation of 3- [(phenylsulfonyl) aminoJ-N- (4-aminobutyl) benzamide (29) 3- (Phenylsulfonyl) aminobenzoic acid prepared in Example 9 (139 mg, 0.5 mmol), Castro's reagent (benzo-triazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) (221 mg, 0.5 mmol), 4- Tert-butyl aminobutylaminocarboxylate (100 mg, 0.6 mmol) and triethylamine (0.2 ml) are mixed in dry DMF (5 ml) and stirred at room temperature for 3 hours. The mixture is dissolved in ethyl acetate (100 ml) and washed with saturated NaHCOO (2 x 50 ml), brine (2 x 50 ml) and dried over Na2SO4. After evaporation of the solvent, the residue is mixed with trifluoroacetic acid 1: 1 (TFA): CH? C1? (10 ml), is stirred at room temperature for 2 hours and the sol vent is evaporated to give the title compound (140 mg, 81%) as the TFA salt. XH-NMR (300 MHz, DMS0-dft): delta 1.17 (m, 4H), 2.79 (t, 2H), 3.23 (d, 2H), 7.23 (d, 1H), 7.30 (t, 1H), 7.57 (m, 5H), 7.60 (d, 2H), 8.50 (t, 1H). The mass spectrum (MALDI-TOF) calculated for the i7H2iN3 ° 3S: 370.4 (M + Na). Found: 370.7.

Example 20 Preparation of 3- ((3-nitrophenyl) sulfonyl) aminobenzoic acid (30) To 1.51 g (10 mmol) of methyl 3-aminobenzoate prepared in Example 1 in 40 ml of methylene chloride containing 2 ml of N-methylmorpholine is added 2.21 g (10 mmol) of 3-nitrobenzenesulfonyl chloride. After stirring at room temperature for 3 hours, methylene chloride (200 ml) is added and washed with saturated NaHCOo (2 x 50 ml), IN HCl (2 x 50 ml) and brine (2 x 50 ml). ) and dried over Na2 $ 0 ,. After evaporation of the solvent, the residue is dissolved in THL? (50 ml), 2N NaOH (10 ml) is added and the mixture is heated to 60 ° C for 2 hours. After neutralization with IN HCl, the mixture is extracted with ethyl acetate (4 x 50 ml) and the organic phase is washed with brine (2 x 50 ml), dried over Na, SO, and evaporated to give 3.05. g (94%) of the title compound as a white solid: H-NMR (300 MHz, DMS0-d6): delta 7.38 (m, 2H), 7.65 (t, 1H), 7.70 (s, 1H), 7.87 ( t, 1H), 8.13 (dd, 1H), 8.47 (dd, 1H), 8.50 (t, 1H), 10. "1 (s, 1H), 13.11 (s, 1H).

Example 21 Preparation of 3- [(3'-aminophenylsulfonyl) amino] -N- [4 '- [(N', N'-dimethylamino) phenyl] methyl] -benzamide (31) 3- ((3-Nitrophenyl) sulfonyl) amino-benzoic acid prepared in Example 20 (322 mg, 1.0 mmol), Castro's reagent (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) (442 mg, 1.0 mmol) ), the 4-dimethylaminobenzyl amine dihydrochloride (0.4 ml) are mixed in dry DMF (8 ml) and dried at room temperature for 3 hours. The mixture is dissolved in ethyl acetate (200 ml) and washed with saturated NaHC0 (2 x 50 ml), brine (2 x 50 ml) and dried over Na2SO0. Evaporation of the solvent gives the title compound (410 mg, 89%) as a white solid. 1H-NM (300 MHz, DMS0-d6): delta 3.06 (s, 6H), 4.42 (d, 2H), 7.28 (d, 1H), 7.35 (m, 3H), 7.52 (m, 4H), 7.86 ( t, 1H), 8.15 (d, 1H), 8.48 (m, 2H), 9.13 (t, 1H), . 82 (s, 1H). The mass spectrum (MALDI-T0F) caj. for C22H22N, 05S: 477.5 (M + Na). Found: 477.2.

