WO2011061760A1 - Novel antithrombotic agents - Google Patents

Novel antithrombotic agents Download PDF

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WO2011061760A1
WO2011061760A1 PCT/IN2010/000744 IN2010000744W WO2011061760A1 WO 2011061760 A1 WO2011061760 A1 WO 2011061760A1 IN 2010000744 W IN2010000744 W IN 2010000744W WO 2011061760 A1 WO2011061760 A1 WO 2011061760A1
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methyl
phenyl
carboxamide
thiophene
cyclopropyl
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PCT/IN2010/000744
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French (fr)
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Vrajesh B. Pandya
Bhavesh M. Parmar
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Cadila Healthcare Limited
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

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Abstract

The present invention relates to novel derivatives of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

Description

NOVEL ANTITHROMBOTIC AGENTS
FIELD OF INVENTION
The present invention relates to novel derivatives of the general Formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.
The present invention is directed to compounds, which causes inhibition of factor Xa, & which can be used to treat diseases related to thrombotic disorders.
Figure imgf000002_0001
[I]
BACKGROUND OF THE INVENTION
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex, which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin, which polymerizes to form insoluble fibrin. Factor Xa can be activated by two distinct complexes, by tissue factor-Vila complex on the "Xa burst" pathway and by the factor IXa-VIIIA complex (TENase) of the "sustained Xa" pathway in the coagulation cascade. After vessel injury, the "Xa burst" pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the "sustained Xa" pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the "Xa burst" pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin
l activates protein C, the in vivo anti-coagulant inactivator of factors Va and Villa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteolycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique "tethered ligand" thrombin receptor {Cell 1991; 64: 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
U.S 5576343 describes aromatic amidine derivatives as anticoagulants and also as inhibitors of Factor Xa. U.S 5691364 describes benzamidine derivatives as anti- coagulants.
WO9900121 describes 1, 2-diaminocompounds as inhibitors of Factor Xa. U.S 6140351 describe ortho anthranilamide derivatives as anticoagulants. WO2004026816 describes aromatic benzoate derivatives as Liver X-receptor modulators. WOO 119788 describes benzamide and related inhibitors of Factor Xa
However, the therapeutic potential of many of these compounds to treat diseases has not yet been proven and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, having either lesser side effects or require a lower dosage regime etc.
We herein disclose novel compounds of formula (I), which shows strong anticoagulant effect through its highly specific and reversible FXa-inhibiting activity and is useful as a drug for the prevention and treatment of various thrombosis and embolism-based diseases
The novel compounds of the present invention have a high anticoagulant capacity based on its excellent FXa inhibition activity. The invention also relates to an anticoagulant, or a thrombosis- or embolism preventing or treating agent that contains the novel compounds of formula (I) or a salt thereof of the present invention as an active ingredient. This invention is also directed to pharmaceutical compositions containing the compounds of the invention and methods of using the compounds to treat disease-states characterized by thrombotic activity. SUMMARY OF THE INVENTION
The present invention discloses novel compounds as defined by the general formula (I) that are factor Xa inhibitors and are useful for the prevention and treatment of thrombin-related disorders. The compounds of the present invention are useful in the treatment of human and/or animal body by inhibition of factor Xa. The compounds of this invention are therefore suitable for the prevention and treatment of disease states that are characterized by thrombin activity.
The main objective of the present invention is to provide novel substituted compounds represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.
In an embodiment of the present invention is provided a process for the preparation of novel compounds represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts.
In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In an embodiment the compounds of general formula (I) are useful in the treatment of disease related to thrombotic disorders
The above and other embodiments are described hereinafter.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compounds of the general Formula (I),
Figure imgf000004_0001
and their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, wherein 'B' at each occurrence independently represents a halogen atom selected from F, CI, Br or I; preferred halogens may be selected from chloro and bromo; p represents an integer from 0-3;
'A' represents the group -NR3R4, wherein
i) R3 and R4 independently represents hydrogen, cyano or the groups acyl, alkylsulfonyl, (Ci-C10) alkyl, (C3-C10) cycloalkyl groups, wherein the alkyl chain may further optionally either contain from 1-3 heteroatoms selected from O, S or the groups carbonyl or iminocarbonyl, or the group NRgRb, wherein RaRt, at each occurrence is independently selected from H, (Ci-C3)alkyl groups, (C3-C10) cycloalkyl groups, provided that the alkyl chain does not include a S-S, S-O, or O-O bond; preferred R3 and R4 groups may be selected from hydrogen, cyano, (C1-C10) alkyl, (C3-C10) cycloalkyl groups; or,
ii)R3 and R4 together with the nitrogen atom can be cyclised to form a 4 to 8 membered ring, which may be optionally substituted, wherein the ring may further optionally contain one or more heteroatoms selected from O, S or the group representing NRc, wherein Rc represents H or (C C6)alkyl group and further the ring representing -NR3R4 may optionally include one or more double bonds & wherein the ring may further be substituted with hydroxyl, oxo, amino, alkyl, acyl, alkoxy, iminocarbonyl, iminocarbonyl, acylamino, alkylamino, aminoalkyl, mono, di or trisubstituted amino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonylamino, alkylsulfonyl, aminocarbonyl derivatives;; preferred ring systems may be selected from 5-6 membered ring containing N and O atom and preferred ring substitutions may be selected from oxo, iminocarbonyl or aminocarbonyl groups;
'X' represents oxygen or the group -NR2, wherein R2 represents hydrogen, cyano or the groups selected from (Ci-C6)alkyl, (C3-C]0)cycloalkyl, (Ci-C6)heteroaryl, (Ci-C6)aryl, aralkyl, heterocycle, heteroarylalkyl, heterocyclylalkyl, acyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, aminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aminosulfonyl and alkylsulfonyl derivatives, each of these may further be optionally be substituted; R1 at each occurrence is independently selected from hydrogen, halogen, cyano, optionally substituted mono, di or trisubstituted amino, optionally substituted groups selected from (Ci-C6)alkyl, (Ci-C6)alkoxy, alkylsulfonyl, aminosulfonyl, carbocyclic or heterocyclic groups, each of these groups may further be substituted;
'n' represents integers from 1- 4 and 'm' represents integers from 1-2. When any of the groups mentioned above are substituted, except otherwise stated, the the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, heteroarylthio, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, heteroarylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, heteroarylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, heteroarylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfinyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives;
Preferred substituents on any of the groups mentioned anywhere in the specification, unless otherwise specifically mentioned, at each occurrence is independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino groups.
In a further embodiment the groups, radicals described above may be selected from:
- the "alkyl" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to -ten carbons, selected from methyl, ethyl, n-propyl, wo-propyl, w-butyl, sec-butyl, tert-b tyl, amyl, t-amyl, w-pentyl, n- hexyl, and the like; the "cycloalkyl", or "alicyclic" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to ten carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
the "aralkyl" group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an alkyl radical, as define above, more preferably groups selected from benzyl, napththyl, and the like
the "alkoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n- propoxy, wo-propoxy, n-butoxy, /-butoxy, wo-butoxy, pentyloxy, hexyloxy, and the like;
the "aryloxyalkyl" group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached to an alkyl radicals with oxygen as linker, as defined above, more preferably groups selected from phenoxyalkyl and the like;
the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
the "haloalkoxy" group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;
the "aryl" or "aromatic" group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
the "heterocyclyl" or "heterocyclic" group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2- oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; In one embodiment, the heterocycle group, wherever applicable, may consists of appropriate number of carbon atoms and include from 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p, p = 0-2, wherein the heterocycle may further be substituted with 1-2 carbonyl or 1-2 iminocarbonyl groups or one or more groups selected from R8 wherein R8 is selected from H, hydroxyl, halogen, cyano, optionally substituted groups selected from (Ci-C6)alkyl, alkoxy, amino, mono, di or trisubstituted amino, hydroxyalkyl, aminoalkyl, heterocyclylalkyl, aminocarbonyl groups;
the "heteroaralkyl" group used either alone or in combination with other radicals, is selected from groups containing an heteroaryl radical, as defined above, attached directly to an alkyl radicals, as defined above, more preferably groups selected from pyridinyl, thiophenyl, and the like;
the "heterocyclylalkyl" group used either alone or in combination with other radicals, is selected from groups containing an heterocycle radical, as defined above, attached directly to an alkyl radicals, as defined above, more preferably groups selected from pyrrolidinyl, piperidinyl and the like;
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin);
the "heteroaryl" or "heteroaromatic" group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
the groups "heteroaryloxy", "heteroaralkoxy", "heterocycloxy", "heterocylylalkoxy" are selected from suitable heteroaryl, heteroarylalkyl, heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom;
the "acyl" group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, /so-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
the "mono-substituted amino" group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (Ci- C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n- propylamine, «-butylamine, w-pentylamine and the like;
the 'disubstituted amino" group used either alone or in combination with other radicals, represents an amino group, substituted with two radicals that may be same or different selected from (CpCeialkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like; the "acylamino" group used either alone or in combination with other radicals, is selected from groups containing an acyl group, as defined above, attached to an amino group, as defined above, more preferably groups selected from acetamido and the like;
the "alkylamino" used either alone or in combination with other radicals, represents an alkyl group, as defined above, linked through amino having a free valence bond from the nitrogen atom such as methyl amino, ethyl amino and the like;
the "hydroxyalkyl" group used either alone or in combination with other radicals, is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like;
- the "alkoxyalkyl" group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like;
- the "aminocarbonylamino", "dialkgroups used alone or in combination with other radicals, is a carbonylamino (-CONH2) group, attached to amino(NH2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above; - the "alkoxycarbonylamino" group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like;
- the "aminocarbonyl" group used either alone or in combination with other radicals, may be selected from 'aminocarbonyl', 'aminocarbonylalkyl", "n- alkylaminocarbonyl", "N-arylaminocarbonyl", "Ν,Ν-dialkylaminocarbonyl", "N- alkyl-N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl", and "N-alkyl- N-hydroxyaminocarbonylalkyl", each of them being optionally substituted;
- the "alkoxycarbonyl" group used either alone or in combination with other radicals, is selected from groups containing an alkoxy group, as defined above, attached to carbonyl group, as defined above, more preferably groups selected from -COOCH3, -COOC2H5 and the like.
