WO2004111044A1 - Tricyclic compounds useful for the treatment of inflammatory and allergic disorders:process for their preparation - Google Patents

Abstract

The present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diasteromers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them. The present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the formula (1), their analogs, their tautomers, their enantiomers, their diasteromers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate oxides, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.

Description

TRICYCLIC COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS : PROCESS FOR THEIR PREPARATION

Field of the Invention

This application claims priority to Indian Provisional Patent Application to 631/MUM/2003 (46/MUM-WTO/2003) filed on June 17, 2003, which is herein incorporated by reference in it entirety.

The present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diasteromers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them. The present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the formula (1), their analogs, their tautomers, their enantiomers, their diasteromers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate oxides, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.

The present invention provides a compound of formula (1)

(1) wherein;

R¹, R² and R³ may be same or different and are independently selected for each occurance from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -NR⁵R⁶, -C(=L)-R⁵, -C(O)-R^a , -C(O)O-R^a, -C(O)NR^aR^b , -S(0)_m-R^a, -S(O)_m-NR^aR^b, nitro, -OH, cyano, , formyl, acetyl, halogen, -OR^a, -SR^a, protecting groups or when two R³ substitutents ortho to each other, may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; wherein R⁵ and R⁶ may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, halo, -OH, cyano, -C(O)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_m- R^a, -S(O)_m-NR^aR^b, -C(=NR^a)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b , -C(=S)-R^a, - N=C(R^aR^b), -NR^aR^b, -OR , -SR^a, protecting groups or R⁵ and R⁶ to each other may be joined to a form a optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S; Wherein R^a, R^b may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(O)-R^a, -C(0)O-R^a, -C(0)NR^aR^b , - S(0)_m-R^a, -S(O)_m-NR^aR^b, - R^aR^b, ,-OR^a, -SR^a;

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; Preferably Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents (one or more) may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino wherein L represents O, S or NR ; wherein R^a represents in the above; wherein P represents O or S; wherein n represents 0 - 4; X is O, S(O)_morNR^a;

Wherein m is 0, 1 or 2; Y is -C(=A)C(=B)NR⁴, wherein A represents O, S or NR wherein B represents O, S or NR^a

R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR^a, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring;

The present invention also relates to a process for the preparation of the above said novel heterocyclic compounds of the formula (1) as defined above. The compounds of general formula (1) more particularly, down regulate or inhibit the production of TNF-α as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. The compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD)

Back ground of the Invention Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production. The airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component. The magnitude of asthmatic reactions is correlated with the number of eosinophils present in lungs.

The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When activated, they synthesize and release inflammatory cytokines such as IL-1, IL-3, TNF-α and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and bronchoconstriction. Tumor necrosis factor (TNF-α) was also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states. It has been well demonstrated that TNF-α production in pro-inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP). This second messenger is regulated by the phosphodiesterase (PDE) family of enzymes. The phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophilis are believed to be a critical proinflammatory target for asthma, identification of the expression of the PDE 4 gene family in eosinophils led to PDE 4 as potential therapeutic target for asthma [Rogers, D.F., Giembycz, M.A., Trends Pharmacol. Sci, 19, 160-164(1998); Barnes, P.J., Trends Pharmacol. Sci, 19, 415-423 (1998) herein incorporated by reference in their entirety]. The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [Soderling, S.H., Bayuga, S.J., and Beavo, J.A., Proc. Natl. Acad. Sci., USA, 96, 7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J. Biol. Chem., 274, 18438-18445 (1999) herein incorporated by reference in their entirety]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes.

Phosphodiesterase type 4 (PDE4) is an enzyme which regulates activities in cells which lead to inflammation in the lungs. PDE4, a cAMP-specific and Ca⁺²-independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes. The association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors [Trophy,TJ., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated by reference in their entirety]. Excessive or unregulated TNF-α production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions; septic shock, endotoxic shock, respiratory distress syndrome and bone resorption diseases since TNF-α also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, 1, 211-214 (1995) and ibid., 244-248 herein incorporated by reference in their entirety] .

Strong interest in drugs capable of selective inhibition of PDE 4 is due to several factors. Tissue distribution of PDE-4 suggests that pathologies related to the central nervous and immune systems could be treated with selective PDE-4 inhibitors. In addition, the increase in intracellular cAMP concentration, the obvious biochemical consequence of PDE-4 inhibition, has been well characterized in immuno-competent cells where it acts as a deactivating signal. Recently the PDE4 family has grown to include four subtypes - PDE4A to PDE4D, each encoded by a distinct gene (British Journal of Pharmacology; 1999; v.128; p.1393- 1398), herein incorporated by reference in its entirety.

It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro- inflammatory cytokines such as TNF-cu. Since eosinophilis are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE-4 gene family in eosinophils led to the PDE-4 as a potential therapeutic target for asthma. The usefulness of several PDE-4 inhibitors, unfortunately, is limited due to their undesirable side effect profile which include nausea and emesis (due to action on PDE-4 in the central nervous system) and gastric acid secretion due to action on PDE-4 in parietal cells in the gut. Barnette, M.S., Grous, M., Cieslinsky, L.B., Burman, M., Christensen, S.B., Trophy, T J., J. Pharmacol. Exp. Ther., 273,1396-1402 (1995) herein incorporated by reference in their entirety. One of the earliest PDE-4 inhibitors, Rolipram™, was withdrawn from clinical development because of its severe unacceptable side effect profile. Zeller E. et. al., Pharmacopsychiatr., 17, 188-190 (1984) herein incorporated by reference in its entirety. The cause of severe side effects of several PDE-4 inhibitor molecules in human clinical trials has recently become apparent. There exist two binding sites on mammalian PDE-4 at which inhibitor molecules may bind. Also PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M.M., Livi, G.P., Burman, M., Trophy, T.J., Mol. Pharmaco., 50, 891-899 (1996) herein incorporated by reference in their entirety]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE-4L inhibition. It was also found that human recombinant PDE-4 exists in 4 isoforms A, B, C and D [Muller, T., Engels, P., Fozard, J.R., Trends Pharmacol. Sci, 17, 294-298 (1996) herein incorporated by reference in its entirety]. Accordingly, compounds displaying more PDE-4D isoenzyme selectivity over the A, B or C are found to have fewer side effects than Rolipram [Hughes. B etal., Br. J. Pharmacol. 1996, 118, 1183-1191 herein incorporated by reference in their entirety]. Therefore, selective inhibitors of PDE-4 isozymes would have therapeutic effects in inflammatory diseases such as asthma and other respiratory diseases. Although several research groups all over the world are working to find highly selective PDE-4 isozyme inhibitors, so far success has been limited. Various compounds have shown PDE-4 inhibition.

AR1FLO A CDP-840 B D-4418 C

Roflumilast D Bay-19-8004 E

SmithKline Beecham's "Arifio" which has the formula A, Byk Gulden's Roflumilast which has the formula D and Bayer's Bay-19-8004 which has the formula E have reached advanced stage of human clinical trials. Other compounds which have shown potent PDE-4 inhibitory activity include Celltech's CDP-840 of the formula B, Schering Plough's D-4418 of the formula C, Pfizer' s 5CP-220,629 which has the formula F, Parke Davis's PD-168787 which has the formula G and Wyeth's Filaminast which has the formula H. However, recently due to efficacy and side effects problems, Arifio, CDP- 840 and Bay-19-8004 were discontinued from clinical trials as a treatment for asthma. Other compounds of the formulae C and F are presently undergoing phase- 1 clinical trials.

During the course of our research aimed at the development of novel anti-asthmatic compounds having potential PDE4 inhibitory activity, we have filed a WTO patent application in India bearing No. 922/MUM/2002 dated October 23, 2002 and PCT application No PCT/1B03/04442 dated October 8, 2003, incorporated herein by reference in their entireties, for a novel series of tricyclic compounds useful for the treatment of inflammatory and allergic disorders.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel heterocyclic compounds of the general formula

(1) wherein;

R¹, R² and R³ may be same or different and are independently selected for each occurance from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -NR⁵R⁶, -C(=L)-R⁵, -C(O)-R^a , -C(O)0-R^a, -C(0)NR^aR^b , -S(O)_m-R^a, -S(O)_ra-NR^aR^b, nifro, -OH, cyano, , formyl, acetyl, halogen, -OR^a, -SR^a, protecting groups or when two R³ substitutents ortho to each other, may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; wherein R⁵ and R⁶ may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, halo, -OH, cyano, -C(O)-R^a, -C(0)O-R^a, -C(0)NR^aR^b, -S(0)_m- R^a, -S(0)_m-NR^aR^b, -C(=NR^a)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b , -C(=S)-R^a, - N=C(R^aR^b), -NR^aR^b, -OR^a, -SR^a, protecting groups or R⁵ and R⁶ to each other may be joined to a form a optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S; Wherein R^a, R may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(O)-R^a, -C(O)O-R^a, -C(0)NR^aR^b , - S(0)_m-R^a, -S(0)_m-NR^aR^b, -NR^aR^b, ,-OR^a, -SR^a;

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;

Preferably Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents (one or more) may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino wherein L represents O, S or NR^a; wherein R^a represents in the above; wherein P represents O or S; wherein n represents 0 -4; X is O, S(O)_mor R^a;

Wherein m is 0, 1 or 2; Y is -C(=A)C(=B)NR⁴, Wherein A represents O, S or NR^a

Wherein B represents O, S or NR^a

Preferably Y is C(=O)C(=0)NR⁴

R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR^a, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring;

The present invention also relates to a process for the preparation of the above said novel heterocyclic compounds of the formula (1) as defined above. The compounds of general formula (1) more particularly, down regulate or inhibit the production of TNF-α as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. The compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD)

DETAILED DESCRIPTION OF THE INVENTION The term 'alkyl' refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like . The term "Alkenyl " refers to aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms in the e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.

