FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)



NEW TRICYCLIC COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC
DISORDERS: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING
THEM
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION:


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

in which
R', R2 and R3 may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(0)-R', -Q(O)O-R1, -C(O)NR1R1 , -S(O)m-R1 -S(O)m-NR1R1 , nitro, -OH, cyano, amino, formyl, acetyl, halogen,-OR1, -SR1, oxo(=O), oxime(=NOR1), protecting groups or when two R2

substitutents ortho to each other, may be joined to a form a ring, which may optionally
include up to two heteroatoms selected from O, NR1 or S;
wherein P represents oxygen or sulfur;
wherein b represents 0-5;
wherein n represents 1,2 or 3
Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted
or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;
Preferably Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substiruents one ore more may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino
XisO, S(0)mor NR1;
Wherein m is 0, 1 or 2;
Y is -C(O)NR4, -NR4SO2, -SO2NR4 or -NR4C(O);
R4 is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR1, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring ;
The present invention also relates to a process for the preparation of the above said novel heterocyclic compounds of the formula (I) as defined above. The compounds of general formula (I) more particularly, down regulate or inhibit the production of TNF-a as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome and diabetes.

The compounds of the present invention are particularly useful for the treatment of asthma.
Back ground of the Invention
Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production. The airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component. The magnitude of asthmatic reactions is correlated with the number of eosinophils present in lungs.
The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although they are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When activated, they synthesize and release inflammatory cytokines such as IL-1, IL-3, TNF-a and inflammatory mediators such as PAF, LTD4 and relative oxygen species that can produce edema, bronchoconstriction. Tumor necrosis factor (TNF-a) 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-a 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 cGMP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGMP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophilis are believed to be a critical proinflammatory target for asthma, identification of the expression of PDE 4 gene family in eosinophils led to the PDE 4 as potential therapeutic target for asthma [ Rogers.D.F., Gmbycz.M.A., Trends

Pharmacol. Sci., 19, 160-164(1998); Barnes,P.J., Trends Pharmacol.Sci., 19,415-423(1998)].
The mammalian cyclic nucleotide phosphodiesterases(PDEs) are classified into eleven families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [ Soderling,S.H., Bayuga,S.J., and Beavo,J.A., Proc. Natl. Acad. Sci., US'A,96,7071 -7076(1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi,Si, Okamura,K. and Omori,K., J.Biol.Chem.,.,274, 18438-18445(1999)]. 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 provide 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)]. Excessive or unregulated TNF-a 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, ecdotoxic shock, respiratory distress syndrome, bone resorption diseases ; Since TNF-a also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find tremendous utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, I, 211-214(19195) and ibid., 244-248]. TNF-a is also reported to be a factor of insulin-resistant diabetes because it declines the phosphorylating mechanism of insulin receptors of muscle and fat cells [ J.clin.Invest., 94,1543-1549(1994)].
Interest in the drugs capable of selective inhibition of PDE 4 has taken much attention due to several factors such as (a) the tissue distribution of PDE-4 strongly suggested that the pathologies related to the central nervous and immune systems could be treated

through the selective PDE 4 inhibitors (b) 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 four human cDNA isoforms of PDE-4 (PDE4-A,B,C,D) were identified. mRNA for all these four isoforms was expressed in human lungs. PDE 4-A, B and D were expressed in eosinophils. Of these gene families, PDE-4 characterized as the cAMP-specific gene family has been shown to predominate in pro-inflammatory human lymphoid and myeloid lineage cells.
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-a. Since eosinophilis are believed to be a critical pro-inflammatory target for asthma, identification of the expression of PDE 4 gene family in eosinophils led to the PDE 4 as potential therapeutic target for asthma.
OBJECTIVE OF THE INVENTION
The usefulness of several PDE 4 inhibitors, unfortunately, is limited due to their undesirable side effect profile which include nausea and emesis (due to action on PDE4 in CNS) and gastric acid secretion due to action on PDE4 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)1. One of the earliest PDE4 inhibitor, Rolipram, was withdrawn from the clinical development because of its severe unacceptable side effect profile.[Zeller E.et.al.,Pharmacopsychiatry 17, 188-190(1984)]. It has recently become apparent, to some extent. The cause of severe side effects of several PDE4 inhibitor molecules in human clinical trials has recently become apparent.
There exists two binding sites on mammalian PDE4 at which inhibitor molecules bind. Also PDE4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE4H and Low affinity