The above compound (228 mg, 0.5 mmol) are dissolved in THF (10 ml) and ethanol (10 ml), palladium on carbon (10%, 20 mg) is added to the solution and the mixture is hydrogenated at atmospheric pressure for 4 hours. hours. The mixture is then filtered through Celite and washed with THF and the combined filtrates are evaporated to dryness to give the title compound (200 rag, 94%) as a white solid. H-NMR (300 MHz, DMSO-d, o): delta 3. 05 (s, 6H), 4.45 (d, 2H), 7.20-7.90 (m, 12H), 9.15 (s, 1H), 10.48 (s, 1H). The mass spectrum (MALDI-TOF) calculated for the C? 2H24N4 ° 3S: 4 7.5 (M + Na). Found: 446.9.

Example 22 Preparation of 3- [(2-naphthalenylsulfonyl) amino] -N- (5-aminopentyl) benzamide (32) The title compound is prepared from the identical procedure of Example 6 using 280 uL (2 mmoles) of 1, -diaminopentane. The preparation consists of the following steps. The ethyl acetate extract is acidified with 2N HCl. The aqueous phase is treated with sat. NaHCO 3. in excess and then extracted with ethyl acetate. The organic phase is washed with saturated NaHCO0, dried (Na ^ SQ,), and concentrated to give 43 mg of the title compound as a hardened glass: NMR (DMS0-d6, 300 MHz) delta 8.44 (d, 1H), 1.4 Hz), 8.38 (t, 1H, J = 5 Hz), 8.10 (t, 2H, J = 8 Hz), 7. 99 (t, 1H, J = 8 Hz), 7.77 (dd, 1H, J = 1.8, 8 Hz), 7. 60-7.72 (m, 5H), 7.41-7.45 (m, 1H), 7.23-7.30 (m, 2H), 3.19 (q, 2H), 1.43-1.57 (m, 4H), 1.14-1.34 - ppm (ra , 4H). The mass spectrum (MALDI-TQF) calculated for C22H25N3 ° 3S: 434 «2 (M + Na). Found: 434. 7 Example 23 Preparation of 3- [(2-naph talenylsulf oniD amino] - N- (8- (arainooctyl) benzamide (33) The title compound (13 mg) is prepared from the identical procedure of the Axis 22 using 340 mg of 1,8-diaminooctane. Purification of the product is achieved by silica gel chromatography (CH2Cl2 MeOH / H4OH (85: 10: 5, dried over Na2CO3)): NMR (DMSO-d6, 300 MHz) delta 8.34 (s, 1H), 8.19 (t, 1H, J = 5 Hz), 8.01-8.05 (m, 1H), 7.91-7.97 (m, 2H), 7.76 (dd, 1H), 7.55-7.63 (m, 2H), 7.35 (s, 1H) ), 7.02-7.14 (m, 5H), 3.16 (q, 2H), 2.72 (q, 2H), 1.47 ppm (q, 2H). The mass-spectrum (MALDI-TOF) calculated for C25H3lN3 ° 3S: 4 4. (M + H), 476.2 (M + Na). Found: 454.0, 476.1.