The term " Alkynyl" refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, butnyl and the like. The term "Alkoxy" denotes alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH₃, -OC₂H₅ and the like.

The term "Alkylcarbonyl" denotes alkyl group as defined above attached via carbonyl linkage to the rest of the molecule. Representative examples of those groups are -C(0)CH₃, - C(0)C₂H₅ and the like.

The term "Alkoxycarbonyl" denotes alkoxy group as defined above attached via carbonyl linkage to the rest of the molecule. Representative examples of those groups are -C(0)-OCH₃, - C(O)-OC₂H₅ and the like. The term "Alkylcarbonyloxy" denotes alkylcarbonyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are -0-C(O)CH₃, - 0-C(0)C₂H₅ and the like.

The term "Alkylamino" denotes alkyl group as defined above attached via amino linkage to the rest of the molecule. Representative examples of those groups are - NH₂CH₃, - -NH(CH₃)₂ , -N(CH₃)₃ and the like.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicycic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or spirobicyclic groups e.g sprio (4,4) non-2-yl. The term " cycloalkylalkyl" refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms directly attached to alkyl group which then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure, such as cyclopropylmethyl, cyclobuylethyl, cyclopentylethyl, and the like. The term " cycloalkenyl" refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms with atleast one carbon- carbon double bond such as cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.

The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅, -C₂H₅C₆H₅ and the like. The term "Heterocyclic ring" refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purpose of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated ot aromatic. Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofumyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamo holinyl sulfoxide thiamorpholinyl sulfone, dioxaphospholanyl , oxadiazolyl , chromanyl, isochromanyl and the like.

The term "Heteroaryl" refers to heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "Heteroarylalkyl" refers to heteroaryl ring radical as defined above directly bonded to alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.

The term "Heterocyclyi" refers to a heterocylic ring radical as defined above. The heterocylyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "Heterocyclylalkyl" refers to a heterocylic ring radical as defined above directly bonded to alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure. The term "cyclic ring " refers to a cyclic group containing 3-10 carbon atoms

The term "protecting group" refers to CBZ or BOC and the like The term "Halogen" refers to radicals of Fluorine, Chlorine, Bromine, Iodine

The substituents in the 'substituted alkyl', 'substituted alkoxy' 'substituted alkenyl' ' substituted alkynyl' 'substituted cycloalkyl' substituted cycloalkylalkyl' substituted cyclocalkenyl' 'substituted arylalkyl' 'substituted aryl' 'substituted heterocyclic ring', 'substituted heteroaryl ring,' 'substituted heteroarylalkyl', 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl', 'substituted cyclic ring' 'substituted alkylcarbonyl', 'substituted alkylcarbonyloxy' and 'substituted carboxylic acid' may be the same or different which one or more selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, amino, nitro, oxo (=O), thio (=S), or optionally substituted groups selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclic ring, -COOR^x, - C(0)R\ -C(S)R^X, -C(0)NR^xR^y, -C(0)ONR^xR^y, -NR^xCONR^yR^z, -N(R^x)SOR^y, - N(R^x)S0₂R^y, -(=N-N(R^x)R^y), - NR^xC(0)OR^y, -NR^xR^y, -NR^xC(O)R^y-, -NR^xC(S)R^y - NR^xC(S)NR^yR^z, -SONR^xR^y-, -SO₂NR^xR^y-, -OR^x, -OR^xC(O)NR^yR^z, -OR^xC(0)OR^y-, - OC(0)R^x, -OC(O)NR^xR^y, -R^xNR^yR^z, -R^xR^yR^z, -R^XCF₃, -R^xNR^yC(O)R^z, -R^xOR^y, - R^xC(0)OR^y, -R^xC(0)NR^yR^z, -R^xC(0)R^x, -R^xOC(O)R^y, -SR^X, -SOR^x, -S0₂R^x, - ON0₂,(wherein R^x, R^y and R^z in each of the above groups can be hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl substituted or unsubstitued heterocyclic ring, substituted or unsubstitued heterocyclylalkyl, substituted or unsubstitued heteroaryl or substituted or unsubstitued heteroarylalkyl ) Another object of the invention is a method of treating inflammatory conditions and immune disorders in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula 1. Preferred inflammatory disorders are chosen from the group consisting of asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uteltis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis and chronic inflammation. Further preferred are allergic inflammatory conditions.

Further preferred inflamatory disorders include, but are not limited to, chronic abstractive pulmonary disease (COPD) and asthma.

Further preferred are inflammatory conditions and immune disorders selected from the group consisting of inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin and heart.

Further preferred are inflammatory conditions chosen from the group consisting of bronchial asthma, nepritis, and allergic rhinitis.

Another object of the invention is a method for abating inflammation in an affected organ or tissue including delivering to the organ or tissue a therapeutically effective amount of a compound represented by a compound according to Formula 1.

Another object of the invention is a method of treating diseases of the central nervous system in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula 1.

Preferred diseases of the central nervous system are chosen from the group consisting of depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease. Another object of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula 1.

"Treating" or "treatment" of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or

(3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The four classic symptoms of acute inflammation are redness, elevated temperature, swelling, and pain in the affected area, and loss of function of the affected organ. Symptoms and signs of inflammation associated with specific conditions include:

• rheumatoid arthritis- pain, swelling, warmth and tenderness of the involved joints; generalized and morning stiffness;

• insulin-dependent diabetes mellitus- insulitis; this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease, and cerebrovascular disease;

• autoimmune thyroiditis- weakness, constipation, shortness of breath, puffiness of the face, hands and feet, peripheral edema, bradycardia;

• multiple sclerosis- spasticity, blurry vision, vertigo, limb weakness, paresthesias; • uveoretinitis- decreased night vision, loss of peripheral vision;

• lupus erythematosus- joint pain, rash, photosensitivity, fever, muscle pain, puffiness of the hands and feet, abnormal urinalysis (hematuria, cylinduria, proteinuria), glomerulonephritis, cognitive dysfunction, vessel thrombosis, pericarditis; • scleroderma- Raynaud's disease; swelling of the hands, arms, legs and face; skin thickening; pain, swelling and stiffness of the fingers and knees, gastrointestinal dysfunction, restrictive lung disease; pericarditis,; renal failure; • other arthritic conditions having an inflammatory component such as rheumatoid spondylitis, osteoarthritis, septic arthritis and polyarthritis- fever, pain, swelling, tenderness;

• other inflammatory brain disorders, such as meningitis, Alzheimer's disease, AIDS dementia encephalitis- photophobia, cognitive dysfunction, memory loss;

• other inflammatory eye inflammations, such as retinitis- decreased visual acuity;

• inflammatory skin disorders, such as , eczema, other dermatites (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sun rays and similar UV sources)- erythema, pain, scaling, swelling, tenderness; • inflammatory bowel disease, such as Crohn's disease, ulcerative colitis- pain, diarrhea, constipation, rectal bleeding, fever, arthritis;

• asthma- shortness of breath, wheezing;

• other allergy disorders, such as allergic rhinitis- sneezing, itching, runny nose

• conditions associated with acute trauma such as cerebral injury following stroke- sensory loss, motor loss, cognitive loss;

• heart tissue injury due to myocardial ischemia- pain, shortness of breath;

• lung injury such as that which occurs in adult respiratory distress syndrome- shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates; • inflammation accompanying infection, such as sepsis, septic shock, toxic shock syndrome- fever, respiratory failure, tachycardia, hypotension, leukocytosis;

• other inflammatory conditions associated with particular organs or tissues, such as nephritis (e.g., glomerulonephritis)-oliguria, abnormal urinalysis;

• inflamed appendix- fever, pain, tenderness, leukocytosis; • gout- pain, tenderness, swelling and erythema of the involved joint, elevated serum and/or urinary uric acid;

• inflamed gall bladder- abdominal pain and tenderness, fever, nausea, leukocytosis; • chronic obstructive pulmonary disease- shortness of breath, wheezing;

• congestive heart failure- shortness of breath, rales, peripheral edema; • Type II diabetes- end organ complications including cardiovascular, ocular, renal, and peripheral vascular disease ,lung fibrosis- hyperventilation, shortness of breath, decreased oxygenation;

• vascular disease, such as atherosclerosis and restenosis- pain, loss of sensation, diminished pulses, loss of function and alloimmunity leading to transplant rejection- pain, tenderness, fever.

