Field of the invention
The present invention relates to isoxazoline derivatives and their analogues, which can be used as phosphodiesterase (PDE) type IV selective inhibitors.
Compounds disclosed herein can be useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans.
Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds and their use as PDE type IV selective inhibitors are provided.
Background of the invention
It is known that cyclic adenosine-3', 5'-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (E.W. Sutherland, and T.W. Roll, Pharmacol.Rev, 1960,12, 265). Its intracellular hydrolysis to adenosine 5'-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis. The most important role in the control of cAMP (as well as of cGMP) level is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally highly variable super family of enzyme; eleven distinct families with more than 15 gene products are currently recognized. Although PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only PDE IV and PDE VII are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers. Immune cells contain type IV and type III PDE, the PDE IV type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. More recently, distinct classes of PDE's have been recognized (J.A. Bervo and D.H. Reifsnyder, TIPS, 1990,11,150), and their selective inhibition has led to improved drug therapy (C.D. Nicholus, R.A. Challiss and M. Shahid, TIPS, 1991, 12, 19). Thus it was recognized that inhibition of PDE IV could lead to inhibition of inflammatory mediator release (M.W. Verghese et. al, J. Mol. Cell. Cardiol., 1989, 12 (Suppl.II), S 61) and airway smooth muscle relaxation .
WO 94/02465 discloses compounds, which have been stated to be the inhibitors of cAMP phosphodiesterase and TNF release.
WO 95/14680, 95/14681 and U.S. Patent No. 5,686,434 disclose a series of 3-aryl-2-isoxazoline compounds, which have been stated as phosphodiesterase type IV selective inhibitors.
WO 95/24398 and U.S. Patent No. 6,114,367 disclose isoxazoline compounds said to be the inhibitors of TNF release.
WO 95/20578 discloses substituted aromatic compounds, which have been stated as cAMP phosphodiesterase- and TNF- release inhibitors.
WO 95/04046 and WO 95/04045 disclose compounds said to act as PDE IV and TNF release inhibitors.
WO 97/03967 discloses substituted aromatic compounds, which have been stated as inhibitors of TNF release and type IV cAMP phosphodiesterase.
WO 99/32433 discloses thiourea and benzamide compounds, compositions and methods of treating or preventing inflammatory diseases and atherosclerosis.
WO 99/38845 discloses substituted diaryl compounds, which have been stated as PPAR-Gamma modulators.
WO 00/55120 discloses amide derivatives and their use in the treatment of diseases or medical conditions mediated by cytokines.
WO 01/93909 discloses a method for treating cancer including administering to a mammal therapeutically effective amount of an anti-neoplastic agent and a PDE IV inhibitor.
WO 02/100332 discloses isoxazoline compounds, which have been stated as having macrophage inhibitory factor (MIF) antagonist activity.
US Patent no. 5, 935,978 discloses pharmaceutical use of compounds containing phenyl linked to aryl or heteroaryl by an aliphatic or heteroatom containing linking group for inhibiting cyclic AMP phosphodiesterase.
US Patent no. 6,303,789 discloses benzamides with tetrahydrofuranyloxy substituents, which have been stated as PDE IV inhibitors.
Summary of the invention
The present invention provides isoxazoline derivatives and their analogues, which can be used for the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases and the processes for the synthesis of these compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides of these compounds having the same type of activity are also provided.
Pharmaceutical compositions containing the compounds, which may also contain pharmaceutically acceptable carriers or diluents can be used for the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases.
Other aspects will be set forth in the accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there is provided a compound having the structure of Formula I:
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides, wherein
R1 and R6 can independently represent hydrogen, alkyl, alkenyl, alkynyl, un(saturated) cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, (heteroaryl) alkyl or (heterocyclyl) alkyl,
X can represent oxygen, sulphur , NRh {wherein RH can represent hydrogen, alkyl, alkenyl, alkynyl, un(saturated) cycloalkyl, acyl, aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl)alkyl, (heterocyclyl)alkyl, S(O)nRd [wherein Rd can represent alkyl, aryl, heterocyclyl or heteroaryl and n can represent an integer in the range 0-2]},
Y can represent no atom, oxygen, sulphur, NRh (wherein RH is the same as defined above},
X1 can represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl) alkyl, (heterocyclyl) alkyl,
Y1 can represent hydrogen, alkyl, alkenyl, alkynyl, nitro, cyano, halogen, ORh , SRh, NHRh {wherein Rh is the same as defined above}, COOR' ,COR', CONHR' {wherein R' can represent hydrogen, alkyl, alkenyl, alkynyl, (un)saturated cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
(heterocyclyl)alkyl, (heteroaryl)alkyl}, S(O)nRd, {wherein Rd is the same as defined above},
Y1 may be fused to benzene ring if it is aryl, heteroaryl or heterocyclyl,
j can represent an integer in the range of 1 to 3,
R2 and R3 can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, nitro, cyano, amino, substituted amino, alkoxy, aryloxy, COR', COOR' {wherein R' is the same as defined above}, aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl) alkyl, (heterocyclyl) alkyl, (CH2)1-4OR' {wherein R' is the same as defined above including hydroxy group}, C(=O)NRxRy {wherein Rx and Ry can independently represent hydrogen, alkyl, alkenyl of three to six carbon atoms, alkynyl of three to six carbon atoms, (un)saturated cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl)alkyl, (heterocyclyl)alkyl}, (CH2)m-C(=O)Rz {wherein m can be an integer in the range of 0-2 and Rz can represent Rp or Rq wherein Rp can be a 4-12 membered (un)saturated monocyclic or bicyclic ring containing 1-4 heteroatom(s) selected from the group consisting of N, O and S wherein the said ring can be attached to (CH2)mC(=O) through N and Rq can be a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatom(s) selected from the group consisting of N, O and S wherein the said ring can be attached to (CH2)mC(=O) through
C},
R4 can represent hydrogen, alkyl , halogen, hydroxy, cyano, carboxy, nitro, C(=0)NRxRy {wherein RxandRy are the same as defined above },
R5 can represent hydrogen, alkyl, aryl, aralkyl, un(saturated) cycloalkyl, heteroaryl, heterocyclyl, (heteroaryl) alkyl, (heterocyclyl) alkyl,
R2, R3, R4 or R5 can be replaced by the floating bond. The following definitions apply to terms as used herein.
The term "alkyl" unless and otherwise specified refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl and the like.
It may further be substituted with one or more substituents selected from the group alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and -SO2-heteroaryl. Unless otherwise constrained by the definition, all 1-3 substituents chosen from alkyl, carboxy, carboxy-alkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S (O)nRd, where Rd is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or an alkyl group as defined above that is interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur, a phenylene , sulphinyl , sulphonyl group and -NRc-, where RC is
chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)nRd, where n and Rd are the same as defined earlier; or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "alkenyl" unless and otherwise specified refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry. Preferred alkenyl groups include ethenyl or vinyl (CH=CH2), 1-propylene or allyl (-CH2CH=CH2), iso-propylene (-C(CH3)=CH2), bicyclo[2.2.1]heptene, and the like.
In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, S02-aryl and -SO2-heteroaryl or an alkenyl group as defined above that is interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur, a phenylene , sulphinyl, sulphonyl group and -NRc-, where RC is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S (0)nRd, where Rd is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term "alkynyl" unless and otherwise specified refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms (Preferred alkynyl groups include ethynyl, (-C≡ CH), propargyl (or propynyl, -CH2C≡ CH), and the like) and it can be interrupted by an oxygen or sulphur atom, a phenylene, imino (-NH-) or alkyliminolinkage, or a sulphinyl or sulphonyl group.
In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl,
aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, S02-aryl and -SOa-heteroaryl or an alkynyl group as defined above that is interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur, a phenylene , sulphinyl , sulphonyl group and -NRc-, where RC is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFs, amino, substituted amino, cyano, and -S(0)nRd, where Rj is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term "cycloalkyl" refers to (un) saturated cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylene, cyclobutylene and the like, or multiple ring structures such as adamantanyl, and bicyclo [2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and -SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFs, amino, substituted amino, cyano, and -S(O)nRd, where Rd is alkyl, aryl or heteroaryl and n is 0, 1 or 2.
The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.
The term "aryloxy" refers to the group O-aryl wherein aryl is the same as defined below.
The term "cycloalkoxy" refers to the group O-cycloalkyl wherein cycloalkyl is the same as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "aralkyl" refers to (CH2)P aryl, wherein p is an integer in the range of 1 -6 and aryl is as defined below.
The term "aryl" herein refers to phenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy,alkoxy, aryloxy, cyano, nitro, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, C(=O)R" wherein R" is selected from the group of hydrogen,
alkyl, cycloalkyl, aryl, aralkyl, hydroxy, alkoxy, heteroaryl, heterocyclyl; (CH2)o-3C(=O)NRxRy wherein Rx and Ry are same as defined earlier.
The term "carboxy" as defined herein refers to -C(=O)O-Rf wherein Rf is selected from the group hydrogen, alkyl, alkenyl, alkynyl or cycloalkyl.
The term "heteroaryl" unless and otherwise specified refers to an aromatic ring structure containing 5 or 6 carbon atoms, or a bicyclic aromatic group having 8 to 10 carbon atoms, with one or more heteroatom(s) independently selected from the group consisting of N, O and S optionally substituted with 1 to 3 substituent(s) selected from the group consisting of halogen, hydroxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxy, aralkyl, cyano, nitro, optionally substituted amino wherein the substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl; carboxy, -C(=O)R"wherein R" is the same as defined earlier and C(=O)NRxRy wherein Rx and Ry are the same as defined earlier. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
The term 'heterocyclyl" unless and otherwise specified refers to a non aromatic cycloalkyl group having 5 to 14 atoms in which one or more carbon atom(s) in a ring are replaced by heteroatoms selected from the group comprising of O, S or N, in which the point of attachment can be carbon or nitrogen and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, alkaryl, heteroaryl, cyano, nitro, optionally substituted amino wherein the substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl; carboxy, C(=O)R" wherein R" is the same as defined earlier; C(=O)NRxRy wherein Rx and Ry the same as defined earlier. One or more carbon(s) of heterocyclyl can also be replaced by carbonyl or thionyl group. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, piperidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like.