Example 24 Preparation of 3- [(phenylsulfonyl) araino] -N- [3-quinuclidinyl-1-benzamide (34) 3- (phenylsulfonyl) aminobenzoic acid prepared in Example 9 (139 mg, 0.5 mmol), Castro's reagent (benzothiazole-1-yloxytrisium hexafluorophosphate (dimethylaminophosphonium) (221 mg, 0.5 mmol), hydrochloride 3- Aminoquinuclidine (100 mg, 0.5 mmol) and N, N-diisopropylethylamine (0.5 ml) are dissolved in dry DMF (2 ml) and the reaction mixture is stirred at room temperature all night.The reaction mixture is diluted with Saturated NaHCO3 and extracted with ethyl acetate (3x) The combined ethyl acetate is washed with brine and dried over Na2SO, After the evaporation, the residue is purified by silica gel chromatography using 86% chloride of methylene and 14% methanol containing 0.25 ml of acetic acid to give 65 mg (34% yield) H-NMR (300 MHz, DMS0-d6): delta 1.69-2.14 (m, 5H), 3.07-3.35 (m, 6H), 3.63 (t, 1H, J-12 Hz), 4.22 (m, 1H), 7.23-7.77 (m, 9H), 8.53 (d, 1H, J = 6 Hz). (MALDI-T0F) calculated for C2QH23N 303S: 386.2 (M + H). Found: 386.2.

Example 25 In Vitro Inhibition of Purified Enzymes The ease of the compounds of the present invention to act as inhibitors of thrombin, factor Xa and the catalytic activity of plasmin is evaluated by determining the concentration which inhibits the activity of the enzyme by 50% using human enzymes. purified. The concentration of the added inhibitor that causes a 50% decrease in the initial rate of hydrolysis is defined as the value l ^ n * All assays are based on the ease of the test compound to inhibit the hydrolysis of a p-nitroanilide sub-tract of the peptide. In a typical experiment, the appropriate substrate is prepared in DMSO, and diluted in an assay buffer consisting of 50 mM HEPES and = 130 mM NaCl at a pH of 7.5. The final concentration for each of the substrates is listed - below. All concentrations of the substrate are at least 10 times lower than Km to ensure that the inhibition is competitive. The test compounds are prepared as 1 mg / ml solutions in DMSO, and 3 further 10-part dilutions are prepared. The enzyme solutions are prepared at the concentrations listed below in the assay buffer.

In a typical ICc-n determination, in each well of a 96-well plate, 280 μL of subtracted solution, 10 μL of inhibitor solution are pipetted, and the plate is left to thermally equilibrate at 37 ° C in a Reader. of Molecular Devices Plate for at least 10 minutes. The reactions are initiated by the addition of an aliquot of 20 μL of enzyme, and the increase in absorbance at 405 nm is recorded for 15 minutes. The corresponding data less than 1 * of the hydrolysis of the total substrate is used in the calculations. The rate ratio (the ratio of the change in absorbance as a function of time) for a sample that does not contain an inhibitor, and is plotted as a function of concentration of the inhibitor. The inveism of the slope is the concentration of the inhibitor which produces a 50% decrease in the activity of the enzyme. This concentration is referred to as the Thrombin The activity of thrombin is evaluated as the facility to hydrolyze the N-benzoyl-Fe-Val-Arg-p-nitroanilide sub-tract (BZ-Fe-Val-Arg-pNa), and is obtained from Sigma Chemical Company (St. Louis, M0), the substrate solutions are prepared at a COJI 60 M concentration (60 μM = 1.2 mM) in the test buffer. The final DMSO concentration is 0.3%. Human alpha-thrombin is obtained from Enzyme Research Laboratories, Inc., and diluted in a test buffer at a concentration of 1.2 μM. The final reagent concentrations are: [thrombin] = 36 nM, [Bz-Fe-Val-Arg-pNa] = 66 μM, [inhibitor] = 60 to 0.06 iM.

Factor Xa The activity of factor Xa is evaluated as the facility to hydrolyze the Bz-Ile-Glu-Gli-Arg-pNa sub-strand, and is obtained from Sigma. The solutions of the substrate are prepared at a concentration of 26 μM (26 μM = 1.3 mM) in a test buffer. The final DMSO concentration is 0.3%. Activated factor Xa is obtained from Enzyme Research Laboratories, Inc., and diluted in a test buffer at a concentration of 12 μM. The final reagent concentrations are: [.factor XaJ = 10 nM, [Bz-Ile-Glu-Gli-Arg-pNa] = 26 uM, [inhibitor] = 60 has-ta 0.06 μM.