Subclinical symptoms include without limitation diagnostic markers for inflammation the appearance of which may precede the manifestation of clinical symptoms. One class of subclinical symptoms is immunological symptoms, such as the invasion or accumulation in an organ or tissue of proinflammatory lymphoid cells or the presence locally or peripherally of activated pro-inflammatory lymphoid cells recognizing a pathogen or an antigen specific to the organ or tissue. Activation of lymphoid cells can be measured by techniques known in the art.

"Delivering" a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished , e.g., by local or by systemic administration of the active ingredient to the host.

"A subject" or "a patient" or "a host" refers to mammalian animals, preferably human.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, and the like; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, , benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.

Some of the representative compounds according to the present invention are specified below but should not construed to be limited thereto;

1. Nl-(3, 5-dichloro-4-pyridyl)-2-(4-methoxy dibenzo[έ,^furan-l-yl)-2- oxoacetamide

2. Nl-(4-pyridyl)-2-(4-methoxy dibenzo[&,(f|furan-l-yl)-2-oxoacetamide

3. N 1 -(3 -pyridyl)-2-(4-methoxy dibenzo [b, d] furan- 1 -yl)-2-oxoacetamide 4. Nl-(3, 5-dichloro-4-pyridyl)-2-(4-Ethoxy dibenzo[t>,^furan-l-yl)-2-oxoacetamide

5. Nl-(4-pyridyl)-2-(4-Ethoxy dibenzo[o_J ]furan-l-yl)-2-oxoacetamide

6. Nl-(3-pyridyl)-2-(4-Ethoxy dibenzo[t),^furan-l-yl)-2-oxoacetamide

7. N 1 -(3 ,5 -dichloro-4-pyridyl)-2-(4-isopropyloxy ibenzo [b, d] furan- 1 -yl)-2- oxoacetamide 8. Nl-(3, 5-dichloro-4-pyridyl)-2-(4-cyclopentyloxy dibenzo [t>,d] furan- l-yl)-2- oxoacetamide

9. N 1 -(4-pyridyl)-2-(4-cyclopentyloxy dibenzo [b, d] furan- 1 -yl)-2-oxoacetamide

10. Nl-(3-pyridyl)-2-(4-cyclopentyloxy dibenzo[Zj,< ]furan-l-yl)-2-oxoacetamide

11. Nl-(3, 5-dichloro-4-pyridyl)-2-(4-difluoromethoxy dibenzo[t,rf]furan-l-yl)-2- oxoacetamide

12. Nl-(4-pyridyl)-2-(4-difluoromethoxy dibenzo[t>,c |furan-l-yl)-2-oxoacetamide

13. NI -(3-pyridyl)-2-(4-difluoromethoxy dibenzo[&, d]furan- 1 -yl)-2-oxoacetamide and pharmaceutically acceptable salts of the preceding representative compounds

The compounds according to the invention may be prepared by the following processes.

The symbols P, Ar, X, Y, R¹, R², R³ and R⁴ when used in the formulae below are to be understood to present those groups described above in relation to formula (1) unless otherwise indicated

The present invention discloses a process for the preparation of compounds of general formula (1). r

The desired compounds of the formula la wherein Y is -COCONR⁴ and P, Ar, X, Y, R¹, R , R , R are as described in the general descπption, can be synthesized as described in the general synthetic scheme I. SYNTHETIC SCHEME I.

13 14 15

As shown in the above scheme I, the compound of the formula 10 (obtained from ref. J Org. Chem.; 1986; 51; 1821-1829) is alkylated using appropriate alkyl halide or alkyl mesylate or alkyl tosylate under standard basic conditions to obtain the intermediate of the general formula 11. The intermediate of the general formula 11 is then acylated to the intermediate of the formula 12 by appropriate acylation techniques practiced in the literature. Willegerodt-Kindler rearrangement of the intermediate of the general formula 12 provides the intermediate of the general formula 13 which is oxidized to the dicarbonyl ester intermediate 14 using appropriate oxidizing agent like selenium dioxide. The intermediate of the formula 14 is hydrolyzed using standard acidic or basic conditions reported in the literature to the dicarbonyl acid intermediate 15. The compounds of formula la are obtained by reacting the appropriately activated carboxylic acid (acid halide or mixed anhydride or active ester ) intermediate of the general formula 15 with the optionally substituted aryl or heteroaryl amines (ArNHR⁴) under appropriate basic conditions reported in the literature.

The desired compounds of the formula la obtained are then converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula la obtained are then converted into the free compounds

Alternatively, the desired compounds of the formula la wherein Y is -

COCONR⁴ and P, Ar, X, Y, R¹, R², R³, R⁴ are as described in the general description, can also be synthesized as described in the general synthetic scheme II.

SYNTHETIC SCHEME II.

As in scheme II, the intermediate of the formula 11 can be directly acylated under appropriate Lewis acidic condition with ethyl oxalyl chloride to the intermediate of the formula 14 which can then be converted to the desired compounds of the formula la as described in the synthetic scheme I.

The desired compounds of the formula la obtained are then converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula la obtained are then converted into the free compounds

The N-oxidation is carried out in a manner likewise familiar to the person skilled in the art, e.g with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. The person skilled in the art is familiar with the reaction conditions which are necessary for carrying out the process on the basis of his expert knowledge.

The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent, e.g in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecepiting, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.

In general, the ethereal solvents used in the above described processes for the preparation of compounds of the formula la are selected from diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like. The chlorinated solvent which may be employed may be selected from dichloromethane, 1,2- dichloroethane, chloroform, carbontetrachloride and the like . The aromatic solvents which may be employed may be selected from benzene, toluene. The alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert.butanol and the like. The aprotic solvents which may be employed may be selected from N, N-dimethylformamide, dimethyl sulfoxide and the like.

In general, the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, iso propanol, water or their combinations, or column chromatography using Alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations. Various polymorphs of a compound of general formula (1) forming part of this invention may be prepared by crystallization of compound of formula (1) under different conditions, example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

The present invention provides novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastreomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides and their pharmaceutically acceptable solvates.

The present invention also provides pharmaceutical compositions, containing compounds of the general formula (1) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their enantiomers, their diasteromers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like. The pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders.

It will be appreciated that some of the compounds of the general formula (1) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in the compounds of the general formula (1) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures.

The invention may also contain E & Z geometrical isomers wherever possible in the compounds of the general formula (1) which includes the single isomer or mixture of both the isomers The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The active compounds of the formula (1) will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds of the formula (1) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds of the formula (1) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of the formula (1). The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

The compounds can also be administered by inhalation when application within the respiratory tract is intended. Formulation of the present compounds is especially significant for respiratory inhalation, wherein the compound of Formula (1) is to be delivered in the form of an aerosol under pressure. It is preferred to micronize the compound of Formula (1) after it has been homogenised, e.g., in lactose, glucose, higher fatty acids, sodium salt of dioctylsulfosuccinic acid or, most preferably, in carboxymethyl cellulose, in order to achieve a microparticle size of 5 μm or less for the majority of particles. For the inhalation formulation, the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substance. An inhaler or atomizer or nebulizer may be used. Such devices are known. See, e.g., Newman et al., Tliorax, 1985, 40:61-676; Berenberg, M., J. Asthma USA, 1985, 22:87-92; incorporated herein by reference in their entirety. A Bird nebulizer can also be used. See also U.S. Patents 6,402,733; 6,273,086; and 6,228,346, incorporated herein by reference in their entirety. The compound of the structure (1) for inhalation is preferably formulated in the form of a dry powder with micronized particles. The compounds of the invention may also be used in a metered dose inhaler using methods disclosed in U.S. Patent 6, 131,566, incorporated herein by reference in its entirety.

In addition to the compounds of formula (1) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful therapeutic agents.

Usually dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from 0.05mg to about lOOOmg preferably from about 0.5mg to about 250mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Intermediate 1

Step 1: 4-methoxydibenzo[6,«flfuran

4-hydroxy dibenzofuran (prepared according to JOC, 1986, 51, pl821-1829), (2.5 gm, 0.0136 mol), was dissolved in 7 % sodium hydroxide solution (25 ml) and stirred at room temperature for 30 min. Dimethyl sulphate (3.4 gm, 0.02716 mol) was added dropwise to the above solution and stirred for 12 h. Reaction mixture was diluted with water (100 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 50 ml). The organic layer was washed with water (50 ml), saturated sodium bicarbonate solution (25 ml), brine and dried over anhydrous sodium sulphate. Removal of the organic solvent in vacuo gave the product as a white solid (2.0 gm).

^!H nmr (300 MHz, CDC13) δ 3.97 (s, 3 H), 7.15 (d, IH, J= 8.4 Hz), 7.31 (t, IH, J= 8.4 Hz), 7.38 (t, IH, J= 8.4 Hz), 7.50 (t, IH, J= 8.4 Hz), 7.67 (d, IH, J= 8.1 Hz), 7.70 (d, 1H, J= 8.4 Hz), 8.10 (d, 1H, J= 6.9 Hz).

