WO2006040645A1

WO2006040645A1 - N-(3,5-dichloropyridin-4-yl)-2,4,5-alkoxy and 2,3,4-alkoxy benzamide derivatives as pde-iv (phophodiesterase type-iv) inhibitors for the treatment of inflammatory diseases such as asthma

Info

Publication number: WO2006040645A1
Application number: PCT/IB2005/003017
Authority: WO
Inventors: Ramnik Sharma; Kumar Hari Bhushan; Bhargav Pandya; Ram Chander Aryan; Yatendra Kumar
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2004-10-11
Filing date: 2005-10-11
Publication date: 2006-04-20
Anticipated expiration: 2007-04-11

Abstract

The present invention relates to benzamide derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV, having the structure of Formula (I), its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers of N-oxides wherein R1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl; R2 is aryl, heteroaryl, heterocyclyl of cycloalkyl; and R3 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl. Compounds disclosed herein can be useful in the treatment of inflammatory diseases, AIDS, asthma, arthritis, bronchitis, chronic obstructer pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn’ s disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis and ulcerative colitis.

Description

N- ( 3 , 5-DICHLOROPYRIDIN^ -YL ) -2 , 4 , 5-ALKOXY AND 2 , 3 , 4-ALKOXY BENZAMIDE DERIVATIVES AS PDE-IV ( PHOPHODIESTERASE TYPE-IV) INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES SUCH AS ASTHMA

INHIBITORS OF PHOPHODIESTERASE TYPE-IV

Field of the Invention

The present invention relates to benzamide derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. 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 the compounds described herein are provided, as well as pharmaceutical compositions containing these compounds, and their use as phosphodiesterase (PDE) type IV inhibitors.

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 (Sutherland, et al., Pharmacol. Rev., 1960,12, 265). Its intracellular hydrolysis to adenosine 5'- monophosphate (AMP) causes a number of inflammatory conditions which include, but 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) levels is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally, highly variable superfamily of the enzyme; eight 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 the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE IV inhibitors, such as roflumilast or rolipram 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 have been recognized (Bervo et al, TIPS, 1990, JJ., 150), and their selective inhibition has led to improved drug therapy (Nicholus, et al , TIPS, 1991, 12, 19). Thus it was recognized that inhibition of PDE IV could lead to inhibition of inflammatory mediator release (Verghese et al, J. MoI. Cell. Cardiol.. 1989, 12 (Suppl.II), S 61).

U.S. Patent No. 5,712,298 and PCT application WO 95/01338 disclose fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors. U.S. Patent Application No. 2003/0232859 and PCT application WO

02/062750 disclose cannabinoid receptor ligands which exhibit anti-inflammatory and immunodulatory activity. WO 00/42020 discloses phenylphenanthridines with PDE-IV inhibiting activity.

Summary of the Invention The present invention provides benzamide derivatives, 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, enantiomers, diastereomers 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, 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

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides wherein Ri is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl;

R₂ is aryl, heteroaryl, heterocyclyl or cycloalkyl; and

R₃ is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl. The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)R_f, -NR_fR_q, -C(=O)NR_fR_q,

-NHC(=O)NR_fR_q,, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NR_fR_q {wherein R_f and R_q are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO₂R₆ (wherein R₆ is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1 -3 substituents selected from alkyl, carboxy, -NRfR_q, -C(=O)NR_fRq,

(wherein R_f and R_q are the same as defined earlier), hydroxy, alkoxy, halogen, CF₃, cyano, and -SO₂R₆, (wherein R₆ are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NR_a- {wherein R₃ is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)OR_f (wherein R_f is the same as defined earlier), SO₂R₆ (where R₆ is as defined earlier), or -C(=O)NR_fR_q (wherein R_f and R_q are as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NRfR_q, -C (=O)NR_fR_q, -O-C(=O)NR_fR_q (wherein R_f and Rq are the same as defined earlier) hydroxy, alkoxy, halogen, CF₃, cyano, and -SO₂R₆ (where R₆ is 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 otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC (=O)R_f, -NR_fR_q, C(=O)NR_fRq, -NHC(=0)NR_fRq, -O-C(=O)NR_fR_q (wherein R_f and Rq are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, or SO₂R₆ (wherein R₆ are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF₃, cyano, -NR_fR_q, -Q=O)NR_fRq, -O-C(=O)NR_fRq (wherein R_f and R_q are the same as defined earlier) and - SO₂R_ό( where R₆ is same as defined earlier). The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=O)R_f, -NR_fRq, -NHC(=O)NR_fRq , - C(=O)NR_fR_q, -O-C(=O)NR_fRq (wherein R_f and Rq are the same as defined earlier), or - SO₂R₆ (wherein R₆ is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF₃, -NR_fR_q, -C(=O)NR_fR_q, -NHC(=O)NR_fRq , -C(=O)NR_fRq (wherein R_f and Rq are the same as defined earlier), cyano, or -SO₂R₆ (where R₆ is same as defined earlier). The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NR_fRq, -NHC (=0) NR_fR_q, -NHC (=0) R_f, C (=0) NR_fRq, -O-C (=O)NR_fRq (wherein R_f and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or SO₂-R₆ (wherein R₆ is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF₃, -NRfRq, -C(O)NR_fR₄,, -NHC(=0)NR_fR_q , -OC(=O)NR_fR_q (wherein R_f and Rq are the same as defined earlier), cyano or -SO₂R₆ (where R₆ is same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.