- the "arylcarbonyl" group used either alone or in combination with other radicals, is selected from groups containing an aryl group, as defined above, attached to carbonyl group, as defined above, more preferably groups selected from benzoyl, napthoyl and the like;
- the "heterocyclyl carbonyl" group used either alone or in combination with other radicals, is selected from groups containing an heterocyclyl group, as defined above, attached to carbonyl group, as defined above, more preferably groups selected from pyridinoyl, thiophenoyl, and the like;
- the "cycloalkylcarbonyl" group used either alone or in combination with other radicals, is selected from groups containing an cycloalkyl group, as defined above, attached to carbonyl group, as defined above, more preferably groups selected from cyclopropanoyl, cyclopentanoyl and the like; - the term "aminooxy" represents an amino group as defined above attached to an oxygen atom, such that oxygen acts as the point of attachement;
- the "aminosulfonyl" group used either alone or in combination with other radicals, may be selected from 'aminosulfonyl', 'aminosulfonylalkyl", "n- alkylaminosulfonyl", "N-arylaminosulfonyl", "Ν,Ν-dialkylaminosulfonyl", "N- alkyl-N-arylaminosulfonyl", "N-alkyl-N-hydroxyaminosulfonyl", and "N-alkyl-N- hydroxyaminosulfonylalkyl", each of them being optionally substituted;
- the "sulfonyl" group or "sulfones derivatives" used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical -S02-, or RxS02-, where Rx is as defined above. More preferably, the groups may be selected from "alkylsulfonyl" wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl" wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
Preferred compounds according to the present invention include but not limited to:
5 -chloro-N-((3-(4-(l -((dimethylam ino)methyl) cyclopropyl) phenyl)-2-oxooxazolidin- 5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-( 1 -((4-methylpiperazin- 1 -yl)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((4-hydroxypiperidin-l-yl) methyl) cyclo propyl) phenyl) - 2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((diethylamino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5- yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-(((2-hydroxyethyl) amino) methyl) cyclo propyl) phenyl)- 2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-(morpholinomethyl) cyclopropyl) phenyl) - 2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((isopropylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin- 5-yl)methyl)thiophene-2-carboxamide; 5-chloro-N-((2-oxo-3-(4-(l-(pyrrolidin-l- ylmethyl) cyclo propyl) phenyl) oxazolidin- 5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((2-oxo-3-(4-(l-((3-oxopiperazin-l-yl) methyl) cyclopropyl) phenyl) oxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((2-oxo-3-(4-(l-(piperidin-l-ylmethyl) cyclopropyl) phenyl) oxazolidin-5- yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((dimethylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
(-)-5-chloro-N-((2-oxo-3-(4-(l-(pyrrolidin-l-yImethyl)cyclopropyl)phenyI)oxazolidin- 5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((ethylamino)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((diethylamino)methyl)cyclopropyl)phenyl)-2-oxooxazolidin- 5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((methylamino)methyl)cyclopropyl)phenyl)-2-oxooxazolidin- 5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-(((-)-3-(4-( 1 -(((R)-3-hydroxypyrrolidin- 1 -yl)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((N-methylmethylsulfonamido)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((N-ethylacetamido)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-(((2-hydroxyethyl)(methyl)amino)methyl)
cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-N-((3-(4-(l-((bis(2-hydroxyethyl)amino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)-5-chlorothiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-( 1 -((4-hydroxypiperidin- 1 -yl)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-( 1 -((4-methyl- 1 ,4-diazepan- 1 -yl)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((cyclopentylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-(((2-hydroxyethyl)amino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide; (-)-5-chloro-N-((2-oxo-3-(4-(l -((2-oxooxazolidin-3- yl)methyl)cyclopropyl)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((dimethylamino)methyl)cyclopropyl)-3-fluorophenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((cyclopropylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
(-)-5-chloro-N-((2-(cyanoimino)-3-(4-(l-((N-cyclopropylcyanamido)methyl) cyclopropyl) phenyl) oxazolidin-5-yl) methyl) thiophene-2-carboxamide.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The various alternative routes represent processes for preparing compounds of the present invention and include the preferred modes for preparing the compounds of the invention as known to the inventors. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of one or more of the compounds of the present invention. It is also to be appreciated that the scheme as described may be suitably modified as required, so as to obtain specific compounds of the present invention. Such modifications/alterations should also be considered to be within the scope of the present invention as they are within the perview of a person skilled in the art.
Scheme 1: Synthesis of compounds of general formula (I). (When X=0)
Figure imgf000014_0001
Figure imgf000014_0002
[XII] [I]
•Pht' denotes a phthalimide group; U denotes a suitable leaving group such as halogen, mesyl etc; TV
represents suitable alkyl group
The compound (III) can be obtained by reaction of 1, 2-dibromoethane and potassium hydroxide using general techniques described in Bioorganic and medicinal chemistry 16(2008) 8922-8931. The compounds of general formula (IV) can be obtained by nitration of (ΙΠ) using various techniques reported in literature. Most preferred techniques are nitration with sodium nitrate in sulfuric acid, nitric acid in sulfuric acid etc. The compounds of the general formula (V) are prepared using general procedure for esterification. The compound (VI) can be obtained by reduction of compound (V) using various reducing reagents like SnCl2, H2-Pd-C etc. Compound (VI) may be converted to compound (VII) by coupling with 2-(oxiran-2-ylmethyl) isoindoline-1, 3-dione in suitable protic solvents like ethanol, isopropyl alcohol etc or their suitable mixture.
Compound (VII) is then reacted with 1, Γ-carbonyldiimidazole and catalytic amount of Dimethyl amino pyridine to give compound (VIII) in suitable solvents such as chloroform, THF, DCM etc. Compound (VIII) is deprotected using suitable agents such as aquous methyl amine solution, hyadrazine hydrate in solvents like ethanol, THF etc. or their suitable mixture, to give compound (IX). Compound (IX) on reaction with halogen substituted thiophene carboxylic acid using various amide bond formation techniques as described in Tetrahedron 61 (2005) 10827-10852 provides compound (X). Alternatively, halogen substituted thiophenecarboxylic acid can be converted into its correponding acid chloride derivative which is then reacted with compound (IX) using suitable base and suitable solvent to get compound (X). Preferred bases are TEA, pyridine etc. Preferred solvents are DCM, toluene, and THF etc. or their suitable mixture. The compounds of the formula (XI) can be obtained by treating compound (X) with Lithium borohidride or sodiumborohydride. Preferred solvents are THF, Methanol etc. or their suitable mixture. The compounds of the formula (ΧΠ) can be obtained by treating compound (XI) with several halogenating reagents like phosphorous tribromide; thionyl chloride etc. or alternatively, the hydroxyl group can be converted into a good leaving group (L) mesyl by general procedures known in the literature. The compounds of formula (XII) can be converted to compound (I) using suitable primary or secondary amino compounds. Preferred solvents for this conversion are DMF, DCM, pyridine, toulene, THF and the like or their suitable mixtures.
Scheme 2: Synthesis of compounds of general formula (I). (When X=0)
Figure imgf000016_0001
Alternatively, compound (VI) is reacted with benzyloxy carbonyl chloride to give compound (ΧΙΠ) using base such as TEA, pyridine, K2C03 etc. in solvents like DCM, tolune, THF, water, etc. The compound of the general formula (XTV) is prepared from (ΧΙΠ) by using n-BuLi and R (-) glycidyl butyrate at -78°C in THF. The compounds of the general formula (VIII) are then prepared from (XIV) using pthalimide in mitsunobu reaction conditions. The compound of general formula (VIII) are then converted to (I) by using series of steps as described in scheme 1.
