FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION:
" Amine oxazolidinones derivatives and use in Thromboembolic disorders"
2.APPLICANT (S)
(a) NAME: Wanbury Ltd.,(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Wanbury Ltd
BSEL Tech park, B-wing, 10th floor,
sec -30A, opp. Vashi Railway station,
Vashi, Navi- Mumbai-400703, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Amine oxazolidinones derivatives and use in Thromboembolic disorders
Field of invention
The present invention relates to the novel amine oxazolidinones derivatives of compound formula (I), and their use in Thromboembolic disorders. Further the present invention relates to the process for preparation of compound formula (I).

In which,
E is (C1-C6)-alkylcarbonyl represent straight chain or branched alkoxy radical having 1 to 6 carbon atoms which are attached via carbonyl group.
And
M is any heterocycle including cyclohexane or substituted cyclohexane, benzyl, halo alkyl, benzo-fused thiophene group which may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C1-C8) -alkyl which for its part may optionally be mono- or polysubstituted by halogen; {C3-C7)-cycloalkyl; (C1-C8)-alkoxy; imidazolinyl; —C(=NH)NH2; carbamoyl; and mono- and di-(C1-C4)-alkyl-aminocarbonyl,
Or its pharmaceutically accepted salt or solvate form or hydrate form.

Background of Invention
Rivaroxaban, also known as 5-chloro-N-[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5(S)-ylmethyl]thiophene-2-carboxamide, acts by inhibition of the active form of coagulation factor Xa. Rivaroxaban is currently in clinical trials for pulmonary embolism, stroke, thromboembolism, deep venous thrombosis, thrombosis, and acute coronary syndrome (http://clinicaltrials.gov/).
Thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries. [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th edition, 1997, W.B. Saunders Company, Philadelphia].
The anticoagulants, i.e. substances for inhibiting or preventing blood coagulation, which are known from the prior art, have various, often grave disadvantages. Accordingly, in practice, an efficient treatment method or prophylaxis of thromboembolic disorders is very difficult and unsatisfactory.
In the therapy and prophylaxis of thromboembolic disorders, use is firstly made of heparin, which is administered parenterally or subcutaneously. Owing to more favorable pharmacokinetic properties, preference is nowadays more and more given to low-molecular-weight heparin; however, even with low-molecular-weight heparin, it is not possible to avoid the known disadvantages described below, which are involved in heparin therapy. Thus, heparin is ineffective when administered orally and has only a relatively short half-life. Since heparin inhibits a plurality of factors of the blood coagulation cascade at the same time, the action is nonselective. Moreover, there is a high risk of bleeding; in particular, brain hemorrhages and gastrointestinal bleeding may occur, which may result in thrombopenia, drug-induced alopecia or osteoporosis [Pschyrembel, Klinisches Worterbuch,

257th edition, 1994, Walter de Gruyter Verlag, page 610, entry "Heparin"; Rompp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry "Heparin"].
US 7,932,27 8, discloses the 2-aminoethoxyacetic acid derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular thromboembolic disorders.
US2010/0292230, discloses the prodrug derivatives of 5-chloro-N-({(5S)-2-OXO-3-[4-{3-oxomorpholin-4-yl}phenyl]-2,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially of thromboembolic disorders.
WO2009023233 Al, discloses the oxazolidinones compounds that are derivatives of rivaroxaban. The patent application further provides the pyrogen free composition in method of treating disease and condition to the inhibitor of factor Xa such as rivaroxaban.
Rivaroxaban is converted to two major metabolites in vivo, the CYP3A4 mediated product of morpholinone ring oxidation (Ml) , and the product of chlorothiophenyl amide hydrolysis and subsequent glycine conjugation (M4) . Neither metabolite is active. {Weinz,C et al., Drug Metab Rev, 2004, 36{suppl 1): 98).
Adverse events associated with the use of rivaroxaban include, but are not limited to, ageusia (loss of taste), ecchymosis (bruising) and headache (Kubitza, D et al., Cl PharmacolTherapeutics, 2005, 78(4): 412-421).

Despite the beneficial activities of rivaroxaban, there is a continuing need for new compounds for treating the aforementioned diseases and conditions.
This instant application discloses amine oxazolidinones derivatives of compound formula (I) and the process for preparation thereof. The compounds of the formula (I), can be employed as medicament active ingredients in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexies, angina pectoris, restenosis after angioplasty, claudicated intermittent, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina and strokes based on thrombosis.
Summary of Invention
The main aspect of present invention is to provide the novel amine oxazolidinones derivatives of formula (I).

