This application claims priority to Indian patent application No. 1324/CHE/2008 filed on June 02, 2008, the contents of which are incorporated by reference in their entirety

Field of invention

The present invention relates to novel heterocyclic compounds that may be useful as phosphodiesterase inhibitors (PDEs), in particular phosphodiesterase type 4 inhibitors represented by general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides .their pharmaceutically acceptable salts , their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor(TNF-α).

Background of the invention

Bronchial asthma is a complex multifactorial disease characterized by hyperactivity of the respiratory tract to external stimuli. Airway inflammation leads to a number of severe lung diseases including Asthma and Chronic Obstructive Pulmonary Diseases (COPD, also known as Chronic Obstructive Airway Disease, Chronic Obstructive lung Disease or chronic airflow limitation and chronic airflow obstruction.). The airflow limitation is usually progressive and associated with abnormal inflammatory response of the lungs to noxious particles or gases.

Many biological responses are mediated by levels of cyclic nucleotides mainly cAMP and cGMP which in turn are synthesized by adenylyl cyclases (ACs) and guanylate cyclases (GCs). To regulate levels of cAMP and cGMP, all cells have Phosphodiesterases (PDEs) that hydrolyze cAMP and cGMP to 5'-AMP and 5'-GMP. In humans there are 21 different PDE isoforms that are classified into 11 different groups. Basically these PDEs fall into three categories like those that are specific to (i) cAMP, (ii) cGMP and (iii) those that act on both cAMP and cGMP. These 11 groups of PDEs are classified according to their nucleotide selectivity. PDE4 has 4 isoforms and in all these isoforms upstream conserved regions (UCRs) are present which appear to modulate dimerisation and may bind to signaling molecules such as lipids. There are atleast 18 different splice variants of the four PDE4 isoforms exist. Because of the critical role of cAMP in mediating cytokine responses cAMP specific PDE (PDE-4) play important role in the progression of inflammatory diseases. Many of the mediators of inflammatory response such as T cells, B cells, monocytes, neutrophils, eosinophils and macrophages have PDE4 enzymes as their primary cAMP specific PDE. Among the inflammatory diseases that are implicated by these cellular mediators are asthma, chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and multiple sclerosis. Consequently the development of PDE4 inhibitors as therapeutic agents for these diseases has been a major pharmaceutical focus. PDE4 indirectly controls the degree of bronchodilation. In the inflammatory cells cAMP is a negative regulator of the primary activating pathways such as cytokine release by T-cells. Inhibition of the PDE4 isozymes in these cells results in elevated cAMP levels and consequent inactivation of the inflammatory response. In addition to the direct role of cAMP in inflammatory cell function, elevated cAMP levels also lead to smooth muscle relaxation. Consequently inhibition of PDE4 activity leading to higher cAMP levels cause bronchodilation thereby alleviating symptoms of respiratory diseases such as asthma or COPD.

Also Inhibition of PDE4 enzyme increase levels of cAMP and Cyclic AMP modulates the activity of the most of the cells that contribute to the pathophysiology of allergic asthma. Elevation of cAMP would produce beneficial effects, some of which includes apart from airway smooth muscle relaxation, inhibition of mast cell mediator release, suppression of neutrophil degranulation, inhibition of basophil degranulation and inhibition of monocyte and macrophage activation. The connection between PDE4 activity and cognition has been speculated ever since the discovery that the cAMP -regulating dunce gene of the fruit fly encodes a PDE4 homologue(A/afwre, 1981,289,5793,79-1;J.mol.biol., 1991,222,3,553-565).

Current drug discovery efforts involved the design of the PDE4 inhibitors with reduced side effects at the same time maintaining the anti inflammatory properties of rolipram. Compounds like Cilomilast, roflumilast, Lirimilast and AWD-12-281 belong to the second generation PDE4 inhibitors.

1. Patent application W093/19749 claims the compounds shown below which are useful for allergy and inflammatory states.

One of the representative examples of this patent is as given below.