Scheme 3: Synthesis of compounds of general formula (I). (When X = O)
Figure imgf000017_0001
The compounds of general formula (XVI) can be obtained by reduction of mixed anhydride prepaired using methyl chloroformate and preferred reducing reagents are sodium borohydride or lithium borohydride in THF, water or appropriate mixture or using various techniques reported in literature. The compound of the formula (XVH) can be obtained by treating compound (XVI) with several halogenating reagents like phosphorous tribromide; thionyl chloride etc. or alternatively, the hydroxyl group can be converted into a good leaving group (L) such as mesyl by general procedures known in the literature. The compounds of formula (XVII) can be converted to compound (XVni) using suitable primary or secondary amino compounds. Preferred solvents for this conversion are DMF, DCM, pyridine, toulene, THF and the like or their suitable mixtures. Compound (XVIII) is then converted into compound (XIX) by reduction with suitable reducing agents such as H2-Pd-C, amoniumformate-Pd-C etc. in methanol, ethanol or their suitable mixture. Compound (XX),(XXI) and (XXII) are then prepaired by using similar procedure as described in scheme 2. Compound (ΧΧΠ) can be converted to compound (XXIII) using sodium azaide in solvents like DMF, THF etc. or their suitable mixture. The compound (XXIV) can be obtained by reduction of compound (ΧΧΠΙ) using various reducing reagents like sodium borohydride-Pd-C, TPP etc.in methanol, water etc. or their suitable mixture. The compound of formula [I] are then obtained from [XXIV] using similar procedure as described in scheme 1.
Scheme 4: Synthesis of compounds of general formula (I). (When X=NR2)
Figure imgf000018_0001
P] [XXVI]
The compound [XXV] can be obtained by oxazolidone ring opening of compound [I] with potassium ter-butoxide in DMSO and water. Compound [XXV] can be converted in to compound [XXVI] by reacting with cyanogen bromide in suitable solvents such as chloroform, THF, DMF etc. or suitaible mixture. Compound of formula [I] can be obtained by treating [XXVI] with R2-L. Preferred solvents are DMF, DCM, pyridine, toulene, THF and the like or their suitable mixtures and bases such as TEA, pyridine, potassium carbonate etc.where 'L' = suitable leaving group such as halogen etc.
The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scop of the invention.
IH NMR spectral data given in the examples (vide infra) are recorded using a 400
MHz spectrometer (Bruker Topspin 2.0) and reported in δ scale. Tetramethyl silane is used as the internal standard.
EXAMPLE 1
Preparation of 5-chloro-N-((3-(4-(l-((dimethylamino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Step 1: Preparation of l-phenylcyclopropanecarbonitrile
To a stirred solution of phenylacetonitrile (100 g, 0.8547 mol) in aqueous solution of KOH (447g in 420 mL of water) and 2.7g of tetrabutyl ammonium bromide was added 1,2-dibromoethane (147ml, 1.709mol) drop wise by maintaining exothermicity at 50 °C.The reaction mixture was stirred at 50 °C for 1 hr, and then poured in cold water and extracted in diisopropyl ether .Crude product was purified by high vacuum distillation which afforded 90g of colourless liquid compound in 73 % yield.
Step 2: Preparation of l-(4-nitrophenvn cvclopropanecarbonitrile
To a stirred solution of 1-phenylcyclopropanecarbonitrile (90 g, 0.6293 mol) in Sulfuric acid (234 mL, 2.6v/w), was added Sodium nitrate (59g, 0.692 mol) at 0 °C. After stirring at room temperature for 4-5h, reaction mixture was poured in to ice to get solid product. Filteration afforded 60 g of titled compound in 46 % yield.
Step 3: Preparation of ethyl l-(4-nitrophenyl)cvclopropanecarboxylate
To a stirred solution of l-(4-nitrophenyl) cyclopropanecarbonitrile (30 g, 0.1470 mol) in ethyl alcohol (300 mL, lOv/w) was added Sulfuric acid (60mL, 2v/w) at 25-30 °C.After stirring at reflux temperature for lOh, reaction mixture was concentrated and poured in to ice cold water to get solid. Filteration afforded 30 g of title compound in 86 % yield.
Step 4: Preparation of ethyl l-(4-aminophenyl)cvclopropanecarboxylate
To a solution of ethyl l-(4-nitrophenyl)cyclopropanecarboxylate (23 g, 0.0978 mol) in ethyl acetate (230mL, lOv/w) was added stannous chloride hydrate (110 g, 0.489 mol) at 25 °C. The reaction mixture was stirred at 75 °C for 4h. Reaction was diluted with ethyl acetate and made alkaline by using aqueous ammonia solution. Organic layer was separated out. Drying over sodium sulfate and evaporation afforded 18g of titled compound in 89% yield.
Step 5: Preparation of ethyl l-(4-((3-(l, 3-dioxoisoindolin-2-yl)-2-hvdroxypropyl) amino)phenvDcvclopropanecarboxylate
The solution of ethyl l-(4-aminophenyl)cyclopropanecarboxylate (10 g, 0.0487 mol) and 2-(oxiran-2-ylmethyl)isoindoline-l,3-dione (1 1.8g, 0.058mol) in rectified spirit (200 mL, 20v/w) was heated at 80 °C for 15h. Then reaction mixture was cooled to get yellow solid. Filtration afforded 11 g of titled compound in 55 % yield.
Step 6: Preparation of ethyl l-(4-(5-((l,3-dioxoisoindolin-2-yl)methyl)-2- oxooxazolidin-3-yl)phenyl)cvclopropanecarboxylate
To a stirred solution of ethyl l-(4-((3-(l, 3-dioxoisoindolin-2-yl)-2- hydroxypropyl) amino)phenyl)cyclopropanecarboxylate (1 lg, 0.026 mol) in the solvent chloroform (1 lOmL, 10 v/w) was added CDI (1, Γ-carbonyldiimidazole) (8.7 g, 0.0539 mol). Reaction mixture was stirred at 65 °C for 3 hr and then diluted with diluted HC1, extracted with chloroform which on drying over sodium sulfate and evaporation afforded 11 g of title compound in 94% yield.
Step 7: Preparation of ethyl l-(4-(5-(aminomethvD-2-oxooxazolidin-3- vDphenvDcvclopropanecarboxylate
To a stirred solution of ethyl l-(4-(5-((l, 3-dioxoisoindolin-2-yl)methyl)-2- oxooxazolidin-3-yl)phenyl)cyclopropanecarboxylate (lOg, 0.023 mol) in THF (50 mL) was added 40 % aqueous methyl amine solution (lOmL, lv/w) at 10-15 °C . Reaction mixture was stirred at 25-30 °C for 15 h and then evaporated to dryness. Product was extracted with chloroform (1 L) which on evaporation afforded 6g of title compound in 85% yield.
Step 8: Preparation of ethyl l-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2- oxooxazolidin-3-vOphenyDcvclopropanecarboxylate
To a stirred solution of ethyl l-(4-(5-(aminomethyl)-2-oxooxazolidin-3- yl)phenyl)cyclopropanecarboxylate (6g, 0.0197mol) in DCM (60 mL) was added pyridine (6mL, lv/w). Then slowly added 5-chlorothiophene-2-carbonyl chloride (3.6g, 0.0197mol) at 10-15 °C. Reaction mixture was stirred at 25-30 °C for 4 h. Product was extracted with chloroform which on purification by column chromatography afforded 8g of title compound in 90% yield.
Step 9: Preparation of 5-chloro-N-((3-(4-(l-(hvdroxymethyl) cvclopropyl) phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
To a stirred solution of ethyl l-(4-(5-((5-chlorothiophene-2- carboxamido)methyl)-2-oxooxazolidin-3-yl)phenyl)cyclopropanecarboxylate ( 1 g,
0.0022 mol) in THF (10 mL) was added lithium borohydride (lOOmg, 0.0044mol).
Reaction mixture was stirred at 40-45 °C for 15 h. Reaction mixture was quenched in ice and made acidic by dilute HC1. Product was filtered which on purification by column chromatography afforded 500 mg of titled compound in 55% yield.
Step 10: Preparation of N-((3-(4-n-(bromomethyl)cyclopropyl)phenv0-2- oxooxazolidin-5-yl)methyl)-5-chlorothiophene-2-carboxamide
To a stirring solution of 5-chloro-N-((3-(4-(l-(hydroxymethyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide (270mg, 0.664mmol) in DCM (5 mL) was added triphenyl phosphine (261mg, 0.996mmol). Then slowly added carbon tetrabromide (330mg, 0.996mmol) at 10-15 °C. Reaction mixture was stirred at 40-45°C for 4 h. reaction mixture was purified by column chromatography, which afforded 125mg of titled compound in 40% yield. Step 11: Preparation of 5-chloro-N-((3-(4-(l-((dimethylamino) methyl) cvclopropyl) phenyl) - 2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
To a stirred solution of N-((3-(4-(l-(bromomethyl) cyclopropyl) phenyl)-2- oxooxazolidin-5-yl) methyl)-5-chlorothiophene-2-carboxamide (200mg, 0.425 mmol) in THF (0.5 mL) was added aq.dimethyl amine solution (0.5mL). Reaction mixture was stirred at 25-30 °C for 4 h. Product was extracted with chloroform which on purification by column chromatography afforded lOOmg of titled compound in 54% yield.
'HNMR
(DMSO,400 MHz) :8.97(1H, t), 7.68-7.67(lH, d), 7.39-7.37(2H, dd), 7.30-7.28(2H, dd), 7.18-7.17(1H, d), 4.81-4.78 (1H, m), 4.15-4.11(1H, t), 3.81-3.77(1H, m), 3.58- 3.56(2H, t), 2.41(2H, bs), 2.07(6H, s), 0.79-0.0.77(2H, t), 0.68-0.65(2H, t).
The following compounds were prepared using similar procedures to those discribed for Example 1.
EXAMPLE 2
Preparation of 5-chloro-N-((3-(4-(l-((4-methylpiperazin-l-yl) methyl) cyclo propyl)phenyl)- 2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 1 1 by using compound [XII] and 1-methylpiperazine in 33% yield.