Rolipram binding site PDE4L[ Jacobitz,S., McLaughlin,M.M., Livi,G.P., Burman,M., Trophy,T.J., Mol.Pharmacol .,50, 891-899(1996)]. It was proved that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE4H whereas some beneficial actions are associated with PDE4L inhibition. It was also found that human recombinant PDE4 exists in 4 isoforms A, B, C and D[ Muller,T., Engels,P., Fozard,J.R., Trends Pharmacol, Sci., 17, 294-298(1996)]. Accordingly compounds displaying more PDE4D isoenzyme selectivity over the A, B or C are found to have less amount of side effects than Rolipram [Hughes. B et.al.,, Br. J. Pharmacol. 1996, 118, 1183-1191]. Therefore selective inhibitors of PDE4 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 in this direction for achieving the desired highly selective PDE4 isozyme inhibitors, so far the success is limited. Among the various compounds which showed clinically proven PDE 4 inhibition,

•Ariflo" of the formula 2( Smith Kline Beecham's compound), Byk Gulden's Roflumilast of formula 5 and Bayer's Bay-19-8004 of formula 6 have reached advanced stage of human clinical trials. Some of the other compounds which have shown potent PDE4 inhibitory activity are CDP-840 of the formula 3 (Cellthech's compond), D-4418 of the formula 4 (Schering-Plough's compound), 5CP-220,629 of the formula 7 (Pfizer's), PD-168787 of the formula 8 (Parke-Davis's compound) and Filaminast of the formula 9 (

American Home Products' compound). However, recently due to various reasons such as efficacy and side effects problems, Ariflo, CDP-840 and Bay-19-8004 were discontinued from clinical trials for asthma treatment. Other compounds of the formulae 4 and 7 are presently undergoing phase-1 clinical trials.




CP - 220,629
7

During the course of research aimed at the development of novel anti-asthmatic compounds having potential PDE4 inhibitory activity, we have found in the literature
1. PCT Patent publication WO 02/051806-A1 (published on July 4, 2002 by Astrazeneca UK Limited)
The present invention provides a compound of formula

Wherein;
R1 is selected from C1-4 alkyl, C1-4 alkanoyl, C1-4 alkylsulphonyl, N-(C1-4 alkyl)sulphamoyl and N,N-(C1-4 alkyl)2 sulphamoyll wherein R1 may be optionally substituted on carbon by one or more R ;

