Field
Described are novel hydroxamates of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof, which are hydroxamic acid derivatives of statins such as Atorvastatin, Rosuvastatin, Fluvastatin and the like, that are compounds having inhibitory effect on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA).

Provided herein further is a process for the preparation of the above said novel compounds of the general formula (I), their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts pharmaceutical compositions, metabolites and prodrugs thereof. This invention also relates to intermediates useful in the preparation of such compounds.
The novel compounds herein are useful for the treatment of inflammation, immunological diseases; particularly those mediated by cj^okines such as TNF-a, IL-1, IL-6, IL-ip, IL-8, IL-12 and cyclooxygenases such as COX-2 and COX-3, hyperlipidemia mediated by (HMG-CoA) reductase and cancer.
In particular, provided herein are methods using compound of formula (I) for the treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic p cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; brain . trauma; multiple sclerosis; sepsis; septic. shock; toxic shock syndrome; fever, myalgias due to infection and hyperlipidemia using compound of formula (I).

Background
The present invention relates to potentially pharmaceutical compositions and in particular to new molecules as active ingredients, that are used in particular as anticancer, anti-inflammatory and anti-hyperlipidemic agents. Compounds of the general formula (I) and pharmaceutically acceptable salts thereof according to the present invention have an ability of inhibiting histone deacetylating enzyme, TNF-a, mducing differentiation and are useful as therapeutic or ameliorating agents for diseases with inflammation or proliferation or autoimmunity.
Statins, which are inhibitors 'of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) are the most commonly used class of drugs for the treatment of hypercholesteromia and hence for the management and prevention of cardiovascular diseases. Number of studies have pointed out the therapeutic impact of the so-called "pleiotropic effects" of statins and hence, have raised the ability of this class of compounds responsible for their beneficial effects in atherosclerosis.
In addition to cholesterol biosynthesis; i.e. HMG-CoA reductase pathway, mevalonate, is also a precursor of famesyl and geranylgeranyl moieties, which are critical to post-translationai modification of intracellular signaling pathway protection such as Ras. Inhibition of famesylation and geranylgeranylation of messenger molecules have been major targets of cancer drug development.
Various studies have indicated that statins may reduce the risk of certain types of cancer. But this area remains controversial as certain preclinical studies supported the potential anti-cancer activity of these compounds [Nat. Clin. Pract. Oncol. 2005, 2, 82-89, J. Natl. Cancer. Inst. 2003, 95, 844-846, Cancer. Epidemiol. Biomarkers. Prev. 2008, 17(5), 1028-1033 and BMC cancer 2008, 5, 9b], whereas some have shown negative association warranting further evaluation [J. Natl. Cancer. Inst. 2006,
98, 700-707],
Cancer is one of the leading causes of death in the present society. A great deal of effort has been underway to treat various forms of cancer for decades and until recently, chemo-prevention of cancer is receiving its due share of attention.
The most common treatment for easily accessible cancer is surgical removal of the diseased tissues and radiation. The choice of treatment for inaccessible tumors is chemotherapy. Also chemotherapy is given as additional insurance for most cancers as it is difficult to access the extent of metastasis.

Most clinically revelant anticancer drugs currently used in the clinics, interfere with cell division and hence are not highly selective to cancer cells. There are potential chances that chemotherapy can lead to secondary cancers in due course of time. Also the quality of life is hampered in the patients upon chemotherapy. Hence there is an unmet medical need for treating cancer patients without affecting the quality of life.
The cell cycle deregulation and the molecular basis of cancer cell growth has been thoroughly exploited in the recent years. Inhibition of signal transduction has become a viable and attractive avenue in biomedical cancer research based on the discovery of a large number of somatic mutations in many different types of cancers that lead to deregulated growth signal transduction and subsequent aberrant growth, invasion, tumor-derived angiogenesis and metastasis. Most of the noncytotoxic drugs that have been recently developed include protein kinase inhibitors such as Gleevec, Iressa and Tarceva, Tyrosine kinase inhibitors like Leflunomide. Glivec^^ (STJ57I) is an inhibitor of the bcr-abl kinase and CML. PKI166, on the other hand, is a dual inhibitor of EGF receptor (HER 1) as well as erbB (HER 2). EGF-receptor and PTK787, potent inhibitors of VEGF-receptor 2 (KDR) are able to suppress tumor growth via suppression of tumor angiogenesis and also these agents have entered clinical trials in tumor patients. These types of orally active and relatively well-tolerated compounds can be used in the clinics; either as single agents or in combination with other well established cytotoxic agents.
Cytokines play an important role in the communication between cells of multicellular organisms. Early studies indicate that B cells lineage tend to secrete IL-6 in response to host immune defense mechanisms, but in recent decades studies have indicated elevated levels of IL-6 in various cancer phenotypes.
Elevation of inflammatory cytokine levels, particularly IL-6 and TNF-ct also appears to be associated with Cancer-related cachexia, a syndrome involving loss of adipose and skeletal muscle tissue, and one that is not responsive to increased caloric
intake.
Excessive production of IL-6 is implicated in several disease states, and it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S Patents: 6004813, 5527546 and 5166137.
Given that apoptosis is a crucial factor for cancer progression, HDAC

inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis. Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P.A. et al., J. Natl Cancer Inst. 2000, 92, 1210-1215. More specifically the patents WO 98/55449 and US 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity.
Most extensively studied derivative of hydroxamic acid, inhibiting HDAC is SAHA (suberoylanilide hydroxamic acid), CBHA (m-Carboxycinnamic acid bishydroxamide) and TSA (Trichostatin A). TSA is an antifungal antibiotic isolated from Streptomyces hygroscopius, while SAHA and CBHA have been studied by Sloan Kettering Institute (WO 95/31977) as tumor cell differentiation inducing agents.
Now it has been found that known hydroxamates like trichostatin A and SAHA inhibit the synthesis of pro-inflammatory cytokines and hence can be used for diseases with an inflammatory component.
The present invention is concemed with the treatment of immunological diseases or inflammation. Notably such diseases are mediated by cytokines like TNF-a. Elevated levels of TNF-a have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis etc. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-a mediates the cytokine cascade that leads to joint damage and destruction (Arend et al. Arthritis. Rheum. 1995, 38, 151-160). Inhibitors of TNF-a, including soluble TNF receptors (etanercept) (Goldenberg, Clin. Ther. 1999, 21, 75-87) and anti-TNF-a antibody (infliximab) (Luong et al, Ann. ^ Pharmacother. 2000, 34, 743-760) have been recently approved by the U.S.FDA as agents for the treatment of rheumatoid arthritis.
It can be seen that inhibitors of TNF-a are potentially useful in the treatment of a wide variety of diseases. Compounds that inhibit TNF-a have been described in several patents.
1. WO 03/013493 Al discloses the following compounds of formula A, having pro-inflammation cytokine synthesis inhibition ability, wherein R is alkyl, aryl, 0-aryl, O-alkvl and 0-heteroaryl.