"(Heteroaryl)alkyl" refers to alkyl-heteroaryl group wherein the alkyl and heteroaryl are the same as defined earlier.
"(Heterocyclyl)alkyl" refers to alkyl-heterocyclyl group wherein the alkyl and heterocyclyl are the same as defined earlier.
The term "acyl" as defined herein refers to -C(=O)R", wherein R" is the same as defined earlier.
The term "hydroxy protecting group" includes, but are not limited to, acyl, aroyl, alkyl, aryl, butyldiphenylsilyl, tert-butyldimethylsilyl, methoxymethyl, methylthiomethyl, and the like.
The term "amino protecting group" includes, but is not limited to, acyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, aroyl, and the like.
The compounds of the present invention can be used for treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases.
In accordance with yet another aspect, there are provided processes for the preparation of the compounds as described herein.
Detailed description of the invention
The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of present invention may be prepared by the following reaction sequences as depicted in Schemes I, II, III and IV.
(Formula Removed)
The compound of Formula X can be prepared by following Scheme I. Thus, oxidising a compound of Formula II gives a compound of Formula II (a) (wherein X1, Y1 and Y are the same as defined earlier), which on esterification gives a compound of Formula III, which on reaction with a compound of Formula IV (wherein X3 represents halogen and j is the same as defined earlier) gives a compound of Formula V (wherein R2, R4 and j are the same as defined earlier) which on ester hydrolysis gives a compound of Formula VI, which on reaction with a compound of Formula VII gives a compound of Formula VIII (wherein R1 is the same as defined earlier),which is finally reacted with a compound of Formula IX to give a compound of Formula X (wherein R5 is the same as defined earlier).
The oxidation of a compound of Formula II to give a compound of Formula II (a) can be carried out in a solvent, for example, t-butanol, water, acetonitrile or mixture thereof, in the presence of an organic acid, for example, acetic acid.
The oxidation of a compound of Formula II to give a compound of Formula II (a) can be carried out in the presence of sodium hypochlorite and a co-reagent known in the prior art to prevent liberation of chlorine dioxide or hypochlorous acid, for example, sulphamic acid.
The esterification of a compound of Formula II (a) to give a compound of Formula III can be carried out in the presence of methanol and a mineral acid, for example, sulphuric acid or hydrochloric acid.
The reaction of a compound of Formula III with a compound of Formula IV to give a compound of Formula V can be carried out in an organic solvent, for example, dimethylformamide, dimethylsulphoxide or tetrahydrofuran.
The reaction of a compound of Formula III to give a compound of Formula V can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
The ester hydrolysis of a compound of Formula V to give a compound of Formula VI can be carried out in an alcohol, for example, methanol, ethanol or an alcohol and water mixture.
The ester hydrolysis of a compound of Formula V to give a compound of Formula VI can be carried out in the presence of an inorganic base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
The reaction of a compound of Formula VI with a compound of Formula VII to give a compound of Formula VIII can be carried out in the presence of activating agent known in the prior art, for example, oxalyl chloride, thionyl chloride, phosphoroxy chloride, mixed anhydride, alkyl chloroformate, allyl chloroformate or carbodiimides in an organic solvent, for example, dimethylformamide, dimethylsulphoxide, halogenated solvents, tetrahydrofuran or mixture thereof.
The reaction of a compound of Formula VI with a compound of Formula VII can be carried out in the presence of an inorganic base, for example, sodium hydride, lithium hydride or potassium hydride and an organic base, for example, triethyl amine or trimethyl amine.
The reaction of a compound of Formula VIII with a compound of Formula IX to give a compound of Formula X can be carried out in an organic solvent, for example, tetrahydrofuran, halogenated solvents, dimethylformamide, dimethylsulphoxide or mixture thereof.
The reaction of a compound of Formula VIII with a compound of Formula IX to give a compound of Formula X can be carried out in the presence of an organic base, for example, triethyl amine or pyridine.
The reaction of a compound of Formula VIII with a compound of Formula IX can be carried out in the presence of a reagent, for example, sodium hypochlorite, N-chlorosuccinimide or N-bromochlorosuccinimide.
Scheme II
(Scheme Removed)
The compound of Formula XXII can be prepared by following Scheme II. Thus, protecting a compound of Formula II (a) with a compound of Formula RX3 (wherein X3 represents halogen) to give a compound of Formula XI (wherein Y, Y1 and X1 are the same as defined earlier and R is a hydroxy protecting group), which on reaction with a compound of Formula VII gives a compound of Formula XII (wherein RI is the same as defined earlier), which on deprotection gives a compound of Formula XIII, which on N- protection gives a compound of Formula XIV (wherein Pr is a amino protecting group), which on reaction with a compound of Formula XV( wherein X3 is the same as defined earlier) gives a compound of Formula XVI, (wherein j is the same as defined earlier), which on reduction gives a compound of Formula XVII, which on oxidation gives a compound of Formula XVIII, which on reaction with hydroxylamine hydrochloride gives a compound of Formula XIX, which on reaction with a compound of Formula XX gives a compound of Formula XXI (wherein R2,R3 and R4 are the same as defined earlier), which is finally deprotected to give a compound of Formula XXII.
The protection of a compound of Formula II (a) with a compound of Formula RX3, wherein R is a hydroxy protecting group known in the prior art, for example, tert-butyl dimethyl silyl, triisopropylsilyl, trimethyl silyl, triethyl silyl or tert-butyldiphenylsilyl to give a compound of Formula XI can be carried out in a solvent, for example, dimethylsulphoxide, dimethylformamide, halogenated solvents, chloroform or tetrahydrofuran.
The protection of a compound of Formula II(a) to give a compound of Formula XI can be carried out in the presence of an organic base, for example, imidazole, triethylamine, 4-dimethylaminopyridine or N-ethyldiisopropylamine.
The reaction of a compound of Formula XI with a compound of Formula VII to give a compound of Formula XII can be carried out in the presence of activating agent known in the prior art, for example, oxalyl chloride, thionyl chloride, phosphoroxy chloride, mixed anhydride, alkyl chloroformate, allyl chloroformate or carbodiimides in an organic solvent, for example, halogenated solvents, dimethylsulphoxide, dimethylformamide, tetrahydrofuran or mixture thereof.
The reaction of a compound of Formula XI with a compound of Formula VII can be carried out in the presence of an inorganic base, for example, sodium hydride, lithium hydride or potassium hydride and an organic base, for example, triethyl amine or trimethyl amine.
The deprotection of a compound of Formula XII to give a compound of Formula XIII can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or halogenated solvents.
The deprotection of a compound of Formula XII to give a compound of Formula XIII can be carried out in the presence of deprotecting agent known in the prior art, for example, tetrabutylammonium fluoride or hydrogen fluoride-pyridine.
The N-protection of a compound of Formula XIII to give a compound of Formula XIV can be carried out in the presence of N- protecting reagent known in prior art, for example, di-tert.-butyl dicarbonate in an organic solvent, for example, halogenated solvents, tetrahydrofuran, dimethylformamide or dimethylsulphoxide.
The N-protection of a compound of Formula XIII to give a compound of Formula XIV can be carried out in the presence of an organic base, for example, triethylamine, trimethylamine or diisopropylamine.
The reaction of a compound of Formula XIV with a compound of Formula XV to give a compound of Formula XVI can be carried out in an organic solvent, for example, dimethylsulphoxide, tetrahydrofuran, dimethylformamide or halogenated solvents.
The reaction of a compound of Formula XIV with a compound of Formula XV can be carried out in the presence of a base, for example, potassium carbonate, sodium carbonate or sodium bicarbonate.
The reduction of a compound of Formula XVI to give a compound of Formula XVII can be carried out in an organic solvent, for example, alcoholic solvents, tetrahydrofuran or dimethylformamide.
The reduction of a compound of Formula XVI to give a compound of Formula XVII can be carried out in the presence of reducing agent, for example, sodium borohydride, lithium borohydride or lithium aluminium hydride.
The oxidation of a compound of Formula XVII to give a compound of Formula XVIII can be carried out in the presence of an organic base, for example, pyridine or quinoline.
The oxidation of a compound of Formula XVII to give a compound of Formula XVIII can be carried out in the presence of an oxidizing agent, for example, chromium trioxide, pyridinium chlorochromate or quinolinium chlorochromate.
The oxidation of a compound of Formula XVII to give a compound of Formula XVIII can be carried out in an organic solvent, for example, dimethylformamide, tetrahydrofuran, dimethylsulphoxide, acetone or halogenated solvents.
The reaction of a compound of Formula XVIII to give a compound of Formula XIX can be carried out in the presence of sodium acetate or molecular sieves in an organic solvent, for example, alcoholic solvents, toluene or pyridine.
The reaction of a compound of Formula XIX with a compound of Formula XX to give a compound of Formula XXI can be carried out in an organic solvent, for example, tetrahydrofuran, halogenated solvents, dimethylsulphoxide or dimethylformamide.
The reaction of a compound of Formula XIX with a compound of Formula XX can be carried out in the presence of sodium hypochlorite or N-bromosuccinimide, N-chlorosuccinimide.
The reaction of a compound of Formula XXI to give a compound of Formula XXII can be carried out in an organic solvent, for example, tetrahydrofuran, halogenated solvents, dimethylsulphoxide or dimethylformamide.
The deprotection of a compound of Formula XXI to give a compound of Formula XXII can be carried out in the presence of organic, inorganic or Lewis acids.
Scheme III
(Scheme Removed)
The compound of Formula XXIX can be prepared by following Scheme III. Thus, reacting a compound of Formula XXIII with a compound of Formula IX gives a compound of Formula
XXIV (wherein R2, R4, R5, j and Y1 are the same as defined earlier), which on ester hydrolysis
gives a compound of Formula XXV, which on reaction with a compound of Formula VII gives a
compound of Formula XXVI (wherein R1 is the same as defined earlier), which on demethylation
gives a compound of Formula XXVII, which is finally reacted with a compound of Formula
XXVIII to give a compound of Formula XXIX (wherein X1 is the same as defined earlier).