Step 2: l-(4-methoxydibenzo[δ,< ]furan-l-yI)-l-ethanone 4-methoxydibenzo[6, d]fux (100 mg, 0.555 mmol) was dissolved in chloroform (4 ml) and cooled to 5°C. Anhydrous aluminum chloride (200 mg, 1.515 mmol) was added to the reaction mixture and was stirred for 10 min at 5°C. A solution of acetyl chloride (70 mg, 0.833 mmol) in chloroform (2 ml) was added dropwise to the reaction mixture and was stirred at 5-10°C for 1 h. The reaction mixture was cooled in ice-bath, quenched with crashed ice, diluted with water (50 ml) and extracted with chloroform (2 x 25ml). The organic extract was washed with water (50 ml), saturated sodium bicarbonate solution (25 ml), brine (25 ml) and dried over anhydrous sodium sulphate. Removal of solvent under vacuo gave the product as white solid (110 mg); mp: 180-182°C.

IR (KBr): 3052, 2938, 1819, 1672, 1569, 1448, 1395, 1281, 1202, 1128, 1092, 1011, 912, 831, 791, 749 cm^'1

^!H nmr (300 MHz, CDC13) δ 2.74 (s, 3 H), 4.12 (s, 3H), 6.97 (d, IH, J= 8.7 Hz), 7.36 (t, IH, J= 8.1 Hz), 7.51 (t, IH, J= 8.1 Hz), 7.55 (d, IH, J= 7.8 Hz), 7.86 (d, IH, J= 8.4 Hz), 8.93 (d, 1H, J= 7.8 Hz).

Step 3: Ethyl 2-(4-methoxydibenzo [#,</] furan-l-yl)acetate l-(4-methoxydibenzo[έ,c?]furan-l-yl)-l-ethanone (100 mg, 0.416 mmol), triethylorthoformate (2 ml), lead tetraacetate (185 mg, 0.416 mmol), 70% aqueous perchloric acid (120 mg, 0.832 mmol) were mixed and heated to 60-70°C for 7 h. Reaction mixture was cooled to room temperature, diluted with water (25 ml) and extracted with chloroform (2 x 25 ml). The organic layer was washed with water (2 x 25 ml), saturated bicarbonate solution (10 ml) and dried over anhydrous sodium sulphate. The organic extract was concentrated and the residue was purified by silica gel column chromatography using 5 % ethyl acetate in petroleum ether to give the product (30 mg); mp: 164-165°C.

IR (KBr): 3073, 2970, 2937, 2841, 1720, 1706, 1634, 1520, 1450, 1404, 1306, 1277, 1241, 1163, 1099, 1021, 933, 891, 802, 740, 731 cm-1

^!H nmr (300 MHz, CDC1₃) δ 1.22 (t, 3H), 4.06 (s, 3H), 4.07 (s, 2H) 4.16 (q, 2H), 6.95 (d, IH, J = 8.4 Hz), 7.13 (d, IH, J = 8.4 Hz), 7.34 (t, IH, J = 8.1 Hz), 7.45 (t, IH, J = 8.1 Hz), 7.63 (d, IH, J= 8.4 Hz), 8.02 (d, IH, J= 7.8 Hz).

Step 4: Ethyl 2-(4-methoxydibenzo[6,rf]furan-l-yl)-2-oxoacetate Ethyl 2-(4-methoxydibenzo[ό,(t furan-l-yl)acetate (100 mg, 0.352 mmol), was dissolved in xylenes (7 ml). Selenium dioxide (190 mg, 1.76 mmol) was added to the reaction mixture and refluxed for 10 h. The xylene was distilled off and the residue obtained was tritutrated with chloroform (30 ml) and filtered through celite bed. Chloroform was evaporated to get a sticky solid which was purified by silica gel column chromatography using 8 % ethyl acetate in petroleum ether to give the product (45 mg); mp: 191-193°C.

IR (KBr): 2979, 2941, 1725, 1667, 1599, 1562, 1452, 1402, 1302, 1285, 1200, 1107, 1074, 1011, 919, 803, 752, 741 cm^-1

^!H nmr (300 MHz, CDC13) δ 1.46 (t, 3H), 4.16 (s, 3H), 4.49 (q, 2H), 7.04 (d, IH, J= 8.1 Hz), 7.40 (t, IH, J= 9.3 Hz), 7.55 (t, IH, J= 9.0 Hz), 7.66 (d, IH, J= 6.3 Hz), 7.88 (d, IH, J= 8.4 Hz), 8.98 (d, IH, J= 8.1 Hz).

Step 5: 2-(4-methoxydibenzo[6,rf]furan-l-yl)-2-oxoaceticacid

Ethyl 2-(4-methoxydibenzo[t3,it]furan-l-yl)-2-oxoacetate (40 mg, 0.127 mmol) was dissolved in a mixture of glacial acetic acid (2 ml) and concentrated hydrochloric acid (0.5 ml). The reaction mixture was then refluxed for 3 h, cooled, diluted with water (50 ml) and extracted with ethyl acetate (2 x 25 ml). The organic layer was washed with water (2 x 50 ml), saturated sodium bicarbonate solution (25 ml), water (50 ml) and dried over anhydrous sodium sulphate. Removal of solvent under vacuo gave the product as an off-white solid (40 mg); mp: 235-237°C.

IR (KBr): 2935, 1710, 1666, 1629, 1598, 1556, 1449, 1398, 1285, 1211, 1108, 1075,

1010, 882, 749 cm^"1.

1H nmr (300 MHz, DMSO) δ 4.12 (s, 3H), 7.40 (d, IH, J= 8.7 Hz), 7.47 (t, IH, J= 8.4

Hz), 7.65 (t, IH, J= 8.1 Hz), 7.82 (d, IH, J= 8.1 Hz), 7.91 (d, IH, J= 9.0 Hz), 8.88 (d, lH, J= 7.5 Hz). Intermediate 2

Step 1: 4-Etb.oxy dibenzo [£,</] furan

4-hydroxy dibenzofuran (prepared according to JOC, 1986, 51, pl 821-1829), (500 mg, 1.98 mmol) was dissolved in DMF (5 ml). Anhydrous potassium carbonate (270 mg, 2.18 mmol) and ethyl bromide (257 mg, 2.38 mmol) was added to the above solution. The reaction mixture was heated to 80-90°C for 3 h. After completion, the reaction mixture was cooled to room temperature, poured in water (30 ml) and extracted with ethyl acetate (10 ml x 3). The organic layers were combined and concentrated to get the product as thick oil (550 mg).

IR (KBr): 3061, 2980, 1633, 1630, 1586, 1501, 1450, 1396, 1332, 1310, 1273, 1192, 824, 743 cm^-1

1H nmr (300 MHz, DMSO): δ 1.54 (t, 3H), 4.28 (q, 2H), 6.98 (d, IH, J= 9.0Hz), 7.28 (t, IH, J= 9.0Hz), 7.36 (t, IH, J= 6.0Hz), 7.48 (t, IH, j = 9.0Hz), 7.52 (d, IH, J= 6.0Hz), 7.62 (d, IH, J= 9Hz), 7.62 (d, IH) , 7.92 (d, IH).

Step 2: Ethyl 2-(4-ethoxydibenzo[£,<t]furan-l-yl)-2-oxoacetate

4-Ethoxy dibenzo [b,d] furan (550 mg, 1.95 mmol), was dissolved in ethylene dichloride (5 ml) and the solution was cooled to 0°C. Anhydrous aluminum chloride (782 mg, 5.87 mmol) was added to the above solution followed by drop wise addition of ethyl oxalyl chloride (400 mg, 2.93 mmol). The reaction was stirred for 30 min at room temperature. After completion, the reaction mixture was poured in ice water (30 ml) and extracted with ethyl acetate (10 ml x 3). The organic extracts were combined and concentrated to obtain the product as a viscous oil (650 mg).

IR (KBr): 2986, 2885, 1719, 1664, 1599, 1562, 1499, 1392, 1301, 1285, 1256, 1212, 1106, 1072, 1017, 762, 640, 513 cm^"1 'H nmr (300 MHz, DMSO): δ 1.37 (t, 3H), 1.47 (t, 3H), 4.40 (m, 4H,), 7.37(d, IH, J = 6.0Hz) 7.46 (t, IH, J= 6.0Hz) 7.65 (t, 1H, J= 6.0Hz) 7.85 (d, IH, J= 9.0Hz) 7.90 (d, IH, J= 9.0Hz), 8.85 (d ,1H, J= 9.0Hz) .

Step 3: 2-(4-ethoxydibenzo[6,rf]furan-l-yl)-2-oxoacetic acid

Was synthesized by hydrolysis of Ethyl 2-(4-ethoxydibenzo[&,d]furan-l-yl)-2-oxoacetate (from step 2 above) as described in step 5 of intermediate 1.

IR (KBr): 3094, 2984, 2890, 1705, 1666, 1599, 1562, 1499, 1397, 1308, 1285, 1245, 1220, 1030, 891, 750, 508 cm^{-1 !}Hnmr (300MHz, DMSO): δ 1.61 (t, 3H), 4.41 (q, 2H), 7.05 (d, IH, J= 9.0Hz), 7.39 (t, IH, J = 9.0Hz), 7.56 (t, IH , J = 6.0Hz) , 7.68 (d, IH, J = 9.0Hz) 8.65 (d, IH, J = 9.0Hz), 8.85 (d, IH , J= 6.0Hz).