Formula A
2. WO 2004/105754 discloses compounds of the formula B, having pro-inflammation cytokine synthesis inhibition ability, anti-inflammatory, antiplatelet and antithrombotic activity, wherein R is the statin residue selected from pravastatin, fluvastatin, cerivastatin, etc., X and Y being suitable linker like -0-, -S-, -NH- or -NHR'-, where R' is an alkyl group.
OH OH
R—C—CH,—C—CH,—C X Y ONO^
H H
Formula B
Objectives
One objective herein is to provide novel hydroxamates of the general formula (I), which are hydroxamic acid derivatives of statins such as Atorvastatin, Rosuvastatin, Fluvastatin and the like.
Another objective herein is to provide the process for the preparation of novel hydroxamates of statins such as Atorvastatin, Rosuvastatin, Fluvastatin and the like.
Yet another objective herein is to provide a method of treatment of cancer, including administrating a therapeutic amount of compound of formula (I) or their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
One more objective herein is to provide a method of treatment of inflammation and immunological diseases mediated by cytokines such as TNF-a, IL-1, IL-6, IL-lp, IL-8, IL-12 and also for treatment of hypercholesterolemia using novel hydroxamates of formula (I).
Another objective herein is to provide a pharmaceutical composition with novel hydroxamates of formula (I) in combination with clinically relevant non-cytotoxic agents, which can be used as anti-proliferative agent.

Summary
Described are novel hydroxamates of the general formula (I),
R—O T
{
R
(I)
their derivatives, analogs, tautomeric forms, stereoisomers, clathrates, polymorphs,
hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof which are hydroxamic acid derivatives of statins such as Atorvastatin, Rosuvastatin, Fluvastatin and the like. The novel hydroxamates of the general formula (I) can be used for the treatment of diseases associated with proliferation, inflammation and hyperlipidemia, wherein '—' represents C-C or C=C; R' and R^ may be same or different and independently represent hydrogen, alkyl, aryl, aralkyi and the like;
R represents H, alkyl and aryl; or R and R may be taken together with the atoms to which they are attached to form heterocyclyl ring optionally substituted by R or R^, the heterocyclyl ring is particularly selected from the groups such as (i), (ii), (iii), (iv) and (v);

cP CT^ cr c.
(i) (ii) (iii) (iv) (v)
R" and R^ are at each occurrence independently H, NO2, CN, halogen, alkoxy, COOH, COOR^ CONH2, CONR^R^ NHR^ or NR'^R^
R"" and R^ may be same or different and individually represents hydrogen, alkyl or aryl groups and R represents



0'%

or

or

o

Detailed description
Provided herein are novel hydroxamates of the general formula (I),
, ,NH L^0"R'
R—O T
{
R
0)
their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates,
solvates, pharmaceutically acceptable salts/prodrugs, pharmaceutical compositions thereof; wherein '—' represents C-C or C=C; R' and R may be same or different and independently represent hydrogen, alkyl, aryl, aralkyl and the like; R represents H, alkyl and aryl; or R^ and R^ may be taken together with the atoms to which they are attached to form heterocyclyl ring optionally substituted by R'^ or R^, the heterocyclyl ring is particularly selected from the group


/O^

^'

(i)
(ii)
(V)
(iii)
R"* and R^ are at each occurrence independently H, NO2, CN, halogen, alkoxy, COOH, COOR^ CONH2, CONR^R^ NHR^ NR'^R^
R^ and R^ may be same or different and individually represents hydrogen, alkyl or aryl groups; and

R represents substituted or unsubstituted groups selected from aryl, saturated unsaturated cycloalkyl and saturated or unsaturated heterocyclyl. R particularly represents,

or


Terminology and Abbreviations
As used herein, the term "alkyl" refers to a straight chain or branched hydrocarbon having from 1 to 8 carbon atoms. Representative straight-chain alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; while branched alkyl groups include, but are not limited to, -isopropyl, -sec-butyi, -isobutyl, -tert-butyl. An alkyl group can be substituted or unsubstituted.
As used herein, the term "aryl" refers to a carbocyciic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and anthracenyl. An aryl group can be substituted or unsubstituted.
As used herein, the term "arylalkyl" refers to an aryl group directly bonded to an alkyl group, e.g.: -CH2C6H5 and the like.

J
Representative O—aJkyl or alkoxy groups include, but are not limited to, -0-methyl, —0-ethyl, —0-n-propyl, —0-n-butyl, —0-isopropyl, —O-sec-butyl, -0-isobutyl and -0-tert-butyl. A O—alkyl group can be substituted or unsubstituted.
As used herein, the term "halo" means chloro, iodo, bromo, or fluoro. '
As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic cycloaJkyI in which one to four of the ring carbon aXoms are independently replaced with a heteroatom from the group consisting of O, S and N. Representative examples of a heterocyclyl include, but are not limited to, benzofuranyl, benzothienyl, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, morpholinyl, pyrrolyl, pyrrolidinyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, piperizinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, (l,4)-dioxane, (l,3)-dioxolane, 4,5-dihydro-lH-imidazolyl and tetrazolyl. Heterocyclyls can also be bonded at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclyl group can be substituted or unsubstituted. In one embodiment, the heterocyclyl is a 3-7 membered heterocyclyl. Heterocyclic group may be mono or bi or polycyclic.
As used herein, the term "cycloalkyl" refers to a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or unsaturated non-aromatic carbocyclic ring. Representative Cs-Cg cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, 1,2,3,7,8,8a-hexahydronaphthalene and cyclooctadienyl. A cycloalkyl group can be substituted or unsubstituted. Cycloalkyl group may be mono or bi or polycyclic.
As used herein, the term "Compound(s)" refers to any compound, including pharmaceutically acceptable salts, solvates, hydrates, clathrates, stereoisomers, polymorphs or prodrugs thereof, disclosed herein specifically or generically.
When the groups described herein are said to be "substituted or unsubstituted," when substituted, they may be substituted with one or more of any substituent described herein or represented in a compound described herein. Examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halo (e.g., chloro, iodo, bromo, or fluoro); alkyl; aikenyi; alkynyl; hydroxy!; alkoxy!; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; acetyl; aceloxy;

carbamoyl; oxygen (=0); haloalkyl (e.g., trifluoromethyl); substituted aminoacyl and aminoalkyl; carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobufyi, cyclopentyl, or cyclohexy]), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); amino (primary, secondary, or tertiary); -0-lower alkyl; -O-aryl; aryl; aryl-lower alkyl; CO2CH3; CONH2; OCH2CONH2; NH2; N(CMalkyl)2; NHC(0)CMa]kyl; SO2NH2; S02Ci.4alkyl; OCHF2; CF3; OCF3; and such moieties may also be optionally substituted by a fused-ring structure or bridge, for example -OCH2O- or -O-lower alkylene-0-. These substituents may optionally be further substituted with a substituent selected from such groups.
Various compounds contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. Provided herein are methods comprising the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound can be used in methods and compositions provided herein. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.
It should be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
As used herein, the phrase "pharmaceutically acceptable salt" refers to pharmaceuticaJly acceptable organic or inorganic salts of a compound. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethanesulfonate, benzene sulfonate, p-toluene sulfonate,

and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt can involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt can have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterion.
As used herein, the term "solvate" refers to an association of one or more solvent molecules and a Compound. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water {i.e., hydrate), isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
As used herein, the term "pharmaceutically acceptable hydrate" refers to a Compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
As used herein, the term "polymorph" means a particular crystalline arrangement of a Compound. Polymorphs can be obtained through the use of different work-up conditions and/or solvents. In particular, polymorphs can be prepared by re crystallization of a Compound in a particular solvent.
As used herein, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In one embodiment, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods.
As used herein, the terms "prevent," "preventing" and "prevention" refer to a reduction of the risk of the recurrence, onset, or development of a disorder or one or more symptoms of a disorder in a patient resulting from the administration of a Compound. In one embodiment, a disorder or symptom thereof is prevented in a patient who previously had or currently has the disorder

As used herein, the terms "treat," "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a disorder, or the amelioration of one or more symptoms thereof resulting from the administration of a Compound.