R2 & R3 are both methyl or R2 & R3 together form -(CH2)4- or -(CH)4-; wherein said -
(CH2)4- or -(CH)4- may be optionally substituted by R8;
R4 is C1-4 alkyl;
R5 is -C(O)NR9R10, -C(O)R9 or -C(O)C(O)R9;
R6 and R8 are independently selected from halo, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, C1-4 alkyl, N-(C1-4 alkyl)amino, N,N-(CM alkyl)2amino and C1-4
alkoxy;
R is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino carboxy,
carbamoyl, mercapto, sulphamoyl, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C1-4 alkoxy, C1-4
alkanoyl, C1-4 alkanoyloxy, N-(C1-4 alkyl)amino, N,N-(C1-4 alkyl)2amino, C1-4
alkanoylamino, N-(C1-4 alkyl)carbamoyl, N-(C1-4 alkyl)sulphamoyl, N,N-(C1-4
alkyl)2sulphamoyl, C1-4alkylsulphonylamino, carbocyclyl or heterocyclyl;
R9 and R10 are independently hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-4
alkoxy, carbocyclyl or heterocyclyl wherein R9 and R10 independently may be optionally
substituted on carbon by one or more R11; and wherein if said heterocyclyl contains an -
NH- moiety that nitrogen may be optionally substituted by R12; or R9 and R10 together
with the nitrogen to which they are attached form a heterocyclic ring optionally
substituted on carbon by one or more R13; and wherein if said heterocyclyl contains an -
NH- moiety that nitrogen may be optionally substituted by R14;
R11 andR13 are independently selected from halo, cyano, hydroxyl, ureido, amino, nitro,
carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy, C1-4 alkanoylamino, C2-6 alkenyloxycarbonyl,
C1-4 alkoxycarbonyl, N-(C1-4 alkyl)amino, N,N-(C1-4 alkyl)2amino, C1-4
alkoxycarbonylamino, C1-4 alkoxycarbonyl- N-(C1-4 alkyl)amino, N-(CM
alkyl)carbamoyl, N,N-(C1-4 alkyl)2carbamoyl, C1-4alkylS(O)a wherein a is 0-2, N-(C1-4
alkyl)sulphamoyl, N,N-(C1-4 alkyl)2sulphamoyl, heterocyclyl, heterocyclyloxy,
heterocyclylcarbonyl, heterocyclylthio, carbocyclyl, carbocyclyloxy,
carbocyclylcarbonyl, carbocyclylcarbonylamino, carbocyclyloxycarbonyl,
carbocyclylthio; wherein R11 and R13 independently may be optionally substituted on
carbon by one or more R15; and wherein if said heterocyclyl contains an -NH- moiety
that nitrogen may be optionally substituted by R16;

R12, R14 and R16 are independently selected from C1-4alkyl, C1-4 alkanoyl, C1-4
alkylsulphonyl, sulphamoyl, N-(C1-4 alkyl)sulphamoyl, N,N-(C1-4 alkyl)2Sulphamoyl, C1-4
alkoxycarbonyl, carbamoyl, N-(C1-4 alkyl)carbamoyl, N,N-(CM alkyl)2carbamoyl,
carbocyclyl, carbocyclyl C1-4 alkyl, carbocyclylcarbonyl, carbocyclylsulphonyl,
heterocyclyl, heterocyclylcarbonyl, heterocyclylsulphonyl; wherein R12, R14 and R16
independently may be optionally substituted on carbon by one or more R17;
R15 is selected from halo, cyano, hydroxy, ureido, amino, nitro, carboxy, carbamoyl,
mercapto, sulphamoyl, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-4
4 alkanoyloxy, C1-4 alkanoylamino, C2-6 alkenyloxycarbonyl, C1-4 alkoxycarbonyl, N-
(C1-4 alkyl)amino, N,N-(C1-4 alkyl)2amino, C1-4 alkoxycarbonylamino, C1-4
alkoxycarbonyl- N-(C1-4 alkyl)amino, N-(C1-4 alkyl)carbamoyl, N,N-(CM
alkyl)2carbamoyl, C1-4alkylS(0)a wherein a is 0-2, N-(C1-4 alkyl)sulphamoyl, N,N-(C1-4
alkyl)2Sulphamoyl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl,
heterocyclylmethyloxy, heterocyclyloxycarbonyl,carbocyclyl, carbocyclyloxy,
carbocyclylcarbonyl, carbocyclylmethoxy,carbocyclyloxycarbonyl,; wherein R15 may be optionally substituted on carbon by one or more R18;
R17 and R18 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;
m is 0-2; wherein the values of R6 may be the same or different; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
2. PCT Patent publication WO 02/24672-A2 (published on March 28, 2002 by Warner
Lambert Company) The invention relates BCAT inhibitor compounds of formula 1

