WO2006051390A1 - Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders, pharmaceutical compositions containing them, and methods of preparing them - Google Patents

Abstract

The present invention relates to new phosphodiesterase type 4 (PDE4) inhibitors of the formula (1) and analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs, N-oxides, pharmaceutically acceptable solvates and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and methods of treating allergic and inflammatory diseases, such as asthma or chronic obstructive pulmonary disease (COPD), with them.

Description

HETEROCYCLIC COMPOUNDS USEFUL FOR THE

TREATMENT OF INFLAMMATORY AND ALLERGIC

DISORDERS, PHARMACEUTICAL COMPOSITIONS

CONTAINING THEM, AND METHODS OF PREPARING THEM

This application claims the benefit of U.S. Provisional Application No. 60/626,854, filed November 10, 2004, which is hereby incorporated by reference.

Field of the Invention

The present invention relates to new phosphodiesterase type 4 (PDE4) inhibitors of formula (1), wherein R¹, R², n, Y, and Ar are as defined herein, and analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs, N-oxides, pharmaceutically acceptable solvates and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and methods of treating allergic and inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD).

Background 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-I, IL-3, TNF-α and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and broncho-constriction. 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 eosinophils 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 PDE 4 as a potential therapeutic target for asthma [Rogers, D.F., Giembycz, M.A., Trends Pharmacol. ScI, 19, 160-164(1998); Barnes, PJ., 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, SJ., and Beavo, J.A., Proc. Natl. Acad. ScL, USA, 96,7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si₅ 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,T.J., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated by reference in its 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, X, 211-214 (1995) and ibid., 244-248 herein incorporated by reference in its 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.l 393-1398), 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-α. Since eosinophils 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 includes 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 its 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., Pharmacopsychiatry YL, 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. The binding sites 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, TJ., MoI. Pharmaco., 50, 891- 899 (1996) herein incorporated by reference in its 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 et.al., Br. J. Pharmacol. 1996, U8, 1183-1191 herein incorporated by reference in its 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.

SmithKline Beecham's "Ariflo" 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 stages 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, Ariflo, CDP-840 and Bay-19-8004 were discontinued from clinical trials as a treatment for asthma.

International Publication No. WO 2004/037805, which is hereby incorporated by reference, discloses tricyclic PDE-4 inhibitors useful for the treatment of inflammatory and allergic disorders.

SUMMARY OF THE INVENTION

The present invention provides new heterocyclic compounds of the formula (1)

wherein:

R¹ is hydrogen or substituted or unsubstituted alkyl; R² is hydrogen, -C(O)-R³, -C(O)O-R³, -C(O)NR³R⁴ , -C(O)NR³-C(O)-R⁴,-

S(O)_q-R³, -S(O)_q-NR³R⁴ , -OR³, -SR³ ,or -CR³R⁴-COOR³;

Ar is a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;

Y is-C(O)NR⁵-, NR⁵SO₂, SO₂NR⁵ or NR⁵C(O); n is an integer from 1 to 4; each occurrence of q is 0, 1 or 2;

R³ and R⁴ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano, formyl, acetyl, halogen, a protecting group, -C(O)-R³, -C(O)O-R⁸, -C(0)NR^aR^b, ~S(O)_q-R^a, -S(O),- NR^aR^b, -NR^aR^b, -0R^a and -SR^a or R³ and R⁴ may be joined together with the atom to which they are both attached to form an optionally substituted saturated or unsaturated C₃-C₈ cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S;

R^a and R^b is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted 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 ring, substituted or unsubstituted heterocyclylalkyl , substituted or unsubstituted heteroarylalkyl;

R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring, or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer, polymorph, or N-oxide thereof or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.

The compounds of formula (1) down regulate or inhibit the production of TNF-α as they are PDE4 inhibitors and therefore are useful in the treatment of a variety of allergic and inflammatory diseases including, but not limited to, asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, 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).

Preferably, Ar is an optionally substituted isoxazole, optionally substituted pyridyl (e.g., 4-pyridyl, 3-pyridyl or 2-ρyridyl), or optionally substituted pyridyl-N- oxide (e.g., 4-pyridyl-N-oxide, 3-pyridyl-N-oxide or 2-pyridyl-N-oxide) in which the one or more optional substituents may be the same or different and are independently selected from 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.

Further prefered are when the substituents in the 'substituted alkyl', 'substituted alkoxy', 'substituted alkenyP, 'substituted alkynyl', 'substituted cycloalkyl', 'substituted cycloalkylalkyP, 'substituted cyclocalkenyP, 'substituted arylalkyF, 'substituted aryl', 'substituted heterocyclic ring', 'substituted heteroaryl ring', 'substituted heteroarylalkyl', 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl', 'substituted cyclic ring', 'substituted alkylcarbonyP, and 'substituted alkylcarbonyloxy' are the same or different and are one or more of 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 or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^X, -C(O)R^X, -C(S)R^X, -C(O)NR^xR^y, - C(O)ONR^xR^y, -NR^xCONR^yR^z, -N(R^x)SOR^y, -N(R^x)SO₂R^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(O)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^y, -R^xOC(O)R^y, - SR^X, -SOR^X, -SO₂R^X, or -ONO₂, wherein R^x, R^y and R^z in each of the above groups can be 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, or substituted or unsubstituted heterocyclic ring.

Further preferred is where R¹ is unsubstituted alkyl. Further preferred is where R¹ is methyl. Further preferred is where R¹ is substituted alkyl.

Further preferred is where R¹ is -CHF₂.

Further preferred is when n is 1 and R² is chosen from -S(O)₂NR³R⁴ and COOR³.

Further preferred is when n is 1 and R² is COOH. Further preferred is when R² is SO₂NR³R⁴.

Further preferred is where R² is SO₂NR³R⁴ and R³ and R⁴ are independently hydrogen, alkyl or cycloalkyl or R³ and R⁴ may be joined together with the atom to which they are both attached to form an optionally substituted saturated or unsaturated C₃-Cg cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S.

Further preferred is where R³ is hydrogen and R⁴ is methyl.

Further preferred is where R³ and R⁴ is ethyl. Further preferred is where R³ is hydrogen and R⁴ is cyclopropyl.

Further preferred is where R³ is hydrogen and R⁴ is isopropyl.

Further preferred is where R³ is hydrogen and R⁴ is n-butyl. Further preferred is where R² is SO₂NR³R⁴ and the NR³ R⁴ group is

Further preferred is where Ar is substituted or unsubstituted 4-pyridyl< substituted or unsubstituted 4-pyridyl-N-oxide, or substituted or unsubstituted 3- pyridyl.

Further preferred is where the substituent in the substituted Ar group is halogen (e.g., when Ar is substituted 4-pyridyl, the 4-pyridyl group is substituted with one or more halogens).

Further preferred is where the substituent in the substituted Ar group is chloro. Further preferred is where Ar is

Further preferred is when n=l and R² is hydrogen or:

JΛH • r S)CH, , ° ki ,

or ° kΛ_0H Another embodiment is a pharmaceutical composition comprising at least one heterocyclic compound of the present invention and, optionally, a pharmaceutically acceptable carrier or diluent.

Yet another embodiment is a method of treating an inflammatory disease, disorder or condition (e.g., characterized by or associated with an undesirable inflammatory immune response) or an immune disorder by administering to a subject a therapeutically effective amount of a compound of the present invention. Preferably, the inflammatory disease, disorder or condition or immune disorder is induced by or associated with an excessive secretion of TNF-α and/or PDE-4. Non- limiting examples of such diseases, conditions, and disorders are asthma, bronchial asthma chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoriasis, uticaria, adult vernal conjunctivitis, respiratory distress syndrome, rheumatoid spondylitis, osteoarthritis, gouty arthritis, uveitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative colitis, eczema, atopic dermatitis and chronic inflammation. Preferred inflammatory conditions and immune disorders include, but are not limited to, those of the lungs, joints, eyes, bowels, skin and heart. A preferred inflammatory condition is an allergic inflammatory condition. For example, the inflammatory condition can be bronchial asthma, nepritis, or allergic rhinitis.

Yet another embodiment is a method for abating inflammation in an affected organ or tissue by administering a therapeutically effective amount of a compound of the present invention.

Yet another embodiment is a method of treating a disease of the central nervous system in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention. Non- limiting examples of diseases of the central nervous system are depression, amnesia, dementia, Alzheimer's disease, cardiac failure, shock and cerebrovascular disease.

Yet another embodiment is a method of treating insulin resistant diabetes in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention. The present invention also relates to a process for the preparation of the above said new heterocyclic compounds of the formula (1) as defined above.

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 no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as a C₁^ alkyl, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "Ci_-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms.

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl. The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH₃ and - OC₂H₅.

The term "alkylcarbonyl" denotes an alkyl group as defined above attached via a carbonyl linkage to the rest of the molecule. Representative examples of such groups are -C(O)CH₃ and - C(O)C₂H₅. The term "alkoxycarbonyl" denotes an alkoxy group as defined above attached via a carbonyl linkage to the rest of the molecule. Representative examples of such groups include, but are not limited to, -C(O)-OCH₃, and - C(O)-OC₂H₅.