In which,
E is (Ci-Cg)-alkylcarbonyl represent straight chain or branched alkoxy radical having 1 to 6 carbon atoms which are attached via carbonyl group.
And
M is any heterocycle including cyclohexane or substituted cyclohexane, benzyl, halo alkyl, benzo-fused thiophene group which

may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C1-C8) -alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C3-C7} -cycloalkyl; {C1-C8) -alkoxy; imidazolinyl; —C(=NH)NH2; carbamoyl; and mono- and di-(C1-C4)-alkyl-aminocarbonyl.
Or its pharmaceutically accepted salt or solvate form or hydrate form.
In another aspect, of the present invention to disloses the use of the compounds of formula (I), for treatment and/or prophylaxis of disorders, such as thromboembolic disorders; inhibitor of factor Xa, and/or thromboembolic complications. The "thromboembolic disorders" include in the context of the present invention disorders such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses following coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolisms, deep venous thromboses and renal vein thromboses, transient ischaemic attacks, and thrombotic and thromboembolic stroke.
In yet another aspect, the present invention discloses a use of the compound formula (I) for prevention and treatment of cardiogenic thromboembolisms, such as, for example, cerebral ischaemias, stroke and systemic thromoboembolisms and ischaemias, in patients with acute, intermittent or persistent cardiac arrhythmias such as, for example, atrial fibrillation, and those undergoing cardioversion, also in patients with heart valve diseases or with artificial heart valves. The compound according to the invention is additionally suitable for the treatment of disseminated intravascular coagulation (DIC).

Another aspect of the present invention is to provide the novel process for the preparation of the compound formula (I), which is substantially free from impurities.
Yet another aspect, the present invention discloses a compound formula (I) , in a pharmaceutically accepted salt or hydrate form or solvate form of compound formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment, of present invention comprises the novel amine oxazolidinones derivatives of formula (I), having the structure:

In which,
E is (C1-C6)-alkylcarbonyl represent straight chain or branched alkoxy radical having 1 to 6 carbon atoms which are attached via carbonyl group.
And
M is any heterocycle including cyclohexane or substituted cyclohexane, benzyl, halo alkyl, benzo-fused thiophene group which may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C1-C8)-alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C3-C7) -cycloalkyl; (C1-C88)-alkoxy; imidazolinyl; —C(=NK)NH2; carbamoyl; and mono- and di-(C1-C4)-alkyl-aminocarbonyl.

Or its pharmaceutically accepted salt or solvate form or hydrate form.
The present invention provide novel amine oxazolidinones derivatives of formula (I), exists in stereoisomeric forms (enantiomers, diastereomers) . .Accordingly, the invention comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers, it is possible to isolate the stereoisomerically uniform components in a known manner. If the compounds according to the invention can be present in tautomeric forms, the present invention comprises all tautomeric forms.
The novel amine oxazolidinones derivatives of formula (I), according to the invention are suitable for the prophylaxis and/or treatment of atherosclerotic vascular disorders and inflammatory disorders, such as rheumatic disorders of the locomotor apparatus, and in addition also for the prophylaxis and/or treatment of Alzheimer's disease. Moreover, the compounds according to the invention can be used for inhibiting tumor growth and formation of metastases, for microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular disorders, and also for the prevention and treatment of thromboembolic complications, such as, for example, venous thromboembolisms, in tumor patients, in particular patients undergoing major surgical interventions or chemo- or radiotherapy.
The novel amine oxazolidinones derivatives of formula (I), according to the invention can additionally also be used for preventing coagulation ex vivo, for example for preserving blood and plasma products, for cleaning/pretreating catheters and other medical tools and instruments, for coating synthetic surfaces of medical tools and instruments used in vivo or ex vivo or for biological samples comprising factor Xa.
The present invention furthermore provides the use of the compounds according to the invention for the treatment and/or

prophylaxis of disorders, in particular the disorders mentioned above.
The present invention furthermore provides the use of the compounds according to the invention for preparing a medicament for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
The present invention furthermore provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an anticoagulatory effective amount of the compound according to the invention.
The present invention furthermore provides a method for preventing blood coagulation in vitro, in particular in banked blood or biological samples comprising factor Xa, which method is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.
The present invention furthermore provides medicaments comprising at least one compound according to the invention, usually together with one or more inert nontoxic pharmaceutically acceptable auxiliaries, and their use for the purposes mentioned above.
The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable way, such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as implant or stent.
For these administration routes, it is possible to administer the compounds according to the invention in suitable administration forms.
Suitable for oral administration are administration forms which work as described in the prior art and deliver the compounds according to the invention rapidly and/or in modified form, which comprise the compounds according to the invention in crystalline