'HNMR
(DMSO, 400 MHz) :8.97-8.94(lH, t), 7.68-7.67(1 H, d), 7.39-7.37(2H, d), 7.29- 7.27(2H, d), 7.18-7.17(1H, d), 4.81-4.77(1H, m), 4.16-4.11(1H, t), 3.81-3.78(1H, m), 3.58-3.56(2H, t), 2.45(2H, s), 2.37(2H, bs), 2.22(3H, bs), 2.08(3H, s), 0.77-0.75(2H, t), 0.68-0.65(2H, t).
EXAMPLE 3
Preparation of 5-chloro-N-((3-(4-(l-((4-hydroxypiperidin-l-yI) methyl) cyclo propyl) phenyl) - 2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 11 by using compound [XII] and piperidin-4-ol in 28% yield.
'HNMR
(DMSO, 400 MHz) :8.97-8.96(lH, t), 7.68-7.67(1 H, d), 7.39-7.37(2H, dd), 7.29- 7.27(2H, dd), 7.18-7.17(1H, d), 4.80-4.79(lH, m), 4.44-4.43(lH, d), 4.16-4.1 1(IH, t), 3.81-3.78(1H, m), 3.58-3.56(2H, t), 2.74-2.72(2H, bd), 2.42(2H, s), 1.94(2H, t), 1.61-
1.59(2H, t), 1.23-1.2 l(2H, t),0.76-0.74(2H, t), 0.66-0.64(2H, t). EXAMPLE 4
Preparation of 5-chloro-N-((3-(4-(l-((diethylamino) methyl) cyclopropyl) phenyl)- 2-oxooxazolidin-5-yI) methyl) thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 1 1 ; by using compound [XII] and diethylamine in 30% yield.
'HNMR
(DMSO, 400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.39-7.37(2H, d), 7.29- 7.27(2H, d), 7.18-7.17(1H, d), 4.82-4.76(lH, m), 4.15-4.1 1(1H, t), 3.81-3.77(1H, m),
3.58- 3.56(2H, t), 2.65(2H, s), 2.45-2.42(4H, bd), 0.84-0.80(6H, t), 0.72-0.67(4H, d). EXAMPLE 5
Preparation of 5-chloro-N-((3-(4-(l-(((2-hydroxyethyl) amino) methyl) cyclo propyl) phenyl)- 2-oxooxazoIidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 11 ; by using compound [XII] and 2-aminoethanol in 41% yield.
'HNMR
(DMSO, 400 MHz) :8.95(1H, t), 7.67-7.66(lH, d), 7.42-7.39(2H, d), 7.30-7.28(2H, d), 7.18-7.17(1H, d), 4.80(1H, m), 4.51(1H, s), 4.13(1H, t), 3.90(1H, m), 3.58-3.56(2H, t), 3.38(2H, m), 2.70(2H, s), 2.55-2.52(2H, m), 0.74-0.70(4H,bd).
EXAMPLE 6
Preparation of 5-chloro-N-((3-(4-(l-(morpholinomethyl) cyclopropyl) phenyl) - 2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 1 1; by using compound [XII] and morpholine in 50% yield.
JHNMR
(DMSO, 400 MHz) :8.97-8.94(lH, t), 7.68-7.67(lH, d), 7.40-7.37(2H, d), 7.31- 7.29(2H, d), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.16-4.11(1H, t), 3.82-3.78(lH, m),
3.59- 3.56(2H, t), 3.45-3.43(4H, t), 2.35(4H, bs), 0.78-0.75(2H, t), 0.69-0.67(2H, t). EXAMPLE 7
Preparation of 5-chloro-N-((3-(4-(l-((isopropylamino)methyl)cyclopropyl)phenyl)- 2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example I; step 1 1; by using compound [XII] and propan-2-amine in 42% yield.
'HNMR (DMSO, 400 MHz) :9.00-8.97(lH, t), 7.69-7.68(1 H, d), 7.45-7.43(2H, d), 7.34- 7.32(2H, d), 7.18-7.17(1H, d), 4.82-4.79(lH, m), 4.16-4.12(1H, t), 3.82-3.78(lH, m), 3.59-3.56(2H, t), 2.87(2H, bs), 1.01(6H, bt), 0.85-0.77(4H, bd).
EXAMPLE 8
Preparation of 5-chloro-N-((2-oxo-3-(4-(l-(pyrrolidin-l- ylmethyl) cyclo propyl) phenyl) oxazoIidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 11; by using compound [XII] and pyrrolidine in 55% yield.
'HNMR
(DMSO, 400 MHz) : 8.95(1H, t), 7.67-7.66(lH, d), 7.39-7.37(2H, d), 7.30-7.28(2H, d), 7.18-7.17(1H, d), 4.85(1H, m), 4.15-4.11(1H, t), 3.81-3.77(1H, m), 3.58-3.55(2H, t), 2.55(2H, bs), 2.39(4H, bs), 1.57(4H, bs), 0.75-0.69(4H, bd).
EXAMPLE 9
Preparation of 5-chloro-N-((2-oxo-3-(4-(l-((3-oxopiperazin-l- yl)methyl)cyclopropyl)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 1 1; by using compound [XII] and piperazin-2-one in 74% yield.
'HNMR
(DMSO, 400 MHz) : 8.95-8.94(lH, t), 7.67-7.66(lH, d), 7.62(1H, s), 7.41-7.39(2H, dd), 7.31-7.29(2H, dd), 7.18-7.17(1H, d), 4.81-4.77(1H, m), 4.16-4.11(1H, t), 3.81- 3.78(1H, m), 3.58-3.57(2H, t), 3.01(2H, s), 2.89(2H, s), 2.55(4H, bs), 0.80(2H, s), 0.70(2H, s).
EXAMPLE 10
Preparation of 5-chloro-N-((2-oxo-3-(4-(l-(piperidin-l-ylmethyl) cyclopropyl) phenyl) oxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 1 1 ; by using compound [XII] and piperidine in 55% yield.
'HNMR
(DMSO, 400 MHz) : 8.97-8.94(lH, t), 7.68-7.67(lH, d), 7.39-7.37(2H, d), 7.30- 7.27(2H, d), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.16-4.1 1(1H, t), 3.82-3.78(lH, m), 3.59-3.56(2H, t), 2.42(2H, bs), 2.31(4H, bs), 1.36(4H, bs), 1.31(2H, bs), 0.75(2H, s), 0.66(2H, s). EXAMPLE 11
Preparation of (-)-5-chIoro-N-((3-(4-(l-((dimethylamino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Step 1: Preparation of ethyl l-(4-
(((benzyloxy)carbonyl)amino)phenyl)cyclopropanecarboxylate [XIH]
To a stirring solution of ethyl l-(4-aminophenyl)cyclopropanecarboxylate (62g, 0.3024 mol) and potassium carbonate (62.6g, 0.4536mol) in mixture of THF (626 mL) and water (313mL) was slowly added benzyl choroformate (61.8g, 0.362mol) at 10-15 °C. Reaction mixture was stirred at 20-25 °C for 1 h. Product was extracted with Ethyl acetate to get 88g of titled compound in 85% yield.
Step 2: Preparation of ethyl l-(4-(5-(hvdroxymethyl)-2-oxooxazolidin-3- yl)phenyl)cvclopropanecarboxylate [XIV]
To a stirring solution of isoamyl alcohol 1.58mL (0.0147mol) in 60mL THF at - 78 °C was slowly added 6.2mL [15%W/V (in Hexane)] n-BuLi under nitrogen environment. Then slowly charged l-(4-(((benzyloxy) carbonyl) amino) phenyl) cyclopropanecarboxylate (5g, 0.0147mol) dissolved in 15mL of THF. Again 6.2mL of n-BuLi was added in reaction mix. Then charged R (-) glycidyl butarate (2.05mL, 0.0147mol) at -78 °C and reaction mixture was stirred at room tempreture for lh. Reaction mixture was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate to gave 3.9g titled compound in 86% yield.
Step 3: Preparation of ethyl l-(4-(5-((1.3-dioxoisoindolin-2-yl)methyl)-2- oxooxazolidin-3-yl)phenyl)cvclopropanecarboxylate ΓΥΠΙΙ
To a stirring solution of ethyl l-(4-(5-(hydroxymethyl)-2-oxooxazolidin-3- yl)phenyl)cyclopropanecarboxylate (3.9g, 0.0128mol), pthalimide (1.88g, 0.0128mol), triphenylphosphine (4.02g, 0.0153mol) slowly charged diisopropylazodicarboxylate (3.09g, 0.0153mol) at 10-15 °C under nitrogen environment and stirred for 4h. Extracted with ethyl acetate and purified through coloum to get 4.6g compound in 80% yield.
Step 4: Preparation of Ethyl l-(4-(5-(aminomethyl)-2-oxooxazolidin-3- yDphenvDcvclopropanecarboxylate [IX]
Prepared using similar procedure as that of example 1; step 7; by using compound [VIII] and Aq. Methyl amine solution in 69% yield.
Step 5: Ethyl l-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin-3- yDphenvDcvclopropanecarboxylate [X] Prepared using similar procedure as that of example 1; step 8; by using compound [IX] and 5-chlorothiophene-2-carbonyl chloride in 69% yield.