The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above. The term "haloalkyl" refers to alkyl (wherein alkyl is the same as defined above) substituted with one or more halogen (F, Cl, Br or I).

The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF₃, cyano, nitro, COOR_e (wherein R_e is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)R_f, - NR_fR_q, -C(=O)NR_fR_q, -NHC(=O)NR_fRq , -O-C(=O)NR_fR_q (wherein R_f and R_q are the same as defined earlier), -SO₂R₆ (wherein R₆ is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.

The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like.

The term "carboxy" as defined herein refers to -C(=O)OH.

The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NR_fR₄₁, CH=NOH, -(CH₂)_wC(=O)R_g {wherein w is an integer from 0-4 and R_g is hydrogen, hydroxy, OR_f, NR_fR_q, -NHOR_Z or -NHOH} , C(=O)NR_fRq and -NHC(=O)NR_fRq , -SO₂R₆, -O-C(=O)NR_fR_q, -O-C(=O)R_f, O-C(=O)OR_f (wherein R₆, Rf and Rq are as defined earlier, and R_z is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like.

The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)R_f, -O-C(=O)OR_f, -C(=O)NR_fR_q, SO₂R₆, -O- C(O)NR_fR_q,

-NRfRq (wherein R₆, R_f and Rq are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydro furanyl, dihydro furanyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.

"Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier.

The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)R_f, -O-C(=O)OR_f, -C(=O)NR_fR_q, SO₂R₆, -O-

C(=0)NR_fRq,

-NRfRq (wherein R₆, R_f and R_q are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl

"Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier. " Acyl" refers to -C(=O)R' ' wherein R' ' is selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.

The term "protecting groups" refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2^nd Ed., John Wiley and Sons, New York, N. Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.

In accordance with a further aspect, there are provided methods for treatment or prophylaxis of an animal or a human suffering from an inflammatory disease or disorder wherein the disease or disorder is mediated through phosphodiesterase Type IV enzyme. The method includes administration of at least one compound having the structure of Formula I.

In accordance with another aspect, there is provided a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder associated with phosphodiesterase Type IV enzyme, comprising administering to a patient in need thereof, an effective amount of a phosphodiesterase Type IV inhibitor compound as described above. In accordance with yet another aspect, there is provided a method for treatment or prophylaxis of an animal or a human suffering from AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases including administration of at least one compound having the structure of Formula I.

In accordance with still another aspect, there are provided processes for preparing the compounds described herein.

Detailed Description of the Invention

The compounds of the present invention may be prepared by techniques known in the art. In addition, the compounds of the present invention may be prepared following a reaction sequence, for example, as depicted below.

Scheme I

Formula I Formula IV Formula V

depnotection

VII

H₂NR₂ Formula Xl

Formula XII The compound of Formula XII can be prepared by following the procedure as depicted in Scheme I. Thus, a compound of Formula II (wherein R_p is alkyl, alkenyl or alkynyl) can be deprotected to give a compound of Formula III, which can undergo O- protection with a compound of Formula P-hal (wherein P is aralkyl (for example benzyl) or alkyl (for example methyl, isopropyl or t-butyl)] to give a compound of Formula IV, which can be reacted with a compound of Formula R_k-hal (wherein R_k is alkyl substituted with cycloalkyl, aryl, heterocyclyl or heteroaryl) to give a compound of Formula V, which can be deprotected to give a compound of Formula VI, which can be reacted with a compound of Formula VII (wherein X is -H or -COOCH₃) to give a compound of Formula VIII, which can undergo oxidation to give a compound of Formula IX, which can be converted to a compound of Formula X (wherein hal is Cl, Br or I), which can be further reacted with a compound of Formula XI (wherein R₂ is the same as defined earlier) to give a compound of Formula XII.

The deprotection of a compound of Formula II to give a compound of Formula III can be carried out with phosphorous pentachloride. Alternatively, boron and aluminum halides for example boron trichloride, aluminum tribromide or aluminum trichloride can also be used in an organic solvent, for example, pentane, benzene, toluene or dichloromethane.

The compound of Formula III can undergo O-protection with a compound of Formula P-hal to give a compound of Formula IV in dipolar aprotic solvent, for example, dimethylsulphoxide, dimethylformamide or hexamethylphosphoric triamide in the presence of a base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.

Alternatively, monomethylation of the para-hydroxyl group can be carried out by using controlled quantity of diazomethane in an organic solvent, for example, diethyl ether, ethanol, isopropanol, methanol or dichloromethane.

The compound of Formula IV can be reacted with a compound of Formula R_k-hal to give a compound of Formula V in an organic solvent, for example, dimethylsulphoxide, dimethylformamide, diethyl ether, tetrahydrofuran or dioxane, in the presence of a base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide. The compound of Formula V (when P is benzyl) can undergo deprotection to give a compound VI, in the presence of deprotecting agent, for example, palladium on carbon in the presence of hydrogen gas or palladium on carbon in ammonium formate solution, in an organic solvent, for example, ethyl acetate or by utilizing hydrochloric acid in acetic acid.