Abbreviations
1. DMSO
2. BOP
3. TMSCl
4. TBDMS
5. HOBT
6. DCC
7. DMF
8. DMAP
9. HMDS lO.PTSA

11. TEA
12. HDAC
13. S AH A
14. CBHA 15.PBMC

Dimethylsulphoxide
Benzotriazol-1 -yloxytris(dimethylamino)phosphonium
hexafluorophosphate
Trimethylsilylchloride
Tez-riarybutyldimethylsilylchloride
1 -Hydroxybenzotriazole
N,N'-Dicyclohexylcarbodiimide
Dimethyl formamide
Dim ethyl am inopyridine
Hexamethyldisilazane
/>ara-Toluenesulphonic acid
Triethylamine
Histone deacetylases
Suberoylanilidehydroxamic acid
me/a-Carboxy cinnamic acid bis hydroxamide
Peripheral Blood Mononuclear Cells

Particularly usefiil compounds according to the present invention include:
1. N-BenzyIoxy-2-((4R,6S)-6- {(E)-2-[4-(4-fIuoro-phenyl)-6-isopropy 1-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-
4-yl)-acetamide;
2. l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2-phenyl-l,3-dioxinan-4-yl]-
ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid
phenylamide;
3. 2-((4R,6R)-6-{2-[4-(4-Fluoro-pheny!)-6-isopropyJ-2-(methanesu]fony]-methy]- ,
amino)-pyrimidin-5-yl]-ethyl}-2-phenyl-l,3-dioxinan-4-yl)-N-hydroxy-
acetamide;

4. 5-(4-Fluoro-phenyl)-l-[2-((4R,6R)-6-hydroxycarbamoylmethyl-2-phenyl-l,3-dioxinan-4-yl)-ethyl]-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
5. N-Ben2yloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-acetamide;
6. l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2,2-dimethyl-l,3-dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
7. 2-((4R,6R)-6-{2-[4-(4-Fiuoro-phenyi)-6-isopropyI-2-(methanesulfonyI-methyI-amino)-pyrimidin-5-yl]-ethyl}-2,2-dimethy]-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
8. 5-(4-Fluoro-phenyl)-l-[2-((4R,6R)-6-hydroxycarbamoylmethyl-2,2-dimethyl-l,3-dioxinan-4-yl)-ethyl]-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
9. 2-((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyI-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
10. 2-((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
11. (E)-(3R,5S)-7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoicacidbenzyloxy-amide;
12. 1 -({3R,5R)-6-Benzyloxycarbamoyl-3,5-dihydroxy-hexyl)-5-(4-fluoro-phenyl)-2-isopropyl-4~phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
13. (3R,5R)-7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-heptanoic acid hydroxyamide;
14. l-((3R,5R)-3,5-Dihydroxy-6-hydroxycarbamoyl-hexyl)-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
15. (3R,5R)-7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-
pyrimidin-5-yl]-3,5-dihydroxy-heptanoic acid benzyloxy-amide;
16.1- {2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2-{4-fluoro-phenyl)-1,3 -dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;

17. N-Benzyloxy-2-((4R,6S)-2-(4-fluoro-phenyl)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropy^2-(methanesuIfony^methyl-amino)-pyrimidin-5-yl]-vinyl}-l,3-dioxinan-4-yl)-acetamide;
18. 5-(4-Fluoro-phenyl)-l-{2-[(4R,6R)-2-(4-fiuoro-phenyl)-6-hydroxycarbamoylmethyl-l,3-dioxinan-4-yl]-ethyl}-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
19. 2-((4R,6R)-2-(4-Fluoro-phenyl)-6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-ethyl}-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
20. 2-((4R,6S)-2-(4-Fluoro-phenyl)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
21.N-Benzyloxy-2-((4R,6S)-2-ethyl-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-l,3-dioxinan-4-yl)-acetamide and
22. 2-((4R,6R)-2-Ethyl-6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-ethyl}-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
According to another embodiment, there is provided a process for the preparation of Compounds of forumula (I) (wherein all the groups are as defined earlier), which comprises the steps of:
(a) hydrolyzing calcium salt of formula 1(a) with aqueous acid like dil HCl to yield
compound of the general formula (lb);
(b) protecting 1,3- diol of the compound of the general formula (lb) to yield
compound of formula 1(c);
(c) condensing the compound of formula 1(c) with R1ONH2.HCI using reagents like BOP reagent, hydroxy benzotriazole in presence of a base to yield compound of formula 1(d) and
(d) hydrogenolysis and/or hydrogenation of the compound of the formula 1(d) in presence of Pd/C to yield a compound of formula (I)

Scheme 1:


-0
OH
OH

-|Ca2*
OH.
OH
r
R 1(a)

Step (a)

r
R 1(b

OH
OH

Step (b)
1,3.diol protection

r
R 1(c}

Step (c)

RiONHj.HCI TEA, BOP

,0 ^
R'S^,NH
R (I)

Step (d)
Pd/C, H,

f
R
1(d)

The compound of general formula (I) can be prepared by the following procedure: Step (a):
Free acid of the formula 1(b) was generated from its calcium salt by treating a solution of compound of the formula 1 (a) in solvents like ethyl acetate, chloroform, dichloromethane and dichloroethane, with aqueous mineral acids, like 10% HCl at 0 to 5°C. Step (b):
1, 3-diol of the compound of formula 1(b) is protected by reacting it with reagents like HCHO, CH3CH2CHO, PhCHO, substituted benzaldehyde, cyclohexaldehyde, 2,2-dimethoxy propane, TMSCl, TBDMSCl in organic solvents such as tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethyl acetate, dichlorobenzene or a mixture thereof to get the compound of formula 1(c). Step (c):
Compound of formula 1(c) is reacted with the compound R'ONHZ.HCI, wherein R' is as defined earlier, which is activated with reagents such as BOP, HOBT, DCC, isobutyl chloro formate and the like in organic solvents such as toluene, tetrahydrofuran, DMF, chloroform, dichloromethane, dichloroethane, ethyl acetate, dichlorobenzene or a mixture thereof in the presence of a base such as triethyl amine,

diethylamine, diisopropyl ethylamine, pyridine, DMAP, HMDS to afford a compound of the formula 1(d).
Step (d):
The compound of the formula 1(d) is hydrogenated in solvents like ethyl acetate, methanol, ethanol, etc. or a mixture thereof in the presence of Pd on carbon at room temperature to get compounds of the general formula (I).
According to yet another embodiment, there is provided a process for the preparation of Compounds of forumula (I) (wherein all the groups are as defined earlier), which comprises the steps of:
(1) esterification of the compound of formula 1(c) with methanol to yield compound of formula 1(e) in the presence of acid or activating reagents;
(2) reaction of compound of the formula 1(e) with R ONH2.HCI in the presence of base to yield 1(d);
(3) unmasking compound of formula 1(d) in the presence of an acid to yield 1(f) and
(4) hydrogenolysis and /or hydrogenation of the compound of formula 1(f) in the presence of Pd/C to yield a compound of formula (I).
Scheme 2:

OH L ,0 Step(1) Step (2) R V
J
f R ^' J
r
R R1ONH2.HCI J
r
R

Base

1(c) 1(e) 1(d)
Step (3) deprotection
O^^^.sOH
.NH L,vOH HO y Step (4) R „.NH L,OH


Pd/C, Hj
-0 -f
r
R r
R
(1) 1 (f)
The compound of general formula (I) can be prepared by the following procedure: Step (1):
The compound of formula 1(c) is reacted with methanol in the presence of acid or activating reagents like HOBT, BOP and DCC in solvents like

dichloromethane, dichloroethane and the like or a mixture thereof to get the compound of formula 1(e). Step (2):
The compound of formula 1(e) is reacted with the compound R'ONH2.HC1, wherein R' is as defined earlier, in solvents such as tetrahydrofiiran, ethanol, toluene or a mixture thereof in the presence of a base such as tri ethyl amine, diethylamine, di-isopropylethylamine, KOH, NaOH, NaOMe to afford a compound of formula 1(d). Step (3):
The compound of the formula 1(d) was hydrolyzed with acids such as dilute mineral acids, H^ resin in solvents like acetone, methanol, ethanol, isopropanol and the like or a mixture thereof in the presence of water at room temperature to get compounds of general formula 1(f). Step (4):
The compound of formula 1(f) is hydrogenated in solvents like ethyl acetate, methanol, ethanol, etc. in the presence of Pd on carbon at room temperature at 2Kg of hydrogen pressure to get the compounds of general formula (I).
The invention is explained in detail in the examples given below which are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1: Synthesis of N-BenzyIoxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyI)-6-isopropyI-2-(methanesuIfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyI-1,3-dioxinan-4-yl)-acetamide

Stage (A): Preparation of (E)-(3R,5S)-7-[4-(4-Fluoro-phenyI)-6-isopropyI-2-
(metlianesulfonyl-methy!-amino)-pyrimidin-5-yl]-3,5-diIiydroxy-liept-6-enoic
acid


10.0 g of calcium salt of (E)-(3R,5S)-7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid was dissolved in 400 mL of EtOAc. 400 mL of distilled water was added to it and the pH adjusted to 2-3 with 10% HCl at 0-5 °C. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over Na2S04 and distilled under vacuum to get 9.0 g of the title compound.
Stage (B): Preparation of ((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-aniino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yl)-acetic acid

6.0 g of (E)-(3R,5S)-7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid and 3 mL of benzaldehyde along with catalytic amount of PTSA were stirred at room temperature for 12 hours. Subsequently the reaction mass was subjected to silica gel column chromatography to get 5.8 g of the title compound.
Stage (C): Preparation of N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-plienyl)-6-isopropyI-2-(methanesuIfonyl-metIiyl-amino)-pyrimidin-5-yll-vinyl}-2-phenyI-1,3-dioxinan-4-yl)-acetamide


0 O
1.8 g of ((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yI)-acetic acid were dissolved in 30 mL of dichloromethane. 0.4 mL of TEA and 1.46 g of BOP reagent were added to the above followed by addition of 0.53 g of O-benzyl hydroxylamine HCl and the mixture was stirred at room temperature for 18 hours. The reaction mass was diluted with methylene dichloride and washed with saturated NaHCOa followed by brine. The organic layer was dried overNa2S04, distilled under vacuum and subjected to silica gel column chromatography to get 1.0 g of the title compound.'H NMR (400 MHz, CDCI3): 6 (ppm) 8.35 (s, IH), 7.64 (t, 2H), 7.37-7.30 (m, lOH), 7.08 (t, 2H), 6.65 (d, IH), 5.58-5.53 (m, 2H), 4.90 (s, 2H), 4.43-4.41 (m, IH), 4.27-4.24 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.37-3.34 (m, IH), 2.40 (d, 2H), 1.66 (d, IH), 1.42 (q, IH), 1.27(4 6H). MS m/z: 675.2 (M''+l). m.p: 88.7 °C
Example 2:
Synthesis of l-{2-|(4R,6R)-6-(Benzyloxycarbanioyl-methyl)-2-phenyl-l,3-
dioxinan-4-yll-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyI-lH-pyrrole-3-
carboxylic acid phenylamide

The title compound was prepared from Atorvastatin calcium in 52% yield according to the procedure given in the example l.^H NMR (400 MHz, CDCI3): 5 j:ppm) 8.32 (s, IH), 7.36 (brs, 5H), 7.30 (brs, 5H), 7.20-7.15 (m, 9H), 7.06 (d, 2H), 7.00-6.93 (m, 3H), 6.86 (s, IH), 5.33 (s, IH), 4.88 (s, 2H), 4.15-4.11 (m, 2H), 4.00-

3.94 (m, IH), 3.70-3.64 (m, IH), 3.56-3.52 (m, IH), 2.33 (d, 2H), 1.86-1.76 (m, 2H), 1.53 (d, 6H), 1.48-1.32 (m, 2H). MS m/z: 752.3 (MVI). m.p: 93.5° C
Example 3;
Synthesis of 2-((4R,6R)-6-{2-[4-(4-FIuoro-phenyl)-6-isopropyl-2-
(methanesulfonyl-methyI-aniino)-pyriniidin-5-yl]-ethyl}-2-phenyl-l,3-dioxinan-4-yI)-N-hydroxy-acetamide

1.0 g of N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3 -dioxinan-4-yl)-acetamide was hydrogenated under 1.8 Kg pressure in ethanol in presence of 200 mg of Palladium on charcoal (10% Pd on C) at room temperature for 4 to 5 hours. Subsequently the catalyst was filtered off and the filtrate was evaporated to dryness. The residual mass was subjected to silica gel column chromatography to yield 0.5 g of the title compound.'H NMR (400 MHz, CDCI3): 8 (ppm) 8.68 (s, IH), 7.49-7.46 (m, 2H), 7.39-7.31 (m, 5H), 7.08-7.04 (m, 2H), 5.44 (s, IH), 4.17-4.11 (m, IH), 3,7.5-3.70 (m, IH), 3.53 (s, 3H), 3.50 (s, 3H), 3.35-3.30 (m, IH), 3.00-2.92 (m, IH), 2.75-2.70 (m, IH), 2.50 (d, 2H), 1.71-1.65 (m, 2H), 1.52 (d, IH), 1.41 (t, IH), 1.30 (d, 6H). MS m/z: 587.2 (M^l). m.p: 98.8 °C Example 4:
Synthesis of 5-(4-Fluoro-phenyl)-l-[2-((4R,6R)-6-hydroxycarbamoyl methyl-2-phenyl-l,3-dioxinan-4-yl)-ethyll-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide

The title , compound was prepared from l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2-phenyl-l,3-dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide in 51 % yield according to the procedure given in example 3. 'HNMR (400MHZ, CDCI3): 5 (ppm) 8.60 (brs, IH), 7.52 (brs, 3H), 7.38 (brs, 2H), 7.18-7.13 (m, 9H), 7.06 (d, 2H), 7.01-6.94 (m, 3H), 6.85 (s, IH), 5.41 (s, IH), 4.22-4.11 (m, 2H), 4.04-3.97 (m, IH), 3.72-3.62 (m, IH), 3.55-3.49 (m, IH), 2.47 (d, 2H), 1.85-1.81 (m, 2H), 1.53 (d, 6H), 1.46-1.33(m, 2H). MSm/z:.662.3(M''+l). m.p: 126.3 "C Example 5: Synthesis of N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-nuoro-phenyl)-6-isopropyl-
2-(methanesuIfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yI)-acetamide

Stage (A):
Preparation of ((4R,6S)-6-{(E)-2-[4-(4-FIuoro-phenyl)-6-isopropyl-2-
(methanesulfonyI-methyl-amino)-pyrimidin-5-yll-vinyl}-2,2-dimethyl-l,3-
dioxinan-4-y!)-acetic acid
OH
0 0

3.0 g of (E)-(3R,5S)-7-[4-(4-Fluoro-phenyl)-6~isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid was dissolved in 10 mL of 2,2-dimethoxypropane. 100 mg of camphorsulphonic acid was added to the above and it was stirred at room temperature. After 16 hours the excess reagent was evaporated under vacuum, diluted with dichloromethane, washed with aqueous NaHCOs solution followed by brine. The organic layer was dried over Na2S04, concentrated and the residual mass was subjected to silica gel column chromatography to yield 1.8 g of the title compound.
Stage (B):
Preparation of N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-
isopropyl-2-(methanesulfonyl-methyl-aniino)-pyrimidiii-5-yll-vinyl}'-2,2-
dimethyl-l,3-dioxinan-4-yI)-acetamide

0 0
The title compound was prepared from ((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yI]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-acetic acid in 64.5% yield according to the procedure given in Stage C of the example I.'H NMR (400 MHz, CDCb): 5 (ppm) 8.53 (s, IH). 7.63 (t, 2H), 7.40-7.37 (m, 5H), 7.08 (t, 2H), 6.49 (d, IH), 5.43 (dd, IH), 4.93 (s, 2H), 4.38-4.35 (m, IH), 4.18-4.15 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.36-3.33 (m, IH), 2.30 (d, 2H), 1.49 (d, 2H), 1.27 (d, 12H). MS m/z: 627.5 (M^+1).
Example 6:
Synthesis of l-{2-|(4R,6R)-6-(Benzyloxycarbanioyl-methyI)-2,2-dimethyl-l,3-
dioxinan-4-yll-ethyI}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-
carboxylic acid phenylamide

The title compound was prepared from (3R,5R)-7-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid in 40% yield according to the procedure given in the example 5. 'HNMR (400MH2, CDCI3): 5 (ppm) 8.53 (S, IH), 7.38 (brs, 5H), 7.20-7.14 (m, 9H), 7.06 (d, 2H), 7.01-6.96 (m, 3H), 6.86 (s, IH), 4.90 (s, 2H), 4.13-4.05 (m, 2H), 3.83-3.76 (m, IH), 3.63-3.52 (m, 2H), 2.23 (d, 2H), 1.64-1.55 (m, 2H), 1.51 (d, 6H), 1.32-1.14(m, 8H) MS m/z: 704.3 (M'^+l). m.p; 81.6'C
Example 7:
Synthesis of 2-((4R,6R)-6-{2-|4-(4-Fluoro-phenyl)-6-isopropyl-2-
(methanesulfonyI-methyI-amino)-pyrimidin-5-yl]-ethyl}-2,2-dimethyI-l,3-
dioxinan-4-yl)-N-hydroxy-acetamide

The title compound was prepared from N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-acetamide in 46% yield according to the procedure given in the example 3. 'H NMR (400 MHz, CDCI3): 5 (ppm) 8.79 (s, IH), 7.50 (t, 2H), 7.15 (t, 2H), 4.15-4.10 (m, IH), 3.75-3.70 (m, IH), 3.53 (s, 3H), 3.51 (s, 3H), 3.33-3.27 (m, IH), 2.87-2.79 (m, IH), 2.62-2.55 (m, IH), 2.39 (s, 2H), 1.38 (s, 6H), 1.29-1.11 (m, lOH). MSm/z: 539.2 (MVI). m.p: lOS.l'C.

Example 8:
Synthesis of 5-(4-Fluoro-phenyI)-l-[2-((4R,6R)-6-hydroxycarbamoyl
methyl-2,2-dimethyI-l,3-dioxinan-4-yI)-ethyiJ-2-isopropyI-4-phenyMH-pyrrole-3-carboxylic acid phenylamide

The title compound was prepared from l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2,2-dimethyl-l,3-dioxinan-4-yl]-ethyl}-5-(4-fluoro -phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide in 87% yield according to the procedure given in the example 3. 'H NMR (400 MHz, CDCI3): 5 (ppm) 8.77 (brs, IH), 7.20-7.16 (m, 9H), 7.06 (d, 2HX 7.02-6.98 (m, 3H), 6.86 (s, IH), 4.12-4.04 (m, 2H), 3.87-3.81 (m, IH), 3.63-3.52 (m, IH), 3.58-3.54 (m, IH), 2.35 (d, 2H), 1,67-1.63 (m, 2H), 1.53 (d, 6H), 1.37 (s, 3H), 1.34 (s, 3H), 1.30-1.25 (m, 2H). MS m/z: 614.3 (M'^+l). m.p: 106.8° C.
Example 9:
Synthesis of 2-((4R,6S)-6-{(E)-2-l4-(4-Fluoro-phenyl)-6-lsopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-
yl)-N-hydroxy-acetamide

Stage (A):
Preparation of ((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyI}-2-phenyl-l,3-dioxinan-4-
yl)-acetic acid methyl ester


5.8g of ((4R,6S)~6-{(E)-2-[4-(4-F]uoro-phenyI)-6-isopropyi-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yl)-acetic acid was dissolved in 25 mL of dichloromethane and was cooled to 0 "^C. To it 100 mg of DMAP, followed by 2.52 g of DCC and 40 mL of methanol was added and it was stirred for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residual mass was subjected to silica gel column chromatography to yield 4.6 g of the title compound.
Stage (B):
Preparation of 2-((4R,6S)-6-{(E)-2-|4-(4-FIuoro-pheny!)-6-isopropyI-2-
(methanesulfonyl-methyI-amino)-pyrimidin-5-yll-vinyl}-2-phenyl-l,3-dioxinan-4-
yl)-N-hydroxy-acetamide

To freshly prepared NaOMe solution (prepared from 0.96 g of Na metal and 40 mL of dry MeOH), 2.38 g of hydroxylamine hydrochloride was added and it was stirred for 0.5 hours. To this solution 2.0 g of ({4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yl)-acetic acid methyl ester was added and it was stirred further at room temperature. After 3 hours the solvent was distilled off. To the residue, 60 mL of water was added and it was extracted with ethyl acetate (3 times). The combined organic layer was dried over Na2S04, concentrated and subjected to silica gel column chromatography to yield 0.7 g of the title compound. 'HNMR (400MHz, CDCI3): 5