Wherein:
R3 is H, or F, Br, alkyl, carboxy, alkoxy, substituted alkoxy,
Rl, R2, R4, and R5 are independently H, halogen, alkyl, substituted alkyl, alkoxy,
substituted alkoxy, cyano, nitro, amino, alkylamine and thioalkyl,
Ar is bicyclic heteroaryl, tricyclic heteroaryl, substituted bicyclic heteroaryl, substituted
tricyclic heteroaryl except (6-methoxybenzofuran)-2-nyl or 3-quinolinyl;
Where there is more than one stereoisomer, each chiral centre may be independently R or
S; or a pharmaceutically acceptable salt, ester, prodrug or amide thereof.
3. PCT Patent publication WO 98/55115 (published on December 10,1998 by Eli Lilly & Company)
The present invension provides novel 3-amino-l,2,3,4-tetrahydro-9H-carbazole-6-carboxamides and 4-amino-10H-cyclohepta[7,6-b] indole-7-carboxamides of formula

Wherein:
Rl and R2 are independently hydrogen, C1-C4 alkyl, or -CH2CH2-Aryl where Aryl is
phenyl, phenyl monosubstituted with halo, or 1-(C1-C6 alkyl)pyrazol-4-yl;
R3 is C3-C6 cycloalkyl, or a heterocycle;

n is 1 or 2 and pharmaceutically acceptable salts and hydrates thereof.
4. US patent no. US5708187 (granted on January 13, 1998 by Eli Lilly & Company )
The present invension provides novel 6-substituted-l,2,3,4-tetrahydro-9H-carbazoles and 7-substituted -10H-cyclohepta[7,6b]indoles of formula

Wherein:
Rl and R2 are independently hydrogen, C1-C4 alkyl, or -CH2CH2-Aryl where Aryl is
phenyl, phenyl monosubstituted with halo, or 1-(C1-C6 alkyl)pyrazol-4-yl;
X is -OH, -NHC(0)R3, -NHC(Y)NR4, -NHC(0)OR5, -C(0)R6 or -NHS02R7;
R3 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, phenyl, substituted phenyl,
naphthyl, (C1-C4 alkylene)phenyl, thienylmethyl, or a heterocycle;
R4 is C1-C6 alkyl, phenyl or phenyl disubstituted with halo;
R5 is C1-C6 alkyl, C2-C6 alkenyl, benzyl or phenyl monosubstituted with halo;
R6 is C1-C6 alkyl, phenyl or phenyl monosubstituted with halo or C1-C4 alkyl;
m is Oorl;
n is 1 or 2; and
Y is S or O; and pharmaceutically acceptable salts and hydrates thereof.
5. US patent no. US6492422 (granted on December 10, 2002 by Warner-Lambert Company)
The present invention provides compound of formula

Wherein n is zero or an integer of 1 or 2; X is -O-,
-S(O)p- where p is zero or an integer of 1 or 2, —N—
R2 wherein R2 is hydrogen, alkyl, acyl, benzyl, -CH2-, or
—C— •
II ' O
R is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, trifluoromethyl, alkanoyloxyalkyl,
alkanoylaminoalkyl, alkylthioalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, N-alkylpiperazinoalkyl, N-
phenylalkylpiperazinoalkyl, morphilinoalkyl, piperidinoalkyl, N-
alkylalkylpiperidinoalkyl, pyridylalkyl, thienylalkyl, quinolinylalkyl, thiazolylalkyl,
cycloalkyl, cycloalkylalkyl, phenyl, phenyl is substituted by one to three substituents
selected from the group consisting of: hydroxyl, alkoxy, alkyl, alkylthio, alkylsulfinyl,
alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, cyano, nitro, trifluoromethyl or
on adjacent carbon atoms by either a one to two carbon alkenylenedioxy group or a two
to three carbon alkenyleneoxy group, phenylalkyl wherein the phenyl is substituted by
alkyl, alkoxy, halogen or trifluoromethyl, heteroaryl substituted by one to two
substituents selected from the group consisting of: alkyl or halogen, biphenyl, biphenyl
substituted by alkyl, alkoxy, halogen, trifluoromethyl or cyano, biphenylalkyl,
biphenylalkyl wherein biphenyl is substituted by alkyl, alkoxy, halogen, trifluoromethyl
or cyano;
D is zero or an integer of 1 to 3;
L is zero or an integer of 1 to 3;
R1 is hydrogen, a side chain of a natural amino acid or a side chain of an unnatural amino
acid;

Y is OR3 wherein R3 is hydrogen, methyl, ethyl, benzyl or -NH-R4 wherein R4 is
hydrogen, alkyl or benzyl;
and corresponding isomers thereof, or a pharmaceutically acceptable salt thereof.