The compound of Formula V (when P is alkyl) can be deprotected to give a compound of Formula VI by following the procedure as described in T. W. Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis." 2^nd Ed, John Wiley and Sons, New York, N.Y. The compound of Formula VI can be reacted with a compound of Formula VII

(when X is -COOCH₃) to give a compound of Formula VIII in an organic solvent, for example, dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethyl ether or dioxane in the presence of a base, for example, cesium carbonate, sodium carbonate, lithium carbonate or potassium carbonate. The compound of Formula VI can be reacted with a compound of Formula VII

(when X is -H) to give a compound of Formula VIII, in an organic solvent, for example, dimethylsulphoxide, dioxane, dimethylformamide, toluene, tetrahydrofuran or diethyl ether, in the presence of a base, for example, potassium hydroxide, sodium hydroxide, butyl lithium, triethyl amine or pyridine with catalyst, for example, benzyltriethyl ammonium chloride, benzyltrimethyl ammonium chloride, benzyltributyl ammonium chloride, tetrabutyl ammonium bromide.

The compound of Formula VIII can be oxidized to give a compound of Formula IX with an oxidizing agent, for example, sodium chlorite, sodium dichromate, potassium permanganate or potassium dichromate, in an organic solvent, for example, acetic acid or formic acid.

The compound of Formula IX can be converted to a compound of Formula X with an acid activating agent, for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride, in an organic solvent, for example, toluene, benzene or xylene.

The compound of Formula X can be reacted with a compound of Formula XI to give a compound of Formula XII in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane, in the presence of a base, for example, sodium hydride, diisopropylethylamine or butyl lithium.

Particular illustrative compound(s) which can be prepared following Scheme I include:

5-Cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-2-methoxy benzamide (Compound No. 1)

Scheme Il

Formula XJV Formula XV

Rk — hal

The compound of Formula XIX can be prepared, for example, by following the reaction procedure as depicted in Scheme II. Thus, a compound of Formula XIII can undergo formylation to give a compound of Formula XIV, which can be reacted with a compound of Formula VII (wherein X is -H or -COOCH₃) to give a compound of Formula XV, which can be reacted with a compound of Formula R_k-hal to give a compound of Formula XVI, which can undergo oxidation to give a compound of Formula XVII, which can be converted to a compound of Formula XVIII (wherein hal is Br, Cl or I), which can be reacted with a compound of Formula XI to give a compound of Formula XIX.

The compound of Formula XIII can undergo formylation to give a compound of Formula XIV with a formylation agent, for example, dimethyl formamide, triformamide, tris(diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformylhydrazine in the presence of a Lewis acid, for example phosphorous oxychloride, aluminum trichloride or boron trichloride, followed by deprotection with a strong mineral acid, for example, hydrochloric acid, nitric acid or sulphuric acid.

The compound of Formula XIV can be reacted with a compound of Formula VII (wherein X is -COOCH₃) to give a compound of Formula XV in an organic solvent, for example dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane, in the presence of a base, for example, cesium carbonate, sodium carbonate, lithium carbonate or potassium carbonate.

The compound of Formula XIV can be reacted with a compound of Formula VII (when X is -H) to give a compound of Formula XV in an organic solvent, for example, dioxane, dimethylformamide, toluene, dimethylsulphoxide, tetrahydrofuran or diethyl ether, in the presence of a base, for example, sodium hydroxide, butyl lithium, triethyl amine or pyridine with catalyst for example, benzyltriethyl ammonium chloride, benzyltrimethyl ammonium chloride, benzyltributyl ammonium chloride, tetrabutyl ammonium bromide. The compound of Formula XV can be reacted with a compound of Formula R_k-hal to give a compound of Formula XVI in an organic solvent, for example, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane, in the presence of a base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide. The compound of Formula XVI can be oxidized to give a compound of Formula

XVII with oxidizing agent, for example, sodium chlorite, sodium dichromate, potassium permanganate or potassium dichromate, in an organic solvent, for example, acetic acid, or formic acid.

The compound of Formula XVII can be converted to a compound of Formula XVIII with an acid activating group, for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride, in an organic solvent, for example, toluene, xylene or benzene.

The compound of Formula XVIII can be reacted with a compound of Formula XI to give a compound of Formula XIX in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane, in the presence of a base, for example, sodium hydride, diisopropylethylamine or butyl lithium.

Particular illustrative compound(s) which can be prepared following Scheme II include:

3-Cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-2-methoxy benzamide (Compound No. 3)

Scheme III

The compounds of Formula XXI can be prepared, for example, following the procedure as depicted in Scheme III. Thus, the compound of Formula XX can undergo N- oxidation to give a compound of Formula XXI. The compound of Formula XX can be reacted with an oxidizing agent, for example, magnesium monoperoxyphthalate hexahydrate (MMPP), metachloroperbenzoic acid (m-CPBA), hydrogen peroxide (H₂O₂) or oxone (KHSO₅) in the presence of a solvent mixture, for example, dichloromethane in methanol to give a compound of Formula XXI.