The term "alkylcarbonyloxy" denotes an alkylcarbonyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups include, but are not limited to, -0-C(O)CH₃ and -0-C(O)C₂H₅. The term "alkylamino" denotes an alkyl group as defined above attached via an amino linkage to the rest of the molecule. Representative examples of such groups include, but are not limited to, -NH₂CH₃, -NH(CH₃)₂, and -N(CH₃)₃.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅ and -C₂H₅C₆H₅.

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 nitrogen, phosphorus, oxygen and sulfur. For purposes 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 (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, 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, indoliny], isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, ftiryl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamoφholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic 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 "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclyl 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 heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. 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 a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^X, -C(O)R^X, -C(S)R^X, -C(O)NR^xR^y, -C(O)ONR^xR^y, -NR^xCONR^yR^z, - N(R^x)SOR^y, -N(R^x)SO₂R^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(O)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^y, -R^xOC(O)R^y, -SR^X, -SOR^X, -SO₂R^X, and -ONO₂, wherein R^x, R^y and R^z are independently selected from 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 cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. According to one embodiment, the substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "protecting group" refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethylenoxycarbonyl (Fmoc). For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, and the like; salts of 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, ornithine, lysine, arginine, serine, and the like; quaternary ammonium salts of the compounds of invention with alkyl halides, alkyl sulphates such as MeI, (Me)₂SO₄ and the like; salts of non-natural amino acids such as D- isomers or substituted amino acids; salts of guanidine, salts of substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl; ammonium or substituted ammonium salts and aluminum salts. Other suitable salts include, but are not limited to, acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, 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.

Another embodiment of the invention is a method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response or a disease or condition induced by or associated with an excessive secretion of TNF-α and/or PDE-4 which comprises administering to a subject a therapeutically effective amount of a compound according to Formula I.

Another embodiment of the invention is a method of treating an inflammatory condition or immune disorder in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to Formula I. Preferred 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, psoriasis, uticaria, adult vernal conjunctivitis, respiratory distress syndrome, rheumatoid spondylitis, osteoarthritis, gouty arthritis, uveitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative colitis, eczema, atopic dermatitis and chronic inflammation. Further preferred are allergic inflammatory conditions.

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

Another embodiment of the invention is a method of treating a disease of the central nervous system in a subject in need thereof which comprises administering to the 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, Alzheimer's disease, cardiac failure, shock and cerebrovascular disease. Another embodiment of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to the 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 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 pro-inflammatory 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.

By "pharmaceutically acceptable" is meant those components (e.g., salts and esters) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like.

Representative compounds according to the present invention are specified below but should not construed to be limited thereto:

1. 3,5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxydibenzo[έ,</|furan-l- ylcarboxamido)pyridine 2. 3,5-dichloro-4-(8-diethylsulfamoyl-4-difluoromethoxydibenzo[έ,^furan-l- ylcarboxamido)pyridine

3. 3,5-dichloro-4-(8-cyclopropylsulfamoyl-4-difluoromethoxydibenzo[ό,</|furan- 1 -ylcarboxamido)pyridine

4. 3,5-dichloro-4-(8-isopropylsulfamoyl-4-difluoromethoxydibenzo[έ,^fUran-l- ylcarboxamido)pyridine

5. 3,5-dichloro-4-(8-n-butylsulfamoyl-4-difluoromethoxydibenzo[δ,</]furan-l- ylcarboxamido)pyridine 6. 3,5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxydibenzo[έ,£/Jfuran-l- ylcarboxamido)pyridine sodium salt

7. Methyl 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[Z^furan-2- carboxylate 8. 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[Z>,d]furan-2- carboxylic acid

9. 3,5-dichloro-4-(8-N,N-diethylsulfamoyl-4-difluoromethoxydibenzo[£,^furan- l-ylcarboxamido)pyridine sodium salt

10. 3,5-dichloro-4-(4-difluoromethoxy 8-morpholinosulfonyl dibenzo [b,d]faran- l-ylcarboxamido)pyridine

11. 3,5-dichloro-4-(4-difluoromethoxy 8-N-methylpiperazinosulfonyl dibenzo b,d]fαran- 1 -ylcarboxamido)pyridine

12. 3,5-dichloro-4-{4-difluoromethoxy 8-(4-hydroxypiperidino)sulfonyl dibenzo 6,d]furan-l-ylcarboxamido}pyridine 13. 9-(3 , 5 -dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo [b, d\ furan-2- carboxylic acid sodium salt

14. 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[έ,cf]furan-2- carboxylic acid disodium salt and free acid forms and pharmaceutically acceptable salts of the preceding. The compounds according to the invention may be prepared by the following processes. The symbols Ar, Y, R¹, R², R³ and R⁴ when used in the below formulae 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 formula (1).

(1) In one embodiment, the desired compounds of the formula (1) wherein Y is - CONH- (or -CONR⁵-); R² is -S(O)₂-NR³R⁴ or -S(O)₂-R³; n = 1 ; and Ar, R¹, R³ and R⁴ are as described in the general description, can be synthesized described in general scheme I.

General Scheme I

In the above mentioned scheme, the compound of formula (10) wherein FG is CH₃, CHO, COCH₃, CN or -COOR^a can be chlorosulfonylated, for example, using chlorosulfonic acid (neat), to give an intermediate of formula (11). The intermediate of formula (11) can then be reacted with an appropriate reagent such as R³-OH or NHR³R⁴ to give the corresponding intermediate of the formula (Ha) or (lib). The intermediate of formula (Ha) or (lib) can then be oxidized, for example, using KMnO₄, NaOCl₂ or the like (if FG is CHO or COCH₃) or hydrolysed, for example, by using NaOH or H₂SO₄ (if FG is CN or -COOR^a) to give the respective intermediate of the formula (12a) or (12b). The intermediate of the formula (12a) or (12b) can then be converted to the desired compound of the formula (1), wherein Y is -CONH-, by reacting the appropriately activated carboxylic acid (acid halide, mixed anhydride or active ester) group of the inteπnediate of formula (12a) or (12b) with the optionally substituted aryl or heteroaryl amines (ArNH₂) under appropriate basic conditions (for example, NaH in DMF, diisopropylamine or triethylamine or pyridine in THF), such as that reported in the literature. In yet another embodiment, the desired compounds of the formula (1) wherein Y is -CONH- (or -CONR⁵-); R² is -C(O)-R³, -C(O)O-R³, -C(O)NR³R⁴, or -C(O)NR³- C(O)-R⁴; n = 1; Ar, R¹, R³ and R⁴ are as described in the general description, can be synthesized described in general scheme II. General Scheme II

In the above mentioned scheme II, the compound of formula (13), wherein FG is FG is CH₃, CHO, COCH₃, CN or -COOR^a can be reacted with a compound of formula (14) under basic conditions (such as with potassium salts in DMF or DMSO, NaH in DMF or DMSO or the like) to give an intermediate of formula (15) which can then be cyclised using a metal compound or metal catalysed coupling conditions such as nickel chloride, palladium acetate or the like (preferably palladium acetate), to obtain the intermediate of formula (16). The intermediates of formula (16) can then be oxidized, for example, using KMnO₄, NaOCl₂ or the like (if FG is CHO or COCH₃) or hydrolysed, for example, by using NaOH or H₂SO₄ ( if FG is CN or -COOR^a) to give the intermediate of formula (17). The intermediate of the formula (17) can then be converted to the desired compound of the formula (1), wherein Y is -CONH-, by reacting the appropriately activated carboxylic acid (acid halide, mixed anhydride or active ester) group of the intermediate of formula (17) with the optionally substituted aryl or heteroaryl amines (ArNH₂) under appropriate basic conditions (e.g., NaH in DMF, diisopropylamine or triethylamine or pyridine in THF and the like), such as that reported in the literature. Alternatively, the desired compounds of the formula (1) wherein Y is - CONH- (or -CONR⁵-); R² is -S(O)₂-NR³R⁴; n = 1; Ar, R^R³ and R⁴ are as described in the general description, can be synthesized described in general scheme III.

General Scheme III

(10) (18) (19) (20)

In the above mentioned scheme the compound of formula (10) wherein FG is CH₃, CHO, COCH₃ or CN can be converted to the intermediate (18), for example, using standard conditions (such as oxidation, for example, using KMnO₄ OrNaOCl₂ if FG is CHO or COCH₃ or hydrolysis, for example, by using NaOH or H₂SO₄ if FG is CN). The intermediate (18) can then be esterified to intermediate (19) using a suitable alcohol (such as ethanol) in the presence of an acid (such as sulfuric acid). The intermediate (19) can then be chlorosufonylated, for example, using chlorosulfonic acid (neat) to give an intermediate of formula (20). The intermediate of formula (20) can then be reacted with an appropriate reagent such as NHR³R⁴ to give the corresponding intermediate of the formula (21). The intermediate of formula (21) can then be hydrolyzed to the intermediate of formula (22), for example, using NaOH or H₂SO₄, The intermediate of the formula (22) can then be converted to the desired compound of the formula (1), wherein Y is -CONH-, by reacting an appropriately activated carboxylic acid (acid halide, mixed anhydride or active ester) group of the intermediate of formula (22) with the optionally substituted aryl or heteroaryl amines (ArNH₂) under appropriate basic conditions (e.g., NaH in DMF, diisopropylamine or triethylamine or pyridine in THF or the like), such as that reported in the literature.