(ppm) 7.68-7.64 (m, 2H), 7.52-7.48 (m, 2H), 739-731 (m, 3H), 7.09 (t, 2H), 6.66 (d, IH), 5.65 (s, IH), 5.58 (dd, IH), 4.47-4.45 (m, IH), 4.38-4.34 (m, IH), 3.58 (s, 3H), 3.52 (s, 3H), 3.39-3.35 (m, IH), 1.93 (d, 2H), 1.67 (d, IH), 1.50-1.42 (m, IH), 1.27 (d, 6H). MS m/z: 585.2 (M'^+l). m.p: 99.1''C.
Example 10:
Synthesis of 2-((4R,6S)-6-{(E)-2-|4-(4-Fluoro-phenyl)-6-isopropyl-2-
(methanesuIfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-
dioxinan-4-yI)-N-hydroxy-acetamide

The title compound was prepared from ((4R,6S)-6-((E)-2r[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-acetic acid in 22% yield according to the procedure given in the example 9. 'HNMR (400MHZ, CDCI3): 5 (ppm) 7.66-7.62 (m, 2H), 7.11-7.06 (m, 2H), 6.52 (d, IH), 5.49-5.42 (m, IH), 4.44-4.42 (m, IH), 4.27-4.24 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.39-3.34 (m, IH), 2.42-2.40 (m, 2H), 1.60-1.56 (m, IH), 1.48 (s, 3H), 1.45 (s, 3H), 1.26 (d, 6H), 1.23-1.20 (m, IH). MS m/z: 537.2-(M-'+l).
Example 11:
Synthesis of (E)-(3R,5S)-7-[4-(4-FIuoro-phenyl)-6-isopropy!-2-(methanesulfonyl-
methyI-amino)-pyrimidin-5-yll-3,5-dihydroxy-hept-6-enoic acid benzyloxy-amide


2.0 g of N-Benzyloxy-2-((4R,6S)-6-{(E)-244-(4-fluoTO-phenyl)-6-isopropyI-2-(methanesulfonyl-methyl-aniino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-acetamide were dissolved in 20 mL of acetone. To it 1.0 g of Amberiite-IR-120-H^ form resin and 0.5 mL of water were added and it was stirred at room temperature for 16 hours. Subsequently the resin was filtered off, the filtrate was concentrated under vacuum and was subjected to silica gel column chromatography to yield 0.8 g of the title compound. 'HNMR (400MHZ, CDCI3): 6 (ppm) 7.63-7.62 (m, 2H), 7.38 (brs, 5H), 7.11-7.07 (m, 2H), 6.62 (d, IH), 5.43 (dd, IH), 4.93 (s, 2H), 4.45-4.42 (m, IH), 4.12-4.09 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.35-3.32 (m, IH), 2.23 (d, 2H), 1.57-1.49 (m, 2H), 1.26 (d, 6H). MS m/z: 587.2 (MVI).
Example 12: Synthesis of l-((3R,5R)-6-BenzyloxycarbamoyI-3,5-dihydroxy-hexyl)-5-(4-fIuoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide

The title compound was prepared from l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2,2-dimethyl-l,3-dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide in 22% yield following the procedure given in example 11. ^HNMR (400MHz, CDCI3): 5 (ppm) 8.38 (S, IH), 7.38 (brs, 5H), 7.20-7.12 (m, 9H), 7.06 (d, 2H), 7.02-6.98 (m, 3H), 6.87 (s, IH), 4.92 (s, 2H), 4.15-4.10 (m, 4H), 3.98-3.91 (m, IH), 3.80-3.70 (m, IH), 3.49-3.47 (m, IH), 2.15 (brs, 2H), 1.64-1.55 (m, 2H), 1.53 (d, 6H). MS m/z: 664.2 (M^+1). m.p:97.8''C.
Example 13: Synthesis of (3R,5R)-7-[4-(4-FIuoro-phenyl)-6-isopropyl-2-(methanesulfonyI-methyl-amino)-pyrimidiii-S-yll-3,5-dihydroxy-heptanoic acid hydroxyamide

The title compound was prepared from (E)-(3R,5S)-7-[4-(4-FIuoro-phenyI)-6~ isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid benzyloxy-amide in 56% yield following the procedure given in example 3. 'HNMR (400MHz, CDCI3): 5 (ppm) 7.49-7.45 (m, 2H), 7.13 (t, 2H), 4.13-4.10 (m, IH), 3.65 (s, IH), 3.52 (s, 3H), 3.50 (s, 3H), 3.29-3.26 (m, IH), 2.80-2.75 (m, IH), 2.66-2.64 (m, IH), 2.27-2.16 (m, 2H), 1.51-1.41 (m,4H), 1.26 (d, 6H). MS m/z: 499.2 (M''+l).
Following compounds were prepared following above procedures:



Example
14
15

Structure

Analytical data
'H NMR (400 MHz, CDCI3): 6 (ppm) 7.20-7.10 (m, 8H), 7.07-6.91 (m, 6H), 4.15-4.08 (m, 2H), 3.97-3.93 (m, IH), 3.66 (s, IH), 3.552-3.48 (m, IH), 2.54-2.38 (m, 2H), 1.75-1.55 (m, 5H), 1.51 (s, 3H), 1.50 (s, 3H). MS m/z: 574.2 (M+1).
'H NMR (400 MHz, CDCI3): 6 (ppm) 8.34 (s, IH), 7.49-7.46 (m, 2H), 7.39 (brs, 5H), 7.15 (t, 2H), 4.92 (s, 2H), 4.16-4.14 (m, 2H), 3.73 (brs, IH), 3.53 (s, 3H), 3.50 (s, 3H), 3.35-3.30 (m, IH), 2.83-2.79 (m, IH), 2.70-2.62 (m, IH), 2.17 (brs, IH), 1.52-1.40 (m, 4H), 1.31 (s, 3H), 1.30 (s, 3H), 1.26 (brs, 2H). MS m/z: 589.3 (M+1).


16

'H NMR (400 MHz, CDCI3): 5.(ppm) 8.29 (s, IH), 7.31 (brs, 5H), 7.25-7.10 (m, lOH), 7.07-6.9 (m, 8H), 6.86 (s, IH), 5.29 (s, IH), 4.88 (s,2H),4.15-4.U (m,2H), 4.02-3.95 (m, IH), 3.67-3.60 (m, IH), 3.55-3.51 (m, IH), 2.32 (brs, 2H), 1.85-1.75 (m, 2H), 1.53 (d, 6H), 1.48-1.32 (m, 2H). MS m/z: 770.3 (M+1).

17

^H NMR (400 MHz, CDCI3): 5 (ppm) 8.35 (s, IH), 7.64 (t, 2H), 7.31 (brs, 7H), 7.11-7.02 (m, 4H), 6.63 (d, IH), 5.60-5.52 (m, 2H), 4.90 (s, 2H), 4.43-4.41 (m, IH), 4.27-4.24 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.37-3.30 (m, lH),2.39(d, 2H), 1.65(d, IH), 1.40 (q, IH), 1.27 (d, 6H). MS m/z; 693.2 (M+1).