Particular illustrative compounds which may be prepared following Scheme III include: 5-Cyclopropylmethoxy-N-(3,5-dichloro-l-oxido-pyridin-4-yl)-4-difluoromethoxy-2- methoxy benzamide (Compound No. 2),

3-Cyclopropylmethoxy-N-(3,5-dichloro-l-oxido-pyridin-4-yl)-4-difluoromethoxy-2- methoxy benzamide (Compound No. 4).

Also, in all the above representative examples wherever ethers are specified at a position ortho to the amide group, one skilled in the art could optionally deprotect them to their respective alcohols, for example deprotection of alkyl ethers (such as methyl or ethyl ethers) to their corresponding alcohols can be carried out with hydrochloric acid or hydrobromic acid in aqueous acetic acid or following the procedure a described in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2^nd Ed, John Wiley and Sons, New York, N. Y.,

In the above scheme, where specific bases, condensing agents, protecting groups, deprotecting agents, solvents, catalysts, temperatures, etc. are mentioned, it is to be understood that other bases, protecting groups, deprotecting agents, solvents, temperatures, 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.

Suitable salts of the compounds represented by the Formula I can also be prepared so as to solubilize the compound in aqueous medium for biological evaluations, as well as to be compatible with various dosage formulations and also to aid in the bioavailability of the compounds. Examples of such salts include pharmacologically acceptable salts such as inorganic acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic acid salts (for example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate). These salts may be prepared by various techniques, such as treating the compound with an equivalent amount of inorganic or organic, acid or base in a suitable solvent.

Particular illustrative compounds which may be produced by Schemes I, II and III, are listed below in Table I

Table I

Because of their valuable pharmacological properties, the compounds described herein may be administered to an animal for treatment orally, or by a parenteral route. The pharmaceutical compositions described herein can be produced and administered in dosage units, each unit containing a certain amount of at least one compound described herein and/or at least one physiologically acceptable addition salt thereof. The dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity. The compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient. The compounds described herein can be produced and formulated as their enantiomers, diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as metabolites having the same type of activity. Pharmaceutical compositions comprising the molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipient can also be produced.

The examples mentioned below demonstrate general synthetic procedures, as well as specific preparations of particular compounds. The examples are provided to illustrate the details of the invention and do not limit the scope of the present invention. EXPERIMENTAL

Example 1: Synthesis of 5-cvclopropylmethoxy-N-(3,5-dichloropyridin-4-yl^')-4- difluoromethoxy-2-methoxy benzamide (Compound No. 1) Step a: 4,5-dihydroxy-2-methoxy benzaldehyde

To the compound 2-methoxy-4,5-methylenedioxy benzaldehyde (available commercially) (4 g, 0.022 mol) was added phosphorous pentachloride (13.72 g, 0.066 mol) and stirred the reaction mixture for 3 hours at 8O⁰C. The reaction mass was poured in water with constant stirring and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtained was triturated with a mixture of isopropanol (10 ml) and hexane (20 ml). The reaction mixture was filtered and dried under reduced pressure to furnish the title compound. Yield = 0.4 g. ¹H NMR (DMSO-d₆):δ 3.79 (s, 3H), 6.54 (s, IH), 7.06 (s, IH), 9.2 (bs, IH), 10.1 (s, IH), 10.3 (bs, IH); Mass (M⁺+l): 169.15.

Step b: 4-(Benzyloxy)-5-hydroxy-2-methoxy benzaldehyde

To a solution of the compound obtained from step a above (30 g, 0.17 mol) in dimethyl sulphoxide (210 ml), was added pulverized potassium hydroxide (9.6 g, 0.17 mol) and stirred at room temperature for 20 minutes. To it was added benzyl chloride (20.4 ml, 0.176 mol) and stirred the reaction mixture at 70⁰C for 5 hours followed by addition of next lot of benzyl chloride (2.0 ml). The resulting reaction mixture was again stirred for 1 hour at 7O⁰C. The reaction contents were cooled to room temperature and subsequently poured into water. The product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using dichloromethane as eluent to furnish the title compound. Yield = 18 g.

¹R NMR (CDCl₃):δ 3.85 (s, 3H), 5.20 (s, 2H), 5.38 (bs, IH), 6.54 (s, IH), 7.30-7.42 (m, 6H), 10.29 (s, IH); Mass (M⁺+l): 259.1.

Step c: 4-Benzyloxy-5-(cyclopropyImethoxy)-2-methoxy benzaldehyde

To a solution of the compound obtained from step b above (10 g, 0.0387 mol) in dimethylsulphoxide (65 ml), was added pulverized potassium hydroxide (2.47 g, 0.044 mol) and stirred for 20 minutes followed by the addition of cyclopropylm ethyl bromide (5.2 g, 0.0391 mol). The reaction mixture was stirred at 5O⁰C for 3 hours followed by cooling it to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with sodium hydroxide (5%), water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to furnish the title compound. Yield = 11.5 g. ¹H NMR (CDCl₃):δ 0.33-0.36 (m, 2H), 0.59-0.65 (m, 2H), 1.26-1.34 (m, IH), 3.81 (s, 3H), 3.87-3.89 (d, 2H), 5.25 (s, 2H), 6.5 (s, IH), 7.31-7.46 (m, 6H), 10.27 (s, IH); Mass (M⁺+l): 312. Step d: 5-(Cyclopropylmethoxy)-4-hydroxy-2-methoxy benzaldehyde