and/or amorphous and/or dissolved form, such as, for example, tablets (uncoated and coated tablets, for example tablets provided with enteric coatings or coatings whose dissolution is delayed or which are insoluble and which control the release of the compound according to the invention), tablets which rapidly decompose in the oral cavity, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
The compounds according to the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable auxiliaries. These auxiliaries include, iriter alia, carriers (for example microcrystalline cellulose, lactose, mannitol) , solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants, such as, for example, ascorbic acid), colorants (for example inorganic pigments, such as, for example, iron oxides) and flavour- and/or odour-masking agents.
The present invention carried out the meticulous study on pharmacological activity of amine oxazolidinones derivatives of formula (I),such as Determination of th§ Factor Xa Inhibition, Determination of the selectivity, Determination of anticoagulant activity and Determination of Antithrombotic activity wherein theses study are well exemplified or illustrated with best mode of invention in section (B).
In an important embodiment, the present invention provides for a process for the preparation of compound formula (I) comprising of:

a) Reacting compound formula (A) with compound formula (B) in suitable solvent or mixture of solvents in presence of acid or base to obtain compound formula (I)

Wherein,
E is (C1-C6)-alkylcarbonyl represent straight chain or branched alkoxy radical having 1 to 6 carbon atoms which are attached via carbonyl group.
And
M is any heterocycle including cyclohexane or substituted cyclohexane, benzyl, halo alkyl, benzo-fused thiophene group which may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C1-C8) -alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C3-C7) -cycloalkyl; (C1-C8) -alkoxy; imidazolinyl; —C{—NH)NH2; carbamoyl; and mono- and di-(Ci~ C4)-alkyl-aminocarbonyl.
Q is a leaving group.
Abbreviations and Acronyms
HPLC High performance liquid chromatography RT room temperature DMSO dimethyl sulphoxide BSA Bovin serum albumin

Section A
Example 1)
Preparation of N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl} methyl) cyclohexyl carboxamide

To a solution of N-({ (5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1, 3~oxazolidin-5-yl}methyl)formamide { 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (5.05 g 0.03 91mol) and then cyclohexane carbonyl chloride (3.4 4g, 0.0234 mol) at 5 tol0°C. heat the solution to reflux temperature and reflux for 10 hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol.suck dry ,stir the solid in 25 ml Acetonitrile for 30 min , filter , suck dry and dry for 5.0 hrs.to give 2.0 g compound .
NMR data:
4.221 (4, 1H, d, J-14.5 9 6) , 4.3 91 (4, 1H, d, J=14.596), 3.675 (6, 1H, ddd, J=15.525, J=10.110, J=3.680), 3.701 (6, 1H, ddd, J=15.525, J=3.660, J=2.060), 7.583 (8, 1H, ddd, J=8.607, J-2.568, J-0.000), 7.583 (9, 1H, ddd, J=8.607, J-2.574, J=0.000), 3.617 (10, 1H, ddd, J=13.367, J=3.680, J=2.060), 3.507 (10, 1H, ddd, J=13.367, J=10.110, J=3.660), 7.757 (11, 1H, ddd, J=8.607, J=2.57 4, J-0.000), 7.7 57 (12, 1H, ddd, J=8.607, J-2.568, J-0.000), 3.863 (16, 1H, dd, J-16.744, J=4.250), 3.771 (16, 1H, dd, J-16.744, J=8.060), 4.789 (19, 1H, dtd, J-8.060, J=6.706, J=4.250), 3.940 (20, 2H, d, J=6.706), 8.754 (23, 1H) , 2.786 (25, 1H, tt, J=10.260, J=2.790), 1.718 (27, 1H, dq, J=14.820, J=2.790),

2.194 (27, 1H, dtd, J=14.820, J=10.2 60, J=2.7 90) , 2.194 (28, 1H, dtd, J=14.820, J=10.2 60, J-2.7 90), 1.718 (28, 1H, dq, J=14.820, J-2.790), 1.591 (29, 1H, dtt, J=14.366, J=10.260, J-2.790), 1.4 66 (29, 1H, dquint, J-14.366, J-2.790), 1.466 (30, 1H, dquint, J-14.366, J=2.7 90), 1.591 (30, 1H, dtt, J=14.366, J=10.2 60, J=2.790), 1.355 (31, 1H, dquint, J=12.218, J=2.790), 1.372 (31, 1H, dtt, J=12.218, J=10.260, J-2.790
Example 2)
Prepration of 2-chloro-N-formyl-N- ({(5S)-2-oxo-3-[4-(3-
oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)acetamide