Summary of the invention:
Accordingly, the present invention provides novel heterocyclic compounds of the general formula (I)

®—Ar
in which
R , R and R may be same or different and are independently selected from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R1, -C(O)O-R1, -C(O)NR1R1 , -S(O)m-R', -S(O)m-NR1R1 , nitro, -OH, cyano, amino, formyl, acetyl, halogen,-OR1, -SR1, oxo(=O), oxime(=NOR1), protecting groups or when two R2 substitutents ortho to each other, may be joined to a form a ring, which may optionally include up to two heteroatoms selected from O, NR1 or S; wherein P represents oxygen or sulfur; wherein b represents 0-5; wherein n represents 1,2 or 3

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;
Preferably Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents one ore more may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino
Xis O, S(O) or NR1;
Wherein m is 0, 1 or 2;
Y is -C(O)NR4, -NR4SO2, -SO2NR4 or -NR4C(O);
R4 is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR1, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring ;
DETAILED DESCRIPTION OF THE INVENTION
The term 'alkyl' refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like .
The term "Alkenyl " refers to aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms in the e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
The term " Alkynyl" refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon

atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, butnyl and the like.
The term "Alkoxy" denotes alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH3, -OC2H5 and the like
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicycic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g sprio (4,4) non-2-yl.
The term " cycloalkylalkyl" refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms directly attached to alkyl group which then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure, such as cyclopropylmethyl, cyclobuylethyl, cyclopentylethyl, and the like.
The term " cycloalkenyl" refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms with atleast one carbon- carbon double bond such as cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5, -C2H5C6H5 and the like.
The term "Heterocyclic ring" refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purpose of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. 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, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone, dioxaphospholanyl , oxadiazolyl, chromanyl, isochromanyl and the like.
The term "Heteroaryl" refers to heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "Heteroarylalkyl" refers to heteroaryl ring radical as defined above directly bonded to alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
The term "Heterocyclyl" refers to a heterocylic ring radical as defined above. The heterocylyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "Heterocyclylalkyl" refers to a heterocylic ring radical as defined above directly bonded to alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
The term "carbocyclic" refers to a cyclic group containing 3-10 carbon atoms
The term "protecting group" refers to CBZ or BOC and the like

The term "Halogen" refers to radicals of Fluorine, Chlorine, Bromine, Iodine.
The substituents in the 'substituted alkyl', 'substituted alkoxy' 'substituted alkenyl' 'substituted alkynyl' 'substituted cycloalkyl' substituted cycloalkylalkyl' substituted cyclocalkeny1 'substituted arylalkyl' 'substituted aryl' 'substituted heterocyclic ring', 'substituted heteroaryl ring,' 'substituted heteroarylalky1, 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl' 'substituted alkylcarbonyl', 'substituted alkylcarbonyloxy' and 'substituted carboxylic acid' may be the same or different which one or more selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, amino, nitro, oxo (=0), thio (=S), formyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic ring, -COORx, -C(O)Rx, -C(S)Rx, -C(O)NRxRy, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)S02Ry, -N(Rx)CO-, -(=N-N(Rx)Ry), -N(Rx)RyCO-, -NRxRyC(0)ORz, -NRxRy, -NRxC(0)Ry-, -NRxC(S)Ry -NRxC(S)NRyRz, -N(Rx)SO-, -NRxS02-, -0RX, -ORxC(O)NRyRz, -ORxC(O)ORy-, -OC(O)Rx, -OC(O)NRxRy, -RxNRyRz, -RxRyRz, -RXCF3, -RxNRyC(0)Rz, -RxORy, -RxC(0)ORy, -RxC(0)NRyRz, -RxCS, -RxC(0)Rx, -RxOC(O)Ry, -SRX, -SORx, -SO2Rx, or -ONO2,(wherein Rx, Ry and RZ in each of the above groups can be hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstitued heterocyclic ring, substituted or unsubstitued heterocyclylalkyl, substituted or unsubstitued heteroaryl or substituted or unsubstitued heteroarylalkyl)
Pharmaceutically acceptable salts forming part of this invention include salts derived
from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases
such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-
dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,
hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine,
procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'-
diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine,