The desired compounds of the formula (1) obtained can be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula (1) obtained can be converted into the free form. The N-oxidation can be carried out in a manner likewise familiar to the person of ordinary skill in the art, e.g., with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature.

The substances according to the invention can be isolated and purified by any method known in the art, such as 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 can be 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 (e.g., ethanol or 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, re-precipitating, 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 (1) 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 and 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 can be obtained in pure form by techniques known in the art, such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (petether), chloroform, ethyl acetate, acetone, methanol or their combinations. Various polymorphs of a compound of formula (1) forming part of this invention may be prepared by crystallization of the compound of formula (1) under different conditions, for example, using different solvents commonly used or their mixtures for recrystallization, and 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 other techniques. The present invention also provides pharmaceutical compositions containing one or more compounds of 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 a pharmaceutically acceptable carrier or diluent. 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 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 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 and Z geometrical isomers wherever possible in the compounds of formula (1) which includes the single isomer or mixture of both the isomers

The pharmaceutical compositions may be in the form of tablets, capsules, powders, syrups, solutions, or suspensions, he compounds may be in a suitable solid or liquid carrier or diluent, or in suitable sterile media to form injectable solutions or suspensions. The active compounds of formula (1) may 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 formula (1) can be combined with a suitable solid or 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 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, where 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., Thorax, 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. Patent Nos. 6,402,733; 6,273,086; and 6,228,346, incorporated herein by reference in their entirety. The compound of formula (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 No. 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, such as other clinically useful therapeutic agents.

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. Example 1

3,5-dichIoro-4-(8-methyIsuIfamoyl-4-difluoromethoxydibenzo[6,</]fiiran-l- ylcarboxamido)pyridine

Step 1: N2-methyl-6-difluoromethoxy-9-formyIdibenzo[6,rf]furan-2-sulfonamide

4-difluoromethoxydibenzo[έ,</]furan-l-carboxaldehyde (1.0 g, 2.52 mmol) was added to a pre-cooled (0-5⁰C) chlorosulfonic acid (4.0 ml) and stirred at room temperature for 15 min. The reaction mixture was again cooled to 0-5oC and then quenched with ice water (25 ml) and extracted with ethyl acetate (25 x 2 ml). The organic layer was washed with water (25 x 2 ml), dried using anhydrous sodium sulfate and concentrated to obtain the sulfonyl chloride as thick oil (1.2 g). This was dissolved in THF (5.0 ml) and under cooling was treated with 40 % aqueous methylamine (1.1 mole eq.) and stirred for 30 min at room temperature. The reaction mixture is diluted with ice water (15 ml) to precipitate the product as a off-white solid which is filtered, washed with water and dried (650 mg).

IR (KBr) 3285, 3102, 2866, 1694, 1633, 1578, 1440, 1422, 1378, 1285, 1156, 1118, 1046, 1004, 853. Cm-¹.

¹H nmr (300 MHz, DMSOd₆) δ 3.66 (s, IH), 7.56 (t, IH, J= 72 Hz), 7.59 (d, IH, J= 9.0 Hz), 7.81 (d, IH, J= 9.0 Hz), 7.83(s, IH), 7.99 (m, 2H), 8.79 (s, IH), 9.55 (s, IH).

Step 2: 8-methyIsuIfamoyl-4-difluoromethoxydibenzo[^,</]furan-l-carboxylic acid

To a solution of N2-methyl-6-difluoromethoxy-9-formyldibenzo[έ,βf|furan-2- sulfonamide (650 mg, 1.9 mmol) ( from step 1) in acetone-water mixture in 7:3 ratio (21 ml) was added sulfamic acid (238 mg, 2.4 mmol) while stirring at O⁰C. A solution of sodium chlorite (340 mg, 2.9 mmol) in water (5.0 ml) was added drop wise to the above reaction mixture over a period of 10 min. and was allowed to stir at O⁰C for additional 30 min. The reaction mixture was diluted with water (21 ml) and concentrated to half the volume and the precipitated solid was filtered, washed with water and dried to give 630 mg of the product as white solid.

IR (KBr) 3439, 3294, 3110, 2983, 1678, 1633, 1578, 1412, 1385, 1325, 1251, 1164,

1118, 1064, 853. Cm^"1 .

¹H nmr (300 MHz, DMSOd₆) δ 2.56 (d, IH), 7.55 (t, IH, J= 72 Hz)₃ 7.58 (d, IH, J=

9.0 Hz), 8.05-8.13 (m, 4H), 9.38 (s, IH), 13.35 (s broad, IH).

Step 3: S-methylsulfamoyM-difluoromethoxydibenzo^^furan-l-carboxylic acid chloride

A suspension of 8-methylsulfamoyl-4-difluoromethoxydibenzo[ό,</|furan-l- carboxylic acid (630 mg, 1.6 mmol) (from step 2) in freshly dichloromethylmethyl ether (2 ml) was heated to reflux temperature for 1.5 h. The dichloromethylmethyl ether was removed under vacuum to get the corresponding acid chloride which was subjected the next reaction as such.

Step 4: 3,5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxydibenzo[^,</|furan- l-ylcarboxamido)pyridine

To a pre-washed suspension of sodium hydride (230 mg, 3.0 equiv., 5.09 mmol, 60% oil dispersion) in DMF (2 ml) was added drop wise a solution of 4-amino-3,5- dichloropyridine (553 mg, 3.39 mmol) in DMF (2 ml) at -1O⁰C. A pre-cooled solution of above acid chloride (from step 3) in THF (2 ml) was added, all at once, to the reaction mixture and the contents were stirred at -1O⁰C for 30 min. The reaction was quenched with brine, diluted with water and acidified with 10 % hydrochloric acid to obtain a white precipitate which was filtered and dried (720 mg). The crude solid was purified by column silica gel chromatography using 20 % acetone in chloroform as the eluent to provide 3,5-dichloro-4-(8-methylsulfamoyl-4- difluoromethoxydibenzo[έ,<f]furan-l-ylcarboxamido)pyridine as a white solid ( 520 mg); mp:267°C.

IR (KBr) 3439, 3255, 2927, 2932, 1676, 1635, 1556, 1489, 1455, 1393, 1280, 1219, 1130, 1096, 902. cm⁴ . ¹H nmr (300 MHz, DMSO-d₆) δ 2.41 (d, IH, J= 3 Hz), 7.54 (q, IH), 7.61 (t, IH, J= 72 Hz), 8.01 (d, 2H, J= 9.0 Hz), 8.08 (d, IH, J= 9.0 Hz), 8.84 (s, 2H) 8.94 (s, IH), 11.14 (s, IH).

Example 2

3,5-dichloro-4-(8-N,N-diethylsulfamoyI-4-difluoromethoxydibenzo[Z»,(/lfuran-l- ylcarboxamido)pyridine

Step 1 : N2,N2-diethyl-6-difluoromethoxy-9-formyldibenzo[6,tf]furan-2- sulfonamide

Was synthesized in a similar way as described in step 1 of example 1 using freshly distilled diethylamine instead of 40% aqueous methyl amine. IR (KBr) 3118, 2940, 2985, 2879, 1698, 1634, 1578, 1470, 1439, 1383, 1334, 1284, 1184, 1112, 1070, 947, 931, 693 cm-¹; ¹H nmr (300 MHz, DMSOd₆) δ 1.1 (t, 6H), 3.2 (q, 4H), 7.69 (t, IH, J= 72 Hz), 7.75 (d, IH, J= 9.0 Hz), 8.10 (m, 2H), 8.24 (d, IH, J= 6.0 Hz), 9.44 (s, IH), 10.28 (s, IH).

Step 2: S-diethylsulfamoyM-diflupromethoxydibenzotøi/lfuraii-l-carboxylic acid Was synthesized in a similar way as described in step 2 of example 1.

IR (KBr) 3421, 3220, 2937, 2877, 1717, 1700, 1635, 1602, 1579, 1470, 1455, 1386,

1275, 1200, 1152, 1017,928. cm^"1 _.

¹H nmr (300 MHz, DMSOd₆) δ 1.1 (t, 6H), 3.2 (q, 4H), 7.59 (t, IH, J= 72 Hz), 7.61

(d, IH, J = 9.0 Hz), 8.06 (m, 2H), 8.13 (d, IH, J =9.0 Hz), 9.39 (s, IH), 13.50 (s broad, IH).