To a solution of N-({ (5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (5.05 g 0.0391mol) and then cbloro acetyl chloride(2.66g,0.0234 mol) at 5 tolO°C. heat the solution to reflux temperature and reflux for 6.0 hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml hexane, sticky sold observed so stir for 4 to5 hrs and filter the solid . wash the solid with 10 ml hexane.suck dry , dry for 5.0 hrs.to give 3.0 g compound .
NMR data:
4.267 (2, 2H), 8.738 (6, 1H), 3.928 (7, 2H, d, J=6.700), 4.773 (9, 1H, dtd, J=8.060, J-6.700, J=4.260), 3.862 (11, 1H, dd, J=16.473, J=4.260), 3.770 (11, 1H, dd, J=16.473, J=8.060), 7.757 (16, 1H, ddd, J=8.607, J-2.574, J=0.000), 7.7 57 (17, 1H, ddd, J=8.607, J=2.55 6, J=0.000), 7.583 (18, 1H, ddd, J=8.607, J=2.55 6, J=0.000),

7.583 {19, 1H, ddd, J-8.607, J=2.574, J=0.000), 3.68 4 (23, 1H, ddd, J=15.524, J=10.110, J-3.680), 3.655 (23, 1H, ddd, J=15.524, J=3.660, J=2.060), 4.222 (25, IH, d, J-14.602), 4.452 (25, 1H, d, J=14.602), 3.626 (26, IH, ddd, J=13.364, J-3.680, J=2.060), 3.544 (26, IH, ddd, J=13.364, J=10.110, J-3.660)
Example 3)
Prepration of 2-phenyl-N-formyl-N- ({(55)-2-oxo-3-[4-(3-
oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide

To a solution of N-({(bS)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide { 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine {6.06 g 0.04 69mol) and then phenyl acetyl chloride(3.61g,0.0234 mol) at 5 tol0°C. heat the solution to reflux temperature and reflux for 10.0 hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and purify obtained residue by column chromatography to give 1.0 g compound.
NMR Data:
4.221 (4, IH, d, J=14.596), 4.391 (4, IH, d, J-14.596), 3.675 (6, IH, ddd, J-15.525, J=10.110, J=3.680), 3.701 (6, IH, ddd, J=15.525, J=3.660, J=2.060), 7.583 (8, IH, ddd, J-8.607, J=2.556, J=0.000), 7.58 3 (9, IH, ddd, J=8.607, J-2.57 4, J-0.000), 3.617 (10, IH, ddd, J=13.367, J-3.680, J=2.060), 3.507 {10, IH, ddd, J=13.367, J=10.110, J-3.660), 7.757 (11, IH, ddd, J-8.607, J=2.574, J=0.000), 7.757 (12, IH, ddd, J=8.607, J-2.556, J=0.000), 3.8 63 (16, IH, dd, J=16.739, J=4.2 50), 3.771 (16, IH, dd, J=16.739, J=8.060), 4.788 (19, IH, dtd, J=8.060, J=6.706,

J=4.250), 3.931 (20, 2H, d, J=6.706), 8.751 (23, 1H), 3.7 03 (25, 2H) , 7.38 3 (28, 1H, dcldd, J-7.7 73, J-4.932, J=1.54 7, J=0.000) , 7.383 (29, 1H, dddd, J-7.773, J-4.932, J=1.547, J=0.000), 7.354 (30, 1H, dddd, J=7.773, J=7.711, J-4.932, J-0.000), 7.354 (31, 1H, dddd, J-7.773, J=7.711, J-4.932, J=0.000), 7.2 97 (32, 1H, tt, J=7.711, J=1.547).
Example 4)
Prepration of N-formyl-N-{{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide

To a solution of N-{{(5S)-2-oxo-3-[4-{3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide { 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then Acetyl chloride(1.80g,0.0234 mol) at 5 to!0°C. heat the solution to reflux temperature and reflux for 6. Ohrs. cool the rm to rt and wash with water (5x25ml) . seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol ,suck dry and dry for 5.0 hrs.to give 1.2 g compound .
Example 5)
Prepration of N-formyl-N- ({(5S)-2-oxo-3-[4-{3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)benzothiophene-2-carboxamide