Plasmin The activity of plasmin is evaluated co-or the facility to hydrolyze the substrate Tos-GÜ- Pro-Lis-pNa, and is obtained from Sigma. The substrate solutions are prepared at a concentration of 22 μM (22 μM K = 240 μM) in a test buffer. The final DMSO concentration is 0.3%. Purified human plasmin is obtained from Enzyme Research Laboratories Inc., and diluted in a test buffer at a concentration of 1.2 μM. The final reagent concentrations are: Tplas- raine] = 15 nM, [Bz-Ile-Glu-Gli-Arg-pNal = 26 μM, [inhibitor] = 60 to 0.06 μM.

The results obtained using the compounds 14, 16, 27, 32, 20, 22 and 31 are given in Table 1.

Table 1 The results indicate that the compounds of the present invention are highly selective and potent factor Xa inhibitors.

Having now fully described this invention, it will be understood by these. specialty - ordinary that the same can be done within a broad and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any modality thereof. All patents and publications cited herein are hereby incorporated by reference herein in their entirety.

It is noted that with respect to this date, the best method known to the applicant to carry out the said invention is that which is clear from the present description of the invention.

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

Claims (19)

R IVTNDICACIONFS

1. A compound that has the Formula T or pharmaceutically acceptable salts thereof; characterized in that R is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; 2 R "is one of hydrogen, alkyl, cycloalkyl, aryl or aralkyl; 3 R is one of hydrogen, hydroxy, or alkoxy, is one of -NH, phenyl, or heterocyclic Co ip Which has one or two nitrogen atoms , wherein said phenyl and said het rocycle C,) (1) are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, dialkylamino, aminoalyl, monoalkylaminoalkyl, and / or dialkylaminoalkyl. X is one of -CH2 or -C (0) -; n is from zero to 11, and where X is attached to the benzene ring in an ortho-, meta- or para- position to the sulfonylamino group; 4 3 given that when R is -NH ?, then R is hydrogen and n is other than zero, and also given that when R 3 is hydroxy or alkoxy, then R4 is other than -NH.-,, and n is other than zero Also, given that when R is hydrogen or methyl, while P is hydrogen, R is pyridyl, X is -C (0) -, and n is zero or one, then R is another -that phenyl unsubstituted.

2. The compound according to claim 1, characterized in that R 1 is optionally substituted aryl 6-1; is one of hydrogen, C 1-8 alkyl 'C' t3-a8 aryl cycloalkyl 6-l129 R is one of hydrogen, hydroxy or C.sub.1 -C0 alkoxy; R is one of -NW phenyl, piperidinyl, 7 ?. quinuclidinyl or pyridyl, wherein said phenyl and pyridyl are optionally substituted with one or two of halogen, hydroxy, alkoxy C, Q, amino, mono (C,,) alkylamino, di (C,,) alkylamino, amino (C , ,) I rent; X is -C (0) -; and n is zero to eight.

3. The compound according to claim 2, characterized in that R is aryl C,, n which is optionally substituted amino.

4. The composition in accordance with claim 2, characterized in that it is phenyl, aminophenyl or naphthyl; is hydrogen C 1-4 alkyl is hydrogen, hydroxy C 1-4 alkoxy * R is one of -H 2, phenyl, pyridyl, 3-hydroxyphenyl, 4-hydroxy phenyl, 4-hydroxy-3-methoxyphene, 3- hydroxy-4-methoxyphene, 4-dimethylaminophenyl and 3-aminomethylphenyl, when R is optionally substituted phenyl or substituted p-pyridyl ODC, the most preferred values of n include zero and one.

5. The compound according to claim 4, step 4, characterized in that R is -NH ", and n is from 1-i.

6. The compound according to claim 5, characterized in that n is one of 3, 4 or 7.

7. The compound according to claim 4, characterized in that R is one of, pyridyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-dimethylamino phenyl and -aminometilfení lo, and n is one of zero or one.