The compound obtained from step c above (4.5 g, 0.0144 mol) was dissolved in ethyl acetate (90 ml) followed by the addition of palladium on carbon (10% w/w, 0.8 g). Hydrogenation was carried out under hydrogen atmosphere at 45°C for 5 hours. The reaction mixture was filtered through celite pad and solvent was evaporated under reduced pressure. The residue thus obtained was triturated with a mixture of hexane (20 ml) and isopropylalcohol (5 ml) to furnish the title compound. Yield = 2.5 g. ¹H NMR (CDCl₃):δ 0.31-0.36 (m, 2H), 0.62-0.68 (m, 2H), 1.23-1.28 (m, IH), 3.87 (s, 3H), 3.89 (bs, 2H), 6.40 (s, IH), 6.59 (s, IH), 7.30 (s, IH), 10.28 (s, IH); Mass (M⁺+l): 223.0.

Step e: 5-(Cyclopropylmethoxy)-4-(difluoromethoxy)-2-methoxy benzaldehyde

Route I: To a solution of the compound obtained from step d above (4.0 g, 0.018 mol) in dimethylformamide (28 ml) was added cesium carbonate (5.9 g, 0.018 mol) and stirred the mixture for 15 minutes at 27°C followed by the addition of methyl chlorodifluoroacetate (3.3 g, 0.0229 mol). The resulting reaction mixture was stirred at 80°C for 3 hours followed by cooling it to room temperature. The reaction mixture was poured into water and extracted the product with ethyl acetate. The solvent was removed under reduced pressure and the residue thus obtained was purified by column chromatography to furnish the title compound. Yield = 1.1 g.

Route II: To a solution of the compound obtained from step d above (0.1 g, 0.00045 mol) in dimethylsulphoxide was added pulverized potassium hydroxide (0.063g, 0.0012mole) and potassium iodide (O.lg, 0.0006 mole). Chlorodifluoromethane was bubbled through it and stirred the reaction mixture for 2 hours followed by the addition of , sodium hydroxide (0.5g, 0.0125 mol). The reaction mixture was again stirred for 3 hours and subsequently poured into water. The product was extracted with ethyl acetate, washed the organic layer with sodium hydroxide solution (5%) and water, dried over anhydrous sodium sulphate and evaporated the solvent under reduced pressure to furnish the title compound. Yield = 0.6 g.

¹H NMR (CDCl₃):δ 0.33-0.34 (m, 2H), 0.61-0.65 (m, 2H), 1.23-1.30 (m, IH), 3.8-3.92 (m, 5H), 6.81 (t, IH), 6.83 (s, IH), 7.41 (s, IH), 10.37 (s, IH).

Step f: 5-(Cyclopropylmethoxy)-4-difluoromethoxy-2-methoxy benzoic acid

The compound obtained from step e above (1.1 g, 0.004 mol) in acetic acid (5.5 ml), was added sulfamic acid (0.7 g) and cooled the reaction mixture to 10⁰C followed by the addition of sodium chlorite solution dropwise (0.8 g in 1.65 ml H₂O). The reaction mixture was stirred for 20 minutes in ice bath followed by stirring it at 27°C for approx 2 hours. The reaction contents were poured into water (50 ml) and extracted with ethyl acetate (150 ml). The solvent was evaporated under reduced pressure to furnish the title compound. Yield = 1.0 g.

¹H NMR (CDCl₃):δ 0.32-0.37 (m, 2H), 0.62-0.66 (m, 2H), 1.24-1.30 (m, IH), 3.88-3.91 (d, 2H), 4.04 (s, 3H), 6.83 (t, IH), 6.90 (s, IH), 7.75 (s, IH), 10.68 (bs, IH); Mass (M⁺+l): 289.

Step g: 5-Cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-2- methoxy benzamide (Compound No. 1)

To a solution of the compound obtained from step/above (1.0 g, 0.0035 mol) in toluene (6.6 ml) was added thionyl chloride (8.32 g, 0.0699 mol) and toluene (6.6 ml) and stirred for 2 hours at 85⁰C. Excess of thionyl chloride and toluene were distilled off under reduced pressure. The acid chloride thus obtained was dissolved in tetrahydrofuran (5 ml) and this mixture was added dropwise to an already 15 minutes stirred mixture of 3,5- dichloro-4-amino pyridine (0.7 g, 0.0043 mol) and sodium hydride (60%, 0.38 g, 0.0095 mol) in tetrahydrofuran (5 ml) at 15⁰C. The reaction mixture was stirred for approximately 2 hours and subsequently poured the reaction mass into water (50 ml) with constant stirring. It was acidified with hydrochloric acid (3 ml) and extracted the product with ethyl acetate, washed with water, dried over anhydrous sodium sulphate and evaporated the solvent under reduced pressure. The residue thus obtained was crystallized from a mixture of isopropanol (3 ml) and dichloromethane (3 ml) followed by the addition of charcoal (30 mg) in isopropyl alcohol to furnish the title compound. The compound was again recrystallised from isopropanol (3 ml). Yield = 0.34 g. ¹H NMR (CDCl₃):δ 0.33-0.38 (m, 2H), 0.62-0.68 (m, 2H), 1.22-1.30 (m, IH), 3.93 (d,