The reaction of a compound of Formula XXIII with a compound of Formula IX to give a compound of Formula XXIV can be carried out in an organic solvent, for example, tetrahydrofuran, halogenated solvents, dimethylformamide or dimethylsulphoxide.
The reaction of a compound of Formula XXIII with a compound of Formula IX to give a compound of Formula XXIV can be carried out in the presence of an organic base, for example, triethyl amine or pyridine.
The reaction of a compound of Formula XXIII with a compound of Formula IX can be carried out in the presence of a reagent, for example, sodium hypochlorite, N-chlorosuccinimide or N-bromochlorosuccinimide.
The ester hydrolysis of a compound of Formula XXIV to give a compound of Formula
XXV can be carried out in an alcohol, for example, methanol, ethanol or an alcohol and water
mixture.
The ester hydrolysis of a compound of Formula XXIV to give a compound of Formula XXV can be carried out in the presence of an inorganic base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
The reaction of a compound of Formula XXV with a compound of Formula VII to give a compound of Formula XXVI can be carried out in the presence of activating agent known in the prior art, for example, oxalyl chloride, thionyl chloride, phosphoroxy chloride, mixed anhydride, alkyl chloroformate, allyl chloroformate or carbodiimides in an organic solvent, for example, halogenated solvents, dimethylsulphoxide, dimethylformamide, tetrahydrofuran or mixture thereof.
The reaction of a compound of Formula XXV with a compound of Formula VII can be carried out in the presence of an inorganic base, for example, sodium hydride, lithium hydride or potassium hydride and an organic base, for example, triethyl amine or trimethyl amine.
The demethylation of a compound of Formula XXVI to give a compound of Formula XXVII can be carried out in a solvent, for example, tetrahydrofuran, halogenated solvents, dimethylformamide or dimethylsulphoxide.
The demethylation of a compound of Formula XXVI to give a compound of Formula
XXVII can be carried out in the presence of a cleavage reagent, for example, aluminium chloride-
bromonitrobenzene, boron trihalide- dimethyl sulphide, boron triiodide- N,N-diethylaniline, lewis
acid- sodium iodide or sodium salt of N-methylaniline.
The reaction of a compound of Formula XXVII with a compound of Formula XXVIII to give a compound of Formula XXIX can be carried out in a solvent, for example, acetonitrile, acetone, ethanol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or toluene.
The reaction of a compound of Formula XXVII with a compound of Formula XXVIII can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium carbonate or sodium bicarbonate.
Schemed
(Scheme Removed)
The compound of Formula XXIX can also be prepared by following Scheme IV. Thus, demethylating a compound of Formula XXIV to give a compound of Formula XXX (wherein R2, R4, R5, j and Y1 are the same as defined earlier), which on reaction with a compound of Formula
XXVIII gives a compound o Formula XXXI (wherein X1 is the same as defined earlier), which on
ester hydrolysis gives a compound of Formula XXXII, which is finally reacted with a compound
of Formula VII to give a compound of Formula XXIX (wherein R1 is the same as defined earlier).
The demethylation of a compound of Formula XXIV to give a compound of Formula XXX can be carried out in a solvent, for example, tetrahydrofuran, halogenated solvents, dimethylformamide or dimethylsulphoxide.
The demethylation of a compound of Formula XXIV to give a compound of Formula XXX can be carried out in the presence of a cleavage reagent, for example, aluminium chloride-bromonitrobenzene, boron trihalide- dimethyl sulphide, boron triiodide- N,N-diethylaniline, lewis acid- sodium iodide or sodium salt of N-methylaniline.
The reaction of a compound of Formula XXX with a compound of Formula XXVIII to give a compound of Formula XXXI can be carried out in a solvent, for example, acetonitrile, acetone, ethanol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or toluene.
The reaction of a compound of Formula XXX with a compound of Formula XXVIII can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium carbonate or sodium bicarbonate.
The ester hydrolysis of a compound of Formula XXXI to give a compound of Formula XXXII can be carried out in an alcohol, for example, methanol, ethanol or an alcohol and water mixture.
The ester hydrolysis of a compound of Formula XXXI to give a compound of Formula XXXII can be carried out in the presence of an inorganic base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
The reaction of a compound of Formula XXXII with a compound of Formula VII to give a compound of Formula XXIX can be carried out in the presence of activating agent known in the prior art, for example, oxalyl chloride, thionyl chloride, phosphoroxy chloride, mixed anhydride, alkyl chloroformate, allyl chloroformate or carbodiimides in an organic solvent, for example, dimethylformamide, dimethylsulphoxide, halogenated solvents, tetrahydrofuran or mixture thereof.
The reaction of a compound of Formula XXXII with a compound of Formula VII can be carried out in the presence of an inorganic base, for example, sodium hydride, lithium hydride or potassium hydride and an organic base, for example, triethyl amine or trimethyl amine.
In the above schemes, where the specific solvents, bases, reducing agents, oxidizing agents etc., are mentioned, it is to be understood that other solvents, bases, reducing agents, oxidizing agents etc., known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.
An illustrative list of compounds of the invention are listed below:
-3-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (Compound No. 1),
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide(Compound No. 2),
-3-(5-Cyano-5-methyl-4,5-dihydro-isoxazol-4-ylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide(Compound No. 3),
- 4-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-
isoxazole-5-carboxylic acid methyl ester(Compound No. 4),
- 4-[5-(3,5-Dichloro-pyridin-4-ylcarbornoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-
isoxazole-5-carboxylic acid ethyl amide(Compound No. 5),
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid (Compound No. 6),
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid amide(Compound No. 7),
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid methyl amide(Compound No. 8),
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid dimethyl amide(Compound No. 9),
-N-(3,5-dichloro-pyridin-4-yl)- 3 -(5 -methyl-3 -phenyl-4,5-dihydro-isoxazol-5 -ylmethoxy) -4-methoxy-benzamide(Compound No. 10),
-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide(Compound No. 11),
-N-(3,5-dichloro-pyridin-4-yl)-3-(3-(4-difluoromethoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide(Compound No. 12),
-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 13),
- N-(3,5-dichloro-pyridin-4-yl)- 3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-
hydroxy-benzamide(Compound No. 14),
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(2-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-methoxy-benzamide(CompoundNo. 15),
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(2,6-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-methoxy-benzamide(CompoundNo. 16),
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-hydroxy-
benzamide(Compound No. 17),
- N-(3,5 -dichloro-pyridin-4-yl)- 3 - [3 -(4-fluoro-phenyl)-5 -methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-methoxy-benzamide(Compound No. 18),
-N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-hydroxy-benzamide(CompoundNo. 19),
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-methoxy-benzamide(Compound No. 20),
- N-(3,5-dichloro-pyridin-4-yl)-4-ethoxy-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-
ylmethoxy)-benzamide (Compound No.21),
-N-(3,5-dichloro-pyridin-4-yl)-4-ethoxy-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 22),
-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-propoxy-benzamide (Compound No. 23),
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-propoxy-benzamide (Compound No. 24),
-N-(3,5-dichloro-pyridin-4-yl)-4-isopropoxy-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 25),
-N-(3,5 -dichloro-pyridin-4-yl)-3 - [3 -(3 -fluoro-phenyl)-5 -methyl-4,5 -dihydro-isoxazol-5-ylmethoxy]-4-isopropoxy-benzamide (Compound No. 26),
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 27),
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 28),
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 29),
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 30),
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 31),
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 32),
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-ethoxy-benzamide (Compound No. 33),
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-propoxy-benzamide (Compound No. 34),
-N-(3,5-dichloro-pyridin-4-yl)-4-isopropoxy-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 35),
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-isopropoxy-benzamide (Compound No. 36),
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 37),
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 38),
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 39),
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 40),
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 41),
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 42),
-N-(3,5-dichloro-pyridin-4-yl)-4-hydroxy-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 43),
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-[5-methyl-3-(l-phenyl-ethyl)-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 44),
-3-(3-Cyclohexyl-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (Compound No. 45 ),
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 46),
-3-[3-(4-tert-Butyl-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (Compound No. 47),
-N-(3,5 -dichloro-pyridin-4-yl)-4-methoxy-3 -(5 -methyl-3 -0-tolyl-4,5-dihydro-isoxazol-5 -ylmethoxy)-benzamide (Compound No. 48),
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-[3-(3-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 49),
-2-{5-[5-(3,5-Dichloro-pyridin-4-ylcarbamoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazol-3-yl}-piperidine-l-carboxylic acid tert-butyl ester (Compound No. 50),
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3,4-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide (Compound No. 51),
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(2,4-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide (Compound No. 52),
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(4-fluoro-3-methyl-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide (Compound No. 53),
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3,5-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide (Compound No. 54),
-4-Benzyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 55),
-4-Cycloheptyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 56),
-3 - [3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5 -methyl-4,5 -dihydro-isoxazol-5 -ylmethoxy] -N-(3,5-dichloro-pyridin-4-yl)-benzamide (Compound No. 57),
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides, thereof.
The term "pharmaceutically acceptable" means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term "pharmaceutically acceptable salts" refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.
The salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for purposes of this invention.
The term "pharmaceutically acceptable solvates" refers to solvates with water (i.e. hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
The present invention also includes within its scope prodrugs of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985.
The disclosed compounds may get metabolized in vivo and these metabolites are also encompassed within the scope of this invention.
The term "polymorphs" includes all crystalline form as well as amorphous form for compounds described herein and as such are intended to be included in the present invention.
All stereoisomers of the compounds of the invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including all the substituents. Consequently, compounds of present invention can exist in enantiomeric or diastereomeric forms or in mixture thereof. The processes for the preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, for example, chromatographic or fractional crystallization.
There may be tautomers for some of the disclosed compounds, and the present invention covers all the possible isomers including tautomers and mixtures thereof.
In another aspect, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the disclosed compound or a pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent. Compounds disclosed herein may be administered to human or animal for treatment by any route, which effectively transports the active compound to the appropriate or desired site of action such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal). The pharmaceutical composition of the present invention comprises a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation of any type.
The term "patient" means all mammals including humans.