Step 3: 8-diethylsulfamoyl-4-difluoromethoxydibenzo[6,rf]furan-l-carboxylic acid chloride

Was synthesized in a similar way as described in step 3 of example 1. Step 4: 3,5-dichloro-4-(8-N,N-diethylsulfamoyl-4-difluoromethoxy dibenzo[6,tf]furan-l-ylcarboxamido)pyridine

Was synthesized in a similar way as described in step 4 of example 1 . Mp: 257⁰C

IR (KBr) 3438, 3255, 2975, 2932, 1674, 1634, 1556, 1487, 1455, 1400, 1383, 1335, 1283, 1199, 1120, 1056, 819. cm^"1 .

¹H nmr (300 MHz, DMSOd₆) δ 1.1 (t, 6H), 3.2 (q, 4H), 7.60 (t, IH, J= 72 Hz), 7.69 (d, IH, J= 9.0 Hz), 7.97 (d, IH, J= 9.0 Hz), 8.05 (m, 2H), 8.85 (s, 2H) 8.91 (s, IH), 11.16 (s, IH).

Example 3

3,5-dichloro-4-(8-cycIopropylsulfamoyl-4-difluoromethoxydibenzo[Λ,</]furan-l- ylcarboxamido)pyridine

Step 1 : N2-cycIopropyl-6-difluoromethoxy-9-formyIdibenzo[b,d]furan-2- siilfonamide

Was synthesized in a similar way as described in step 1 of example 1 using freshly distilled cyclopropylamine instead of 40% aqueous methyl amine.

IR (KBr) 3267, 2965, 2867, 1698, 1640, 1579, 1514, 1453, 1396, 1382, 1282, 1254,

1159, 1136, 1070, 1014,813. cm^'1.

¹H nmr (300 MHz, DMSOd₆) δ 0.3-0.5 (m, 4H), 2.1 (m, IH), 7.56 (t, IH, J= 72 Hz),

7.59 (d, IH, J = 9.0 Hz), 7.81 (d, IH, J= 9.0 Hz), 7.89(s, IH), 8.01 (m, 2H), 8.91 (s, IH), 9.60 (s, IH).

Step 2: 8-cycIopropylsulfamoyl-4-difluoromethoxydibenzo[b,d]furan-l- carboxylic acid

Was synthesized in a similar way as described in step 2 of example 1. IR (KBr) 3267, 2965, 2867, 1698, 1640, 1579, 1514, 1453, 1396, 1382, 1282, 1254, 1159, 1136, 1070, 1014,813. cm^'1.

¹E nmr (300 MHz, DMSO-(J₆) δ 0.3-0.5 (m, 4H), 2.1 (m, IH), 7.56 (t, IH, J= 72 Hz), 7.61 (d, IH, J= 9.0 Hz), 8.02 (d, IH, J= 6.0 Hz), 8.07-8.13 (m, 3H), 9.44 (s, IH).

Step 3: 8-cyclopropylsulfamoyl-4-difluoromethoxydibenzo[b,d]furan-l- carboxylic acid chloride

Was synthesized in a similar way as described in step 3 of example 1.

Step 4:3,5-dichloro-4-(8-cycIopropylsulfamoyl-4- difluoromethoxydibenzo[6,(/]furan-l-ylcarboxamido)pyridine

Was synthesized in a similar way as described in step 4 of example 1. Mp: 264⁰C ( dec).

IR (KBr) 3438, 3274, 2928, 2958, 1675, 1635, 1586, 1514, 1489, 1385, 1313, 1219, 1282, 1195, 1121, 1028, 1014, 998. CnV¹ .

¹H nmr (300 MHz, DMSOd₆) δ 0.3-0.5 (m, 4H), 2.1 (m, IH), 7.61 (t, IH, J= 72 Hz), 7.69 (d, IH, J= 9.0 Hz), 8.00-8.12 (m, 4H), 8.84(s, 2H), 8.99 (s, IH), 11.14 (s, IH).

Example 4 3,5-dichloro-4-(8-isopropylsulfamoyl-4-difluoromethoxydibenzo[6,rf]furan-l- ylcarboxamido)pyridine

Step 1: N2-isopropyl-6-difluoromethoxy-9-formyldibenzo[b,d]furan-2- sulfonamide

Was synthesized in a similar way as described in step 1 of example 1 using freshly distilled isopropylamine instead of 40% aqueous methyl amine. IR (KBr) 3285, 2962, 2932, 2864, 1651, 1630, 1515, 1519, 1455, 1381, 1316, 1286, 1159, 1137, 1070, 1014, 813. cm⁴ _.

¹H nmr (300 MHz, DMSO-d₆) δ 0.9 (d, 6H), 3.3 (m, IH), 7.68 (t, IH, J= 72 Hz), 7.75 (d, 2H, J= 9.0 Hz), 8.11 (d, 2H), 8.23(d, IH, J= 9.0 Hz), 9.45 (s, IH), 10.29 (s, IH).

Step 2: 8-isopropylsulfamoyl-4-difluoromethoxydibenzo[b,d]furan-l-carboxylic acid

Was synthesized in a similar way as described in step 2 of example 1.

IR (KBr) 3267, 2965, 2867, 1698, 1640, 1579, 1514, 1453, 1396, 1382, 1282, 1254, 1159, 1136, 1070, 1014,813. cm^'1 _.

¹H nmr (300 MHz, DMSOd₆) δ 0.9 (d, 6H), 3.3 (m, IH), 7.63 (t, IH, J= 72 Hz), 7.75

(d, 2H, J= 9.0 Hz), 8.16 (d, IH, J= 9.0 Hz), 8.23-8.26(m, 2H), 9.49 (s, IH).

Step 3: 8-isopropylsulfamoyl-4-difluoromethoxydibenzo[b,d]furan-l-carboxylic acid chloride Was synthesized in a similar way as described in step 3 of example 1.

Step 4: 3,5-dichloro-4-(8-isopropylsulfamoyl-4- difluoromethoxydibenzo[£,</]furan-l-ylcarboxamido)pyridine

Was synthesized in a similar way as described in step 4 of example 1. mp = 245⁰C

IR (KBr) 3438, 3274, 2928, 2971, 1681, 1632, 1556, 1514, 1486, 1386, 1335, 1274,

1242, 1194, 1140, 1098, 1009, 899. cπf¹ _.

¹H nmr (300 MHz, DMSOd₆) δ 0.9 (d, 6H), 3.3 (m, IH), 7.60 (t, IH, J = 72 Hz),

7.67-7.71 (m, 2H), 8.00 (d, IH, J= 9.0 Hz), 8.06 ( d, 2H), 8.80 (s, 2H), 9.01 (s, IH), 11.14 (s, IH).

Example 5

SjS-dichloro^^S-n-butylsuIfamoyM-difluoromethoxydibenzo^t/jfuran-l- ylcarboxamido)pyridine

Step 1: N2-n-butyI-6-difluoromethoxy-9-formyldibenzo[b,d]furan-2-sulfonamide

Was synthesized in a similar way as described in step 1 of example 1 using freshly distilled n-butylamine instead of 40% aqueous methyl amine.

IR (KBr) 3285, 2962, 2932, 2864, 1651, 1630, 1515, 1519, 1455, 1381, 1316, 1286, 1159, 1137, 1070, 1014, 813. cnf¹ .

¹H nmr (300 MHz, DMSO-d₆) δ 0.9 (t, 3H), 1.2-1.4 (m, 4H), 2.7 (m, 2H), 7.47 (t, IH, J= 72 Hz), 7.47 (d, IH₅ , J= 9.0 Hz), 7.56 (m, IH), 7.72-7.88 (m, 3H), 8.84 (s, IH), 9.14(S₅ IH).

Step 2: 8-n-butyIsulfamoyl-4-difluoromethoxydibenzo[b,d]furan-l-carboxyIic acid

Was synthesized in a similar way as described in step 2 of example 1. IR (KBr) 3485, 3285, 2979, 2875, 1697, 1634, 1579, 1426, 1388, 1277, 1212, 1144,

1043, 988, 893. cm^'1 .

¹H nmr (300 MHz, DMSOd₆) δ 0.9 (t, 3H), 1.2-1.4 (m, 4H), 2.7 (m, 2H), 7.57 (d, IH,

, J= 9.0 Hz), 7.58 (t, IH, J= 72 Hz), 7.67 (t, IH), 8.01-8.20 (m, 3H), 9.39 (s, IH),

12.5(s broad, IH).

Step 3 : 8-n-butylsulfamoyl-4-difluoromethoxydibenzo[b4]fui'an-l-carboxylic acid chloride

Was synthesized in a similar way as described in step 3 of example 1.

Step 4 : 3,5-dichloro-4-(8-n-butylsulfamoyI-4-difluoromethoxydibenzo[6,</jfuran- l-ylcarboxamido)pyridine

Was synthesized in a similar way as described in step 4 of example 1. Mp: 259⁰C. IR (KBr) 3446, 3248, 3103, 2956, 2872, 1693, 1673, 1553, 1489, 1393, 1361, 1287, 1258, 1195, 1150, 1087, 1055, 926, 815. cm^"1 _.