To a solution of N- ({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm , 0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.04 69mol) and then 2-Chloroacetyl benzothiazole (7.67g,0.039 mol) at 5 tol0°C. heat the solution to reflux temperature and reflux for G.Ohrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 3.2 g compound .
NMR Data:
7.979 (5, 1H, dddd, J=7.760, J=5.471, J-4.377, J=1.870), 8.061 (7, 1H, ddd, J-4.37 7, J=1.330, J=0.526), 7.8 33 (8, 1H, dddd, J-7.778, J=5.471, J=1.736, J=1.330), 7.458 (9, 1H, ddd, J-7.760, J=7.193, J=1.7 36), 7.4 38 (12, 1H, dddd, J-7.778, J-7.193, J-1.870, J=0.526) , 8.7 68 (13, 1H) , 4.03 6 (14, 2H, d, J=6.700) , 4.783 (16, 1H, dtd, J=8.060, J=6.700, J=4.260), 3.863 (18, 1H, dd, J=16.486, J=4.260), 3.770 (18, 1H, dd, J=16.486, J=8.060), 7.618 (23, 1H, ddd, J-8.607, J=2.611, J=0.000), 7.618 (24, 1H, ddd, J-8.607, J-2.585, J=0.000), 7.583 (25, 1H, ddd, J-8.607, J-2.585, J-0.000), 7.583 {26, 1H, ddd, J-8.607, J=2.611, J-0.000), 3.684 (30, 1H, ddd, J=15.524, J-10.110, J=3.680), 3.655 (30, 1H, ddd, J=15.524, J=3.660, J-2.060), 4.222 (32, 1H, d, J=14.602), 4.452 (32, 1H, d, J=14.602), 3.626 (33, 1H, ddd, J=13.364, J-3.680, J=2.060), 3.545 (33, 1H, ddd, J=13.364, J=10.110, J=3.660)

Example 6)
Prepration of N-f ormyl-N- {{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-6-bromo benzothiophene-2 carboxamide

To a solution of N-({(5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.04 69mol) and then 6-bromo benzothiazole (10.74g,0.039 mol) at 5 tol0°C. heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs. to give 2.2 g compound .
NMR data:
7.907 (3, 1H, ddd, J=1.92 9, J=1.4 39, J=0.8 61) , 7.602 (4, 1H, ddd, J=8.901, J=1.929, J=1.312), 7.951 (6, 1H, ddd, J=8.901, J-1.796, J=0.8 61), 8.04 8 (10, 1H, ddd, J=1.7 96, J=1.4 3 9, J=1.312), 8.7 68 (14, 1H), 4.047 (15, 2H, d, J=6.713), 4.799 (17, 1H, dtd, J-8.060, J=6.713, J=4.260), 3.854 (19, 1H, dd, J-16.396, J=4.260), 3.761 (19, 1H, dd, J-16.396, J=8.060), 7.293 (24, 1H, ddd, J=8.694, J=5.499, J=0.000), 7.293 (25, 1H, ddd, J=8.694, J-5.496, J=0.000), 6.788 (26, 1H, ddd, J=8.694, J-5.496, J=0.000), 6.788 (27, 1H, ddd, J=8.694, J=5.499, J=0.000), 3.007 (30, 1H, ddd, J=14.972, J=10.240, J=2.510), 2.986 (30, 1H, ddd, J-14.972, J=3.100, J=2.520), 2.986 (31, 1H, ddd, J-14.972, J=3.100, J=2.520), 3.007

(31, 1H, ddd, J=14.972, J=10.24 0, J=2.510) , 3.686 (32, 1H, ddd,
J=15.207, J=3.100, J=2.510) , 3.706 (32, 1H, ddd, J-15.207,
J-10.240, J=2.520), 3.706 (33, 1H, ddd, J=15.207, J=10.240,
J=2.520), 3.686 (33, 1H, ddd, J-15.207, J=3.100, J=2.510)
Example 7)
Prepration of N-formyl-N- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-nitrobenzothiophene-2-
carboxamide

To a solution of N- ({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm , 0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.04 69mol) and then 5-nitro benzothiazole (9.42g/0.039 mol) at 5 to!0°C. heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 3.4 g compound .
Example 8)
Prepration of N-formyl-N- ({<5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-3-Chlorobenzothiophene-
2 carboxamide