Step 6: 5-chloro-N-((3-(4-n-(hvdroxymethvD cyclopropyl) phenyl)-2-oxooxazolidin-5- yl) methyl) thiophene-2-carboxamide ΓΧΙ1
Prepared using similar procedure as that of example 1; step 9; by using compound [X] and lithium borohydeide in 53% yield.
Step 7: N-((3-(4-(l-(bromomethyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl)-5-chlorothiophene-2-carboxamide [XII]
Prepared from [XI] using similar procedure as that of example 1 ; step 10; in 47% yield.
Step 8: 5-chloro-N-((3-(4-(l-((dimethylamino) methyl) cyclopropyl) phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 11 ; by using compound [XII] and aq.dimethyl amine (40%) solution in 69% yield.
'HNMR
(DMSO, 400 MHz) :8.973-8.944(lH, t), 7.68-7.67(1 H, d), 7.3(2H, dd), 7.28(2H, dd), 7.187-7.177(1H, d), 4.815-4.779(1 H, m), 4.156-4.1 1 1(1H, t), 3.812-3.775(1H, m), 3.588-3.56(2H, t), 2.41(2H, bs), 2.084(6H, s), 0.79-0.65(4H, bd).
S.O.R= -31.74° in 0.1% in DMSO at 25°C)
The following compounds were prepared by using similar procedures to those discribed above and also in the general schemes described earlier
EXAMPLE 12
Preparation of (-)-5-chloro-N-((2-oxo-3-(4-(l-(pyrrolidin-l- ylmethyl)cyclopropyl)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 1 1; by using compound [XII] and pyrolidine in 72% yield.
'HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.38-7.36(2H, dd), 7.30- 7.27(2H, dd), 7.18-7.17(1H, d), 4.81-4.76(1H, m), 4.15-4.11(1H, t), 3.81-3.77(1H, m), 3.58-3.55(2H, t), 2.65(2H, s) ,2.38(4H, s), 1.56(4H, d), 0.76-0.74(2H, bs), 0.73- 0.68(2H, bs).
S.O.R = -34.9° (0.1% in DMSO) at 25°C) EXAMPLE 13
Preparation of (-)-5-chloro-N-((3-(4-(l-((ethylamino)methyl)cyclopropyl)phenyl)- 2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 11; by using compound [XII] and Aq. ethylamine (40%) in 36% yield.
'HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.41-7.38(2H, dd), 7.29- 7.26(2H, dd), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.15-4.11(1H, t), 3.81-3.77(1H, m), 3.58-3.56(2H, t), 2.66(2H, s), 2.49-2.48(lH, m), 0.94-0.90(3H, t), 0.75-0.72(2H, q), 0.70-0.66(2H, q).
S.O.R = -35.83° (0.1% in DMSO at 25°C)
EXAMPLE 14
Preparation of (-)-5-chloro-N-((3-(4-(l-
((diethylamino)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 1 1; by using compound [XII] and diethylamine in 30% yield.
!HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.39-7.38(2H, d), 7.29-7.28(2H, d), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.15-4.11(1H, t), 3.82-3.77(lH, m), 3.58- 3.56(2H, t), 2.65(2H, s), 2.44(4H, bs), 0.82(6H, bs), 0.72-0.67(4H, bd).
S.O.R = -33.59° (0.1% in DMSO at 25°C).
EXAMPLE 15
Preparation of (-)-5-chloro-N-((3-(4-(l-
((methylamino)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 11; by using compound [XII] and Aq. methylamine (40%) in 40% yield.
'HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.66(1 H, d), 7.40-7.38(2H, dd), 7.28- 7.26(2H, dd), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.15-4.10(1H, t), 3.81-3.77(1H, m), 3.58-3.56(2H, t), 2.62(2H, s) , 2.21(3H, s), 0.75-0.73(2H, bs), 0.69-0.67(2H, bs).
S.O.R = -39.08° (0.1% in DMSO at 25°C). EXAMPLE 16
Preparation of 5-chIoro-N-(((-)-3-(4-(l-(((R)-3-hydroxypyrrolidin-l- yl)methyI)cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2- carboxamide
Prepared using similar procedure as that of example 1 ; step 1 1; by using compound [XII] and (R)-pyrrolidin-3-ol in 56% yield.
1HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.68-7.67(lH, d), 7.38-7.36(2H, dd), 7.29-
7.27(2H, dd), 7.18-7.17(1H, d), 4.81-4.79(1H, m), 4.58-4.57(lH, d), 4.15-4.11(1H, t),
4.07(1H, m), 3.81-3.77(1H, m), 3.58-3.55(2H, t), 2.72-2.68(lH, q), 2.53(2H, s), 2.45-
2;42(2H, m), 2.22-2.19(1H, dd), 1.87-1.82(1H, m), 1.43-1.39(1 H, m), 0.75-0.73(2H, bs), 0.68-0.66(2H, bs).
S.O.R= -27.07° (0.1% in DMSO at 25°C).
EXAMPLE 17
Preparation of (-)-5-chioro-N-((3-(4-(l-((N- methylmethylsulfonamido)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide
To a stirred solution of (-)-5-chloro-N-((3-(4-(l-((methylamino) methyl) cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide [Example 15](50mg, 0.1169mmol) and TEA (18mg,0.178mmol) in DCM (lmL, 20v/w) was added methane sulfonyl chloride (15mg,0.130mmol) at 10°C. Reaction mixture was stirred for 1 h at room tempreture. Then quenched in water and extracted with DCM. Organic layer was washed with brine and dried over sodium sulfate. DCM layer was evaporated to give titled compound 35mg in 59% yield.
'HNMR
(DMSO, 400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.45-7.43(2H, d), 7.35- 7.33(2H, d), 7.18-7.17(1H, d), 4.83-4.78(lH, m), 4.16-4.12(1H, t), 3.84-3.78(lH, m), 3.58-3.55(2H, t), 3.27(2H, s), 2.65-2.64(2H, d), 0.86-0.82(4H, t).
EXAMPLE 18
Preparation of (-)-5-chloro-N-((3-(4-(l-(( -ethylacetamido) methyl)
cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 17; by using compound (-)- 5-chloro-N-((3-(4-(l-((ethylamino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5- yl) methyl) thiophene-2-carboxamide [Example 13] and acetyl chloride in 57% yield. 'HNMR
(DMSO,400 MHz) :8.96-8.93(lH, t), 7.67-7.65(1 H, t), 7.45-7.39(2H, m), 7.31- 7.25(2H, m), 7.25-7.17(lH, t), 4.80-4.79(lH, m), 4.13-4.12(1H, m), 3.81-3.79(1H, t), 3.58-3.56(2H, t), 3.52(1H, s), 3.42(21, s), 3.01-3.08(1H, q), 1.89-1.88(1.5H, d), 1.46(1.7H, s), 1.00-0.93(3H, m), 0.86-0.81(2H, m), 0.80-0.73(2H, m).
EXAMPLE 19
Preparation of (-)-5-chloro-N-((3-(4-(l-(((2- hydroxyethyl)(methyl)amino)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxaraide
Prepared using similar procedure as that of example 1 ; step 1 1 ; by using compound [XII] and 2-(methylamino)ethanol in 65% yield
'HNMR
(DMSO, 400MHz): 8.95(1H, t), 7.676(1H, d), 7.66(2H, dd), 7.398(2H, dd), 7.183(1H, d), 4.81(1H, m), 4.788(2H, m), 4.158(1H, t), 3.801(2H, t), 3.560(2H, m), 2.544(2H, s), 2.281(2H, t), 2.141(3H, s), 0.780(2H, S) 0.684(2H, s).
S.O.R = -31.42° (0.1% in DMSO at 25°C).
EXAMPLE 20
Preparation of (-)-N-((3-(4-(l-((bis(2-hydroxyethyl) amino)methyI)
cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-5-chlorothiophene-2- carboxamide
Prepared using similar procedure as that of example 1; step 1 1 ; by using compound [XII] and 2,2'-azanediyldiethanol in 42% yield
'HNMR
(DMSO, 400MHz): 8.975(1H, t), 7.680(1H, d), 7.411(2H, dd), 7.311(2H, dd), 7.187(1H, d), 4.826(1H, m), 4.762(3H, bs), 3.816(1H, m), 3.78(2H, t), 3.319(4H, s), 0.842(4H, s).
EXAMPLE 21
Preparation of (-)-5-chloro-N-((3-(4-(l-((4-hydroxypiperidin-l- yl)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2- carboxamide
Prepared using similar procedure as that of example 1; step 1 1 ; by using compound [XII] and piperidin-4-ol in 52% yield.
'HNMR (DMSO, 400 MHz) : 8.97(1H, t), 7.681(1H, d), 7.399(2H, dd), 7.297(2H, dd), 7.189(1H, d), 4.81(1H, m), 4.792(1H, s), 4.425(1H, t), .820(1H, m), 3.804(2H, t) 2.752(2H,m), 2.494(3H, s), 1.977(2H, t), 1.615(2H, d), 1.263(2H, bs), 0.849(2H, s), 0.707(2H, s).
S.O.R = -34.52° (0.1% in DMSO at 25°C).
EXAMPLE 22
Preparation of (-)-5-chIoro-N-((3-(4-(l-((4-methyl-l,4-diazepan-l- yl)methyl)cycIopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2- carboxamide
Prepared using similar procedure as that of example 1 ; step 11; by using compound [XII] and l-methyl-l,4-diazepane in 47% yield.
'HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.67(lH, d), 7.41-7.37(2H, dd), 7.29- 7.26(2H, dd), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.15-4.11(1H, t), 3.81-3.77(1H, m),
3.58- 3.56(2H, t), 2.66(6H, s) , 2.49-2.48(4H, m), 0.94-0.90(3H, t),1.59(2H,m) 0.75- 0.72(2H, q), 0.70-0.66(2H, q).
S.O.R= -48.22° (0.1% in DMSO at 25°C).
EXAMPLE 23
Preparation of (-)-5-chloro-N-((3-(4-(l- ((cyclopentylamino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Prepared using similar procedure as that of example 1 ; step 11 ; by using compound [XII] and cyclopentanamine in 67% yield.
1HNMR
(DMSO, 400 MHz) : 8.98-8.95(lH, t), 7.68-7.67(lH, d), 7.42-7.40(2H, dd), 7.3- 7.28(2H, dd), 7.18-7.17(1H, d), 4.82-4.78(lH, m), 4.15-4.1 1(1H, t), 3.80-3.78(lH, m),
3.59- 3.56(2H, t), 3.00(1H, s), 2.74(2H, s), 2.49-2.48(lH, m), 1.68-1.66(2H, d), 1.57- 1.55(2H, t), 1.51-1.5(2H, d), 1.23-1.22(2H, d), 0.79(2H, s), 0.72(2H, s).
S.O.R= -74.52° (0.1% in DMSO at 25°C).
EXAMPLE 24
Preparation of (-)-5-chIoro-N-((3-(4-(l-(((2-hydroxyethyl) amino) methyl) cyclopropyl)phenyl)-2-oxooxazolidin-5-yI)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 11 ; by using compound [XII] and 2-aminoethanol in 45% yield.
'HNMR (DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.41-7.39(2H, d), 7.29-7.27(2H, d), 7.18-7.17(1H, d), 4.81-4.78(1H, m), 4.40-4.37(lH, t), 4.15-4.11(1H, t), 3.81- 3.77(1H, dd), 3.58-3.56(2H, t), 3.38-3.36(2H, m), 2.68-2.66(2H, s), 2.52(2H, m), 0.75- 0.68(4H, dt).
S.O.R= -36.47° (0.1% in DMSO at 25°C).
EXAMPLE 25
Preparation of (-)-5-chloro-N-((2-oxo-3-(4-(l-((2-oxooxazolidin-3- yl)methyl)cyclopropyl)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide
To a stirred solution of (-)-5-chloro-N-((3-(4-(l-(((2-hydroxyethyl) amino) methyl) cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide [Example 24] (110mg,0.02mmol) and DMAP (2mg) in chloroform (2.2mL,20v/w) was added CDI (158mg, 0.08mmol). Reaction mixture was heated at 60°C for lh. After lh reaction mixture was diluted with chloroform and washed with dil.HCl. Organic layer was dried over sodium sulfate and evaporated to give 90mg of titled compound in 77% yield.
'HNMR
(DMSO,400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.44-7.42(2H, d), 7.32-7.29(2H, d), 7.18-7.17(1H, d), 4.81-4.77(1H, m), 4.15-4.11(3H, t), 3.81-3.77(1H, m), 3.58- 3.55(2H, t), 3.47-3.37(2H, t), 0.82-0.79(4H, t).
S.O.R = -65.37° (0.079% in DMSO at 25°C).
EXAMPLE 26
Preparation of (-)-5-chloro-N-((3-(4-(l-((dimethylamino)methyl)cyclopropyl)-3- fluorophenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
Step 1: l-(2-fluorophenyl)cyclopropanecarbonitrile
Prepared using similar procedure as that of example 1; step 1; by using 2-(2- fluorophenyl)acetonitrile in 52% yield.
Step 2: l-(2-fluoro-4-nitrophenyl) cyclopropanecarbonitrile
Prepared using similar procedure as that of example 1; step 2; by using l-(2- fluorophenyl) cyclopropanecarbonitrile in 69% yield.
Step 3: Ethyl l-(2-fluoro-4-nitrophenyl)cyclopropanecar boxy late
Prepared using similar procedure as that of example 1; step 3; by using l-(2- fluoro-4-nitrophenyl)cyclopropanecarbonitrile in 58% yield.
Step 4: ethyl l-(4-amino-2-fluorophenyl)cyclopropanecarboxyIate Prepared using similar procedure as that of example 1; step 4; by using ethyl 1- (2-fluoro-4-nitrophenyl) cyclopropanecarboxylate in 78% yield.
Step 5: ethyl l-(4-(((benzyloxy)carbonyl)amino)-2- fluorophenyl)cyclopropanecarboxylate
Prepared using similar procedure as that of example 11 ; step 1 ; by using ethyl 1- (4-amino-2-fluorophenyl)cyclopropanecarboxylate in 68% yield.
Step 6: Ethyl l-(2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3- yl)phenyl)cyclopropaaecarboxylate
Prepared using similar procedure as that of example 11; step 2; by using ethyl 1- (4-(((benzyloxy)carbonyl)amino)-2-fluorophenyl)cyclopropanecarboxylate in 89% yield.
Step 7: Ethyl l-(4-(5-((l^-dioxoisoindolin-2-yl)methyl)-2-oxooxazolidin-3-yl)-2- fluorophenyl)cyclopropanecarboxylate
Prepared using similar procedure as that of example 1 1; step 3; by using Ethyl l-(2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3- yl)phenyl)cyclopropanecarboxylate in 52% yield.
Step 8: Ethyl l-(4-(5-(aminomethyI)-2-oxooxazolidin-3-yl)-2- fluorophenyl)cyclopropanecarbox late
Prepared using similar procedure as that of example 1; step 7; by using Ethyl 1- (4-(5-((l,3-dioxoisoindolin-2-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl) cyclopropanecarboxylate and Aq. Methyl amine solution in 29% yield.
Step 9: Ethyl l-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin- 3-yl)-2-fluorophenyl)cyclopropanecarboxylate
Prepared using similar procedure as that of example 1; step 8; by using Ethyl-1- (4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)cyclopropanecarboxylate and 5-chlorothiophene-2-carbonyl chloride in 40% yield.
Step 10: l-(4-((3-(5-chlorothiophene-2-carboxamido)-2-hydroxypropyl)amino)-2- fluorophenyl)cyclopropanecarboxylic acid
Charged Ethyl l-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2- oxooxazolidin-3-yl)-2-fluorophenyl)cyclopropanecarboxylate (2.7g, 0.0057mol) in DMSO (14mL, 5v/w) followed by water (0.2g,0.01 14mol) and potassium ter-butoxide (2.6g,0.0231mol) at room tempreture. Reaction mixture was stirred for 2h. After 2h reaction mixture was poured in ice cold water and stirred for 15min. extracted with ethyl acetate. Then organic layer was washed with brine and dried over sodium sulfate and evaporated to affored 1.6g titled compound in 67% yield.
Step 11 : 1 -(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin-3- yI)-2-fluorophenyl)cyclopropanecarboxylic acid
Prepared using similar procedure as that of example 1 ; step 6; by using l-(4-((3-
(5-chlorothiophene-2-carboxamido)-2-hydroxypropyl)amino)-2- fluorophenyl)cyclopropanecarboxylic acid and CDI in 36% yield.
Step 12: 5-chloro-N-((3-(3-fluoro-4-(l-(hydroxymethyl)cycIopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
To a stirring solution of l-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2- oxooxazolidin-3-yl)-2-fluorophenyl)cyclopropanecarboxylic acid (0.6g, 0.00136mol) in THF (6mL, lOv/w) was added TEA (0.41g, 0.0041mol) at room tempreture. Methyl chloroformate (0.38g, 0.0041mol) was added in reaction mixture at 0-10 °C under nitrogen environment, precipitated salt was removed by filtration. Mother Liqur was drowpwise added to a stirred solution of NaBRt (0.155g, 0.0041mol) and water (lmL) at 0°C and stirred for lh. Then reaction mixture was poured in ice cold water (20mL) and extracted with ethyl acetate. Organic layer was washed with brine and dried over Na2S04and evaporated to get titeled compound 0.58g in 78 % yield.
Step 13: N-((3-(4-(l-(bromomethyl)cycIopropyl)-3-fluorophenyl)-2-oxooxazolidin - 5-yI)methyI)-5-chIorothiophene-2-carboxatnide
Prepared using similar procedure as that of example 1; step 10; by using 5- chloro-N-((3-(3-fluoro-4-(l-(hydroxymethyl)cyclopropyl)phenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide, CBr4 and TPP in 40% yield.
Step 14: (-)-5-chloro-N-((3-(4-(l-((dimethyIamino)methyl)cyclopropyl)-3-fluoro phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide
Prepared using similar procedure as that of example 1; step 11; by using (-)-N- ((3-(4-(l-(bromomethyl)cyclopropyl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-5- chlorothiophene-2-carboxamide and aq.dimethyl amine (40 %) solution in 54 % yield.
'HNMR
(DMSO, 400 MHz): 8.97(1H, t), 7.684(1H, d), 7.674(1H, dd), 7.495(1H, m), 7.479(1H, d), 7.189(1H, m), 4.81(1H, m), 4.168(1H, m), 4.123(1H, t), 3.831(1H, m), 3.598(2H, t), 2.367(2H, s), 2.081(6H, s), 0.866(2H, s), 0.715(2H, s).