Where desired, the compounds of Formula I and/ or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides may be advantageously used in combination with one or more other therapeutic agents. Examples of other therapeutic agents, which may be used in combination with compounds of Formula I of this invention and/ or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides include corticosteroids, beta agonists, leukotriene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors and muscarinic receptor antagonists.
Examples set forth below demonstrate the synthetic procedures for the preparation of the representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
Experimental details
Example 1: Preparation of 4-difluoromethoxy benzaldehyde
To a stirred solution of 4-hydroxy benzaldehyde (1.00 g, 8.19 mmol) in dimethylformamide was added benzyltriethyl ammonium chloride (0.93 g, 4.00 mmol) at room temperature. Freon gas was purged along with simultaneous addition of sodium hydroxide solution (0.82 g in 2.3 ml water, 20.5 mmol) for about 5-10 minutes. Freon gas was purged again for about 5 minutes along with simultaneous addition of sodium hydroxide solution (0.82 g in 2.3 ml water, 20.5 mmol). Water was added to the reaction mixture and the compound was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulphate and concentrated to give oily residue. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate, 95:5) to get pure product. Yield: 0.83 g (59%) The following compound was prepared similarly
- 4-Difluoromethoxy -3-hydroxy benzaldehyde
Example 2: Preparation of 4-difluoromethoxy -3-hydroxy benzoic acid
To a previously cooled and stirred mixture of 4-difluoromethoxy -3-hydroxy benzaldehyde (0.3 g, 1.59 mmol) (Example 1) and sulphamic acid (0.23 g, 2.39 mmol) in 80% acetic acid (6.7 ml), was added aqueous solution of sodium chlorite (0.22 g in 0.7 ml water, 2.39 mmol) drop wise maintaining the temperature at 10 °C. The reaction mixture was stirred at room temperature for overnight, water was added to the reaction mixture and it was stirred for about 15 minutes. Extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum to provide white solid. Yield: 0.25 g (77%)
Example 3: Preparation of 3-hydroxy-4-methoxy-benzoic acid methyl ester
To a stirred solution of 3-hydroxy- 4 -methoxy benzoic acid (4.00 g, 23.7 mmol) (commercially available) in methanol, was added sulfuric acid (catalytic amount) and the reaction mixture was heated at 65-70 °C for about 15 h. Methanol was evaporated off; water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to give the product. Yield: 4.0 g (93%) The following compound was prepared similarly
- 4-Difluoromethoxy -3-hydroxy benzoic acid methyl ester
Yield: 0.25 g (94%)
Example 4: Preparation of 4- methoxy-3-(2-methyl-allyloxy)-benzoic acid methyl ester
To a solution of 3-hydroxy- 4 -methoxy benzoic acid methyl ester (4.0 g, 20.0 mmol) (Example 3) in dry dimethylformamide, potassium carbonate (6.0 g, 43.0 mmol) and ß- methallyl chloride (3.89 g, 43.0 mmol) were added. The reaction mixture was stirred at 60 °C for about 5 h. The reaction mixture was filtered, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to afford pure product. Yield: 4.20 g (82%)
The following compound was prepared similarly
- 4- Difluoromethoxy-3- (2-methyl-allyloxy)-benzoic acid methyl ester
Yield: 0.30 g (97%)
Example 5: Preparation of 4- methoxy-3-(2-methyl-allyloxy)-benzoic acid
To a stirred solution of 4-methoxy-3-(2-methyl-allyloxy)-benzoic acid methyl ester (4.2 g,
17.7 mmol) ( Example 4) in methanol -water (80:20) , potassium hydroxide (2.9 g, 53.0 mmol) was added and the reaction mixture was heated at 60 °C for about 2 h. Methanol was evaporated off, water was added, and the reaction mixture was acidified with hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to give product. Yield: 3.75 g (95%)
The following compound was prepared similarly
- 4- Difluoromethoxy-3-(2-methyl-allyloxy)-benzoic acid
Yield: 0.256 g (90%)
Example 6: Preparation of N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide
Oxalyl chloride (0.33 g, 2.20 mmol) was added dropwise to a stirred solution of 4-methoxy-3- (2-methyl-allyloxy)-benzoic acid (0.5 g, 2.2 mmol) (Example 5) in dichloromethane (3 ml) and dimethylformamide (2 drops) at 0 °C. The reaction mixture was further stirred at room temperature for about 3 h. The solvent was evaporated off and the residue thus obtained was dissolved in dry dimethylformamide under nitrogen atmosphere. It was added dropwise to the pre stirred suspension of 3,5- dichloro -4 -amino pyridine (0.36 g, 2.2 mmol) and sodium hydride (0.11 g, 4.40 mmol) in dry dimethylformamide at 0 °C under anhydrous condition. After completion of the reaction, the reaction mixture was acidified with dilute hydrochloric acid, water was added and the extraction was carried out with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated.
The residue thus, obtained was subjected to column chromatography to afford the desired product
as white solid.
Yield: 0.22 g (27%), m/z: 367.00 (M++l), 389 (M++23)
The following compound was prepared similarly
-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-3-(2-methyl-allyloxy)-benzamide Yield: 0.32 g (73%)
Example 7: Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde
To a solution of 3- hydroxy- 4 -methoxy benzaldehyde (25.0 g, 160 mmol) (commercially available) in dimethylformamide, potassium carbonate (45.3 g, 320 mmol) and potassium iodide (2.73 g, 16 mmol) were added. The reaction mixture was heated to 60 °C and further cyclopentyl bromide (35.8 g, 240 mmol) was added slowly over a period of 20 min and the reaction mixture was stirred at that temperature for about 22 h. The reaction mixture was extracted with ethyl acetate. The combined organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to give product.
Yield : 32.0 g (89%)
Example 8: Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde oxime
To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (9.5 g, 43.0 mmol) (Example 7) in ethanol, hydroxylamine hydrochloride (6.0 g, 86.0 mmol) and sodium acetate (7.0 g, 86.0 mmol) were added. The reaction mixture was stirred at room temperature for about 2 h. The solvent was evaporated, water was added and the reaction mixture was extracted with ethyl acetate. After extraction, combined organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to get the product. Yield: 9.4 g (95%)
The following compound was prepared similarly
- 4-Difluoromethoxy benzaldehyde oxime, Yield: 1.74 g (99%)
- 4-Methyl benzaldehyde oxime, Yield: 1.0 g (74%)
-4-tert-Butyl benzaldehyde oxime, Yield: 1.15 g (95%)
- 2-Phenyl propionaldehyde oxime, Yield: 5.9 g (93 %)
- Cyclohexanecarbaldehyde oxime, Yield: 5.1 g (91%)
Example 9: Preparation of 3-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide( Compound No. 1)
To a solution of N- (3,5-dichloro-pyridin-4-yl)-4-methoxy-3- (2-methyl-allyloxy)-benzamide (0.2 g, 0.54 mmol) (Example 6) and 3-cyclopentyloxy-4-methoxybenzaldehyde oxime (0.25 g, 1.08 mmol) (Example 8) in tetrahydrofuran, sodium hypochlorite (4% solution, 2 ml) was added drop wise over a period of 30 min. After stirring the reaction mixture for about 2 h, tetrahydrofuran was evaporated off. The reaction mixture was diluted with water and extracted
with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, and filtered. The solvent was evaporated off and the residue thus obtained was subjected to column chromatography to provide the desired product.