To a solution of N-({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine {6.06 g 0.0469mol) and then 3-Chloro benzothiazole {9.01g,0.039 mol) at 5 tol0°C. heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 2 5 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol ,suck dry and dry for 5.0 hrs.to give 4.1 g compound .
NMR data:
8.491 (8, 1H, ddd, J-8.492, J-5.284, J=1.451), 7.744 (11, 1H, ddd, J-8.028, J-5.284, J=1.617), 7.521 (12, 1H, ddd, J-8.4 92, J-7.7 95, J-1.617), 8.775 (13, 1H) , 4.071 (14, 2H, d, J=6.704), 7.479 (15, 1H, ddd, J-8.028, J-7.7 95, J=1.4 51) , 4.800 (17, 1H, dtd, J=8.0 60, J-6.704, J-4.260), 3.864 (19, 1H, dd, J=16.474, J=4.260), 3.770 (19, 1H, dd, J-16.474, J-8.060), 7.618 (24, 1H, ddd, J=8.607, J-2.597, J-0.000), 7.618 (25, 1H, ddd, J=8.607, J-2.585, J=0.000), 7.583 (26, 1H, ddd, J-8.607, J-2.585, J=0.000), 7.583 (27, 1H, ddd, J-8.607, J-2.597, J=0.000), 3.684 (31, 1H, ddd, J=15.524, J=10.110, J=3.680), 3.655 (31, 1H, ddd, J-15.524, J-3.660, J-2.060), 4.222 (33, 1H, d, J=14.602), 4.452 (33, 1H, d, J=14.602), 3.626 (34, 1H, ddd, J=13.364, J-3.680, J-2.060), 3.545 (34, 1H, ddd, J-13.364, J=10.110, J=3.660)

Example 9)
Prepration of W-formyl-N- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-methylbenzothiophene-2-
carboxamide

To a solution of N- ({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.015611101) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then 5-methyl benzothiazole (8.21g,0.0 39 mol) at 5 tolO°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x2 5ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 4.1 g compound .
Example 10)
Prepration of N-formyl-N- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-5-aminol-H-Imidazole-4-
carboxamide


To a solution of N-{{ (5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide { 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.04 69mol) and then 5-amino 1-H-Imidazole-4-carbonylchloride (5.67g,0.039 mol) at 5 tol0°C-. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 2.1 g compound.
Example 11)
Prepration of N-formyl-N- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-l,3-oxazolidin-5-yl}methyl)- 2-phenyl-l-H-Imidazole-4-
carboxamide

To a solution of N- ({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.04 69mol) and then 2-phenyl-l-H-Imidazole-4-carbonylchloride (8.05g, 0.039 mol) at 5 tolO°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 2 0 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 3.2g compound

Examplell)
Preparation of N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl)- 2,5-difluoro-lH-Imidazole-
4-carboxamide

To a solution of N- ({ (55)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide { 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine {6.06 g 0.0469mol) and then 2,5-difluoro-lH-Imidazole-4-carbonyl chloride (6.50g,0.039 mol) at 5 tol0°C. Heat the solution to reflux temperature and reflux for 6. Ohrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 2.2g compound Example 12)
Prepration of 1-formyl-3,3-dimethyl-l-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)urea


To a solution of N-({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm , 0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then dimethyl -carbonyl chloride (5.03g,0.04 68 mol) at 5 tol0°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol ,suck dry and dry for 5.0 hrs.to give 2.5g compound
Example 13)
Preparation of W-formyl-W- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]- 1,3- oxazolidin-5-yl}methyl) ethyl methyl
carboxamide

To a solution of W- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.04 69mol) and then methyl ethyl carbonyl chloride (4.742g,0.039 mol) at 5 tol0°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 2.6g compound

NMR data:
4.221 {4, 1H, d, J=14.596), 4.391 (4, 1H, d, J=14.596), 3.675 (6, 1H, ddd, J=15.525, J=10.110, J=3.680), 3.701 {6, 1H, ddd, J=15.525, J=3.660, J=2.060), 7.583 (8, 1H, ddd, J=8.607, J=2.551, J=0.000), 7.583 (9, 1H, ddd, J=8.607, J=2.574, J-0.000), 3.617 (10, 1H, ddd, J-13.367, J=3.68 0, J=2.0 60), 3.507 (10, 1H, ddd, J=13.367, J=10.110, J=3.660), 7.757 (11, 1H, ddd, J-8.607, J=2.574, J=0.000), 7.757 (12, 1H, ddd, J=8.607, J=2.551, J-0.000), 3.863 (16, 1H, dd, J=16.697, J=4.250), 3.771 (16, 1H, dd, J=16.697, J=8.060), 4.768 (19, 1H, dtd, J-8.060, J=6.788, J-4.250), 4.017 (20, 2H, d, J=6.788) , 8.781 (23, 1H) , 3.28 7 (27, 2H, q, J=7.109), 2.790 (28, 3H), 1.221 (29, 3H, t, J=7.109)
Example 14)
Preparation of N-formyl-N- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3- oxazolidin-5-yl}methyl) diethyl carboxamide

To a solution of N-({ (5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then diethyl carbomyl chloride(5,28g,0.039 mol) at 5 tol0°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 2.2g compound.