^H NMR (400 MHz, DMSO-de): 6 (ppm) 10.25 (brs, IH), 9.81 (s, IH), 8.8 (brs, IH), 7.51 (d, 2H), 7.27-7.12 (m, lOH), 7.07 (brs, 4H), 7.01-6.98 (m, 2H), 5.41 (s, IH), 4.18-4.12 (m, IH), 4.04-3.91 (m, 2H), 3.80-3.75 (m, IH), 3.26-3.22 (m, IH), 2.23-2.10 (m, 2H), 1.75-1.70 (m,2H), 1.52 (d,2H), 1.36 (d, 6H). MS m/z: 680.2 (M+1).


19

'H NMR (400 MHz, CDCI3): 5 (ppm) 8.66 (s, IH), 7.49-7.45 (m, 2H), 7.33-7.29 (m, 2H), 7.09-7.04 (m, 4H), 5.39 (s, IH), 4.15-4.10 (m, 2H), 3.68-3.67 (m, IH), 3.53 (s, 3H), 3.50 (s, 3H), 3.33-3.27 (m, IH), 2.97-2.90 (m, IH), 2.78-2.70 (m, IH), 2.43 (d, 2H), 1.72-1.63 (m,2H), 1.49 (d, IH), 1.40-1.35 (m, IH), 1.28 (s, 3H), 1.26 (s, 3H). MS m/z: 605.2 (M+1).

20 ,N L ,0 HO >*
0' 'O 'H NMR (400 MHz, CDCI3): 5 (ppm) 8.58 (s, IH), 7.66-7.62 (m, 2H), 7.45-7.42 (m, 2H), 7.11-7.06 (m, 4H), 6.65 (d, 1H),.5.60 (s, IH), S.SA (dd, IH), 4.4 (brs, IH), 4.34 (brs, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.35-3.32 (m, IH), 2.51 (d, 2H), 1.49-1.40 (m, 2H), 1.28 (s, 3H), 1.26 (s, 3H). MS m/z: 603.2 (M+1).
21 o.^,.o^
NyN
o'' 'o 'H NMR (400 MHz, CDCI3): 5 (ppm) 8.51 (s, IH), 7.66-7.62 (m, 2H), 7.40-7.37 (m, 5H), 7.0.8 (t, 2H), 6.56 (d, IH), 5.47 (dd, IH), 4.92 (s, 2H), 4.45 (brs, IH), 4.16-4.11 (m, IH), 3.95-3.92 (m, IH), 3.57 (s, 3H), 3.51 (s, 3H), 3.36-3.32 (m, IH), 2.34 (d, 2H), 1.56-1.50 (m, 2H), 1.30-1.21 (m, 8H), 0.90-0.82 (m, 3H). MSm/z: 627.2 (M-M).
22 HO'"" k»°
o'' '0 'H NMR (400 MHz, CDCI3): 6 (ppm) 8.79 (brs, IH), 7.52-7.44 (m, 2H), 7.15 (t, 2H), 4.38 (t, IH), 3.89 (brs, IH), 3.53 (s, 3H), 3.50 (s, 3H), 3.45-3.43 (m, IH), 3.30-3.29 (m, IH), 2.87-2.83 (m, IH), 2.70-2.68 (m, IH), 2.41 (d, 2H), 1.60-1.56 (m,2H), 1.40-1.36 (m, 2H), 1.31 (s, 3H), 1.29 (s,3H), 1.26-1.21 (m, 2H), 0.90-0.82 (m, 3H). MS m/z: 539.2 (M-t-1).
Anti-cancer experimental methods Anti-cancer screen:
Experimental drugs are screened for anti-cancer activity in three cell lines for their GI50, TGI and LC50 values (using five concentrations for each compound). The cell lines are maintained in DMEM containing 10% fetal bovine serum. Ninety six well micro titer plates are inoculated with cells in 100 fiL for 24 hours at 37°C, 5% CO2, 95% air and 100% relative humidity. 5000 HCT 116 cells/well, 5000 NCIH 460 cells/well and 5000 U251 cells/well «^^ "l«tpH A ^fnaratp nlatn with these cell lines

is also inoculated to determine cell viability before the addition of the compounds
(To).
Addition of experimental drugs:
Following 24-hour incubation, experimental drugs are added to the 96 well plates. Each plate contains one of the above cell lines and the following in triplicate: five different concentrations (0.01, 0.1, 1, 10 and 100 ^M) of four different compounds, appropriate dilutions of a cytotoxic standard and control (untreated) wells. Compounds are dissolved in DMSO to make 20 mM stock solutions on the day of drug addition and frozen at -20°C. Serial dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 jiL of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100 \iM can be added to the cells in triplicate. Standard drugs whose anti-cancer activity has been well documented and which are regularly used are doxorubicin and SAHA. End-point measurement:
For To measurement, 24 hours after seeding the cells, 10 |iL of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) solution per well is added and incubation carried out for 3 hours at 37 °C, 5% CO2, 95% air and 100% relative humidity, protected from light. Cells incubated with compounds for 48 hours are treated similarly except with the addition of 20 fiL MTT solution per well and a subsequent incubation under the same conditions. After 3 hours of MTT incubation, well contents are aspirated carefully followed by addition of 150 faL DMSO per well. Plates are agitated to ensure solution of the formazan crystals in DMSO and absorbance read at 570 nm. Calculation of GI50, TGI and LC50:
Percent growth is calculated for each compound's concentration relative to the control and zero measurement wells (To; viability right before compound addition). If a test well's O.D. value is greater than the To measurement for that cell line % Growth = (test - zero) / (control - zero) X 100
If a test well's O.D. value is lower than the To measurement for that cell line, then, % Growth = (test - zero) / zero X 100
Plotting % growth versus experimental drug concentration, GI50 is the concentration required to decrease % growth by 50%; TGI is the concentration required to decrease

% growth by 100% and LC50 is the concentration required to decrease % growth by 150%. Representative results of growth are shown below in the Table 1.

Table 1: Anticancer activity and % HDAC Inhibition
Example NICH460
(GI50) HCTlie
(GI50) U251
(GIso) Mean
(GI50) %HDAC Inhibition
1 ^M 10 ^iM
1 >100 >100 50.8 >100 4.58 8.43
2 >100 >100 >100 >100 6.22 6.19
3 28.0 33.0 40.0 33.67 8.40 15.50
4 19.2 6.1 44.0 23.1 7.09 0.81
5 >100 79.1 >100 >100 8.71 6.25
6 99.8 50.0 40.1 63.3 5.11 5.57
7 8.4 6.7 4.8 6.63 10.14 10.72
8 33.5 40.0 50.0 41.17 4.52 10.01
9 32.5 30.0 48.5 37.0 NA 11.90
10 56.2 60.9 >100 >100 11.46 14.81
11 46.5 21 24.8 30.8 - -
12 19.0 2.2 1.2 7.5 - -
13 39.2 62.5 22.0 41.2 - -
15 22 12 .0.75 16.3 - -
18 16.8 42.0 47.0 35.3 11.03 99.47
19 8.5 4.0 0.95 4.48 - -
NA = Not active
In vitro measurement of Tumor Necrosis Factor Alpha (TNF-a)
This assay determines the effect of test compounds on the production of TNF-a in human Peripheral Blood Mononuclear Cells (PBMC). Compounds were tested for their ability to inhibit the activity of TNF-a in human PBMC. PBMC were isolated from blood (from healthy volunteers) using BD Vacutainer CPT^'^ (Cell preparation tube, BD Bio Science) and suspended in RPMI medium {Physiol. Res. 2003, 52, 593-598.). The test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37 ^C and then stimulated with Lipopolysaccharide {Escherichia coli: B4; 1 M-g/ml) for 18 hours at 37 "C in 5% CO2.