2H), 4.05 (s, 3H), 6.84 (t, IH), 6.93 (s, IH), 7.88 (s, IH), 8.57 (s, 2H), 9.88 (s, IH); Mass (M⁺+l): 433.1. Example 2: Synthesis of 3-Cvclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4- difluoromethoxy-2-methoxy benzamide (Compound No. 3) Step a: 4-methoxy-benzo[l,3,2]dioxaborol-2-ol

To 3-methoxycatechol (3 g, 0.021 mol) (available commercially) was added borax (8.0 g, 0.021 mol) and water (150 ml) and stirred for 3 hours at 45-50°C. Water was evaporated under reduced pressure. Traces of water were removed azeotropically with toluene (150 ml) under reduced pressure. The residue thus obtained was diluted with dimethylformamide followed by evaporating it under reduced pressure to furnish the title compound. Yield = 8.5 g. ¹H NMR (D₂O):δ 3.88 (s, 3H), 6.49-6.74 (m, 3H).

Step b: 3,4-Dihydroxy-2-methoxy benzaldehyde

To dimethylformamide (260 ml) was added phosphorous oxychloride dropwise maintaining the temperature below 7O⁰C and stirred at room temperature for 1 hour. To it was added the compound obtained from step a above (94 g) in small lots keeping the temperature below 6O⁰C and stirred for 3 hours at 60⁰C. The reaction mixture was cooled to room temperature and subsequently poured into water (1000 ml) and hydrochloric acid (50 ml) solution maintaining the temperature below 55°C. The mixture was stirred at room temperature for approx. 2 hour and extracted with ethyl acetate. The mixture of isomers was purified by column chromatography using mixture of methanol (1%) and chloroform (99%) as eluent to furnish the title compound. Yield = 4.2 g.

¹H NMR (CDC1₃):5 3.99 (s, 3H), 5.72 (s, IH), 5.93 (s, IH), 6.81-6.84 (d, IH), 7.35-7.38 (d, IH), 10.07 (s, IH); Mass (M⁺+l): 169.

Step c: 4-(Difluoromethoxy)-3-hydroxy-2-methoxy benzaldehyde

To a solution of the compound obtained from step b above (0.5 g, 0.0029 mol) in dimethyl formamide (7 ml), was added cesium carbonate (0.8 g, 0.00246 mol) and stirred the reaction mixture at room temperature for 20 minutes followed by the addition of methyl chlorodifluoroacetate (0.5 g, 0.00342 mol). The mixture was again stirred at 65- 7O⁰C for 3 hours and was subsequently poured into water. The product was extracted with ethyl acetate, washed with water, borax solution (10%) and again with water, dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. The residue thus obtained was stirred in a mixture of hexane (20 ml) and isopropyl alcohol (2 ml). The reaction mixture was filtered and evaporated the solvent under reduced pressure to furnish the title compound. Yield = 170 mg.

¹U NMR (CDCl₃):δ 4.06 (s, 3H), 6.43-6.92 (t, IH), 6.99-7.02 (d, IH), 7.39-7.42 (d, IH), 10.28 (s, IH); Mass (M⁺+l): 218.9.

Step d: 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)-2-methoxy benzaldehyde

To a solution of compound obtained from step c above (0.55 g, 0.0025 mol) in dimethyl sulphoxide (10 ml), was added pulverized potassium hydroxide (0.132 g, 0.00233 mol) and stirred for 20 minutes followed by the addition of cyclopropylmethyl bromide (0.33 g, 0.0024 mol). The reaction mixture was stirred for 2 hours at room temperature and subsequently poured into water and extracted with ethyl acetate. The organic layer was washed with sodium hydroxide (5%) and water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was stirred in hexane and filtered. The solvent was evaporated under reduced pressure to furnish the title compound. Yield = 0.56 g.

¹H NMR (CDC1₃):6 0.28-0.32 (m, 2H), 0.59-0.65 (m, 2H), 1.26-1.31 (m, IH), 3.89-3.91 (d, 2H), 4.08 (s, 3H), 6.45-6.94 (t, IH), 6.97-6.99 (d, IH), 7.57-7.60 (d, IH), 10.32 (s, IH); Mass (M⁺+l): 273.

Step e: 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)-2-methoxy benzoic acid To a solution of the compound obtained from step d above (0.2 g, 0.00073 mol) and sulfamic acid (0.154 g, 0.00015 mol) in acetic acid at 8°C, was added sodium chlorite solution (0.16 g, 0.0017 mol in 0.5 ml OfH₂O) maintaining the temperature below 15°C. The resulting reaction mixture was stirred at 8°C for 1 hour and then at room temperature for 1 hour followed by the addition of water. The product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound. Yield = 220 mg.