NMR data:
4.221 (4, 1H, d, J=14.596), 4.391 (4, 1H, d, J=14.596), 3.675 (6, 1H, ddd, J=15.525, J=10.110, J=3.680), 3.701 (6, 1H, ddd, J=15.525, J=3.660, J=2.060) , 7.58 3 {8, 1H, ddd, J-8.607, J=2.556, J-0.000), 7.583 (9, 1H, ddd, J-8.607, J-2.57 4, J=0.000), 3.617 (10, 1H, ddd, J=13.367, J=3.680, J=2.060), 3.507 (10, 1H, ddd, J=13.367, J=10.110, J-3.660), 7.757 (11, 1H, ddd, J=8.607, J-2.574, J-0.000), 7.757 (12, 1H, ddd, J-8.607, J=2.556, J=0.000), 3.8 63 (16, 1H, ddf J=16.708, J-4.250), 3.771 (16, 1H, dd, J=16.708, J=8.060), 4.7 69 (19, 1H, dtd, J=8.060, J=6.788, J-4.250), 4.006 (20, 2H, d, J-6.788), 8.786 (23, 1H) , 3.252 (27, 2H, q, J-7.109) , 3.252 (28, 2H, q, J=7.10 9) , 1.225 (29, 3H, t, J-7.109), 1.225 (30, 3H, t, J=7.109)
Examplel5)
Preparation of N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-1,3-oxazolidin-5-yl}methyl) cyclopropyl carboxamide

To a solution of N-({ (5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then cyclopropane carbonyl chloride (4.07g,0.039 mol) at 5 tol0°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol ,suck dry and dry for 5.0 hrs.to give 2.8g compound

Example 16)
Preparation of N-formyl-N- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-l,3-oxazolidin-5-yl}methyl) cyclobutayl carboxamide

To a solution of N-({ (5S) -2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm ,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then cyclobutane carbonyl chloride {4.62g,0.039 mol) at 5 tol0°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water {5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs.to give 1.2g compound
Example 17)
Preparation of W-formyl-N- {{<5S)-2-oxo-3-[4-(3-oxomorpholin-4-
yl)phenyl]-l,3-oxazolidin-5-yl}methyl) cyclopentyl carboxamide

To a solution of N- ({ (5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)formamide ( 5.0 gm

,0.0156mol) in 100 ml Dichloromethane, add Diisopropylethyl amine (6.06 g 0.0469mol) and then cyclopantane carbonyl chloride (5.2g,0.039 mol) at 5 tolO°C. Heat the solution to reflux temperature and reflux for 6.0hrs. cool the rm to rt and wash with water (5x25ml). seperate layers . Evaporate Organic layer and add 25 ml methanol, stir for 15 to 20 min. and filter the solid . wash the solid with 10 ml methanol , suck dry and dry for 5.0 hrs. to give 2.8g compound
Section B
Evaluation of the Pharmacological Activity
The amine oxazolidinones derivatives of compound formula (I) (generally represent compound formula I) according to the invention act in particular as selective inhibitors of blood coagulation factor Xa and do not, or only at significantly higher concentrations, inhibit other serine proteases, such as plasmin or trypsin.
sThe advantageous pharmacological properties of the compounds according to the invention can be determined by the following methods:
A) Test Description (In Vitro)
1) Determination of the Factor Xa Inhibition:
The enzymatic action of human factor Xa (FXa) is measured using the conversion of a chromogenic substrate specific for FXa. Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations are carried out in microtiter plates as follows:
The test substances(compounds derive from compound formula I), in various concentrations, are dissolved in DMSO and incubated for 10 minutes at 25° C. with human FXa (0.5 nmol/1 dissolved in 50 mmol/1 of tris buffer [C,C,C-tris(hydroxymethyl)aminomethane] , 150