¹H nmr (300 MHz, DMSO-d₆) δ 0.9 (t, 3H), 1.2-1.4 (m, 4H), 3.4(m, 2H), 7.62 (t, IH, J= 72 Hz), 7.73 (d, IH, J= 9.0 Hz), 8.03 (d, IH, J = 9.0 Hz), 8.18 (d, IH, , J = 9.0 Hz),

8.21 (d, IH, J= 9.0 Hz), 8.28 (d, IH, J= 9.0 Hz), 8.86 (s, 2H), 9.10 (s, IH), 11.21 (s, IH).

Example 6 3,5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxydibenzo[6,d]furan-l- ylcarboxamido)pyridine sodium salt

Was synthesized by treating 5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxy dibenzo[^d]furan-l-ylcarboxamido)pyridine with sodium hydride (1.0 eq.) in THF. ¹H nmr (300 MHz, DMSOd₆) δ 2.41 (d, IH₅ J= 3 Hz), 7.45 (q, IH), 7.40 (t, IH, J= 72 Hz), 7.46 (q, IH, exchanges with D₂O), 7.93 (m, 2H), 8.12 (d, IH, J= 8.4Hz), 8.21 (s, 2H), 9.7 (s, IH).

Example 7

Methyl 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[6,«f]furan-2- carboxylate

Step 1: Methyl-(4-fluoro-3-Bromo) benzoate Methyl-(4-fluoro) benzoate (28 g, 181.81 mmoles) was added to mixture sulphuric acid (93.63 ml) and water (1.6 ml) then bromine (8.4 ml, 163.63 mmoles) was added at O⁰C followed by addition of silver sulphate (51.02 g, 163.63 mmoles) .Reaction was stirred for 24 h. at room temperature. Reaction mass was poured in ice cold water (250 ml) and extracted with diethyl ether ( 100 x 3 ml) , dried and concentrated under reduced pressure to yield pale yellow liquid (36 g).

¹H nmr (300 MHz, DMSOd₆): δ 3.86 (s, 3H), 7.54 (t, IH), 7.98-8.04 (m, IH), 8.19- 8.22 (dd, IH, J= 6.6 Hz).

IR(KBr) cm⁴: 3098, 3052, 2847, 1727, 1599, 1507, 1492, 1436, 1389, 1282, 1226, 1107, 1048, 860, 763, 608.

Step 2: Methyl-3-Bromo-4-(5-formyl-2-methoxyphenoxy) benzoate

Isovaniline (10 g, 65.78 mmoles) was dissolved in 50 ml DMSO. To this solution was added Methyl-(4-fluoro-3-Bromo) benzoate (22.98 g, 98.68 mmoles) followed by potassium fluoride (5.73 g, 98.68 mmoles) and heated at 12O⁰C for 12h. Reaction mass was poured in water (500 ml) and extracted with dichloromethane (100 x 3 ml) , dried and concentrated to get brown solid which was purified by silica gel column chromatography ( solvent -10 % ethyl acetate and petroleum ether) to yield white solid ( 16.5 g) . mp: 96⁰C ¹H nmr (300 MHz, DMSO-d₆): δ 3.84 (s, 3H), 3.87(s, 3H), 6.79 (d, IH, J= 8.4 Hz), 7.46 (d, IH, J= 8.7Hz), 7.62 (s, IH), 7.85-7.90 (m, 2H), 8.20 (s, IH), 9.88 (s, IH). IR (KBr) cm-¹: 3006, 2951, 2845, 2606, 1707, 1682, 1605, 1507, 1429, 1283, 1255, 1116, 1019, 975, 766.

Step 3: Methyl 9-formyI-6-methoxydibenzo [b, d\ furan-2-carboxyIate

Methyl-3-Bromo-4-(5-formyl-2-methoxyphenoxy) benzoate (3 g,8.22mmoles) was dissolved in DMF (50 ml ) and was added sodium carbonate (1.3 g 12.33 mmoles ) followed by palladium acetate trimer (0.553 g, 2.47 mmoles ) in 3 lots at interval of Ih. Reaction was heated at 12O⁰C for 24h.Reaction was filtered through celite and washed with THF (100 ml). Filtrate was concentrate under vacuum and water was added (100 ml) solid precipitated was filtered out to yield brown solid (1.5 g) mp: 182-185⁰C. ¹H nmr (300 MHz, DMSOd₀): δ 3.94 (s, 3H), 4.13 (s, 3H), 7.52 (d, IH, J= 8.4 Hz), 7.92 (d, IH, J= 9Hz), 8.15 (d, IH, J= 9 Hz), 8.24 (d, IH, J= 8.4 Hz), 9.63 (s, IH), 10.18 (s, IH).

IR(KBr) cm^"1: 3437, 3095, 2955, 2841, 2735, 2709, 1690, 1630, 1573, 1428, 1307, 1249, 1109, 967, 764.

Step 4: 4-methoxy-8-(methoxycarbonyI) dibenzo [b, d] furan-l-carboxylicacid

Methyl 9-formyl-6-niethoxydibenzo [b, d] furan-2-carboxylate( 830 mg , 2.92 mmoles) was taken acetone(25 ml) to form a suspension and refluxed for 10 min.KMnO₄ (0.554 g, 3.50 mmoles) in 10 ml water was added drop wise and refluxed for 5 h. Reaction mass was filtered through celite and washed with hot acetone .Filtrate was concentrated under vacuum and to this 50 ml water was added and acidified with 1 N HCl (lOml).The precipitate was filtered and dried to yield white solid (650 mg) mp: above 250⁰C ¹H nmr (300 MHz, DMSO-d₆): δ 3.91 (s, 3H), 4.08 (s, 3H), 7.35 (d, IH, J= 8.7 Hz), 7.88 (d, IH, J= 9Hz), 8.06 (d, IH, J= 9 Hz), 8.20 (d, IH, J= 8.7 Hz), 9.60 (s, IH), 13.24 (br, s, IH). IR (KBr) cm-¹: 2924, 2853, 1712, 1690, 1574, 1421, 1282, 1109, 1088, 977, 836, 750.

Step 5: Methyl 9-(3,5-dichIoro~4-pyridylcarbamoyl)-6- methoxydibenzo[Z>,</]furan-2-carboxyIate

To 4-methoxy-8-(methoxycarbonyl) dibenzo [b, d] furan-1-carboxylic acid (85 mg, 0.283 mmoles) was added thionyl chloride (4 ml) and refluxed for 2 h. Thionyl chloride was distilled off and residue was dried under vacuum . The acid chloride thus obtained was dissolved in dry THF (3 ml). In another flask sodium hydride ( 40 mg , 0.84 mmoles ) was taken in 2 ml dry DMF cooled to -10⁰C and to this 4-amino-3,5 -dichloropyridine (46 mg, 0.28 mmole) in 2 ml DMF was added and stirred for 30 min. To this was added above prepared acid chloride and stirred for 1 h. Reaction was quenched with brine(5 ml) and acidified with IN HCl to yield solid which was filtered dried and purified by silica gel column chromatography (3% Methanol in dichloromethane ) to get 60 mg white solid . mp: above 250⁰C ¹H nmr (300 MHz, DMSOd₆): δ 3.891 (s, 3H), 4.09 (s, 3H), 7.42 (d, IH, J= 8.7 Hz), 7.89 (d, IH, J= 8.4Hz), 7.96 (d,lH, J= 8.4 Hz), 8.19 (d, IH, J= 8.7 Hz), 8.8 (s, 2H ), 9.18 (s, IH), 10.98 (s, IH exchangeable with D₂O).

IR (KBr) cm^"1: 3202, 2923, 2854, 1717, 1660, 1599, 1579, 1552, 1485, 1434, 1307, 1238, 1150, 1109, 1035, 836, 571.

Example 8

9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[Z>,rf]furan-2-carboxy-ic acid

9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[6,rf]furan-2-carbox ylic acid

Methyl 9- { [(3 , 5 -dichloropyridin-4-yl)amino] carbonyl } -6-methoxydibenzo [b,d]faran-

2-carboxylate (example 7) ( 60 mg, 0.13 mmoles) was taken in 3 ml methanol and to this sodium hydroxide ( 50 mg, 0.269 mmoles) in 3 ml water added and stirred for 24 hrs at room temperature. Then methanol was evaporated and 5 ml water was added to residue which was acidified with IN HCl and solid was filtered dried to yield white solid 30 mg. mp: above 250⁰C

¹H nmr (300 MHz, DMSOd₆): δ 4.10 (s, 3H), 7.40 (d, IH, J= 8.7 Hz), 7.84 (d, IH, J = 8.4Hz), 7.98 (d, IH, J= 8.4 Hz), 8.15 (d, IH, J= 8.7 Hz), 8.8 (s, 2H), 9.16 (s, IH),

10.98 (s, IH exchangeable with D₂O), 13.0 (br, s, IH, exchanges with D₂O).