aminopyridine, purine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, and phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
Some of the representative compounds according to the present invention are specified below but should not construed to be limited thereto;
1) 3,5-dichloro-4-(6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-yl carboxamido)pyridine
The compounds according to the present invention may be prepared by the following processes. The symbols P, X, Y, Ar, R1, R2, R3, R4 when used in the formulae below are to be understood to present those groups described above in relation to formula (I) unless otherwise indicated.
The present invention discloses a process for the preparation of compounds of general formula (I) wherein Y = -CONR4 using the general synthetic scheme I.

GENERAL SCHEME I.
In the above general scheme I where P, X, Ar, R , R , R , R have the meanings described above and wherein Z is a halogen, intermediate 12 can synthesized by reacting the appropriately substituted or unsubstituted halocyclohexanone of the formula 10 with appropriately substituted aryl group of the formula 11 under standard basic conditions. Intermediate 12 can be cyclized under standard acidic conditions to obtain the tricylic hydrocarbon of the formula 13 which further can be formylated using standard literature methods to give the intermediate of the formula 14. The formyl group of intermediate of the formula 14 can be oxidized to the carboxylic acid to obtain the intermediate of the formula 15. The carboxylic acid of the formula 15 can be transformed into the desired compounds of the formula (I) by reacting the suitably activated carboxylic acid of intermediate 15 with appropriate optionally substituted aminopyridine or optionally substituted aniline under basic conditions. The heteroatom, in cases where Ar is a heteroaryl ring can be also converted to its oxide by using appropriate oxidizing agents

such as m-chloroperbenzoic acid or hydrogen peroxide as permitted by the synthetic scheme.
The present invention also discloses a process for the preparation of compounds of general formula (I) wherein Y = -SO2NR4 using the general synthetic scheme II.
GENERAL SCHEME II.

In the above scheme II wherein P, X, Ar, R1, R2, R3, R4 have the meanings described above the desired compounds of the formula (I) can prepared by chlorosulfonylation of the compound of formula 13 to obtain an intermediate of the formula 16 followed by sulfonamide formation by reacting intermediate 16 with the amine of the formula ArNHR4 using conventional methods. The heteroatom, in cases where Ar is a heteroaryl ring can be also converted to its oxide by using appropriate oxidizing agents such as m-chloroperbenzoic acid or hydrogen peroxide as permitted by the synthetic scheme. The present invention also discloses a process for the preparation of compounds of general formula (I) wherein Y = -NR4SO2 or -NR4CO using the general synthetic scheme III.

GENERAL SCHEME III.

In the above scheme III wherein P, X, Ar, R1, R2, R3, R4 have the meanings described above the desired compounds of the formula (I) can prepared by nitration of the compound of formula 13 to obtain an intermediate of the formula 17 followed by reduction of the nitro to amino group to obtain intermediate 18 using conventional methods. The intermediate 18 can be reacted with an appropriate carboxylic acid chloride of the formula ArCOCl or with an appropriate sulfonyl chloride of the formula ArSO2Cl to obtain the carboxamide 19 or the sulfonamide 20. Both 19 and 20 can be alkylated to the desired compounds of the formula (I) using conventional methods. The carboxamide 19 and the sulfonamide 20 are also the desired compounds wherein R4 is hydrogen. The heteroatom, in cases where Ar is a heteroaryl ring can be also converted to its oxide by using appropriate oxidizing agents such as m-chloroperbenzoic acid or hydrogen peroxide as permitted by the synthetic scheme.
The N-oxidation is carried out in a manner likewise familiar to the person skilled in the art, e.g with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. The person skilled in the art is familiar with the reaction conditions which are necessary for carrying out the process on the basis of his expert knowledge.