Yield: 0.04 g (13%), mp: 108 °C, m/z: 600 (M++l), 601 (M++2) The following compound was prepared similarly
-N-(3,5-dichloro-pyridin-4-yl)-3-(3-(4-difluoromethoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide(Compound No. 12)
Yield: 10 mg (7%), m/z: 552 (M++l)
Example 10: Preparation of N-(3,5-dichloro-pyridin-4-yl)- 3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide(CompoundNo. 10)
To a stirred solution of N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide (0.1 g, 0.27 mmol) (Example 6), benzaldehyde oxime (0.098 g, 0.81 mmol) and triethylamine (4 drops) in dichloromethane, sodium hypochlorite (4%, 2 ml) was added drop wise over a period of about 20 min at room temperature. The reaction mixture was stirred for about 3 h and water was added to that mixture. The organic layer was washed with water, brine and dried over sodium sulphate. The reaction mixture was evaporated under vacuum and purified by column chromatography to afford product as white solid. Yield: 0. 04 g (31%), m/z : 486 (M++l) The following compound was prepared similarly
- N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide(Compound No. 11) Yield: 0. 030 g (23%), m/z: 487 (M++l)
Example 11: Preparation of N-(3,5-dichloro-pyridm-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide (Compound No.2)
To a solution of acetaldoxime (0.03 g, 0.49 mmol, commercially available) in dichloromethane was added N-chloro succinimide (0.06 g, 0.49 mmol) and pyridine (1 drop). The reaction mixture was stirred at room temperature for about 20 min. N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide (0.18 g, 0.49 mmol) (Example 6) in dichloromethane (2 ml) was added and the reaction mixture was stirred at 40-50 °C. Triethylamine (0.05 g, 0.51 mmol) was added dropwise at 40-50 °C over a period of 10 min. Heating was continued for about 30 min at same temperature. The reaction mixture was cooled to room temperature, water was added and the extraction was carried out with dichloromethane. Organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated. The residue thus obtained was subjected to column chromatography to separate desired product. Yield: 0.03 g (15%), m.p.: 232 °C, m/z : 424 (M++l) The following compound was prepared similarly
-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide(Compound No. 13) Yield: 10 mg (3%), m/z: 460 (M++l)
Example 12: Preparation of 3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoic acid
To a solution of 3-hydroxy-4-methoxybenzoic acid (0.5 g, 2.98 mmol) (commercially available) in dry dimethylformamide was added imidazole (0.3 g, 4.46 mmol) at room temperature. The reaction mixture was allowed to stir for about 10 min and tert-butyldimethylsilyl chloride (0.54 g, 3.57 mmol) was added portion wise over a period of about 15 min. After stirring the reaction mixture for about 15 h, ice-cold water was added. After extracting with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulphate, the solvent was evaporated and the residue was purified by column chromatography to give the desired product. Yield: 0.65 g (72%), m/z : 305 (M++23)
Example 13: Preparation of 3-(tert-butyl-dimethyl-silanyloxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide
Oxalyl chloride (3.0 g, 23.70 mmol) was added drop wise to a stirred solution of 3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoic acid (4.1 g, 14.5 mmol) (Example 12) in dichloromethane (40 ml) and dimethylformamide (4 drops) at 0 °C under inert atmosphere. The reaction mixture was then warmed to room temperature and the stirring was continued for about 2 h. The solvent was evaporated off and the residue thus obtained was dissolved in dry dimethylformamide and it was added drop wise to a pre stirred suspension of 3,5-dichloro-4-aminopyridine (2.96 g, 18.1 mmol) and sodium hydride (1.45 g, 36.3 mmol) in dry dimethylformamide at 0 °C under inert atmosphere. The stirring was continued for about 30 minutes and then quenched with water. After extracting with ethyl acetate, the organic layer was separated, washed with brine, dried over sodium sulphate and concentrated under vacuo. The reaction mixture was purified using column chromatography to afford the desired product. Yield: 2.90 g (51%) Example 14: Preparation of N-(3,5-dichloro-pyridin-4-yl)-3-hydroxy-4-methoxy-benzamide
To a stirred solution of 3-(tert-butyl-dimethyl-silanyloxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (2.93 g, 6.86 mmol) (Example 13) in tetrahydrofuran, tetrabutyl ammonium fluoride (1.79 g, 6.86 mmol) was added at 0 °C under inert atmosphere. After stirring the reaction mixture for about 30 min, water was added. Extraction was done with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulphate and evaporated. The compound was further purified using column chromatography to afford the final product. Yield: 1.82g(85%)
Example 15: Preparation of (3,5-dichloro-pyridin-4-yl)-(3-hydroxy-4-methoxy-benzoyl)-carbamic acid tert-butyl ester
To a solution of N-(3,5-dichloro-pyridin-4-yl)-3-hydroxy-4-methoxy-benzamide (0.40 g, 1.28 mmol) (Example 14) in dichloromethane , triethylamine (0.39 g, 3.85 mmol) was added. The reaction mixture was allowed to stir for about 10 min and ditertiary butyl dicarbonate (0.42 g, 1.92 mmol) was added drop wise. After stirring the reaction mixture for additional 2 h, water was added and the reaction mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated. Purification was done using column chromatography to afford the product. Yield: 0.45 g (85%)
Example 16: Preparation of {5-[tert-butoxycarbonyl-(3,5-dichloro-pyridin-4-yl)-aminocarbonyll-2-methoxy-phenoxy}-acetic acid ethyl ester
To a solution of (3,5-dichloro-pyridin-4-yl)-(3-hydroxy-4-methoxy-benzoyl)-carbamic acid tert-butyl ester (0.45 g, 1.09 mmol) (Example 15) in dimethylformamide, potassium carbonate (0.45 g, 3.28 mmol) was added. The reaction mixture was stirred for about 10 min and ethylbromo acetate (0.27 g, 1.64 mmol) was added. After stirring the reaction mixture for about 16 h at room temperature, water was added and the extraction was carried out with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent was evaporated. Yield: 0.44 g (81%), m/z: 499(M++1)
Example 17: Preparation of (3,5-dichloro-pyridin-4-yl)-[3-(2-hydroxy-ethoxy)-4-methoxy-benzoyl]-carbamic acid tert-butyl ester
Sodium borohydride (0.34 g, 8.80 mmol) was added slowly to a stirred solution of {5-[tert-butoxycarbonyl-(3,5-dichloro-pyridin-4-yl)-aminocarbonyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.44 g, 0.88 mmol) (Example 16) in methanol at 0 °C under inert atmosphere. After stirring the reaction mixture for about 2 h, saturated solution of ammonium chloride was added followed by ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulphate and the solvent was evaporated. Purification was done using column chromatography to give the required product. Yield: 0.35 g (90%), m/z: 457 (M++l)
Example 18: Preparation of (3,5-dichloro-pyridin-4-yl)-[3-(2-hydroxyimino-ethoxy)-4-methoxy-benzoylj-carbamic acid tert-butyl ester
To a solution of chromium trioxide (0.45 g, 4.47 mmol) in dichloromethane and pyridine (0.71 g, 8.95 mmol) was added dropwise the solution of (3,5-dichloro-pyridin-4-yl)-[3-(2-hydroxy-ethoxy)-4-methoxy-benzoyl]-carbamic acid tert-butyl ester (0.34 g, 0.75 mmol) (Example 17) in dichloromethane. After stirring the reaction mixture for about 15 min,
dichloromethane was evaporated off to reduce the volume by half, supernatant was decanted into another flask and hydroxylamino hydrochloride (0.21 g, 2.99 mmol) sodium acetate, (0.25 g, 2.99 mmol) and ethanol were added. After stirring the reaction mixture for about 15 h, solvent was evaporated off and water was added. Extraction was carried out with ethyl acetate and organic layer was separated, washed, dried and the solvent was evaporated to afford the desired product.
Yield: 0.24 g (52%)
Example 19: Preparation of 4-[5-(3,5-dichloro-pyridin-4-ylcarbamoyl)-2-methoxy-
phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester (Compound No.
4}
To a solution of (3,5-dichloro-pyridin-4-yl)-[3-(2-hydroxyimino-ethoxy)-4-methoxy-
benzoyl]-carbamic acid tert-butyl ester (0.19 g, 0.41 mmol) (Example 18) in tetrahydrofuran , methylmethacrylate (0.08 g, 0.81 mmole) and sodium hypochlorite (2 ml) was added drop wise over a period of 30 min under inert atmosphere. After stirring the reaction mixture for about 30 min, tetrahydrofuran was evaporated off and water was added. Extraction was done with ethyl acetate and the organic layer was separated, washed with brine, dried over sodium sulphate and solvent was evaporated. The residue, thus obtained, was taken in dichloromethane (5 ml) and to this was added trifluoroacetic acid (0.1 ml). After stirring the reaction mixture for about 30 min, residue was adsorbed on silica gel and purified using column chromatography. Yield: 25 mg (11%), m/z: 457 (M++23)
Example 20-.Preparation of 3-(5-cyano-5-methyl-4,5-dihydro-isoxazol-4-ylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (Compound No.3)
To a solution of (3,5-dichloro-pyridin-4-yl)-[3-(2-hydroxyimino-ethoxy)-4-methoxy-benzoylj-carbamic acid tert-butyl ester (0.07 g, 0.14 mmol) (Example 18) and methacrylonitrile (0.02 g, 0.27 mmol) in tetrahydrofuran, sodium hypochlorite (2 ml) was added dropwise over a period of about 30 min under inert atmosphere. After stirring the reaction mixture for about 30 min at an ambient temperature, solvent was evaporated off and water was added .The reaction mixture was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over anhydrous sodium sulphate and the solvent was evaporated. The residue thus obtained was taken in dichloromethane and to this trifluoroacetic acid (0.1 ml) was added. After stirring the reaction mixture for about 30 min, the residue was adsorbed on silica gel and purified by column chromatography to afford the desired product. Yield: 0.02 g (28%), m/z: 469 (M++l)
Example 21: Preparation of 4-[5-(3,5-dichloro-pyridin-4-ylcarbamoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid ethyl amide (Compound
No.5)
Ethyl amine (0.5 ml) was added to a stirred solution of 4-{5-[tert-butoxycarbonyl-(3,5-dichloro-pyridin-4-yl)-aminocarbonyl]-2-methoxy-phenoxymethyl}-5-methyl-4,5-dihydro-
isoxazole-5-carboxylic acid methyl ester (0.03 g, 0.05 mmol) in tetrahydrofuran and the reaction
mixture was stirred for about 16 h at room temperature. The solvent was evaporated, and the
residue thus obtained was adsorbed on silica gel and purified using column chromatography to
afford the required product.
Yield: 14 mg (44%), m/z: 481(M+ +1)
The following compounds can be prepared similarly
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid (Compound No. 6)
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid amide(Compound No. 7)
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid methyl amide (Compound No. 8)
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid dimethyl amide (Compound No. 9)
Example 22: Preparation of 4-methoxy -3-[(5-methyl-3-phenyl-4, 5-dihydroisoxazol-5-yl) methoxy] benzoic acid methyl ester
To a solution of 4- methoxy-3-(2-methyl-allyloxy)-benzoic acid methyl ester (1.0 g, 4.20 mmol) (Example 4) and commercially available benzaldehyde oxime (0.76 g, 6.30 mmol) in tetrahydrofuran, sodium hypochlorite (4% w/w, 2 ml) was added drop wise over a period of 30 min. After stirring the reaction mixture for about 2 h, tetrahydrofuran was evaporated off; water and ethyl acetate were added. After extraction, the organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and filtered. The solvent was evaporated off and the residue thus obtained was subjected to column chromatography to afford the desired product. Yield: 1.0g(67%)
The following compounds were prepared similarly
- 4-Methoxy-3-[(5-methyl-3-pyridin-4-yl-4,5-dihydroisoxazol-5-yl) methoxy]benzoic acid methyl
ester
- 3-{[3-(2-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl] methoxy}-4-methoxybenzoic acid
methyl ester
- 3-{ [3-(2,6-difluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl] methoxy}-4-methoxybenzoic
acid methyl ester
-3-{[3-(4-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl] methoxy}-4-methoxybenzoic acid methyl ester
-3-{[3-(3-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl] methoxy}-4-methoxybenzoic acid methyl ester
Example 23: Preparation of 4-methoxy -3-[(5-methyl-3-phenyl-4, 5-dihydroisoxazol-5-yl) methoxy] benzoic acid
To a solution of 4-methoxy -3-[(5-methyl-3-phenyl-4, 5-dihydroisoxazol-5-yl) methoxy] benzoic acid methyl ester (1.0 g, 2.80 mmol) (Example 22) in ethanol-water (90:10), sodium hydroxide (0.33 g, 8.40 mmol) was added and the reaction mixture was stirred with heating at 60
°C for about 2 h. Ethanol was evaporated off, water was added, and the reaction mixture was
acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated to give
required product.