Intermediate s

Step 1: 4-IsopropyIoxydibenzo[6,«f]furan

Was synthesized as described in step 1 of intermediate 2 using isopropyl bromide instead of ethyl bromide. Η nmr (300 MHz, DMSO): δ 1.37 (d, 6H), 4.87 (m, IH) , 7.18 (d, IH, J = 7.8Hz), 7.30 (t, IH), 7.39 (t, IH), 7.52 (t, IH), 7.68 ( d, IH, J = 7.8Hz), 7.74 (d, IH, J = 8.4Hz), 8.1(d, lH, J= 6.9Hz).

Step 2: Ethyl 2-(4-isopropyloxydibenzo[6,«7]furan-l-yl)-2-oxoacetate Was synthesized as described in step 2 of intermediate 2 using 4-Isopropyloxy dibenzo[δ,c(jfuran instead of 4-Ethoxydibenzo[ό,cT|furan.

IR (KBr): 2980, 1722, 1628, 1597, 1562, 1449, 1386, 1300, 1281, 1237, 1214, 1193, 1067, 964, 753, 698cm^{-1 l}E nmr (300 MHz, DMSO): δ 1.38-1.55 (m, 9H), 4.33 (q, 2H), 4.95 (m, IH) , 7.02 (d, IH, J= 9.0Hz), 7.39 (t, IH), 7.50 (t, IH, J= 9.0Hz), 7.66 ( d, IH, J= 9.0Hz), 7.84 (d, IH), 9.00(d, lH, J= 6.0Hz).

Step 3: 2-(4-isopropyloxydibenzo[6,<flfuran-l-yl)-2-oxoacetic acid

Was synthesized by hydrolysis of Ethyl 2-(4-isopropyloxydibenzo[ό,^furan-l-yι)-2- oxoacetate (200 mg) (from step 2 above) using IN potassium hydroxide (3 ml) in methanol (10 ml) at room temperature. After completion reaction mixture was poured in water, acidified with 7% aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was concentrated in vacuo to give the product as pale yellow solid (190 mg).

^!H nmr (300 MHz, DMSO): δ 1.34 (d, 6H), 4.88 (m, IH), 4.95 (m, IH) , 7.45 (t, IH), 7.60 (t, lH), 7.69 ( d, lH, J= 7.8Hz), 7.76 (d, lH, J= 7.8Hz), 7.89 (d, lH, J= 7.8Hz), 8.20 (d, lH, J= 7.8Hz).

Intermediate 4

Step 1: 4-Cyclopentyloxydibenzo[6,<flfuran Was synthesized as described in step 1 of intermediate 2 using cyclopentyl bromide instead of ethyl bromide.

Step 2: Ethyl 2-(4-cyclopentyloxydibenzo[ό,<f|furan-l-yl)-2-oxoacetate

Was synthesized as described in step 2 of intermediate 2 using 4-Cyclopentyloxy dibenzo[δ,d]furan instead of 4-Ethoxydibenzo[ό, d]furan.

IR (KBr): 2928, 2873, 1735, 1672, 1560, 1597, 1450, 1401, 1281, 1235, 1212, 1105,

1017, 979, 753 cm^"1.

Η nmr (300 MHz, DMSO): δ 1.35 (t, 3H), 1.67-208 (m, 8H), 4.44 (q, 2H), 5.25 (m, IH), 7.37 (d, IH, J = 9.0Hz), 7.45 (t, IH, J= 9.0Hz), 7.64 (t, IH, J = 9.0Hz) 7.86 (d, IH, J= 9.0Hz), 7.89 (d, IH, J= 9.0Hz), 8.88 (d, IH, J= 9.0Hz).

Step 3: 2-(4-cycIopentyloxydibenzo[6,</]furan-l-yI)-2-oxoacetic acid Was synthesized by hydrolysis of Ethyl 2-(4-cyclopentyloxydibenzo[t>,^furan-l-yl)-2- oxoacetate ( from step 2 above) as described in step 3 of intermediate 3.

IR (KBr): 2955, 2872, 1728, 1715, 1652, 1627, 1596, 1562, 1449, 1400, 1298, 1281, 1216, 1108, 981, 753 cm-¹ H nmr (300MHz, DMSO): δ 1.67-208 (m , 8H) 5.22 (m, IH), 7.39 (d, IH, J = 9.0Hz), 7.48 (t, IH, J = 6.0Hz), 7.63 (t, IH, J = 9.0Hz), 7.85-7.90 (m, 2H), 8.89 (d, IH, J = 9.0Hz).

Step 1: Ethyl 2-(4-Hydroxydibenzo[6,rf]furan-l-yl)-2-oxoacetate

Ethyl 2-(4-isopropyloxydibenzo[έ,(t]furan-l-yl)-2-oxoacetate (800 mg, 2.61 mmol) (from step 2, intermediate 3) was dissolved in methylene dichloride (10 ml) and cooled to 0°C. Titanium tetrachloride (0.494 mg, 2.61 mmol) was added all at once to the above solution and stirred for 48 h at room temperature. The reaction mixture was poured in 10 % hydrochloric acid solution (30 ml) and extracted in chloroform (20 ml x 3). The organic extracts were combined, concentrated in vacuo to give the product as thick oil. The crude oil was purified by silica gel column chromatography using 10 % ethyl acetate in chloroform to give the product (250 mg) as solid.

IR (KBr): 3242, 2997, 1720, 1639, 1602, 1548, 1449, 1341, 1317, 1219, 1182, 1102, 1065, 937, 752 cm^-1

1H nmr (300 MHz, DMSO): δl.61 (t, 3H), 4.41 (q, 2H,), 7.11 (d, IH, J= 9.0Hz), 7.41 (t, IH, J= 9.0Hz), 7.58 (m, 3H, J= 9.0Hz) 8.61 (d, IH, J= 9.0Hz), 8.87 (d, IH, J= 9.0Hz). Step 2: Ethyl 2-(4-difluoromethoxydibenzo[6,rf]furan-l-yl)-2-oxoacetate

Ethyl 2-(4-Hydroxydibenzo [b, d] furan- l-yl)-2-oxoacetate (600 mg, 2.38 mmol) (from step 1 above) was dissolved in DMF. To this solution was added anhydrous potassium carbonate and heated to 60-70°C for 15 min. Chlorodifluoromethane gas was purged into the above reaction mixture for 1 h. After completion, the reaction mixture was cooled to room temperature, poured in water (30 ml) and extracted with ethyl acetate (10 ml x 3). The organic layers were combined and concentrated to get the product as thick oil (550 mg).

IR (KBr): 3111, 3000, 1734, 1685, 1585, 1569, 1450, 1392, 1275, 1240, 1213, 1186, 1139,112,1045,1014,754 cm-¹.

^!H nmr (300 MHz, DMSO): δ 1.44 (t, 3H), 4.48 (q, 2H,), 7.08 (t, IH, J = 74Hz), 7.41 (m, 2H), 7.61 (t, IH, J= 9.0Hz), 7.68 (d, IH), 7.88 (d, IH), 8.90 (d ,1H, J= 9.0Hz).

Step 3: 2-(4-difluoromethoxydibenzo[6,d]furan-l-yl)-2-oxoacetic acid

Was synthesized by hydrolysis of Ethyl 2-(4-difluoromethoxydibenzo[έ,fiT|furan-l-yι)-2- oxoacetate (from step 2 above) as described step 3 of intermediate 3.

IR (KBr): 3114, 3004, 2922, 1736, 1702, 1677, 1634, 1568, 1450, 1400, 1280, 1242, 1147, 758 cm^'1 H nmr (300 MHz, DMSO): 6.83-7.32 (m, IH), 7.37-7.46 (m, 2H), 7.56-7.69 (m, 2H), 7.99 (d, IH), 8.90 (d, IH, J= 9.0Hz).

Example 1

Nl-(3, 5-dichloro-4-pyridyl)-2-(4-methoxy dibenzo[£,</]furan-l-yI)-2-oxoacetamide

2-(4-methoxydibenzo[t),^furan-l-yl)-2-oxoaceticacid (intermediate 1) (40 mg, 0.148 mmol) was suspended in 1,1-dichloromethyl methyl ether (1 ml) and refluxed for 3 h. Excess of 1,1-dichloromethyl methyl ether was removed under vacuo to give the acid chloride as a solid.

To a pre-washed suspension of sodium hydride (11.0 mg, 2.0 eq. 0.296 mmol, 60% oil dispersion) in DMF (2 ml) was added dropwise a solution of 4-amino-3,5- dichloropyridine (24 mg, 0.148 mmol) in DMF (2 ml) at -10°C. A pre-cooled solution of above acid chloride in THF (4 ml) was added, all at once, to the reaction mixture and the contents were stirred at — 10°C for 30 min. The reaction was quenched with brine, diluted with water and extracted with ethyl acetate. The organic layer was washed with water,

5% HCI, 5% sodium bicarbonate and brine solution. Evaporation of solvent and washing of the resulting crude solid with ether-pentane mixture provided Nl-(3, 5-dichloro-4- pyridyl)-2-(4-methoxy dibenzo[t,cT]furan-l-yl)-2-oxoacetamide as a white solid (22 mg); mp: 267-269 °C.