The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent, e.g in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecepiting, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.
In general, the ethereal solvents used in the above described processes for the preparation of compounds of the formula (I) are selected from diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like. The chlorinated solvent which may be employed may be selected from dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride and the like . The aromatic solvents which may be employed may be selected from benzene, toluene. The alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert.butanol and the like. The aprotic solvents which may be employed may be selected from N, N-dimethylformamide, dimethyl sulfoxide and the like.
In general, the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, iso propanol, water or their combinations, or column chromatography using Alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.

Various polymorphs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions, example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
The present invention also provides pharmaceutical compositions, containing compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their enantiomers, their diasteromers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like. The pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders.
It will be appreciated that some of the compounds of the general formula (I) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in the compounds of the general formula (I) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures.
The invention may also contain E & Z geometrical isomers wherever possible in the compounds of the general formula (I) which includes the single isomer or mixture of both the isomers
The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain

flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The active compounds of the formula (I) will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds of the formula (I) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds of the formula (I) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of the formula (I). The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
In addition to the compounds of formula (I) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful therapeutic agents.
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 N-(3,5-dichloropyrid-4-yl)-4-methoxy dibenzo [b, d] furan-1-carboxamide-N-oxide


Step 1: 2-(2-methoxyphenoxy)-l-cyclohexanone ; To a stirred suspension of potassium carbonate (16.68 gm, 0.1209 mol) in dry DMF (30 ml) was added a solution of guaicol (5.0 gm, 0.0404 mol) in DMF (10 ml). The reaction contents were heated at 140°C for 1-2 h. Bromocyclohexanone (14.26 gm, 0.0806 mol) in DMF (5 ml) was added to the above suspension and the reaction mixture was stirred at room temperature for 24 h. The reaction were poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The organic extracts were combined and washed with IN sodium hydroxide (50 ml x 2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vaccuo to obtain the product as a pale yellow oil which was purified by silica gel column chromatography using 20 % ethyl acetate in petroleum ether to give 5.82 gm of off-white solid m.p; 62-68°C.
IR (KBr) 2936, 2861, 1721, 1504, 1468, 1323, 1252, 1220, 1127, 1069, 1026, 923, 756 cm-1.
1H nmr (300 MHz, CDC13) 8 1.67-1.8 (brm, 2H), 1.97-2.11 (brm, 3H), 2.29-2.39 (brm, 2H), 2.59-2.67 (brm, 1H), 3.84 (s, 3H), 4.60-4.65 (brm, 1H), 6.81-6.97 (brm, 4H).
Step 2: 6-methoxy-l,2,3,4-tetrahydrobenzo [b,d] furan; 2-(2-methoxyphenoxy)-1 -cyclohexanone (0.384 gm, 0.00174 mol) was added as fine powder at room temperature to viscous polyphosphoric acid [prepared from o-phosphoric acid (2.13 gm, 0.0217 mol) and phosphorus pentoxide (3.2 gm, 0.0112 mol)] and stirred with a glass rod manually to homogeneity for 15 min. Ice (10 gm) was added to the above reaction mass and stirred for 15 min. followed by extraction with ethyl acetate (25 ml x 3). The organic layer was washed with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulphate. The organic layer was concentrated under vaccuo to give the crude product as a pale yellow oil which was taken to the next step without purification.
Step 3: 6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-carbaldehyde; 6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan (obtained from step 2) was dissolved in dichloromethane (5 ml) and the solution was cooled to -10°C. To this solution was added tin (IV) chloride (0.29 gm, 0.0018 mol) all at once at -10°C under nitrogen atmosphere followed by dropwise addition of a solution of dichloromethyl methyl ether (0.125 gm,