8. The compound according to claim 1, characterized in that it is one of 3 - [(2-naphthalenylsulfonyl) amino] -N- [2-hydroxy-2- (3'-hydroxy-phenyl) -aminoamide; naphthalenylsulfonyl) amino] -N- [2-hydroxy-2- (4 '-hydroxyphenyl) -ethyl-benzamide; 3 - [(2-na phthaleni: sulphonic acid) araino] -N- [' - [(N ', N' - dimethylamino) -phenyl] methyl] benzamide; 3- [(2-naphthalenylsulfonyl) amino] -M - [(4-amidinoamino) butyl] enzamide; 3 - [(phenylsulphyl) aminoJ-N - [(4-hydroxy -3-methoxy phenyl) methyl] benzamide; 3- [(phenylsulfonyl) aminoJ-N- [2-hydroxy-2- (3'-hydroxyphenyl) ethylJ-benzamide; 3 - [(phenylsulfonyl) amine-N- [2- hydroxy-2- (4'-hydroxy-3'-methoxy-phenyl) -ethyl] -en-enoamide; 3- [(phenylsulfonyl) amino] -I- [2- (3 '-hydroxy-4'-methoxyphenyl) ethyl] benzamide; [(phenylsulfonylDamino] -N - [(3'-B0C-aminomethylphenyl) methyl-1-benzamide; salt of 3 - [(phenyl sulfonyl) amino] - [(3'-aminomethylpheniDmethyl-eneamide; 3 - [(2-naphthalenylsulfonyl ) amino] -N - [(2'-pyridyl) methyl-J-benzamide; 3 - [(2-naphthalenylsulfonyl) amino] -N- [(3'-amino methylphenyl) methyl] benzamide; 3 - [(phenylsulfonyl) amino1-N- (4-aminobutyl) benzamide; 3 - [(3'-aminophenylsulfonyl) amino] -N'-r 4 '- T (N', N'-dimethylamino) -phenylmethyl] benzamide; 3 - [(2-naphthalenylsulfonylDamino] -N- (5-aminopentyl) benzamide; or 3 - [(2-naphthalenylsulfonyl) amino] -N- (8-aminooctyl) benzamide.

9. The compound according to claim 1, characterized in that it is 3-T (2-naphthalene, fonulyl) amino] -N- [2-hydroxy-2- (3'-hydroxyphenyl) ethyl-benzamide.

10. The compound according to claim 1, characterized in that it is 3 - [(2-naphthalenylsulfonyl) amino] -N- [4 '- [(N', N * -diemthylamino) phenyl] methyl] benzamide.

11. The compound according to claim 1, characterized in that it is 3 - [(2-naphthalenylsulfonylDamino] -N - [(2'-pyridyl) methyl benzamide,

12. The compound according to the claim is 3- [(2-naphthalenylsulfonyl) aminoJ-N- (5-aminophenyl) benzamide.

13. The compound according to claim 1, characterized in that it is 3 - [(phenyl sulfonyl) aminoJ-N - [(4-hydroxy-3'-methoxyphenyl) methyl] benzamide.

14. The compound according to claim 1, characterized in that it is 3 - [(phenyl sulfonyl) amino] -N- [2-hydroxy-2- (4'-hydroxy-3'-methoxyphenyl) -ethyl-benzamide.

15. The compound according to the claim is 3- [(3'-aminophenylsulfonyl) aminoJ-N- '-L (N', N'-dimethylamino) phenylmethyl] benzamide.

16. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1.

17. The pharmaceutical composition according to claim 8, characterized in that it also comprises a pharmaceutically acceptable carrier or diluent.