IR (KBr): 3162, 2939, 1696, 1662, 1598, 1559, 1512, 1449, 1398, 1285, 1194, 1107,

1071, 1012, 881, 799, 747 cm^"1. ^lE nmr (300 MHz, DMSO) δ 4.13 (s, 3H), 7.47-7.52 (brm, 2H), 7.66 (t, IH, J= 9.0 Hz),

7.83 (d, IH, J= 8.4 Hz), 8.15 (d, IH, J= 8.1 Hz), 8.80 (s, 2H), 8.93 (d, IH, J= 7.8 Hz),

11.55 (s, lH).

Example 2 Nl-(4-pyridyl)-2-(4-methoxy dibenzo [6,rf]furan-l-yl)-2-oxoacetamide

Example 2 was synthesized as described for example 1 using intermediate 1 and 4- aminopyridine. The crude product was purified by silica gel column chromatography using 30 % acetone in chloroform, mp: 224°C IR (KBr): 3133, 2932, 1689, 1667, 1597, 1563, 1518, 1400, 1280, 1189, 1107, 1010,

746, 538 cm^"1 H nmr (300 MHz, DMSO): 4.12 (s, 3H,), 7.38 (d, IH, J = 8.7 Hz), 7.50 (t, IH), 7.73-

7.66 (m, 3H), 7.83 (d, IH, J= 8.4 Hz), 8.06 (d, IH, J= 9.00 Hz), 8.54 (s, 2H ), 8.87 (d,

1 H, J= 7.5 Hz), 11.43 (s, lH). Example 3

Nl-(3-pyridyl)-2-(4-methoxy dibenzo[6,rf]furan-l-yl)-2-oxoacetamide

Example 3 was synthesized as described for example 1 using intermediate 1 and 3- aminopyridine. The crade product was purified by silica gel column chromatography using 30 % acetone in chloroform, mp: 209°C

IR (KBr): 3077, 2925, 2852, 1674, 1625, 1599, 1574, 1398, 1274, 1172, 1106, 1013,

748, 545 cm^'1

Η nmr (300 MHz, DMSO): 4.12 (s, 3H,), 7.36 (d, IH, J = 9.00 Hz), 7.51-7.43 (m, 2H),

7.65 (t,lH), 7.81 (d, IH, J= 8.1 Hz), 8.09 (d, IH, J= 8.7 Hz), 8.17 (d, IH, J= 8.4 Hz ),

8.37 (d, IH, J=7.2 Hz), 8.87-8.91(m, 2H), 11.29 (s, IH).

Example 4 Nl-(3, 5-dichloro-4-pyridyl)-2-(4-Ethoxy dibenzo [6,rf]furan-l-yl)-2-oxoacetamide

Example 4 was synthesized as described for example 1 using intermediate 2 and 4- amino-3,5-dichloropyridine. The crude product was purified by silica gel column chromatography using 10 % ethyl acetate in chloroform, mp: 268°C

IR (KBr): 3152, 2932, 1698, 1661, 1599, 1560, 1513, 1393, 1285, 1275, 1189, 1108,

1015, 951, 808, 725, 508 cm^"1

^!H nmr (300 MHz, DMSO): δ 1.50 (t, 3H), 4.44 (q, 2H,), 7.48-7.48 (m, 2H), 7.66 (t, IH), 7.88 (d, IH, J = 8.4 Hz), 8.15(d, IH, J= 8.4 Hz), 8.82 (s, 2H), 8.95 (s, d, IH, J =

7.8 Hz),l 1.50 (s, lH).

Example 5 Nl~(4-pyridyl)-2-(4-Ethoxy dibenzo[6,^furan-l-yI)-2-oxoacetamide

Example 5 was synthesized as described for example 1 using intermediate 2 and 4- aminopyridine. The crude product was purified by silica gel column chromatography using 20 % ethyl acetate in chloroform, mp 212°C IR (KBr): 3077, 2984, 2938, 2900, 1692, 1663, 1596, 1515, 1450, 1393, 1308, 1283, 1245, 1106, 1070, 875, 735, 505 cm^"1 H nmr (300 MHz, DMSO): δ 1.47 (t, 3H), 4.11 (q, 2H), 7.36 (d, IH, J= 9.0Hz), 7.47 (t, IH, J= 9.0Hz), 7.65 (t, IH, J= 9.0Hz), 7.71 (t, 2H, J= 9.0Hz), 7.86 (d, IH, J= 9Hz).

.04 (d, IH, J= 6.0Hz), 8.54 (d, 2H, J= 6.0Hz), 8.91 (d, IH, J= 6.0Hz), 11.47 (s, IH).

Example 6 Nl-(3-pyridyl)-2-(4-Ethoxy dibenzo[&,<flfuran-l-yI)-2-oxoacetamide

Example 6 was synthesized as described for example 1 using intermediate 2 and 3- aminopyridine. The crade product was purified by silica gel column chromatography using 20 % ethyl acetate in chloroform, mp: 207°C

IR (KBr): 3237, 2977, 2938, 2836, 1674, 1564, 1431, 1392, 1273, 1255, 1105, 1015, 951, 808, 735, 698 cm^"1

Η nmr (300 MHz, DMSO): δ 1.47 (t, 3H), 4.39 (q, 2H,), 7.36 ( d, IH, J = 9.0Hz), 7.45-7.53 (m, 2H), 7.65 (t, IH, J = 9.0Hz), 7.86 (d, IH, J= 9.0Hz), 7.95 (s, IH), 8.08 (d, IH, J= 9.0Hz), 8.19 (d, IH, J= 9.0Hz) , 8.39 (d, IH, J= 6.0Hz), 8.91 (d, IH, J = 6Hz), 11.30 (s, lH).

Example 7 Nl-(3, 5-dichloro-4-pyridyl)-2-(4-isopropyloxy dibenzo [6,</]furan-l-yl)-2- oxoacetamide

Example 7 was synthesized as described for example 1 using intermediate 3 and 4- amino-3,5-dichloropyridine. The crude product was purified by silica gel column chromatography using 40 % ethyl acetate in petroleum ether. mp:176°C IR (KBr): 3432, 3084, 2927, 2865, 1670, 1635, 1600, 1554, 1400, 1278, 1168, 1107, 1010, 768, 535m^"1

*H nmr (300 MHz, DMSO): 1.43 (s, 3H), 1.44 (s, 3H), 2.50 (m, IH), 77.44-7.49( m, 2H ), 7.64 (t, IH), 7.83 (d, IH, J= 8.4 Hz), 8.04 (d, IH, J= 8.4 Hz), 8.80 (s,2 H), 8.93 (d, 1H, J= 7.5 Hz), 11.18 (s, lH).

Example 8 Nl-(3, 5-dichIoro-4-pyridyI)-2-(4-cyclopentyloxy dibenzo [6,«T|furan-l-yl)-2- oxoacetamide

Example 8 was synthesized as described for example 1 using intermediate 4 and 3,5- dichloro-4-aminopyridine. The crude product was purified by silica gel column chromatography using 10 % ethyl acetate in chloroform, mp: 201°C

IR (KBr): 3153, 2954, 1698, 1656, 1556, 1449, 1399, 1297, 1106, 981, 699, 505 cm^"1. •H nmr (300 MHz, DMSO): δ 1.67-208 (m, 8H), 5.28 (m, IH), 7.48 (m, 2H), 7.65 (t, IH, J= 9.0Hz), 7.80 (d, IH, J= 9.0 Hz), 8.13 (d, IH, J= 9.0Hz), 8.82 (s, 2H), 8.94 (d, IH, J= 9.0Hz), 11.57 (s, IH).

Example 9 Nl-(4-pyridyI)-2-(4-cyclopentyloxy dibenzo[6,rf]furan-l-yl)-2-oxoacetamide

Example was synthesized as described for example 1 using intermediate 4 and 4- aminopyridine. The crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 189°C IR (KBr): 3068, 2964, 2874, 1691, 1595, 1515, 1398, 1229, 1281, 1209, 1162, 1015, 996, 752, 502 cm^"1.

^]H nmr (300 MHz, DMSO): δ 1.67-2.08 (m, 8H), 5.23 (m, IH), 7.36 (d, IH, J= 9.0Hz), 7,47 (t,lH, J= 9.0Hz), 7.64 (t, IH, J= 9.0Hz), 7.73 (d, IH , J= 9.0 Hz), 7.86 ( d, IH, J =9.0Hz) 8.02 (d,lH, J= 6.0Hz), 8.55 (s, 2H) 8.90 (s IH, J= 9.0Hz), 11.45 (s,lH).