S.O.R= -32.59° (0.1% in DMSO at 25°C). EXAMPLE 27
Preparation of (-)-5-chloro-N-((3-(4-(l-((cyclopropylamino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide
Step 1: (l-(4-nitrophenyl) cyclopropyl) methanol
To a stirring solution of l-(4-nitrophenyl) cyclopropanecarboxylic acid (235g,
1.135mol) in THF (1.17L, 5v/w) was added TEA (126.1g, 1.248mol) at room tempreture. Methyl chloroformate (96.2mL, 1.248mol) was added in reaction mixture at 0-10 °C under nitrogen environment, precipitated salt was removed by filtration. Mother Liqur was drowpwise added to a stirred solution of NaBH^ (86.3g, 2.270mol) and water (1.175L) at 0°C and stirred for lh. Then reaction mixture was poured in ice cold water (3L) and extracted with ethyl acetate. Organic layer was washed with brine and dried over sodium sulfate and evaporated to get titled compound 162g in 73% yield.
Step 2: (l-(4-nitrophenyI) cyclopropyl) methyl methanesulfonate
To a stirred solution of (l-(4-nitrophenyl) cyclopropyl) methanol (142g,
0.735mol) and TEA (111.5g, 1.105mol) in DCM (1.42 L) was slowly added methane sulfonyl chloride (68.5mL, 0.882mol) at 0-5 °C. Reaction mixture was stirred at 0-5°C for 1 h. Product was extracted with DCM and dried over sodium sulfate which on evaporating afforded 130g of titled compound in 65% yield.
Step 3: N-((l-(4-nitrophenyl) cyclopropyl) methyl) cyclopropanamine
To a stirred solution of (l-(4-nitrophenyl) cyclopropyl) methyl methanesulfonate (130g, 0.479 mol) and sodiumbicarbonate (120.9g, 1.439mol) in ACN (650mL, 5v/w) was slowly added cyclopropyl amine (lOOmL, 1.439mol) at room tempreture and heated at 70 °C for 5h. Product was diluted with water and extracted with DCM and dried over sodium sulfate which on evaporation afford 103g of titled compound in 92% yield.
Step 4: tert-butyl cyclopropyl((l-(4-nitrophenyl)cyclopropyl)methyl)carbamate
To a stirring solution of N-((l-(4- nitrophenyl)cyclopropyl)methyl)cyclopropanamine (lOOg, 0.431 mol) in ethyl acetate (500mL, 5v/w) was slowly added di-tert-butyl carbonate (99mL, 0.431 mol) at room tempreture and stirred for 4h. Ethyl acetate layer was washed with water and organic layer was dried over sodium sulfate which on evaporation afford 85g of titled compound in 59% yield.
Step 5: tert-butyl ((l-(4-aminophenyl)cyclopropyl) methyl)(cyclopropyl)carbamate Charged Pd/C (5g) in methanol (850mL,3v/w) under nitrogen environment followed by tert-butyl cyclopropyl ((l-(4-nitrophenyl) cyclopropyl) methyl) carbamate (85g, 0.256mol) and ammonium formate (64g, 1.02mol). Then reaction mixture was heated at 60°C for lh. After lh reaction mixture was filtered through sintered funnel and then methanol is evaporated to afford 69.5g of titeled compound in 89% yield. Step 6: tert-butyl ((l-(4-
(((beozyloxy)carbonyl)amino)phenyl)cyclopropyl)metbyl)(cyclopropyl)carbaniate
To a stirred solution of tert-butyl ((l-(4-aminophenyl)cyclopropyl)methyl) (cyclopropyl)carbamate (66g, 0.2185mol) and potassium carbonate (27.5g, 0.3278mol) in mixture of THF (330mL) and water (127mL) was slowly added benzyl chloroformate (81.9g, 0.240mol) at 10-15 °C. Reaction mixture was stirred at 20-25 °C for 1 h. Product was extracted with Ethyl acetate which on evaporation gave 90.5g of titled compound in 95% yield.
Step 7: tert-butyl cyclopropyI((l-(4-(5-(hydroxymethyl)-2-oxooxazolidin-3- yl)phenyl)cycIopropyl)metbyl)carbamate (XXI)
Prepared by using similar procedure as described example 1 1; step 2.
Step 8: (3-(4-(l-(((tert-butoxycarbonyI) (cyclopropyl) amino) methyl) cyclopropyl) phenyI)-2-oxooxazolidin-5-yl) methyl methanesulfonate (XXII)
To a stirred solution of tert-butyl cyclopropyl ((l-(4-(5-(hydroxymethyl)-2- oxooxazolidin-3-yl) phenyl) cyclopropyl) methyl) carbamate (XXI)
(58g, 0.144mol) and TEA (21.8g, 0.216mole) in DCM (580mL, lOv/w) was slowly added methane sulfonyl chloride (19.8g, 0.173mol) at 0°C and stirred for lh. After lh reaction mixture was diluted with DCM (500mL) and washed with water (1L). Organic layer was washed with brine, dried over sodium sulfate and evaporated to affored 69g of titled compound in 99% yield.
Step 9: tert-butyl ((l-(4-(5-(azidomethyl)-2-oxooxazolidin-3-yl)phenyI)cyclopropyl) methyl)(cyclopropyl)carbamate
To a stirred solution of (3-(4-(l-(((tert-butoxycarbonyl) (cyclopropyl) amino) methyl) cyclopropyl) phenyl)-2-oxooxazolidin-5-yl) methyl methanesulfonate (69g, 0.143mol) and TBAB (300mg) in DMF (207mL, 3v/w) was slowly added sodium azide (14g, 0.215mol) at room tempreture and heated at 70°C for 4h. After 4h reaction mixture was poured in water (2.5L) and extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and evaporated to affored 59g of titled compound in 96% yield. Step 10: tert-butyl ((l-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl) phenyl)cyclopropyl)metbyl)(cycIopropyl)carbamate
Charged 5% Pd/C (lOg) in methanol (480mL, lOv/w) under nitrogen environment followed by tert-butyl ((l-(4-(5-(azidomethyl)-2-oxooxazolidin-3-yl) phenyl) cyclopropyl) methyl) (cyclopropyl) carbamate (48g, 0.112mol) and sodiumborohydride (12.8g, 0.337mol). Then reaction mixture was stirred at 25°C for 3h. After 3h reaction mixture was filtered through sintered funnel then methanol is evaporated and product was extracted in ethyl acetate. Organic layer was washed with brine and dried over Na2S04. Ethyl acetate was evaporated to afford 45g of titeled compound in 99% yield.
Step 11: tert-butyl ((l-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2- oxooxazolidin-3-yl)phenyl)cyclopropyl)methyl)(cyclopropyl)carbamate
Prepaired by using similar procedure as described for example 1; step 8.
Step 12: (-)-5-chloro-N-((3-(4-(l-((cycIopropylamino)methyl)cyclopropyl)phenyl)-
2-oxooxazolidin-5-yl)metbyl)thiophene-2-carboxamide
40g of (-)-tert-butyl ((l-(4-(5-((5-chlorothiophene-2-carboxamido) methyl)-2- oxooxazolidin-3-yl) phenyl) cyclopropyl) methyl) (cyclopropyl) carbamate was dissolved in dry ethyl acetate (400mL, lOv/w). Dry HC1 gas was purged for lh. Ethyl acetate was then stirred in saturated Aq. K2C03 solution for lh and seperated. Organic layer was washed with brine and dried over Na2S04 and evaporated to afford 30g of titled compound in 91% yield.
'HNMR
(DMSO, 400 MHz) :8.97-8.94(lH, t), 7.67-7.66(lH, d), 7.41-7.39(2H, dd), 7.29- 7.26(2H, dd), 7.18-7.17(lH,d), 4.81-4.78(1H, m), 4.15-4.1 1(1H, t), 3.81-3.77(1H, m), 3.583.56(2H, t), 2.74(2H, bs), 2.04-2.017(1H, m), 0.80-0.76(2H, t) 0.75-0.73(2H, t), 0.31 1-0.3(4H, bd).
S.O.R= -75.38° in 0.1% in DMSO at 25°C)
EXAMPLE 28
Preparation of (-)-5-chIoro-N-((2-(cyanoimino)-3-(4-(l-((N- cyclopropylcyanamido)methyl)cyclopropyI)phenyl)oxazolidin-5- yl)methyl)thiophene-2-carboxamide
Step 1: 5-chloro-N-(3-((4-(l-
((cycIopropylamino)methyl)cyclopropyl)phenyl)amino)-2- hydroxypropyl)thiophene-2-carboxamide Charged 5-chloro-N-((3-(4-(l-((cyclopropylamino)methyl)cyclopropyl)phenyl)- 2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide, example 27, (3g, 0.0067mol) in DMSO (15mL, 5v/w) followed by water (0.12g,0.0067mol) and potassium ter- butoxide (1.5g,0.0134mol) at room tempreture then reaction mixture was heated at 100 °C for 2h. After 2h reaction mixture was poured in ice cold water and stirred for 15min. extracted with ethyl acetate.
Then organic layer was washed with brine and dried over Na2S04 and evaporated to affored 2.5g titled compound in 89% yield.