18. A method of treating thrombosis, ischemia, attack, restenosis or inflammation, characterized in that it comprises the administration to a mammal of said treatment of a therapeutically or prophylactically effective amount of a compound having the Formula I: or pharmaceutically acceptable salts thereof; wherein R is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; 2 R is one of hydrogen, alkyl, cycloalkyl, aryl or aralkyl; is one of hydrogen, hydroxy alkoxy R is one of -NH phenyl, or heterocycle C,] n having one or two nitrogen atoms, wherein said phenyl and said heterocycle C _? r | they are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamine, dialkylamino, aminoalkyl, monoalkylaminoalkyl, and / or dialkylaminoalkyl; X is one of -CH2 ~ or -C (0) -; n is from zero to 11; and wherein X is attached to the benzene ring in an ortho-, meta- or para- position to the sulfonylamino group; 4 3 given that when R is - \ 'H9, then R is hydraulic and n is other than zero; and also given that how 3 4 of R is hydroxy or alkoxy, then R is other than -NH ,,, and n is other than zero.

19. The method according to claim 18, characterized in that said compound administered to the mention i. mammal is one of 3-L (2-naphthalenylsulfonyl) aminoJ- \ '- IO-hydroxy-2- (3, -hydroxy phenyl) ethyl] benzamide; 3- [(1-v. '' F? Lenylsulfonyl) amino] - - [2-hydroxy-2- (4'-hydroxypheni I '* •• ri' Jbenzamide; 3- [(2-naphthalenylsulfonyl) amino] - \ '- [-' - [i \ ',' -dimethylamino) phenylJ me il] benzamide; 3- [(2-naphthaleniulphyl) ami] - - [(4-a -dinoaminobutyl] benzamide; 3- (phenylsulfonyl) amino] - [- [(4-hydroxy-3-methoxyphenyl) methyl] benzamide; [(phenyl sulphonyl) amino] -N- [2-hydroxy-2- (3'-hydroxyphenyl) ethyl] benzamide; 3 - [(phenylsulfonyl) aminol-N-r2-hydroxy-2- (4'-hydroxy) 3'-methoxyphenyl) ethyl] benzamide; 3 - [(phenylsulfonyl) amino] -N- [2- (3 '-hydroxy-4' -methoxy phenyl) ethyl] benzamide; 3 - [(phenylsulfonyl) amino] -N- [(3'-BOC-aminomethylphenyl) methyl] benzamide; 3 - [(phenyl sulfonyl) amino] -N - [(3'-aminomethylphenyl) methyl] benzamide hydrochloride salt; 3 - [(2-naphthalenylsulfonyl) amino] -N - [(2'-pyridyl) methyl benzamide; 3 - [(2-naphthalenylsulfonyl) aminol-Nr ('-aminomethyl-phenyl] methyl] benzamide; 3- [(phenylsulfonyl) amino] -N- (4-aminobutyl) ) benzamide; 3 - [(3'-aminophenylsulfonyl) amino] -N- [4 '- [(',, -dimethylamino-) phenyl] methyl] benzamide; 3- [(2-naphthalenylsulphyl) amino] -N- (5-aminophenyl) benzamide; or 3 - [(2-naphthalenylsulfonyl) amino] -N- (8-aminooctyl) benzamide. SUMMARY OF THE INVENTION The present invention is directed to inhibitors of non-peptic factor Xa, which are useful for the treatment of occlusive-thrombotic disorders of the vein and the artery. Factor Xa inhibitors provide structure compounds (I) or pharmaceutically acceptable salts thereof; wherein R is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heter 2 aryl or substituted heteroaryl; R is a hydrogen, alkyl, cycloalkyl or aryl; R "is one of 4 hydrogen, hydroxy, or alkoxy; P is one of -NH", -phenyl or pyridyl, wherein said phenyl and said pipdoyl are optionally substituted-with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino, monoa lq ui lami no, dialkylamino, aminoalkyl, monoalkyl laminoa lchi lo and / or dialkylaminoalkyl, X is one of -CH-- or -C (0) -; and n is from zero to 11; that when R is - H ", then R is hydrogen and n is other than zero, and am 3 well that when R is hydroxy or alkoxy then R is other than - N ^ 9 -, an n is other than zero. 10 15