Example 10 Nl-(3-pyridyl)-2-(4-cyclopentyloxy dibenzo[6,«f]furan-l-yl)-2-oxoacetamide

Example' 10 was synthesized as described for example 1 using intermediate 4 and 3- aminopyridine. The crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 191°C IR (KBr): 3193, 3066, 2958, 2735, 1672, 1567, 1449, 1399, 1273, 1169, 1107, 1072, 981, 748, 538. cm^"1

Η nmr (300 MHz, DMSO): δ 1.67-2.08 (m ,8H), 5.22 (m,lH,), 7.36 (d, IH, J=9.0Hz), 7.45 (m, 2H) 7.64 (t, IH, J= 9.0Hz), 7.87 (d, IH, J= 9.0 Hz) 8.06 (d, IH, J= 9.0Hz), 8.19 (d, lH, J= 6.0Hz), 8.39 (d, lH, J=4.5.0Hz), 8.91 (m, 2H), 11.45 (s ,1H).

Example 11 Nl-(3, 5-dichloro-4-pyridyl)-2-(4-difluoromethoxy dibenzo [Λ,rfjfuran-l-yl)-2- oxoacetamide

Example 11 was synthesized as described for example 1 using intermediate 5 and 3,5- dichloro-4-aminopyridine. The crude product was purified by silica gel column chromatography using 5 % ethyl acetate in chloroform, mp: 206°C IR (KBr): 3165, 3100, 2952, 1698, 1671, 1560, 1510, 1449, 1400, 1282, 1274, 1183, 1155, 1108, 917, 892, 748. cm^"1

•H nmr (300 MHz, DMSO): δ 7.54 (t, IH, J= 6.0Hz), 7.68-7.78 (m, 3H), 7.92 (d, IH, J = 9.0 Hz), 8.16 (d, IH, J= 9.0Hz), 8.83 (s, 2H), 8.86 (d, IH, J= 9.0Hz), 11.68 (s, IH).

Example 12 Nl-(4-pyridyl)-2-(4-difluoromethoxy dibenzo[6,< ]furan-l-yl)-2-oxoacetamide

Example 12 was synthesized as described for example 1 using intermediate 5 and 4- aminopyridine. The crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 215°C IR (KBr): 3162, 3031, 2961, 1687, 159, 1520, 1401, 1283, 1207, 1156, 1106, 1057, 1001, 857, 822, 741. cm^"1 H nmr (300 MHz, DMSO): δ 7.52-7.61 (m, 2H), 7.68 (s, 1Hz, J= 72Hz), 7.71-7.78 (m, 3H), 7.92 (d, IH), 8.13 (d, IH, J= 9.0Hz), 8.56 (d, 2H), 8.78 (d, IH, J= 9.0Hz), 11.52 (s, IH).

Example 13 Nl-(3-pyridyl)-2-(4-difluoromethoxy dibenzo[6,rf)furan-l-yl)-2-oxoacetamide

Example 13 was synthesized as described for example 1 using intermediate 5 and 3- aminopyridine. The crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 174°C IR (KBr): 3234, 3075, 2987, 2849, 1675, 1575, 1432, 1390, 1283, 1273, 1168, 1184, 1108, 1044, 809, 749 cm^"1

^!H nmr (300 MHz, DMSO): δ 7.44-7.61 (m, 3H), 7.61(s, IH, J= 90Hz), 7.71 (t, IH, J= 6.0Hz), 7.92(t, IH, J= 6.0Hz), 8.16-8.23(m, 2H), 8.41 (d, IH), 8.78 (d, IH, J= 9.0Hz), 8.96 (s, lH) , 11.52 (s, IH).

In vitro Studies

Inhibition of Phosphodiesterase Enzymes (PDE4)

In this assay, PDE4 enzyme converts [³H] cAMP to the corresponding [³H] 5'- AMP in proportion to the amount of PDE4 present. The [³H] 5'-AMP then was quantitatively converted to free [³H] adenosine and phosphate by the action of snake venom 5'-nucleotidase. Hence, the amount of [³H] adenosine liberated is proportional to PDE4 activity.

The assay was performed with modification of the method of Thompson and Appleman (Biochemistry; 1971; 10; 311-316) and Schwartz and Passoneau (Proc. Natl. Acad. Sci. U.S.A. 1974; 71; 3844-3848), both references incorporated herein by reference in their entirety, at 34°C. In a 200 ul total reaction mixture, the reaction mixture contained 12.5mM of Tris, 5 mM MgCl₂, 1 μM cAMP (cold) and ³H cAMP (0.1 uCi), (Amersham). Stock solutions of the compounds to be investigated were prepared in DMSO in concentrations such that the DMSO content in the test samples did not exceed 0.05 % by volume to avoid affecting the PDE4 activity. Drag samples were then added in the reaction mixture (25 μl/tube). The assay was initiated by addition of enzyme mix (75 μl) and the mixture was incubated for 20 minutes at 34° C. The reaction was stopped by boiling the tubes for 2 mins at 100°C in a water bath. After cooling on ice for 5 minutes and addition of 50 ug/reaction of 5'-nucleotidase snake venom from Crotalus atrox incubation was carried out again for 20 min. at 34°C. The unreacted substrate was separated from (³H) Adenosine by addition of Dowex AG 1-X8 ( Biorad Lab), (400 ul) which was prequilibrated (1:1:1) in water and ethanol. Reaction mixture was then thoroughly mixed, placed on ice for 15 minutes, vortexed and centrifuged at 14,000 r.p.m. for 2 mins. After centrifugation, a sample of the supernatant was taken and added in 24 well optiplates containing Scintillant (1 ml) and mixed well. The samples in the plates were then determined for radioactivity in a Top Counter and the PDE4 activity was estimated. PDE4 enzyme was present in quantities that yield <30% total hydrolysis of substrate (linear assay conditions).

Additionally, activity of the compounds were tested against other Phosphodiesterase enzymes, namely, PDE l(Ca.sup.2+/calmodulin-dependent), PDE 2(cGP-stimulated), PDE 3 (cGP-inhibited), PDE 5 (cGP-specific) and PDE 6 (cGP- specific, photoreceptor).

Results were expressed as percent inhibition (IC50) in nM/uM concentrations. The IC50 values were determined from the concentration curves by nonlinear regression analysis.

Claims

Claims:

1. A compound of general formula (I)

(1) wherein

R¹, R² and R³ may be same or different and are independently selected for each occurance from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -NR⁵R⁶, -C(=L)-R⁵, -C(O)-R^a , -C(O)O-R^a, -C(O)NR^aR^b , -S(O)_m-R^a, -S(O)_m-NR^aR^b, nitro, -OH, cyano, , formyl, acetyl, halogen, -OR^a, -SR^a, protecting groups or when two R³ substitutents are ortho to each other, may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; wherein R⁵ and R⁶ may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, halo, -OH, cyano, -C(O)-R^a, -C(0)O-R^a, -C(O)NR^aR^b, -S(0)_m- R^a, -S(O)_m-NR^aR^b, -C(=NR^a)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b , -C(=S)-R^a, -

N=C(R^aR^b), -NR >a^a _DRb , -OR^a, -SR^a, protecting groups or R⁵ and R^b may be joined to a form a optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S;

Wherein R^a, R^b may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(O)-R^a, -C(0)O-R^a, -C(0)NR R^b , - S(0)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, ,-OR^a, and -SR^a;

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; wherein L is chosen from the group consisting of O, S NR^a; wherein P is chosen from the group consisting of O and S; wherein n represents 0 - 4; X is chosen from the group consisting of O, S(0)_m and NR^a;

Wherein m is 0, 1 or 2; Y is -C(=A)C(=B)NR⁴, Wherein A is chosen from the group consisting of O, S or NR^a

Wherein B is chosen from the group consisting of O, S and NR^a

R⁴ is chosen from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR^a, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring; and their analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastereomerspolymorphs, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or a pharmaceutical acceptable salts thereof.

2. The compound according to claim 1 wherein Ar is chosen from the group consisting of optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which one or more optional substituents may be same or different and are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted and unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino

3. The compound according to claim 1 wherein the substituents in the 'substituted alkyl', 'substituted alkoxy' 'substituted alkenyl' 'substituted alkynyl' 'substituted cycloalkyl' 'substituted cycloalkylalkyl' 'substituted cyclocalkenyl' 'substituted arylalkyl' 'substituted aryl' 'substituted heterocyclic ring', 'substituted heteroaryl ring,' 'substituted heteroarylalkyl', 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl', 'substituted cyclic ring' 'substituted alkylcarbonyl', 'substituted alkylcarbonyloxy' and may be the same or different which one or more are selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio(=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 'substituted heterocyclylalkyl ring' substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^x, -C(0)R^x, -C(S)R^X, -C(O)NR^xR^y, -C(0)ONR^xR^y, - NR^xCONR^yR^z, -N(R^x)SOR^y, -N(R^x)S0₂R^y, -(=N-N(R^x)R^y), - NR^xC(O)OR^y, -NR^xR^y, - NR^xC(O)R^y-, -NR^xC(S)R^y -NR^xC(S)NR^yR^z, -SONR^xR^y-, -SO₂NR^xR^y-, -OR^x, - OR^xC(O)NR^yR^z, -OR^xC(O)OR^y-, -OC(0)R^x, -OC(O)NR^xR^y, - R^xNR^yC(O)R^z, -R^xOR^y, - R^xC(O)OR^y, -R^xC(O)NR^yR^z, -R^xC(O)R^x, -R^xOC(O)R^y, -SR^X, -SOR^x, -SO₂R^x, -ONO₂, wherein R^x, R^y and R^z in each of the above groups is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 'substituted heterocyclylalkyl ring' substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring.