¹H NMR (CDCl₃):δ 0.27-0.32 (m, 2H), 0.6-0.66 (m, 2H), 1.25-1.31 (m, IH), 3.88-3.9 (d, 2H), 4.16 (s, 3H), 6.42-6.92 (t, IH), 7.04-7.07 (d, IH), 7.89-7.92 (d, IH); Mass (M⁺+!): 289.2. Step f: 3-Cyclopropylmthoxy-N-(3,5-dichloropyridin-4-yI)-4-difluoromethoxy-2- methoxy benzamide (Compound No. 3)

To a solution of the compound obtained from step e above (220 mg, 0.000764 mol) in toluene (3.0 ml), was added thionyl chloride (0.6 ml, 0.008 mol) and stirred at 80⁰C for approx. 2 hours. Excess of thionyl chloride and toluene were evaporated under reduced pressure. The residue thus obtained was dissolved in tetrahydrofuran (3 ml) and the resulting mixture was added dropwise to an already 15 minutes stirred mixture of 3,5- dichloro-4-aminopyridine (154 mg, 0.00095 mol) and sodium hydride (60%, 0.083 g, 0.002 mol) in tetrahydrofuran (3 ml) at 10-12⁰C. The reaction mixture was stirred at 10⁰C for 1 hour and subsequently poured into water (50 ml). The product was extracted with ethyl acetate, washed with hydrochloric acid solution (5%), water and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound. Yield = 260 mg.

¹H NMR (CDCl₃):δ 0.32-0.34 (m, 2H), 0.63-0.66 (m, 2H), 1.26-1.31 (m, IH), 3.91-3.93 (d, 2H), 4.21 (s, 3H), 6.44-6.94 (t, IH), 7.06-7.09 (d, IH), 7.97-8.00 (d, IH), 8.58 (s, 2H), 9.89 (s, IH); Mass (M⁺+l): 433.

Example 3: Synthesis of 3-cycIopropylmethoxy-N-(3,5-dichIoro-l-oxido-pyridin-4- yl)-4-difluoromethoxy-2-methoxy benzamide (Compound No. 4)

The compound No. 3 (140 mg, 0.00032 mol) was dissolved in a mixture of dichloromethane (1 ml) and methanol (1 ml) followed by the addition of magnesium monoperoxyphthalate hexahydrate (0.32 g, 0.00064 mol). The reaction mixture was stirred at room temperature for 6 hours followed by the addition of magnesium monoperoxyphthalate hexahydrate (0.2 g). This procedure was repeated four times. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with ammonium acetate solution and water. The solvent was evaporated under reduced pressure to furnish the title compound. Yield = 100 mg. ¹H NMR (CDC1₃):5 0.26-0.29 (m, 2H), 0.57-0.62 (m, 2H), 1.21-1.26 (m, IH), 3.86-3.91 (d, 2H), 4.15 (s, 3H), 6.4-6.89 (t, IH), 7.02-7.05 (d, IH), 7.90-7.93 (d, IH), 8.26 (s, 2H), 9.70 (s, IH); Mass (M⁺+l): 449. Example 4: Synthesis of 5-Cyclopropylmethoxy-N-(3,5-dichloro-l-oxido-pyridin-4- yl)-4-difluoromethoxy-2-methoxy benzamide (Compound No. 2)

The compound No. 1 (0.2 g, 0.00046 mol) was dissolved in a mixture of dichloromethane (1 ml) and methanol (1 ml) followed by the addition of magnesium monoperoxy- phthalate hexahydrate (MMPP) (0.457 g) and stirred for 24 hours at 40°C. To the resulting reaction mixture was added dichloromethane (1 ml), methanol (1 ml) and magnesium monoperoxyphthalate hexahydrate (0.248 g) and stirred for 12 hours. This process was repeated one more time. To the resulting reaction mixture was added magnesium monoperoxyphthalate hexahydrate (MMPP) (0.248 g) and stirred the reaction mixture for 24 hours with a constant addition of methanol (1 ml) after every 4 hours. The reaction mixture was diluted with water and extracted the product with ethyl acetate (50 ml). The organic layer was washed with ammonium acetate solution (25%), water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was recrystallised using a mixture of isopropanol (1.5 ml) and dichloromethane (2 ml) to furnish the title compound. Yield = 140 mg.

¹H NMR (CDCl₃):δ 0.34-0.38 (m, 2H), 0.62-0.69 (m, 2H), 1.22-1.31 (m, IH), 3.91-3.93 (d, 2H), 4.05 (s, 3H), 6.85 (t, 3H), 6.94 (s, IH), 7.86 (s, IH), 8.26 (s, 2H), 9.67 (s, IH); Mass (M⁺+l): 449.2.

PDE-IV Enzyme Assay The efficacy of compounds as PDE-4 inhibitor was determined by an enzyme assay (Burnouf et al.; J. Med. Chem., 2000, 43:4850-4867). The PDE-4 enzyme source used was U937 cell cytosolic fraction prepared by sonication. The enzyme reaction was carried out, with the cytosolic fraction as the enzyme source, in the presence of cAMP (1 μM) at 30⁰C in the presence or absence of NCE for 45 -60 min. An aliquot of this reaction mixture was taken further for the ELISA assay to determine level of cAMP in the sample. The concentration of the cAMP in the sample directly correlates with the degree of PDE-4 enzyme inhibition. Results were expressed as percent control and the IC₅₀ values of test compounds 1 and 2 (three test repetitions each) were found to be approximately 1.9 (±0.7) and 2.3 (±0.9) nM, respectively. The values for rolipram (7 repetitions) and rofiumilast (two repetitions) were 463 (±103 and 0.051 (±0.028) nM, respectively.