The levels of TNF-a in the cell culture medium were estimated using enzyme linked Immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer (R&D Systems, Inc. 614 McKinley Place NE, Minneapolis, MN 55413, USA). Representative results of TNF-a inhibition are shown in Table 2.
Table 2: TNF-a Inhibition

Example % TNF-a Inhibition (10 ^M) ICso (^M)
1 20.28 -
3 86.4 2.0
7 91.19 0.6
8 38.73 -
10 90.99 1.27
NA ~ Not active

We Claim:
1. Compounds of the general formula (I),

individually represents hydrogen, alkyl, aryl groups and
R represents substituted or unsubstituted groups selected from aryl, saturated or
unsaturated cycloalkyl and saturated or unsaturated heterocyclyl.
2. Compounds according to claim 1, their derivatives, analogs, tautomeric forms,
stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable
salts/prodrugs, pharmaceutical compositions thereof wherein;
R' represents H, alkyl comprising methyl ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, trifluoroethyl, diethoxyethyl, hydroxypropyl, dihydroxypropyl, isopropyl and t-butyl; benzyl; aryl comprising phenyl, naphthyl; and aralkyl comprising phenylmethyl, phenylethyl, naphthyl methyl and naphthylethyl; R^ represents H, alkyl and aryl; R^ represents H, alkyl and aryl;
R^ and R^ may be taken together with the atoms to which they are attached to fonn heterocyclyl ring selected from the group comprising


3. Compounds according to claim 1 or 2, selected from the group consisting of: N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yl)-acetamide;
l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2-phenyl-l,3-dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;
2-((4R,6R)-6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-ethyl}-2-phenyl-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;

5-(4-Fluoro-phenyl)-l-[2-((4R,6R)-6-hydroxycarbamoylmethyl-2-phenyl-],3-
dioxinaTi-4-yl)-ethyl]-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid
phenylamide; N-Benzyloxy-2-((4R,6S)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-
{methanesulfonyl-methylamino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-
dioxinan-4-yl)-acetamide;
l,(2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2,2-dimethyl-l,3-dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid
phenylamide;
2-((4R,6R)-6-{2-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-
amino)-pyrimidin-5-yl]-ethyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-N-hydroxy-
acetamide;
5-(4-Fluoro-phenyl)-l-[2-((4R,6R)-6-hydroxycarbamoylmethyl-2,2-dimethyl-l,3-
dioxinan-4-yl)-ethyl]-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid
phenylamide;
2-((4R,6S)-6-{(E)-2-[4-(4-FIuoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2-phenyl-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
2-((4R,6S)-6-{(E)-2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-l,3-dioxinan-4-yl)-N-hydroxy-acetamide;
(E)-(3R,5S)-7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoicacid benzyloxy-amide; l-((3R,5R)-6-BenzyIoxycarbamoyl-3,5-dihydroxy-hexyl)-5-{4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide; (3R,5R)-7-[4-(4-F]uoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-heptanoic acid hydroxyamide; l-{(3R,5R)-3,5-Dihydroxy-6-hydroxycarbamoyl-hexyl)-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide; (3R,5R)-7-[4-(4-FIuoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-heptanoic acid benzyloxy-amide; l-{2-[(4R,6R)-6-(Benzyloxycarbamoyl-methyl)-2-(4-fluoro-phenyl)-l,3-
dioxinan-4-yl]-ethyl}-5-(4-fluoro-phenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide;

N-Benzyloxy-2-((4R,6S)-2-(4-fluoro-phenyl)-6-{(E)-2-[4-(4-fluoro-pheny l)-6-isopropyl-2-(methanesu]fony]-methy]-amino)-pyrimidin-5-yl]-vinyl}-],3-
dioxinan-4-yl)-acetamide;
5-(4-Fluoro-phenyl)-l-{2-[(4R,6R)-2-(4-fluoro-phenyl)-6-
hydroxycarbamoylmethyl-l,3-dioxinan-4-yl]-ethyl}-2-isopropyl-4-phenyl-lH-
pyrrole-3-carboxylic acid phenylamide;
2-{(4R,6R)-2-(4-Fluoro-phenyl)-6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-ethyl}-l,3-dioxinan-4-yl)-N-
hydroxy-acetamide;
2-((4R,6S)-2-(4-Fluoro-phenyl)-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-l,3-dioxinan-4-yl)-N-
hydroxy-acetamide; N-Ben2yloxy-2-({4R,6S)-2-ethyl-6-{(E)-2-[4-(4-fluoro-phenyl)-6-isopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-l,3-dioxinan-4-yl)-
acetamide; and
2-((4R,6R)-2-Ethyl-6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesuIfonyl-
methyl-amino)-pyrimidin-5-yl]-ethyl}-l,3-dioxinan-4-yl)-N-hydroxy-acetamide.
4. A process for the preparation of compound of formula (I) as claimed in claim 1
comprising the steps of:
a) reacting a compound of formula 1(c) with hydroxylamine derivatives in the
presence of appropriate base comprising atleast one of triethylamine,
diisopropylethylamine, pyridine, DMAP and activating agents comprising
atleast one of BOP, HOBT, DCC, ethylchloroformate to produce a compound of
formula 1(d) and
1 (c) 1{d)
b) subjecting a compound of formula 1 (d) to hydrogenation and/or hydrogenolysis
to produce a compound of formula (I).
5. A process for the preparation of compound of formula (I) as claimed in claim 1
comprising the steps of;

a) reacting a compound of formula 1(e) with hydroxylamine derivatives in the
presence of appropriate base comprising atleast one of KOH, NaOH, NaOMe to
produce a compound of formula 1(d);
r'
R 1(e)
b) subjecting a compound of formula 1(d) to hydrolysis to produce a compound of
formula 1(f) and
, .NH L ,0H
R—O I
R 1{f)
c) subjecting a compound of formula 1 (f) to hydrogenation and/or hydrogenolysis
to produce a compound of formula (J).
6. A pharmaceutical composition comprising an effective amount of compound of formula (I) according to claims 1-3, as an active ingredient along with a non-toxic pharmaceutically acceptable carrier, diluent, excipient or solvate.
7. A method for inhibiting TNF-a and HDAC in a cell comprising contacting a cell expressing TNF-a and HDAC with an effective amount of compound of claim 1.

8. A method of treating hypercholesterolemia, proliferative, inflammatory and immunological diseases, which comprises administering an effective amount of a compound of claims 1-3 to a mammal in need thereof.
9. Use of compound of formula (I) as claimed in claims 1-3 for the prophylaxis or treatment of cancer, inflammation and asthma to a mammal in need thereof.