IR: KBr cm^"1: 3439, 3216, 2943, 2845, 2274, 1690, 1668, 1628, 1483, 1389, 1280,

1083, 807.

Example 9 3,5-dichloro-4-(8-N,N-diethylsulfamoyl-4-difluoromethoxydibenzo[6,rf]furan-l- ylcarboxamido)pyridine sodium salt

Was synthesized by treating 5-dichloro-4-(8-N,N-diethylsulfamoyl-4- difluoromethoxy dibenzo[έ,d]furan-l-ylcarboxamido)pyridine with sodium hydride

(1.0 eq.) in THF.

IR(KBr):2979,2936, 1636, 1530, 1445, 1388, 1274, 1202, 1150, 1117, 1053,815. cm^"1 _.

¹H nmr (300 MHz, DMSOd₆) Sψψ (t, 6H), 3.1 (q, 4H), 7.44 (d, IH, J= 9.0 Hz),

7.46 (t, IH, J= 72 Hz), 7.91 (s, 2H), 8.05 (d, IH, J= 9.0 Hz), 8.23 (s, 2H) 9.71 (s,

IH).

Example 10

3,5-dichIoro-4-(4-difluoromethoxy 8-morpholinosulfonyl dibenzo [b,d]furan-l- ylcarboxamido)pyridine

Step 1: 4~Difluoromethoxydibenzo[6,</]furan-l-carboxylic acid

The solution of 4-Difluoromethθxydibenzo[b,d]furan-l-carbaldehyde (2.0 g , 0.793 mmol) in acetone (21 ml) was cooled to 10-20⁰C. Sulfamic acid (0.962 g, 0.990 mmol) was added at once to the reaction mixture at 10-20⁰C. Then solution of sodium chlorite (0.886 g, 1.19 mmol) in water (7 ml) was added drop wise at the same temperature. Progress of reaction was monitored by TLC. Water (40 ml) was added to reaction mixture. Acetone was distilled off under vacuum. The solid obtained was filtered and dried. Yellow colored solid (2.Ig) was obtained.

Step 2: Methyl 4-Difluoromethoxydibenzo[^,rf]furan-l-carboxylate The 4-Difluoromethoxydibenzo[b,d]furan-l-carboxylic acid (from step 1) (2.1 g, 0.783 mmol) was dissolved in methanol (20 ml) and under cooling, sulfuric acid (0.5 ml) was added drop wise and heated to reflux temperature for 3 hrs. Progress of reaction was monitored by TLC. Methanol was removed under vaccum, ice cold water (25 ml) was added to reaction mixture. The solid obtained was filtered and suck dried. Pale Yellow colored solid (1.8 g) was obtained.

Step 3: Methyl 4-Difluoromethoxy-8-morphoIinosulfonyldibenzo[fe,<f]furan-l- carboxylate Methyl 4-Difluoromethoxydibenzo[b,d]furan-l-carboxylate (from step 2) (0.250 g, 0.905 mmol) was added in chlorosulphonic acid (2 ml) under cooling and stirred for 30 min at room temperature. Progress of reaction was monitored by TLC. Water (10 ml) added and extracted with ethyl acetate. The organic extract was concentrated under vacuum. Crude mass (200 mg , 0.534 mmol) dissolved in THF (2 ml) cooled slowly morpholine ( 55 mg, 0.641 mmol) and stirred for 30 mins water added and precipitated solid filtered. Pale yellow colored solid (200 mg) was obtained. IR (KBr):3125, 2958, 2855, 1722, 1634, 1583, 1452, 1436, 1352, 1262, 1219, 1165, 1043, 988, 893 cm^"1 . ¹R nmr (300 MHz, DMSOd₆) 52.9 (m, 4H), 3.6 (m, 4H), 4.02 (s, 3H), 7.64 (d, IH, J = 9.0 Hz), 7.66 (m, IH, J= 72 Hz), 8.01 (d, IH), 8.13 (d, 2H), 9.27 (s, IH).

Step 4: 4-Difluoromethoxy-8-morpholinosulfonyldibenzo[A,</]furan-l-carboxylic acid

Methyl 4-Difluoromethoxy-8-morpholinosulfonyldibenzo[έ, d]furan- 1 -carboxylate (from step 3) (250 mg, 0.453 mmol) was dissolved in methanol (20 ml) to that under cooling potassium hydroxide (88 mg, 1.814 mmol) solution in water was added stirred for 12 h at room temperature. Progress of reaction was monitored by TLC. At the end methanol was removed under vacuum, ice cold water (15 ml) was added and reaction mass was acidified. The solid obtained was filtered and suck dried. White colored solid (21 Omg) was obtained

IR (KBr): 3115, 2903, 2866, 1705, 1637, 1602, 1582, 1454, 1436, 1387, 1266, 1210, 1165, 1043, 985, 893 cm-¹ .

¹H nmr (300 MHz, DMSO-d₆) 52.9 (m, 4H), 3.6 (m, 4H), 7.61 (d, IH, J = 9.0 Hz), 7.60 (m, IH, J= 72 Hz), 7.98 (d, IH), 8.10 (d, 2H), 9.36 (s, IH). Step 5: 4-Nitrophenyl 4-Difluoromethoxy-8- morpholinosulfonyldibenzo[b,d]furan-l-carboxylate

A mixture of 4-Difluoromethoxy-8-moφholinosulfonyldibenzo[b,d]furan-l - carboxylic acid (from step 5) (210 mg, 0.53 lmmol), 4-N,N-dimethyl amino pyridine

(6mg, 0.0531 mmol), p-nitro phenol (110 mg, 0.794 mmol) and EDCI (152 mg, 0.794 mmol) in THF (10 ml) was stirred at room temp for 2-3 hrs. Progress of reaction was monitored by TLC. At the end, reaction mixture was concentrated under vacuum.

Then water (25 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven to get pure product 320 mg as yellow solid.

IR(KBr):3117,2972,2866, 1742, 1635, 1614, 1591, 1490, 1453, 1346, 1289, 1210,

1133,1043,973,861cm-¹.

¹Hnmr(300MHz,DMSO-d₆)52.9(m,4H),3.6(m,4H),6.91 (d,2H),7.74(d, IH,J =9.0Hz),7.71 (m, IH,J=72Hz),8.02(d, IH),8.10(d,2H),8.42(d,2H),9.18(s,

IH).

Step 6: 3,5-dichIoro~4-(4-difluoromethoxy 8-morpholinosulfonyI dibenzo [#,d]furan-l-ylcarboxamido)pyridine A suspension of 4-Nitrophenyl 4-Difluoromethoxy-8-morpholinosulfonyl dibenzo[b,d]furan-l-carboxylate (from step 5) (320 mg, 0.683 mmol) and 4-amino-3, 5-dichloro pyridine (167 mg, 1.02 mmol) in N,N-dimethylformamide (5 ml) was cooled to -10-0⁰C under nitrogen .Then sodium hydride (60 % dispersion) (54 mg, 1.36 mmol) was added at once at the same temp. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10⁰C. Water (25 ml) was added drop wise to the reaction mixture at 0-10⁰C and acidified with dilute HCl. the precipitate obtained was filtered and dried in oven and purified by silica gel column chromatography using 40 % chloroform in acetone to get pure product 60 mg white colored solid was obtained IR (KBr): 3262, 3108, 2925, 2862, 1677, 1605, 1555, 1487, 1385, 1344, 1278, 1217, 1196, 1054, 1044, 993, 815 CnT¹.

¹H nmr (300 MHz, DMSO-d₆) 82.9 (m, 4H), 3.6 (m, 4H), 7.61 (d, IH), 7.71(d, IH, J = 9.0 Hz), 7.97 (d, 2H), 8.13 (d, IH), 8.84 (s, 2H), 8.88 (s, IH), 11.17 (s, IH). Mp: 25O⁰C. Example 11

3,5-dichloro-4-(4-difluoromethoxy 8-N-methylpiperazinosulfonyl dibenzo έ,fif]furan-l-ylcarboxamido)pyridine

Step 1: Methyl 4-Difluoromethoxy-8-N- methylpiperazinosulfonyldibenzo[£,</]furan-l-carboxylate

Was synthesized as described in step 3 of example 10 using N-methylpiperazine instead of morpholine. IR (KBr):3119, 2955, 2852, 1720, 1635, 1602, 1579, 1454, 1436, 1353, 1278, 1205,

1165, 1093, 943, 848 cm-¹ _.

¹H nmr (300 MHz, DMSOd₆) 52.16 (m, 4H), 2.42 (s, 3H), 2.97 (m, 4H), 4.02 (s, 3H),

7.63 (m, IH), 7.64 (d, IH, J= 9.0 Hz), 8.00 (d, IH), 8.12 (d, 2H), 8.15 (d, 2H), 9.26

(s, IH).

Step 2: 4-Difluoromethoxy-8-N-methylpiperazinosulfonyldibenzo[6,rf]furan-l- carboxylic acid

This compound was synthesized as described in step 4 of example 10 from Methyl 4- Difluoromethoxy-8-N-methylpiperazinosulfonyldibenzo[ό, d]furan- 1 -carboxylate.