Yield: 0.85 g (89%)
The following compounds were prepared similarly
- 4- Methoxy-3-[(5-methyl-3-pyridin-4-yl-4,5-dihydroisoxazol-5-yl) methoxy]benzoic acid
-3-{[3-(2-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]methoxy}-4-methoxybenzoicacid
3-{[3-(2,6-difluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]methoxy}-4-methoxybenzoic acid
-3-{[3-(4-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]methoxy}-4-methoxybenzoicacid -3-{[3-(3-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]methoxy}-4-methoxybenzoicacid
Example 24: Preparation of N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(2-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide(Compound No. 15)
To a stirred solution of 3-{[3-(2-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]methoxy}-4-methoxybenzoic acid ( 0.64g, 1.70 mmol) (example 23) and triethyl amine (0.36 ml, 0.25 mmol) in dimethylformamide, isobutyl chloro formate (0.24 ml, 1.90 mmol) was added drop wise at 0 °C over a period of 5 min and the stirring was continued for about 1 h at room temperature. The resulting solution was added to a suspension of 3,5 dichloro -4 -amino pyridine (0.56 g, 3.40 mmol) and sodium hydride (0.17 g, 4.2 mmol, 60% w/w) in dimethylformamide at 0 °C over a period of 10 min under inert atmosphere and the stirring was continued for about 1 h at 0-5 °C. The reaction mixture was quenched with dilute hydrochloride solution (10%, 20 ml) and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulphate and concentrated to get the required compound. Yield : 0.32 g (38%), nip: 197°C, m/z: 503.9(M+ +1)
The following compounds were prepared similarly
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(2,6-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-methoxy-benzamide(CompoundNo. 16)
mp: 170°C, m/z: 522.1(M+ +1)
N-(3,5 -dichloro-pyridin-4-yl)- 3 - [3 -(4-fluoro-phenyl)-5 -methyl-4,5 -dihydro-isoxazol-5 -ylmethoxy) -4-methoxy-benzamide(Compound No. 18) mp:235°C,m/z:504(M++l)
- N-(3,5 -dichloro-pyridin-4-yl)- 3 - [3-(3 -fluoro-phenyl)-5 -methyl-4,5-dihydro-isoxazol-5 -
ylmethoxy) -4-methoxy-benzamide(Compound No. 20)
mp: 234°C, m/z: 504(M+ +1)
The following compounds were prepared following this example also
-N-(3,5-dichloro-pyridin-4-yl)- 3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide(Compound No. 10)
-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide(Compound No. 11)
Example 25: Preparation of N-(3,5-dichloro-pyridin-4-yl)- 3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-hydroxy-benzamide(CompoundNo. 14)
To a stirred solution of N- (3,5-dichloro-pyridin-4-yl)- 3-(5-methyl-3-phenyl-4, 5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide (0.22 g, 0.45 mmol) (example 10 and 24) and 1-bromo-4- nitrobenzene (0.18g, 0.90 mmol) in dichloromethane, aluminium chloride (0.89 g, 6.70 mmol) was added slowly at room temperature and the stirring was continued for 10 h at room temperature. The reaction mixture was poured into ice-cold water (30 ml) and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue thus obtained was adsorbed on silica gel and purified using column chromatography to give the required product. Yield: 0.17 g (81%), m/z: 471.97(M+ +1)
The following compounds were prepared similarly
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-hydroxy-
benzamide(Compound No. 17)
nip: 115.5°C, m/z: 410.0 (M+ +1)
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-
ylmethoxy) -4-hydroxy-benzamide(CompoundNo. 19)
mp: 219°C, m/z: 490.0 (M+ +1)
Example 26: Preparation of 3-[3-(4-tert-Butyl-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (Compound No. 47)
A mixture of N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide (0.10 g, 0.27 mmol) (example 6) and 4-tert-Butyl benzaldehyde oxime (0.06 g, 0.35 mmol) (example 8) was taken in dichoromethane. Pyridine (2-3 drops) was added to it followed with the addition of sodium hypochlorite (5 ml) (dropwise) at 0 °C. The reaction mixture was then allowed to stir at room temperature for about 2 days. The extraction was done with dichloromethane. The organic layer was washed with brine, dried over sodium sulphate and concentrated to obtain the product.
Yield: 0.046 g (31%), m/z: 542 (M++l)
The following compounds were prepared similarly
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(5-methyl-3-O-tolyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 48)
Yield: 30 mg (22%), m/z: 500 (M++l)
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-[3-(3-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 49)
Yield: 39 mg (28%), m/z: 516 (M++l)
Example 27 : Preparation of 4-Methoxy-3-[(5-methyl-3-p-tolyl-4,5-dihydroisoxazol-5-yl) methoxy] benzoic acid methyl ester
A mixture of 4-methoxy-3-(2-methyl allyloxy) benzoic acid methyl ester (1.8 g, 7.62 mmol) ( example 4) and 4-methyl benzaldehyde oxime (1.3 g, 9.10 mmol) was taken in dichloromethane. Pyridine (2 drops) was added to the stirred reaction mixture. It was cooled to 0 °C and sodium hypochlorite (8 ml) was added drop wise. The reaction mixture was then allowed to stir at room temperature for 24 h. It was poured in water (50 ml) and extracted with dichloromethane. Organic layer was dried over sodium sulphate and concentrated to obtain the product. Yield: 0.60 g (21%).
Example 28: Preparation of 4- Methoxy-3-[(5-methyl-3-p-tolyl-4,5-dihydroisoxazol-5-yl) methoxy] benzoic acid
4-Methoxy-3-[(5-methyl-3-p-tolyl-4,5-dihydroisoxazol-5-yl) methoxy] benzoic acid methyl ester (0.60 g, 1.63 mmol) ( example 27) was taken in methanol. Sodium hydroxide (aqueous) (0.13 g, 3.25 mmol) was added to it. The reaction mixture was then heated at 60 °C overnight. Methanol was evaporated and water was poured in to the residue. Aqueous layer was washed with ethyl acetate to remove organic impurities. The aqueous portion was then neutralized with 1.5 N hydrochloride solution to make pH = 5. The aqueous layer was then extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulphate and concentrated to obtain the product Yield: 0.47 g (81%)
Example 29: Preparation of N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 46)
4- Methoxy-3-[(5-methyl-3-p-tolyl-4,5-dihydroisoxazol-5-yl) methoxy] benzoic acid (0.044 g, 0.124 mmol) (example 28) was taken in 3-necked flask, fitted with septum, condenser under inert atmosphere. Dry-dichloroethane (6 ml) and thionyl chloride (0.022 g, 0.19 mmol) were added. The reaction mixture was refluxed at 80 °C for about 1.5 h. Excess of dichloroethane and thionyl chloride were removed under vaccum from the reaction mixture. In another round bottom flask, sodium hydride (0.08 g, 0.2106 moles) was taken in dry tetrahydrofuran (12 ml) at 0 °C and 3,5- dichloro -4 -amino pyridine (0.03 g, 0.19 mmol) was added. After about half an hour, reaction mixture was cooled to 0 °C and the previously prepared acid chloride residue was dissolved in dry tetrahydrofuran (5 ml) and was slowly added to it at 0 °C. The reaction mixture was allowed to stir at 0 °C to room temperature for 2 h.Water (40 ml) was poured into reaction mixture. Extraction was done with ethyl acetate. Organic layer was concentrated and the crude product was crystalised using 2% dichloromethane in hexane to obtain pure product. Yield: 15 mg (24%), m/z: 500(M++1).
Example 30: Preparation of 2-hydroxymethyl-piperidine-l-carboxylic acid butyl ester
Pipridin-2-yl -methanol (1.3 g, 11.3 mmol) was taken in 10 mL of tetrahydrofuran. Aqueous sodium carbonate (10% w/v, 20 ml ) was added to it followed by di-tert-butyl dicarbonate (4.93 g, 22.6 mmol). The reaction mixture was allowed to stir at room temperature for about 1 h. It was cooled, then neutralization was done with 1.5 N hydrochloric acid solution till the solution attained a pH value of 6-6.5. The extraction was done with ethyl acetate. The organic layer was dried and concentrated to obtain the product. Yield: 1.9g(79%). Example 31: Preparation of 2-formyl-pipridine-l-carboxylic acid tert-butyl ester
2-Hydroxymethyl-piperidine-l-carboxylic acid butyl ester (1.0 g, 4.65 mmol ) (example 30) was taken in dichloromethane. Celite and pyridinium chlorochromate (2.0 g, 9.30 mmol) was added to it. The reaction mixture was allowed to stir at room temperature for about 2 h. The reaction mixture was filtered through a celite pad . The filtrate was then concentrated to obtain the product. Yield: 0.55 g (56%).
Example 32: Preparation of 2-(hydroxyiminomethyl)piperidine-l-carboxylic acid tert-butyl ester
2-Formyl-pipridine-l-carboxylic acid tert-butyl ester (0.55 g, 2.58 mmol) (example 31) was taken in ethanol. Hydroxylamine hydrochloride (0.54 g, 7.75 mmol) and sodium acetate (0.64 mg, 7.75 mmol) were added to it. The reaction mixture was then stirred for about 2 h. Methanol was evaporated, water was added and the extraction was done with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to get the product. Yield: 0.40 g (68%).
Example 33: Preparation of 2-{5-[5-(3,5-dichloro-pyridin-4-ylcarbamoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazol-3-yl}-piperidine-l-carboxylic acid tert-butyl ester (Compound No. 50)
A mixture of N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide (0.26 g, 0.71 mmol) (example 6) and 2-(hydroxyiminomethyl)piperidine-l-carboxylic acid tert-butyl ester (example 32) (0.404 g, 1.77 mmol) was taken in dichloromethane. Pyridine was added to it followed by dropwise addition of sodium hypochlorite (5.0 mL) at 0°C. The reaction mixture was then allowed to stir at room temperature for 2 days. The extraction was done with dichloromethane. The organic layer washed with brine and concentrated to obtain product Yield 0.046 g (14%), m/z: 593 (M++l).