4. The compound according to claim 1 wherein R¹ is chosen from the group consisting of unsubstituted alkyl and unsubstituted cycloalkyl.

5. The compound according to claim 4 wherein R¹ is selected from the group consisting of methyl,ethyl,isopropyl and cyclopentyl.

6 The compound according to claim 1 wherein R¹ is substituted alkyl.

7. The compound according to claim 6 wherein R is CHF₂.

8. The compound according to claims 1-6 or 7 wherein P is O.

9. The compound according to claims 1-7 or 8 where X is O.

10. The compound according to claims 1-8 or 9 wherein Y is -C(=O)C(=0)NR⁴.

11. The compound according to claim 10 wherein R⁴ is hydrogen.

12. The compound according to claims 1-10 or 11 wherein Ar is selected from the group consisting of substituted or unsubstituted 4-pyridyl; substituted or unsubstituted 4-pyridyl-N-oxide; and substituted or unsubstituted 3-pyridyl.

13. The compound according to claim 12 wherein said substituent is halogen.

14. The compound according to claim 13 wherein said halogen is chloro.

15. The compound according to claim 12 wherein Ar is selected from the group consisting of

16. The compound according to claim 15 wherein Ar is

17. A compound according to claim 1, Nl-(3, 5-dichloro-4-pyridyl)-2-(4- methoxy dibenzo[ά,cT|furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 1, Nl-(4-pyridyl)-2-(4-methoxy dibenzo[ό,(t]furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 1, Nl-(3-pyridyl)-2-(4-methoxy dibenzo [b, d furan- l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1, Nl-(3, 5-dichloro-4-pyridyl)-2-(4-Ethoxy dibenzo[6,cT|furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

21. A compound according to claim 1, Nl-(4-pyridyl)-2-(4-Ethoxy dibenzo[6,cf]furan-l-yi)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1, Nl-(3-pyridyl)-2-(4-Ethoxy dibenzo [b,d] furan- l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 1, Nl-(3,5-dichloro-4-pyridyι)-2-(4- isopropyloxy dibenzo [b,d\ furan- l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

24. A compound according to claim 1, Nl-(3,5-dichloro-4-pyridyl)-2-(4- cyclopentyloxy dibenzo[t,rf]furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

25. A compound according to claim 1, Nl-(4-pyridyl)-2-(4-cyclopentyloxy dibenzo[έ,<i]furan-l-yι)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

26. A compound according to claim 1, Nl-(3-pyridyl)-2-(4-cyclopentyloxy dibenzo[t,c?]furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

27. A compound according to claim 1, Nl-(3, 5-dichloro-4-pyridyl)-2-(4- difluoromethoxy dibenzo[t>,cT|furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

28. A compound according to claim 1, Nl-(4-pyridyl)-2-(4-difluoromethoxy dibenzo[δ,c(|furan-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

29. A compound according to claim 1, Nl-(3-pyridyl)-2-(4-difluoromethoxy dibenzo[ό,crjfuran-l-yl)-2-oxoacetamide or a pharmaceutically acceptable salt thereof.

30. A method for the preparation of compounds of general formula la r

wherein

R , R and R may be same or different and are independently for each occurance selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl-, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -NR⁵R⁶, -C(=L)-R⁵, -C(0)-R^a , -C(O)0-R^a, -C(O)NR^aR^b , -S(O)_m-R^a, -S(O)_m-NR^aR^b, nitro, -OH, cyano, , formyl, acetyl, halogen, -OR^a, -SR^a, protecting groups or when two R³ substitutents are ortho to each other, may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; wherein R⁵ and R⁶ may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, halo, -OH, cyano, -C(O)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_m- R^a, -S(O)_m-NR^aR^b, -C(=NR^a)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b , -C(=S)-R^a, - N=C(R^aR^b), -NR^aR^b, -OR^a, -SR , protecting groups or R⁵ and R⁶ to each other may be joined to a form a optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S; Wherein R^a, R may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(0)-R^a, -C(O)0-R , -C(O)NR^aR^b , - S(O)_m-R^a, -S(O)_m-NR^aR , -NR^aR^b, ,-OR^a, -SR^a;

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; wherein L represents O, S or NR^a; wherem P is chosen frm the group consisting of O or S; wherein n is 0 -4; X is chosen from the group consisting of O, S(0)_m and NR^a;

Wherein m is 0, 1 or 2;

R⁴ is chosen from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR^a, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring; and their analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastereomers, polymorphs, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or a pharmaceutical acceptable salts thereof ;comprising the steps of: a) reacting a compound of the formula 10 with a reagent chosen from the group consisting of an alkyl halide, alkyl mesylate, alkyl tosylate and a dialkylsulphate in the presence of an inorganic base such as NaH or K₂C0₃ and the like

to obtain the intermediate of the general formula (11)

Λ- flrx

OR-, 11 b) Acylation of the intermediate of formula 11 using an appropriate acylating agent chosen from the group consisting of an acetyl chloride or acetic anhydride in the presence of a lewis acid such as A1C1₃ or tin chloride to obtain an intermediate of the formula 12

c) Willegerodt-kindler rearrangement of the intermediate of the formula 12 with a reagent chosen from the group of lead tetraacetate and triethyl orthoformate in the presence of perchloric acid to obtain the intermediate of the formula 13.

13

d) Oxidation of the intermediate of the formula 13 using selenium dioxide to obtain the intermediate of the formula 14 t

14

e) Hydrolysis of the intermediate of the general formula 14 is under acidic or basic conditions to yield the dicarbonyl acid intermediate of the formula 15

15 f) Reacting an activated carboxylic acid chosen from the group consisting of an acid halide, mixed anhydride and an activated ester of the intermediate of the general formula 15 with (ArNH R⁴) under basic conditions to yield a compound of the Forumal la r

g) and optionally converting the compounds of the general formula la into their corresponding pharmaceutically acceptable salts and/or their corresponding N-oxides.

31. A method for the preparation of compounds of general formula la r

wherein R , R and R may be same or different and are independently selected for each occurance from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -NR⁵R⁶, -C(=L)-R⁵, -C(O)-R^a , -C(O)O-R^a, -C(O)NR^aR^b , -S(0)_m-R , -S(O)_m-NR^aR^b, nitro, -OH, cyano, , formyl, acetyl, halogen, -OR^a, -SR^a, protecting groups or when two R³ substitutents ortho to each other, may be joined to a form a saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; wherein R⁵ and R⁶ may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, halo, -OH, cyano, -C(0)-R^a, -C(0)O-R^a, -C(O)NR^aR^b, -S(0)_m- R^a, -S(O)_m-NR^aR^b, -C(=NR^a)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b , -C(=S)-R^a, - N=C(R^aR^b), -NR^aR^b, -OR^a, -SR^a, protecting groups or R⁵ and R⁶ to each other may be joined to a form a optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S; Wherein R^a, R^b may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(O)-R^a, -C(O)O-R^a, -C(0)NR R^b , - S(O)_m-R^a, -S(0)_m-NR^aR^b, -NR^aR^b, ,-OR^a, -SR^a;

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; wherein L represents O, S or NR^a; wherein P is chosen from the group consisting of O and S ; wherein n is 0 - 4;

X is chosen from the group consisting of O, S(O)m and NR^a

Wherein m is 0, 1 or 2;

R⁴ is chosen from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR³, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring; and their analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastereomers, polymorphs, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or a pharmaceutical acceptable salts thereof; comprising the steps of: a) Acylation of the compound of the formula 11 in the presence of ethyl oxalyl chloride in the presence of a Lewis acid;

to obtain the intermediate of the general formula (14) t

14 b) Hydrolysis of the intermediate of the general formula 14 is under acidic or basic conditions to yield the dicarbonyl acid intermediate of the formula 15

15 c) Reacting an activated carboxylic acid chosen from the group consisting of an acid halide or mixed anhydride and activated ester of the intermediate of the general formula 15 with (ArNH R⁴) under basic conditions to yield a compound of the Formula la

d) and optionally converting the compounds of the general formula la into their corresponding pharmaceutically acceptable salts and/or N-oxides.

32 A method of treating inflammatory conditions and immune disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.

33. The method according to claim 32 wherein said inflammatory conditions and immune disorders are chosen from the group consisting of asthma, bronchial asthma chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uteltis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative colitis, eczema, atopic dermatitis and chronic inflammation.

34. The method according to claim 33 wherein said inflammatory disorders is chosen from the group consisting of asthma and chronic obstructive pulmonary disease.

35. The method according to claim 32 wherein said inflammatory conditions and immune disorders are selected from the group consisting of inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin and heart.

36. The method according to claim 33 wherein said inflammatory condition is chosen from the group consisting of bronchial asthma, nepritis, and allergic rhinitis.

37. A method of treating diseases of the central nervous system comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.

38. The method according to claim 37 wherein said diseases of the central nervous system are chosen from the group consisting of depression, amnesia, dementia,

Alzheimers disease, cardiac failure, shock and cerebrovascular disease.

39. A method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.