IR (KBr): 3110, 2960, 2852, 1724, 1638, 1602, 1573, 1497, 1459, 1357, 1274, 1205,

1160, 1059, 944, 824 cm-¹ .

¹H nmr (300 MHz, DMSO~d₆) 52.16 (m, 4H), 2.42 (s, 3H), 2.97 (m, 4H), 7.60 (m,

IH), 7.61 (d, IH, J= 9.0 Hz), 8.00 (d, IH), 8.10 (d, 2H), 9.35 (s, IH).

Step 3: 4-Nitrophenyl 4-Difluoromethoxy-8- N-methylpiperazinosulfonyldibenzo

[b,d]furan-l-carboxylate

This compound was synthesized as described in step 5 of example 10 from 4-

Difluoromethoxy-S-N-methylpiperazinosulfonyldibenzofέ^furan-l-carboxylic acid. IR (KBr): 3081, 2928, 2857, 1742, 1636, 1614, 1591, 1498, 1454, 1335, 1289, 1208, 1164, 1033, 943, 850 cm^"1 .

¹U nmr (300 MHz, DMSOd₆) 52.16 (m, 4H), 2.42 (s, 3H), 2.97 (m, 4H), 6.92 (d, 2H), 7.71 (m, IH, J= 72 Hz), 7.75 (d, IH, J= 9.0 Hz), 8.04 (d, IH), 8.10 (d, 2H), 8.42 (d, 2H), 9.17 (s, IH).

Step 4: 3,5-dichloro-4-(4-difluoromethoxy 8-morpholinosulfonyl dibenzo [Z>,</]furan-l-ylcarboxaiiiido)pyridine

This compound was synthesized as described in step 6 of example 10 from 4- Nitrophenyl 4-Difluoromethoxy-8- N-methylpiperazinosulfonyldibenzo [b,d]furan-l- carboxylate

IR(KBr)3437,3251,3110,2935,2853, 1678, 1633, 1555, 1491, 1384, 1344, 1288,

1219, 1120, 1054, 1044,993,815cm^"1.

¹H nmr (300 MHz, DMSOd₆) 52.16 (m, 4H), 2.42 (s, 3H), 2.97 (m, 4H), 7.61 (d, IH), 7.71(d, IH, J= 9.0 Hz), 7.97 (d, 2H), 8.12 (d, IH), 8.85 (s, 2H), 8.88 (s, IH),

11.17 (s, IH).

Mp > 250 c

Example 12 3,5-dichloro-4-{4-difluoromethoxy 8-(4-hydroxypiperidino)suIfonyl dibenzo 6,</]furan-l-ylcarboxamido}pyridine

Step 1: Methyl 4-Difluoromethoxy-8-(4-hydroxypiperidino)sulfonyl dibenzo[A,</|furan-l-carboxylate Was synthesized as described in step 3 of example 10 using 4-hydroxypiperidine instead of morpholine.

IR (KBr) 3019, 2954, 2860, 1723, 1634, 1602, 1509, 1454, 1436, 1383, 1277, 1215, 1119, 1092, 927, 848 cm^"1 . ¹H nmr (300 MHz, DMSOd₆) δl.43 (m, 2H), 1.74 (m, 2H), 2.76 (m, 2H), 3.20 (m, 2H broad), 4.02 (s, 3H), 7.63 (m, IH), 7.65 (d, IH, J= 9.0 Hz), 8.00 (d, IH), 8.11 (d, 2H), 9.26 (s, IH).

Step 2: 4-Difluoromethoxy-8-(4-hydroxypiperidino)sulfonyldibenzo[A,</]furan-l- carboxylic acid

This compound was synthesized as described in step 4 of example 10 from Methyl 4-

Difluoromethoxy-8-(4-hydroxypiperidino)sulfonyl dibenzo[b,d]furan-l-carboxylate.

IR (KBr) 3413, 3113, 2928, 2859, 1716, 1636, 1602, 1579, 1445, 1459, 1345, 1289, 1215, 1130, 1052, 944, 824 cm⁴ _.

¹H nmr (300 MHz, DMSOd₆) δl.43 (m, 2H), 1.74 (m, 2H), 2.76 (m, 2H), 3.20

(m,2H), 4.6 (m, IH), 7.67 (d, IH), 7.69(m, IH, J= 72.0 Hz), 8.10 (d, IH), 8.15 (d,

2H), 9.15 (s, IH), 13.5 ( s , lH).

Step 3: 4-Nitrophenyl 4-Difluoromethoxy-8-(4- hydroxypiperidino)sulfonyldibenzo [b,d]furan-l-carboxylate

This compound was synthesized as described in step 5 of example 10 from A-

Difluoromethoxy-8-(4-hydroxypiperidino)sulfonyldibenzo[ό, d]faran- 1 -carboxylic acid.

IR(KBr)3117,2976,2866, 1744, 1635, 1614, 1599, 1490, 1456, 1346, 1284, 1210, 1133,1045,973,861cm-¹.

¹H nmr (300 MHz, DMSOd₆) δl.43 (m, 2H), 1.74 (m, 2H), 2.76 (m, 2H), 3.20 (m,

2H broad), 4.02 (s, 3H),6.91 (d, 2H), 7.74 (d, IH, J = 9.0 Hz), 7.71 (m, IH, J = 72

Hz), 8.02 (d, IH), 8.10 (d, 2H), 8.42 (d, 2H), 9.18 (s, IH).

Step 4: 3,5-dichIoro-4-{4-difluoromethoxy-8-(4- hydroxypiperidino)sulfonyldibenzo [#,d]furan-l-ylcarboxamido)pyridine

This compound was synthesized as described in step 6 of example 10 from 4- Nitrophenyl 4-Difluoromethoxy-8-(4-hydroxypiperidino)sulfonyldibenzo [b,d]furan- 1-carboxylate. IR (KBr) 3446, 3275, 3109, 2931, 2869, 1678, 1650, 1552, 1486, 1399, 1339, 1279, 1218, 1150, 1094, 1094, 993, 815 cm^"1.

¹H nmr (300 MHz, DMSOd₆) δl.43 (m, 2H), 1.74 (m, 2H), 2.76 (m, 2H), 3.20 (m,2H broad), 4.5 ( m,lH), 7.60 (d, IH), 7.70(d, IH, J= 9.0 Hz), 7.75 (d, 2H), 8.10 (d, IH), 8.85 (s, IH), 8.86 (s, 2H), 11.16 ( s ,1H). Mp >250 c.

Example 13

9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[ό,rfJfuran-2-carboxylic acid sodium salt

To a solution of 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[ό,cf]furan-2- carboxylic acid (example 8) (240 mg, 0.55 mmol) in dry THF (5 ml) was added sodium hydride (24.0 mg, 0.50 mmol) and stirred for 30 min. at room temperature. Solid was filtered out washed with THF and dried to get sodium salt as white solid (240 mg).

IR(KBr): 3192, 2933, 2849, 2374, 1632, 1609, 1563, 1488, 1383, 1283, 1080, 782, 722 cm:¹

¹Hnmr(DMSOd₆): δ 4.04(3H,s),7.21 (IH,d,J=6.9Hz),7.55 (IH,d,J=8.4 Hz),7.89( IH,d,J=8.1Hz),8.09(IH,d,J=8.7Hz),8.55(2H,s),9.16(IH,s), 10.9(IH,br).

Melting point-Above 25O⁰C .

Example 14

9-(3,5-dichIoro-4-pyridyIcarbamoyI)-6-methoxydibenzo[Z>,<flfuran-2-carboxyIic acid disodium salt

To a solution of 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[έ,^]furan-2- carboxylic acid (example 8) (250 mg, 0.58 mmol) in dry THF (15 ml) was added sodium hydride (27.8 mg, 1.16 mmol) and stirred for overnight at room temperature. Solid was filtered out washed with THF and dried to get disodium salt as white solid (200 mg).

IR(KBr): 3416, 2250, 1647, 1611, 1525, 1502, 1466, 1437, 1387, 1287, 1204, 1116, 1083, 785 cm.^"1

¹H nmr (DMSOd₆): δ 3.98 ( 3H, s ), 7.05 (IH, d, J= 8.4Hz), 7.45 ( IH, d, J= 8.4 Hz), 7.90 ( IH, d, J= 8.4Hz), 8.04 ( IH, d, J= 8.4Hz), 8.15 ( 2H, s ), 9.47 ( IH, s ).

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 34⁰C. 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. Drug 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 34⁰C. The reaction was stopped by boiling the tubes for 2 mins at 100⁰C 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 34⁰C. 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).