Claims

WE CLAIM: 1. A compound having the structure of Formula I,

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides wherein Ri is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl; R₂ is aryl, heteroaryl, heterocyclyl or cycloalkyl; and R₃ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl. 2. A compound according to claim 1, wherein Ri is alkyl, R₂ is heteroaryl substituted with one or more of halogen and R₃ is cycloalkylalkyl or alkyl substituted with one or more of halogen. 3. A compound according to claim 2, wherein R] is methyl, R₂ is dichloropyridyl, R₃ is difluoromethyl or cyclopropylmethyl. 4. A compound which is selected from 5-cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-difluoro methoxy-2-methoxy benzamide (Compound No. 1), 5-Cyclopropylmethoxy-N-(3,5-dichloro-l-oxido-pyridin-4-yl)-4-difluoromethoxy-2- methoxy benzamide (Compound No.

2), 3-Cyclopropylmethoxy-N-(3,5-dichloropyridine-4-yl)-4-difluoromethoxy-2-methoxy benzamide (Compound No. 3),

3-Cyclopropylmethoxy-N-(3,5-dichloro- 1 -oxido-pyridin-4-yl)-4-difluoromethoxy-2- methoxy benzamide (Compound No.

4), or pharmaceutically acceptable salts, or solvates thereof.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with pharmaceutically acceptable carriers, excipients or diluents.

6. A method of treating an animal or human suffering from AIDS, asthma, arthritis, bronchitis, chronic obstructer 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 an animal or human comprising administering to said animal or human a therapeutically effective amount of a compound according claim.

7. A method of preventing, inhibiting or suppressing inflammatory condition in an animal or human comprising administering to said animal or human a therapeutically effective amount of a compound according to claim 1.

8. A method of preventing, inhibiting or suppressing inflammatory disease in an animal or human comprising administering to said animal or human a therapeutically effective amount of the pharmaceutical composition according to claim 7.

9. A method for preparing a compound of Formula XII and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N- oxides

wherein R_p is alkyl, alkenyl or alkynyl; P is aralkyl (for example benzyl) or alkyl (for example methyl, isopropyl or t-butyl); R_k is alkyl substituted with cycloalkyl, aryl, heterocyclyl or heteroaryl; and R₂ is aryl, heteroaryl, heterocyclyl or cycloalkyl, wherein the method comprises: a) deprotecting a compound of Formula II to give a compound of Formula III;

b) O-protecting the compound of Formula III with a compound of Formula P-hal (wherein P is aralkyl or alkyl) to give a compound of Formula IV;

c) reacting the compound of Formula IV with a compound of Formula R_k-hal (wherein R_k is alkyl substituted with cycloalkyl, aryl, heterocyclyl or heteroaryl) to give a compound of Formula V; d) deprotecting the compound of Formula V to give a compound of Formula VI;

Formula Vl

e) reacting the compound of Formula VI with a compound of Formula VII (wherein X is -H or -COOCH₃) to give a compound of Formula VIII; VII

Formula VIII

f) oxidizing the compound of Formula VIII to give a compound of Formula IX;

g) converting the compound of Formula IX to a compound of Formula X (wherein hal is Cl, Br or I); and

Formula X

H₂NR₂ Formula Xl

h) reacting the compound of Formula X with a compound of Formula XI (wherein R₂ is the same as defined earlier) to give a compound of Formula XII.

10. A method for preparing a compound of Formula XIX and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N- oxides

Formula XX wherein P is aralkyl (for example benzyl) or alkyl (for example methyl, isopropyl or t-butyl); R_k is alkyl substituted with cycloalkyl, aryl, heterocyclyl or heteroaryl; and R₂ is aryl, heteroaryl, heterocyclyl or cycloalkyl, wherein the method comprises: a) formylating a compound of Formula XIII to give a compound of Formula XIV;

Formula XlII

b) reacting the compound of Formula XIV with a compound of Formula VII (wherein X is -H or -COOCH₃) to give a compound of Formula XV;

F₂OCXXXH₃ Formu^laVII

Formula XW c) reacting the compound of Formula XV with a compound of Formula R_k-hal to give a compound of Formula XVI;

Formula XVI d) oxidizing the compound of Formula XVI to give a compound of Formula XVII;

Formula XVII e) converting the compound of Formula XVII to a compound of Formula XVIII (wherein hal is Br, Cl or I); and

Formula Will

F) reacting the compound of Formula XVIII with a compound of Formula XI (H₂NR₂) to give a compound of Formula XIX.

11. A method for preparing a compound of Formula XXI and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N- oxides

wherein

Hal is halogen (Cl, Br or I);

Ri is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl; and

R₃ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl, the method comprising N-oxidizing a compound of Formula XX to give the compound of Formula XXI.