Example 34: Preparation of N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-[5-methyl-3-(l-phenyl-ethyl)-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide (Compound No. 44)
To a stirred mixture of 2-phenyl propionaldehyde oxime (0.081 g, 0.54 mmole) (example 8) and N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide (0.10 g, 0.27
mmole) (example 6) in a mixture of dichloromethane and chloroform (8:2, 20 ml) was added 3-4 drops of pyridine. Sodium hypochlorite solution (0.89 ml, 0.60 mmol) was added dropwise and the reaction mixture was stirred at room temperature for about 24 h. Water was added to the reaction mixture and the compound was extracted with dichloromethane. The extract was washed successively with water, brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the residue. It was purified by column chromatography on silica gel (using n-hexane/ethyl acetate: 70/30). Yield: 10 mg, (7%), m/z: 514 (M++l).
Example 35: Preparation of 3-(3-Cyclohexyl-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide (Compound No. 45 )
To a stirred mixture of cyclohexane carbaldehyde oxime (0.069 g, 0.55 mmol) (example 8) and N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(2-methyl-allyloxy)-benzamide (example 6) (0.10 mg, 0.27 mmol) in a mixture of dichloromethane and chloroform (3:2, 20 ml) was added 3-4 drops of pyridine. Sodium hypochlorite solution (0.87 ml, 0.60 mmol) was added drop wise. The reaction mixture was stirred at room temperature for about 24 h. Water was added to the reaction mixture and the compound was extracted with dichloromethane. The organic portion was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the residue.The crude residue was purified by column chromatography on silica gel (using n-hexane/ethyl acetate: 70/30) to provide pure compound. Yield: 0.03 g(22%), m/z: 492 (M++l).
Example 36: Preparation of N-(3,5-dichloro-pyridin-4-yl)-4-ethoxy-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No.21)
To a stirred solution of the N-(3,5-dichloro-pyridin-4-yl)- 3-
(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)- 4-hydroxy benzamide (0.07 g, 0.14 mmol) (example 25) and potassium carbonate (0.022 g, 0.14 mmol) in acetonirile at 60 °C, ethyl iodide (0.024 ml, 0.15 mmol) was added. Stirring was continued at 50-60 °c for 10 h. Acetonitrile was evaporated off and water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate (2 x 30 mL) and washed with water, brine, dried over sodium sulphate, filtered and the solvent was evaporated off to get the compound. Yield: 0.035 g ( 47%)
Example 37: Preparation of 4-methoxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxyjbenzoic acid methyl ester
To a stirred solution of 4- methoxy-3-(2-methyl-allyloxy)-benzoic acid methyl ester (2.0 g, 8.00 mmol) (example 4) and pyridine-3-carbaldehyde oxime (1.46g, 12.0 mmol) in tetrahydrofuran (15ml), sodium hypochlorite solution (5 ml) was added. Stirring was continued at
room temperature for about 10 h. Tetrahydrofuran was evaporated off from reaction mixture, water was added and the extraction was carried out with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated off to get the compound. Yield: 1.60g(51%)
Example 38: Preparation of 4-hydroxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxy]benzoic acid methyl ester
To a stirred solution of 4-methoxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxy]benzoic acid methyl ester (1.6 g, 4.30 mmol) ( example 37) in dichloromethane (50 mL), aluminium chloride(5.7 g ,43.0 mmol) was added l-Bromo-4- nitro benzene (1.3 g, 6.40 mmol) was added at room temperature. Stirring was continued at room temperature for 17 h. The reaction mixture was poured in to icewater, and extraction was done with dichloromethane. The organic layer was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated off. The residue thus obtained was triturated with 5% dichloromethane-hexane, the solvent was decanted to obtain the product.
Yield: 1.10g(73%)
Example 39: Preparation of 4-butoxy-3-[(5-methyl-3-pyridm-3-yl-4,5-dihydroisoxazol-5-yl) methoxyjbenzoic acid methyl ester
To a stirred solution of the 4-hydroxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxy]benzoic acid methyl ester (0.15 g, 0.43 mmol) ( example 38) and potassium carbonate (1.1 g, 0.84 mmol) in dimethylformamide at 60 °C, n-butyl bromide (0.086 g, 0.63 mmol) was added. Stirring was continued at 60 °C for 10 h. Water was added to the reaction mixture and the extraction was carried out with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated off to obtain the product.
Yield: 0.15 g (82%)
Example 40: Preparation of 4-butoxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxyjbenzoic acid
To a stirred solution of 4-butoxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxyjbenzoic acid methyl ester (0.145 g, 0.35 mmol) (example 39) in ethanol- water (95:5, 1ml), sodium hydroxide (0.072 g, 1.70 mmol) was added. Stirring was continued at 60- 70 °C for about 10 h. Ethanol was evaporated off, water was added to the reaction mixture. It was acidified with 5% hydrochloric acid solution. Extraction was carried out with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated off to get the compound.
Yield: 0.12 g (92%)
Example 41: Preparation of 4-butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 39)
To a stirred solution of 4-butoxy-3-[(5-methyl-3-pyridin-3-yl-4,5-dihydroisoxazol-5-yl) methoxyjbenzoic acid (0.12 g, 0.31 mmol) (example 40) and triethyl amine (0.06 ml, 0.40 mmol) in dimethylformamide (3.0 mL), isobutyl chloro formate (0.04 mL, 0.32 mmol) was added drop wise at 0 °C over a period of 5 min and the stirring was continued for about 1 h at room temperature. The resulting solution was added to a suspension of 3,5 dichloro -4 -amino pyridine (0.10 g, 0.62 mmol) and sodium hydride (0.026 g, 0.65 mmol, 60% w/w) in dimethylformamide (3.0 mL) at 0 °C over a period of 10 min under inert atmosphere and the stirring was continued for about 1 h at 0-5 °C. The reaction mixture was quenched with dilute hydrochloride solution (10%, 20 ml) and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulphate and concentrated to get the required compound. Yield : 0.019 g (15%), m/z: 530 (M++l). The following compounds were prepared similarly
-4-Benzyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 55)
-4-Cycloheptyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 56)
-N-(3,5-dichloro-pyridin-4-yl)-4-isopropoxy-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 35); m/z: 515 (M++l).
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 37); m/z: 527(M++1).
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide (Compound No. 41); m/z: 541 (M++l).
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-isopropoxy-benzamide (Compound No. 36); m/z: 452 (M++l).
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-propoxy-benzamide (Compound No. 34); m/z: 452 (M++l).
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-ethoxy-benzamide (Compound No. 33); m/z: 438 (M++l). Example 42: Efficacy of compounds as PDE IV inhibitors
PDE-IV Enzyme Assay
The efficacy of compounds of PDE-4 inhibitors is determined by an enzyme assay using U937 cell cytosolic fraction (BBRC, 197: 1126-1131, 1993). Hydrolysis of cAMP to AMP was monitored using HPLC and [3H]cAMP in the sample was detected using FLO-ONE Detector.
The enzyme preparation is incubated in the presence and absence of the test compound for 30 min and amount of [3H]cAMP measured in the sample. The IC50 values were found to be in the range of lower µM to nM concentration.

WE CLAIM:
1. A compound having the structure of Formula I,
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides wherein R1 and R6 independently represent hydrogen, alkyl, alkenyl, alkynyl, un(saturated) cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, (heteroaryl) alkyl, (heterocyclyl) alkyl,
X represents oxygen , sulphur , NRh {wherein RH represents hydrogen alkyl, alkenyl, alkynyl, un(saturated) cycloalkyl, acyl, aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl)alkyl, (heterocyclyl)alkyl, S(O)nRd [wherein Rd represents alkyl, aryl , heterocyclyl or heteroaryl and n represents an integer in the range 0-2]},
Y represents no atom, oxygen , sulphur , NRh {wherein RH is the same as defined above},
X1 represents hydrogen, alkyl ,alkenyl, alkynyl, cycloalkyl , aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl)alkyl, (heterocyclyl)alkyl,
Y1 represents hydrogen, alkyl, alkenyl, alkynyl, nitro, cyano, halogen, ORh, SRh, NHRh {wherein Rh is the same as defined above}, COOR' ,COR', CONHR' {wherein R' represents hydrogen, alkyl, alkenyl, alkynyl, (un)saturated cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, (heterocyclyl)alkyl, (heteroaryl)alkyl , S(O)nRd, {wherein Rd is the same as defined above},
Y1 may be fused to benzene ring if it is aryl, heteroaryl or heterocyclyl, j represents an integer in the range of 1 to 3,
R2 and R3 independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl nitro, cyano, amino, substituted amino, alkoxy, aryloxy, COR', COOR' {wherein R' is the same as defined above},aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl) alkyl, (heterocyclyl) alkyl, (CH2)1-4OR' {herein R' is the same as defined above including hydroxy group} C(=O)NRxRy {wherein Rx and Ry independently represent hydrogen,
alkyl, alkenyl of three to six carbon atoms, alkynyl of three to six carbon atoms, (un)saturated cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, (heteroaryl)alkyl, heterocyclyl)alkyl, (CH2)m-C(=O)Rz {wherein m is an integer in the range of 0-2 and Rz represent Rp or Rq wherein Rp is a 4-12 membered (un)saturated monocyclic or bicyclic ring containing 1-4 heteroatom(s) selected from the group consisting of N, O and S wherein the said ring is attached to (CH2)mC(=O) through N and Rq is a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatom(s) selected from the group consisting of N, O and S wherein the said ring is attached to (CH2)mC(=O) through C},
R4 represents hydrogen, alkyl, halogen, hydroxy, cyano, carboxy, nitro, C(=O)NRxRy {wherein RxandRy are the same as defined above },
R5 represents hydrogen, alkyl, aryl, aralkyl, un(saturated) cycloalkyl, heteroaryl, heterocyclyl, (heteroaryl) alkyl, (heterocyclyl) alkyl,
R2, R3, R4 or R5 can be replaced by the floating bond.
(Formula Removed)
2. A compound according to claim 1 wherein R1 is R4, R6 and Y1 are
hydrogen,
X is oxygen, Y is no atom or oxygen, R2 is methyl, j is 1, R3 is replaced by the floating bond, X1 is selected from hydrogen, cycloalkyl, alkyl, heterocyclyl, heteroaryl, (heterocyclyl) alkyl or (heteroaryl) alkyl and R5 is selected from alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, (heterocyclyl) alkyl or (heteroaryl) alkyl.