Results were expressed as percent inhibition (ICs₀) in nM concentrations. The IC₅0 values were determined from the concentration curves by nonlinear regression analysis.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

All patent and non-patent publications and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

We Claim:

1. A compound of general formula (1)

(1) wherein:

R¹ is hydrogen or substituted or unsubstituted alkyl;

R² is hydrogen, -C(O)-R³, -C(O)O-R³, -C(O)NR³R⁴ , -C(O)NR³-C(O)-R⁴,- S(O)_q-R³, -S(O)_q-NR³R⁴, -OR³, -SR³ ,or -CR³R⁴-COOR³;

Ar is substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;

Y is-C(O)NR⁵- NR⁵SO₂, SO₂NR⁵ or NR⁵C(O); n is an integer from 1 to 4; q is 0,1 or 2;

R³ and R⁴ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano, formyl, acetyl, halogen, a protecting group, -C(O)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_q-R^a, -S(0)_q- NR^aR^b , -NR^aR^b, -0R^a and -SR^a or R³ and R⁴ may be joined together with the atom to which they are both attached to form an optionally substituted saturated or unsaturated C₃-C₈ cyclic ring, which may optionally include up to two heteroatoms selected from O₅ NR^a or S;

R^a and R^b are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted 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 ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl;

R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring; or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer, polymorph, N-oxide, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Ar is an optionally substituted isooxazole, optionally substituted pyrimidine, optionally substituted pyridyl, or optionally substituted pyridyl-N-oxide in which the optional substituents are independently selected from 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.

3. A 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, and substituted alkylcarbonyloxy are selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), 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, substitutedor unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -C00R^x, - C(O)R^X, -C(S)R^X, -C(0)NR^xR^y, -C(O)ONR^xR^y, -NR^xCONR^yR^z, -N(R^x)SOR^y, - N(R^x)SO₂R^y, -(=N-N(R^x)R^y), - NR^xC(0)0R^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(O)R^X, -OC(O)NR^xR^y, - R^xNR^yC(0)R^z, -R^xOR^y, -R^xC(O)OR^y ₅ -R^xC(O)NR^yR^z, - R^xC(O)R^y, -R^xOC(O)R^y, -SR^X, -SOR^X, -SO₂R^X, or -ONO₂, wherein R^x, R^y and R² in each of the above groups are independently 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 or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring.

4. The compound according to claim 1-2 or 3, wherein R¹ is unsubstituted alkyl.

5. The compound according to claim 4, wherein R¹ is methyl.

6. The compound according to claim 1-2 or 3, wherein R¹ is substituted alkyl.

7. The compound according to claim 6, wherein R¹ is -CHF₂.

8. The compound according to claim 1-6 or 7, wherein n=l and R² is hydrogen or

9. The compound according to claims 1-7 or 8, wherein Y is -C (O)NH-.

10. The compound according to claims 1-8 or9, wherein Ar is substituted or unsubstituted 4-pyridyl, substituted or unsubstituted 4-pyridyl-N-oxide, or substituted or unsubstituted 3-pyridyl.

11. The compound according to claim 10, wherein the substituent in the substituted pyridyl group is halogen.

12. The compound according to claim 11, wherein the halogen in the substituted pyridyl group is chloro.

13. The compound according to claim 10, wherein Ar is

14. A compound according to claim 1, selected from

3,5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxydibenzo[o,£flfuran-l- ylcarboxamido)pyridine;

3,5-dichloro-4-(8-diethylsulfamoyl-4-difluoromethoxydibenzo[έ, d]furan- 1 - ylcarboxamido)pyridine;

3,5-dichloro-4-(8-cyclopropylsulfamoyl-4-difluoromethoxydibenzo[δ,cf|furan-l- ylcarboxamido)pyridine;

3,5-dichloro-4-(8-isopropylsulfamoyl-4-difluoromethoxydibenzo[έ,d]furan-l- ylcarboxamido)pyridine; 3,5-dichloro-4-(8-n-butylsulfamoyl-4-difluoromethoxydibenzo[Z>,c(]furan-l- ylcarboxamido)pyridine;

3,5-dichloro-4-(8-methylsulfamoyl-4-difluoromethoxydibenzo[6,c/]furan-l- ylcarboxamido)pyridine sodium salt;

Methyl 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[&,<^furan-2- carboxylate; 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[έ,β(]furan-2-carboxylic acid; 3,5-dichloro-4-(8-N,N-diethylsulfamoyl-4-difluoromethoxydibenzo[Z>,c(]furan-l- ylcarboxamido)pyridine sodium salt;

3,5-dichloro-4-(4-difluoromethoxy 8-morpholinosulfonyl dibenzo [h,d]furan-\- ylcarboxamido)pyridine ;

3 , 5 -dichloro-4-(4-difluoromethoxy 8-N-methy lpiperazinosulfonyl dibenzo b, <f]furan- 1 -ylcarboxamido)pyridine; 3,5-dichloro-4-{4-difluoromethoxy 8-(4-hydroxypiperidino)sulfonyl dibenzo b, d\ flιran-l-ylcarboxamido}pyridine; 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-memoxydibenzo[i^ftιran-2-carboxylic acid sodium salt;

9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[Z>_JcT|furan-2-carboxylic acid disodium salt ; or a free acid or a pharmaceutically acceptable salt thereof.

15. A method for the preparation of a compound of claim 1, wherein Y is - CONR⁵-, n is 1, and R² is -SO₂NR³R⁴ or -SO₂R³, comprising the steps of: a) chlorosulfonylating a compound of formula (10)

(10) wherein FG is CH₃, CHO, COCH₃, CN or -COOR^a to obtain an intermediate of formula (11).

(H); b) reacting the intermediate of formula (11) with a reagent of the formula R³-OH or NR³R⁴ to give the corresponding intermediate of formula (lla) or (lib)

(Ha) (lib); c) oxidizing the intermediate of formula (lla) or (lib) to give the respective intermediate of formula (12a) or (12b)

(12a) (12b); d) coverting the intermediate of formula (12a) or (12b) to the compound of formula (1); and e) optionally converting the compound of formula (1) into a corresponding salt and/or N-oxide.

16. A method for the preparation of a compound of claim 1, wherein Y is - CONR⁵-, n is 1, and R² is -C(O)-R³, -C(O)O-R³, -C(O)NR³R⁴, or -C(O)NR³-C(O)-R⁴, comprising the steps of: a) reacting a compound of formula (13) with a compound of formula (14)

wherein FG is CH₃, CHO, COCH₃, CN or -COOR^a, under basic conditions to obtain the intermediate of formula (15)

(15) b) cyclizing the intermediate of formula (15) to yield the intermediate of formula (16)

c) oxidizing the intermediate of formula (16) if FG is CHO or COCH₃, or hydrolysing the intermediate of formula (16) if FG is CN or COOR^a, to yield the intermediate of formula (17)

(17) d) converting the intermediate of formula (17) to yield the compound of formula (1); e) optionally converting the compound of formula (1) into a corresponding salt and/or the N-oxide.

17. A method for the preparation of a compound of claim 1, wherein Y is -

CONR⁵-, n is 1, and R² is -SO₂NR³R⁴, comprising the steps of: a) converting a compound of formula (10)

(10) wherein FG is CH₃, CHO, COCH₃, or CN to obtain the intermediate of formula (18)

(18); b) converting the intermediate of formula (18) to the intermediate of formula (19) wherein R^a is alkyl

(19); c) chlorosulphonating the compound of formula (19) to obtain the intermediate of formula (20)

R^a

(20); d) reacting the intermediate of formula (20) with a reagent of the formula NHR³R⁴ the corresponding intermediate of formula (21) R^a

(21); e) hydrolyzing the intermediate of formula (21) to give the respective intermediate of the formula (22)

(22); f) converting the intermediate of formula (22) into the compound of formula (1); g) optionally converting the compound of formula (1) into a corresponding salt and/or N-oxide.

18. A pharmaceutical composition comprising a compound according to claim 1-13 or 14, and a pharmaceutically acceptable diluent or carrier.

19. A method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response or a disease or condition induced by or associated with an excessive secretion of TNF-α and/or PDE-4 in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to claim 1-13 or 14.

20. A method of treating an inflammatory condition or immune disorder in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to claim 1-13 or 14.

21. The method according to claim 20, wherein the inflammatory condition or immune disorder is chosen from asthma, bronchial asthma chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoriasis, uticaria, adult vernal conjunctivitis, respiratory distress syndrome, rheumatoid spondylitis, osteoarthritis, gouty arthritis, uveitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative colitis, eczema, atopic dermatitis and chronic inflammation.

22. The method according to claim 21, wherein the inflammatory condition or immune disorders is an allergic inflammatory condition.

23. The method according to claim 21, wherein the inflammatory condition or immune disorder is selected from inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin and heart.

24. The method according to claim 21, wherein the inflammatory condition is chosen from bronchial asthma, nepritis, and allergic rhinitis.

25. A method for abating inflammation in an affected organ or tissue comprising delivering to the organ or tissue a therapeutically effective amount of a compound according to claim 1-13 or 14.

26. A method of treating a disease of the central nervous system in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to claim 1-13 or 14.

27. The method according to claim 26, wherein the disease of the central nervous system is chosen from depression, amnesia, dementia, Alzheimer's disease, cardiac failure, shock and cerebrovascular disease.

28. A method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to claim 1-13 or 14.