Step 2: 5-chloro-N-((2-(cyanoimino)-3-(4-(l-((N- cycIopropylcyanamido)methyl)cyclopropyl)phenyl)oxazolidin-5- yl)methyl)thiophene-2-carboxamide
To a stirred solution of 5-chloro-N-(3-((4-(l-
((cyclopropylamino)methyl)cyclopropyl)phenyl)amino)-2-hydroxypropyl)thiophene-2- carboxamide (0.5g, 1.1905mmol) in THF (1.5mL, 3v/w) was added cynogen bromide (0.504g,4.761mmol) at room temperature. Then reaction mixture was stirred for 4h. After 4h reaction mixture was poured in ice cold water and made it basic (pH=10) and extracted with DCM purification by coloumn chromatography to afforded 0.2g of titled compound in 33% yield.
'HNMR
(DMSO, 400 MHz) :9.03-9.01(lH, t), 7.69-7.68(lH, d), 7.50-7.47(2H, dd), 7.43- 7.41(2H, dd), 7.20-7.19(lH,d), 5.21-5.16(1H, m), 4.41-4.36(1H, t), 4.08-4.04(lH, m), 3.78-3.71(lH,m), 3.69-3.63(lH, m), 3.27(2H, s), 2.60-2.50(2H, m), 0.89-0.83(4H, m), 0.62-0.58(2H, t), 0.38-0.32(2H, t).
The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Activity data:
In vitro human factor Xa inhibitory activities and PTCT2(Conc. required to double the prothrombin time using human plasma)values were determined using standard protocols and results are provided in table 1 as a proof of potency of the novel class of compounds. Table 1:
Figure imgf000037_0001
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (I) or pharmaceutical compositions containing them are useful as anticoagulant compound suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5 % to 90 % by weight of the composition.

Claims

We claim:
1. Compounds having the structure of general Formula (I),
Figure imgf000039_0001
ra
and their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, wherein
'B' at each occurrence independently represents a halogen atom; p represents an integer 'A' represents the group -NR3R4, wherein
i) R3 and R4 independently represents hydrogen, cyano or the groups acyl, alkylsulfonyl, (C1-C10) alkyl, (C3-C10) cycloalkyl groups, wherein the alkyl chain may further optionally either contain from 1-3 heteroatoms selected from O, S or the groups carbonyl or iminocarbonyl, or the group NRgRb, wherein Ra b at each occurrence is independently selected from H, (Ci-C3)alkyl groups, (C3-Q0) cycloalkyl groups, provided that the alkyl chain does not include a S-S, S-O, or O-O bond; or,
ii) R3 and R4 together with the nitrogen atom forms a 4 to 8 membered ring, which may be optionally substituted, wherein the ring may further optionally contain one or more heteroatoms selected from O, S or the group representing NRc, wherein Rc represents H or (C]-C6)alkyl group and further the ring representing -NR3R4 may optionally include one or more double bonds; 'X' represents oxygen or the group -NR2, wherein R2 represents hydrogen, cyano or the groups selected from (Ci-Ce)alkyl, (C3- Cio)cycloalkyl, (Ci-C6)heteroaryl, (Ci-C6)aryl, aralkyl, heterocycle, heteroarylalkyl, heterocyclylalkyl, acyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, aminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aminosulfonyl and alkylsulfonyl derivatives, each of these may further be optionally be substituted; Ri at each occurrence is independently selected from hydrogen, halogen, cyano, optionally substituted mono, di or trisubstituted amino, optionally substituted groups selected from (Ci-C6)alkyl, (Cr C6)alkoxy, alkylsulfonyl, aminosulfonyl, carbocyclic or heterocyclic groups, each of these groups may further be substituted; 'n' represents integers from 1- 4 and 'm' represents integers from 1-2.
2. The compounds as claimed in claim 1, wherein 'B' is selected from choro and bromo.
3. The compounds as claimed in claim 1, wherein when R3 and R4 represents groups other than a cyclic group, each of R3 & R4 independently are selected from hydrogen, cyano, (CI-CJO) alkyl, (C3-C10) cycloalkyl groups
4. The compounds as claimed in claim 3, wherein the (Cj-Cio) alkyl chain contains 1-3 heteroatoms selected from O, S.
5. The compounds as claimed in claim 3, wherein the (CrQo) alkyl chain contains the groups selected from carbonyl or iminocarbonyl or NRaRj, wherein Ra & Rb independently represent one or more groups selected from H, (Q-C3) alkyl groups or (C3-C10) cycloalkyl groups.
6. The compound of claim 1 wherein when NR3R4 represents a cyclic group, the substituents on the cyclic group is selected from hydroxyl, oxo, amino, alkyl, acyl, alkoxy, iminocarbonyl, iminocarbonyl, acylamino, alkylamino, aminoalkyl, mono, di or trisubstituted amino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonylamino, alkylsulfonyl, aminocarbonyl derivatives.
7. The compounds as claimed in claim 6, wherein the substituents on NR3R4 are selected from subsitituted group selected from oxo, iminocarbonyl or aminocarbonyl.
8. The compounds according to claim 1, wherein 'Ri' is selected from hydrogen, halogen and (Ci-C6) alkyl.
9. A compound selected from the group consisting of
5-chloro-N-((3-(4-(l-((dimethylamino)methyl) cyclopropyl) phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((4-methylpiperazin-l-yl)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((4-hydroxypiperidin-l-yl) methyl) cyclo propyl) phenyl) - 2-oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((diethylamino) methyl) cyclopropyl) phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide; 5-chloro-N-((3-(4-(l-(((2-hydroxyethyl) amino) methyl) cyclo propyl) phenyl)- 2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-(morpholinomethyl) cyclopropyl) phenyl) - 2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((3-(4-(l-((isopropylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((2-oxo-3-(4-(l-(pyrrolidin-l- ylmethyl) cyclo propyl) phenyl) oxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((2-oxo-3-(4-( 1 -((3-oxopiperazin- 1 -yl) methyl) cyclopropyl) phenyl) oxazolidin-5-yl) methyl) thiophene-2-carboxamide;
5-chloro-N-((2-oxo-3-(4-( 1 -(piperidin- 1 -ylmethyl) cyclopropyl) phenyl) oxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5 -chloro-N-((3 -(4-( 1 -((dimethy lamino)methyl)cyc lopropy l)phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
(-)-5-chloro-N-((2-oxo-3-(4-( 1 -(pyrrolidin- 1 - ylmethyl)cyclopropyl)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((ethylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((diethylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5 -chloro-N-((3 -(4-( 1 -((methylam ino)methyl)cyclopropy l)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-(((-)-3-(4-(l-(((R)-3-hydroxypyrrolidin-l-yl)methyl)cyclopropyl) phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((N-methylmethylsulfonamido)methyl)cyclopropyl) phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((N-ethylacetamido)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-(((2-hydroxyethyl)(methyl)amino)methyl)
cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-N-((3-(4-(l-((bis(2-hydroxyethyl)amino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)-5-chlorothiophene-2-carboxamide; (-)-5-chloro-N-((3-(4-( 1 -((4-hydroxypiperidin- 1 - yl)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2- carboxamide;
(-)-5-chloro-N-((3-(4-(l-((4-methyl-l,4-diazepan-l- yl)methyl)cyclopropyl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2- carboxamide;
(-)-5-chloro-N-((3-(4-(l-((cyclopentylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-(((2-hydroxyethyl)amino)methyl)cyclopropyl)phenyl)- 2-oxooxazoIidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((2-oxo-3-(4-( 1 -((2-oxooxazolidin-3- yl)methyl)cyclopropyl)phenyl)oxazolidin-5-yl)methyl)thiophene-2- carboxamide;
(-)-5 -ch loro-N-((3 -(4-( 1 -((dimethylamino)methyl)cyclopropy l)-3 -fluoropheny 1)- 2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide;
(-)-5-chloro-N-((3-(4-(l-((cyclopropylamino)methyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl) methyl) thiophene-2-carboxamide;
(-)-5-chloro-N-((2-(cyanoimino)-3-(4-(l-((N-cyclopropylcyanamido)methyl) cyclopropyl) phenyl) oxazolidin-5-yl) methyl) thiophene-2-carboxamide.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients
11. The pharmaceutical composition according to claim 10, useful as anticoagulant compound suitable for humans and other warm blooded animals.
12. The pharmaceutical composition according to claim 10, the quantity of active component range between 0.5 % to 90 % by weight of the composition.
13. The pharmaceutical composition according to claim 10, administered either by oral, topical or parenteral administration.
14. A method of treating disease characterized by thrombotic activity comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) according to any of the preceding claims or its pharmaceutical composition according to any of the preceding claims.
15. Use of a compound of Formula (I) or its pharmaceutical composition according to any of the preceding claims for the manufacture of a medicament for inhibition of factor Xa.
16. A medicine for the treatment of disease related to factor Xa which comprises administering a therapeutically effective amount of compound of Formula (I) or its pharmaceutical composition as defined in any of the preceding claims to a patient or subject in need thereof.
17. The compounds of Formula (I) or their pharmaceutical compositions as claimed in any of the preceding claims useful for treating disease related to factor Xa.
PCT/IN2010/000744 2009-11-18 2010-11-16 Novel antithrombotic agents WO2011061760A1 (en)

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