mmol/1 of NaCl, 0.1% BSA [bovine serum albumin], pH=8.3). Pure DMSO is used as control. The chromogenic substrate (150 umol/1 Pefachrome® FXa from Pentapharm) is then added. After an incubation time of 20 minutes at 25° C., the extinction at 4 05 nm is determined. The extinctions of the test mixtures containing the test substances are compared with the control mixtures without test substance, and result found that the test compounds having factor xa inhibiton.
2) Determination of the Selectivity:
To assess selective FXa inhibition, the test substances are examined for their inhibition of other human serine proteases such as trypsin and plasmin. To determine the enzymatic activity of trypsin (500 mU/ml) and plasmin (3.2 nmol/1), these enzymes are dissolved in Tris buffer (100 mmol/1, 20 mmol/1 CaCl2, pH=8.0) and incubated with test substance or solvent for 10 minutes. The enzymatic reaction is then started by adding the corresponding specific chromogenic substrates (Chromozym Trypsin® and Chromozym Plasmin©; from Roche Diagnostics) and the extinction at 405 nm is determined after 20 minutes. All determinations are carried out at 37° C. The extinctions of the test mixtures containing test substance are compared with the control samples without test substance, and the IC50 values are calculated. The result indicated that the test compounds have selectivity for FXa inhibition.
3) Determination of anticoagulant activity
The anticoagulant action of the test substance (compound formula -I) was determined in vitro using human plasma. The human plasma used for this experiment was separated from the blood collected in sodium citrate as anticoagulant. The prothrombin time (PT) was determined by using a commercial test kit (Neoplastin from Stagid) and APTT was determined using (Synthasil kit by IL) . Different concentrations of test substance and rivaroxaban used were from

0.1 to 1.0 ug/mL along with corresponding solvent as control. For determination of PT the test compounds were incubated with the plasma at- 37°C for 10 minutes. Coagulation was then started by addition of thromboplastin, and time when coagulation occurred was determined. The concentration of test substance which effected a doubling of prothrombin time was determined. For determination of a PTT the test compounds were incubated with the plasma at 37°C for 10 minutes after which CaC12 was added .The results of assay indicated that the test compounds (compound formula-I) has significant anticoagulant activity.
4) Determination of the Antithrombotic Activity (In Vivo)
4.1) Arteriovenous Shunt Model (Rabbit):
Fasting rabbits (strain: Esd: NZW) are anesthetized by intramuscular administration of Rompun/Ketavet solution (5 mg/kg and 40 mg/kg, respectively). Thrombus formation is initiated in an arteriovenous shunt in accordance with the method described by C. N. Berry et al. [Semin. Thromb. Hemost. 1996, 22, 233-241] . To this end, the left jugular vein and the right carotid artery are exposed. The two vessels are connected by an extracorporeal shunt using a vein catheter of a length of 10 cm. In the middle, this catheter is attached to a further polyethylene tube (PE 160, Becton Dickenson) of a length of 4 cm which contains a roughened nylon thread which has been arranged to form a loop, to form a thrombogenic surface. The extracorporeal circulation is maintained for 15 minutes. The shunt is then removed and the nylon thread with the thrombus is weighed immediately. The weight of the nylon thread on its own was determined before the experiment was started. Before extracorporeal circulation is set up, the test substances are administered either intravenously via an ear vein or orally using a pharyngeal tube. The results indicated that the test compounds (compound formula-I) has significant Antithrombotic Activity.

Claims:
I) A compound of formula (I)

In which,
E is (C1-C6) -alkylcarbonyl represent straight chain or branched alkoxy radical having 1 to 6 carbon atoms which are attached via carbonyl group.
And
M is any heterocycle including cyclohexane or substituted cyclohexane, benzyl, halo alkyl, benzo-fused thiophene group which may optionally be mono- or polysubstituted by a radical selected from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (C1-C8) -alkyl which for its part may optionally be mono- or polysubstituted by halogen; {C3-C7} -cycloalkyl; (C1-C8) -alkoxy; imidazolinyl; —C(=NH)NH2; carbamoyl; and mono- and di-(C1-C4)-alkyl-aminocarbonyl,
Or its pharmaceutically accepted salt or solvate form or hydrate form.
2) A process for preparing compound formula (I) or salt thereof
comprising:
a) treating compound formula (A) with compound formula (B);
Q—E M
Formula (B)

Wherein,
Q is leaving group;
E & M are as defined in claim 1;
In presence of acid or base to obtained compound formula (I).
3) A pharmaceutical composition comprising the compound formula
(I), as claimed in Claim 1, with combination of suitable
pharmaceutically acceptable excipients.
4) A compound formula (I), as claimed in claim 1, comprised in a medicament for treatment or prevention of thromboembolic disorders in humans and animals.
5) A compound formula (I), as claimed in claim 1,
wherein the compound formula (B) is used as an anti-coagulant.