0.001 mol) in dichloromethane (5 ml) at -10°C. The reaction mixture was allowed to attain room temperature under stirring for 30 min. Cold water (20 ml) was added to the reaction mixture and extracted with ethyl acetate (25 ml x 3). The organic layer was washed with water and dried over anhydrous sodium sulphate. The organic layer was concentrated under vaccuo to give the crude product as greenish oil which was purified by silica gel column chromatography using 20 % ethyl acetate in petroleum ether as the eluent. The product was obtained as a white solid (35 mg). mp 83-89°C.
IR (KBr) 3034, 2930, 2712, 1694, 1678, 1620, 1562, 1438, 1420, 1294, 1274, 1213, 1104,1093,1000,807,798 cm-1.
1H nmr (300 MHz, CDC13) 5 1.83-1.96 (brm, 4H), 2.77-2.81 (brm, 2H), 2.93-2.98 (brm, 2H), 4.06 (s, 3H), 6.81 (d, 1H, J= 8.1 Hz), 7.73 (d, 1H,J= 8.1 Hz), 10.15 (s, 1H).
Step 4: 6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-carboxylic acid; To a
solution of 6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-carbaldehyde (35 mg, 0.152 mmol) in acetone (4 ml) was added sulfamic acid (22 mg, 0.227 mmol) while stirring at 0°C. A solution of 80% sodium chlorite (19 mg, 0.212 mmol) in water (2.0mL) was added drop wise to the above reaction mixture over a period of 10 min. and was allowed to stir at 0°C for additional 30 min. Water (40 ml) was added to obtain a precipitate which was filtered, washed with water and air dried to give 40 mg of the product as white solid. mp 210-214°C.
IR (KBr) 2934, 2854, 2633, 1682, 1624, 1562, 1508, 1417, 1284, 1215, 1151, 1097, 1008,911,780 cm-1.
'H nmr (300 MHz, DMSO) 5 1.69-1.78 (brm, 2H), 1.82-1.88 (brm, 2H), 2.73 (brt, 2H, J = 6 Hz), 2.82 (brt, 2H, J= 6 Hz), 3.94 (s, 3H), 6.90 (d, 1H, J= 8.4 Hz), 7.72 (d, 1H, J = 8.4 Hz).
Step 5a : 6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]fluran-9-carboxylic acid chloride;

A suspension of 6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-carboxylic acid (150 mg, 0.607 mmol) in a mixture of benzene (2.5 ml) and freshly distilled thionyl chloride (2.5 ml) was heated to reflux temperature for 3-4 h. The excess thionyl chloride was removed under vacuum to get the corresponding acid chloride which was subjected the next reaction as such.
Step 5b: 3,5-dichloro-4-(6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-yI carboxamido)pyridine;
To a pre-washed suspension of sodium hydride (36.5 mg, 1.51 mmol, 60% oil dispersion) in DMF (5 ml) was added drop wise a solution of 4-amino-3,5-dichloropyridine (98.9 mg, 0.66 mmol) in DMF (2 ml) at -10°C. A pre-cooled solution of above acid chloride (from step 5a) in THF (5 ml) was added, all at once, to the reaction mixture and the contents were stirred at -10°C for 30 min. The reaction was quenched with brine, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 5 % hydrochloric acid, saturated sodium bicarbonate and brine solution. Evaporation of solvent gave a crude solid which was purified by silica gel column chromatography using 5 % ethyl acetate in chloroform as the eluent. 3,5-dichloro-4-(6-methoxy-l,2,3,4-tetrahydrobenzo[b,d]furan-9-yl carboxamido)pyridine was obtained as a white solid (93 mg). mp 237-239°C.
IR(KBr) 3191, 2925, 2815, 1663, 1513, 1486, 1282,1211, 1098,903,800,723 cm-1. 1H nmr (300 MHz, DMSO) 8 1.66-1.74 (brm, 2H), 1.82-1.88 (brm, 2H), 2.61 (brt, 2H), 2.74 (brt, 2H), 3.97 (s, 3H), 6.97 (d, lH,y= 8.1 Hz), 7.62 (d, 1H, J= 8.4 Hz), 8.72 (s, 2H), 10.55 (s, 1H).
Dated this Seventh (7th)xlay of February 2003
(GLENN SALDANHA)
Managing Director
Glenmark Pharmaceuticals Limited