3. A compound according to claim 2 wherein X1 is selected from methyl, difluoromethyl,
ethyl, propyl, isopropyl, cyclopropyl, butyl, cyclopentyl, benzyl or cycloheptyl and R5 is
selected from methyl, phenyl, 3-pyridyl, 3-cyclopentyloxy-4-methoxy-phenyl, 4-
difluoromethoxy-phenyl, 2-fluorophenyl, 2,6-difluorophenyl, 4-fluorophenyl, 3-
fluorophenyl, 1-phenyl ethyl, cyclohexyl, p-tolyl, 4-tert-butyl phenyl, O-tolyl, 3-methoxy
phenyl, piperidine-1-carboxylic acid tert-butyl ester, 3,4-difluorophenyl, 2,4-
difluorophenyl, 4-fluoro-3- methyl phenyl or 3,5-difluoro phenyl.
4. A compound according to claim 1 wherein R1 is , R4 , R6 and Y1 are
hydrogen, X and Y are oxygen, R3 and X1 are methyl, j is 1 , R5 is replaced by the floating bond and R2 is selected from cyano , -COOR' or C(=O)NRxRy wherein R' ,RX and Ry are selected from hydrogen, alkyl, alkenyl, alkynyl, (un)saturated cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, (heterocyclyl)alkyl or (heteroaryl)alkyl.
5. A compound according to claim 4 wherein R', Rx and Ry are selected from methyl and
ethyl.
6. A compound, which is,
-3-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide,
-3-(5-Cyano-5-methyl-4,5-dihydro-isoxazol-4-ylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide,
-4-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester,
-4-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid ethyl amide,
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid,
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid amide,
-3- [5 -(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl] -5 -methyl-4,5 -dihydro-isoxazole-5-carboxylic acid methyl amide,
-3-[5-(3,5-Dichloro-pyridin-4-ylcarbomoyl)-2-methoxy-phenoxymethyl]-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid dimethyl amide,
-N-(3,5-dichloro-pyridin-4-yl)- 3-(5-methy 1-3-pheny 1-4,5-dihydro-isoxazol-5-yImethoxy) -4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3 -(5-methyl-3 -pyridin-3 -yl-4,5 -dihydro-isoxazol-5 -ylmethoxy)-4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-(3-(4-difluoromethoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-methoxy-benzamide,
-N-(3,5 -dichloro-pyridin-4-yl)-4-difluoromethoxy-3 -(3,5 -dimethyl-4,5 -dihydro-isoxazol-5-ylmethoxy)-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)- 3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-hydroxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(2-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(2,6-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5 -ylmethoxy) -4-methoxy-benzamide,
- N-(3,5-dichloro-pyridin-4-yl)- 3-[3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-hydroxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(4-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-hydroxy-benzamide ,
-N-(3,5-dichloro-pyridin-4-yl)- 3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy) -4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-ethoxy-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-ethoxy-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-propoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-propoxy-benzamide ,
-N-(3,5-dichloro-pyridin-4-yl)-4-isopropoxy-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide ,
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy] -4-isopropoxy-benzamide ,
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide,
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide,
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-phenyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3-fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide ,
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-ethoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-propoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-isopropoxy-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-4-isopropoxy-benzamide,
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-4-Cyclopropoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide ,
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide ,
-4-Butoxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide ,
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-4-Cyclopentyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-hydroxy-3-(5-methyl-3-pyridin-3-yl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-N-(3,5 -dichloro-pyridin-4-yl)-4-methoxy-3 - [5 -methyl-3 -(1 -phenyl-ethyl)-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide,
-3-(3-Cyclohexyl-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(5-methyl-3-p-tolyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-3-[3-(4-tert-Butyl-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-(5-methyl-3-O-tolyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-4-methoxy-3-[3-(3-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-benzamide,
-2-{5-[5-(3,5 -Dichloro-pyridin-4-ylcarbamoyl)-2-methoxy-phenoxymethyl] -5 -methyl-4,5 -dihydro-isoxazol-3-yl}-piperidine-l-carboxylic acid tert-butyl ester,
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3,4-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5 -ylmethoxy] -4-methoxy-benzamide ,
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(2,4-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5 -ylmethoxy] -4-methoxy-benzamide ,
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(4-fluoro-3-methyl-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide,
-N-(3,5-dichloro-pyridin-4-yl)-3-[3-(3,5-difluoro-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-4-methoxy-benzamide,
-4-Benzyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-4-Cycloheptyloxy-N-(3,5-dichloro-pyridin-4-yl)-3-(3,5-dimethyl-4,5-dihydro-isoxazol-5-ylmethoxy)-benzamide,
-3-[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-ylmethoxy]-N-(3,5-dichloro-pyridin-4-yl)-benzamide,
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides, thereof.
7. A combination of a compound of any of the preceding claims 1 to 6 with the therapeutic
agents selected from corticosteroids, beta agonists, leukotriene antagonists, 5-lipoxygenase
inhibitors, chemokine inhibitors and muscarinic receptor antagonists.
8. A pharmaceutical composition comprising a therapeutically effective amount of a
compound of any of the preceding claims 1 to 6 or a combination as claimed in claim 7
together with pharmaceutically acceptable carrier, excipients or diluents.
9. A method for treating, preventing, inhibiting or suppressing an inflammatory condition or
disease in a patient, comprising administering to the said patient a therapeutically effective
amount of a compound of any of the preceding claims 1 to 6 or a combination as claimed
in claim 7 and a pharmaceutical composition of claim 8.
10. A method for the treatment, prevention, inhibition or suppression of AIDS, asthma,
arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic
rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome
(ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis
and other inflammatory diseases in a patient comprising administering to said patient a
therapeutically effective amount of a compound of any of the preceding claims 1 to 6 or a
combination as claimed in claim 7 and a pharmaceutical composition of claim 8.
11. A method for the preparation of a compound of Formula X,
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides wherein R1 ,Y, X1 ,Y1, j ,R2 ,R4 and R5 are the same as defined in claim 1,which method comprises, oxidising a compound of Formula II,
(Formula Removed)
to give a compound of Formula II (a) (wherein X1,Y1 and Y are the same as defined earlier),
(Formula Removed)
which on esterification gives a compound of Formula III,
(Formula Removed)
which on reaction with a compound of Formula IV (wherein X3 represents halogen and j is the same as defined earlier) gives a compound of Formula V (wherein R2, R4 and j are the same as defined earlier),
(Formula Removed)
which on ester hydrolysis gives a compound of Formula VI,
(Formula Removed)
which on reaction with a compound of Formula VII gives a compound of Formula VIII
(Formula Removed)
(wherein R1 is the same as defined earlier),
which is finally reacted with a compound of Formula IX,
(Formula Removed)
to give a compound of Formula X (wherein R5 is the same as defined earlier).
12. A method for the preparation of a compound of Formula XXII,
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides wherein Y, Y1, X1, R1, j, R2, R3 and R4 are the same as defined in claim l,which method comprises, protecting a compound of Formula II (a),
(Formula Removed)
with a compound of Formula RX3 (wherein X3 represents halogen) to give a compound of Formula XI (wherein Y, Y1 and X1 are the same as defined earlier and R is a hydroxy protecting group),
(Formula Removed)
which on reaction with a compound of Formula VII gives a compound of Formula XII (wherein Rj is the same as defined earlier),
(Formula Removed)
which on deprotection gives a compound of Formula XIII,
(Formula Removed)
which on N- protection gives a compound of Formula XIV (wherein Pr is a amino protecting group),
(Formula Removed)
which on reaction with a compound of Formula XV( wherein X3 is the same as defined earlier) gives a compound of Formula XVI, (wherein j is the same as defined earlier),
(Formula Removed)
which on reduction gives a compound of Formula XVII,
(Formula Removed)
which on oxidation gives a compound of Formula XVIII,
(Formula Removed)
which on reaction with hydroxylamine hydrochloride gives a compound of Formula XIX,
(Formula Removed)
which on reaction with a compound of Formula XX gives a compound of Formula XXI (wherein R2,R3 and R4 are the same as defined earlier),
(Formula Removed)
which is finally deprotected to give a compound of Formula XXII. 13. A method for the preparation of a compound of Formula XXVI,
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides wherein R1, Y1 , j, R2, R4 and R5 are the same as defined for claim 1, which method comprises reacting a compound of Formula XXIII with a compound of Formula IX,
(Formula Removed)
to give a compound of Formula XXIV (wherein R2, R4, R5 , j and Y1 are the same as defined earlier),
(Formula Removed)
which on ester hydrolysis gives a compound of Formula XXV,
(Formula Removed)
which is finally reacted with a compound of Formula VII,
(Formula Removed)
to give a compound of Formula XXVI (wherein R1 is the same as defined earlier.
14. A method for the preparation of a compound of Formula XXVII,
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides wherein R1, Y1 , j, R2, R4 and R5 are the same as defined for claim l,which method comprises demethylation of a compound of Formula XXVI
(Formula Removed)
to give a compound of Formula XXVII.
15. A method for the preparation of a compound of Formula XXIX,
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides wherein R1, Y1 , j, R2, R4, X1 and R5 are the same as defined for claim 1,which method comprises (a) reacting a compound of Formula XXVII,
(Formula Removed)
with a compound of Formula XXVIII,
(Formula Removed)
to give a compound of Formula XXIX (wherein X\ is the same as defined earlier) (b) alternatively, a method for the preparation of a compound of Formula XXIX and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides which method comprises demethylating a compound of Formula XXIV to give a compound of Formula XXX (wherein R2, R4, R5, j and Y1 are the same as defined earlier),
(Formula Removed)
which on reaction with a compound of Formula XXVIII gives a compound of Formula XXXI (wherein X1 is the same as defined earlier),
(Formula Removed)
which on ester hydrolysis gives a compound of Formula XXXII,
(Formula Removed)
which is finally reacted with a compound of Formula VII,
(Formula Removed)
to give a compound of Formula XXIX (wherein R1 is the same as defined earlier).