2. Patent US5811455 Claims the compounds of formulae AA and BB


One of the representative examples of this invention is

4. WO2006011024 Patent application claims the compounds of generic formula

One of the representative compounds is as given below and the compounds of invention claims for asthma and chronic obstructive pulmonary disease apart from other disease states.

Challenges that are facing the PDE4 inhibitors are mainly nausea, vomiting, increased gastric acid secretion which may be because of selectivity towards binding sites. Based on the prior art reports compounds with selectivity for the high-affinity rolipram binding site causes side effects where as compounds with selectivity for low-affinity rolipram binding site are expected to have better therapeutic effects compared to rolipram (J. Biol. Chem. 1992,267(3):1798-1804; J. Biol. Chem. 1999,274(17):11796-11810). Other side effects include cardiac dysarhythmias, vasculitis and osteoporosis.

As described above, as regulation of intracellular signaling is coordinated by PDE4, It has become a validated target for the development of therapeutics for inflammatory diseases such as asthma and COPD. PDE4 also has been shown to be a potential target for depression, memory enhancement, cardiovascular disease and osteogenesis.

During the course of our research aimed at the development of novel anti-asthmatic compounds having potential PDE4 inhibitory activity, we have filed a patent application in India bearing No. 1647/MUM/2006 dated September 11, 2006 and corresponding PCT publication No 2008/032171, published on March 20, 2008, incorporated herein by reference in their entireties, for a novel series of heterocyclic compounds useful for the treatment of inflammatory and allergic disorders.

Summary of the invention

According to the present invention the compounds are represented by the general formula (I)

their analogues, derivatives, tautomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable solvates, N-oxides and bioisosteres Wherein Ring A is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl

Z is selected from C(O), NR1, S(O)m, C(O)NR1, NR1(CO), CR2R3, CR2R3C(O), CR2R3O CR2R3, C(O)CR2R3, CR2R3C(O)C(O), C(O)C(O)CR2R3, NR1C(S), C(S)NR1, CR2R3S(O)m, S(O)mCR2R3, S(O)mNR1, NR1S(O)m, NR1S(O)mNR1;

R1 is selected from hydrogen or substituted or unsubstituted alkyl; |

R2 and R3 are independently selected from hydrogen, C1-C6 straight or branched alkyl,

C2-C6 straight or branched alkenyl, alkylamino, alkyl halo, alkyl hydroxy, acyl, alkoxy; or R2 and R3 together with the carbon they are attached form a C3 to C5 substituted or unsubstituted spiro ring;

Ring B is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl

m represents an integer ranging from 0,1 or 2;

In another embodiment the present invention relates to compounds represented by general formula (II)

Wherein

Ring A is as defined above; Z is as defined above;

Hy represents substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

In yet another embodiment the present invention relates to compounds represented by general formula (III)

their analogues, derivatives, tautomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutical^ acceptable hydrates, pharmaceutically acceptable solvates, N-oxides and bioisosteres

Wherein

Z is as defined above;

Hy represents substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

In yet another embodiment, the present invention relates to compounds represented by general formula (III) wherein Z is C(O) and Hy is as defined above.

In yet another embodiment, the present invention relates to compounds represented by general formula (III) wherein Z is NR1 and Hy is as defined above.

In yet another embodiment, the present invention relates to compounds represented by general formula (III) wherein Z is S(O)m, Hy and m are as defined above.

In yet another embodiment, the present invention relates to compounds represented by general formula (III) wherein Z is CR2R3, Hy and m are as defined above

In yet another embodiment, the present invention relates to compounds represented by general formula (I) wherein ring A represents but not limited to substituted or unsubstituted moieties selected from



Wherein

X is selected from hydrogen, hydroxyl, halo, substituted or unsubstituted amino, nitro, cyano, substituted or unsubstituted alkyl, haloalkyl, haloalkyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, amido, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, NR1S(O)mR1, R1C(O)R1, R1OC(O)R1, -SR1, - SOR1, COOR1, -NR2R3, -NR1C(O)R1;

R1, R2 and R3 are as defined above;

n represents an integer ranging from 0,1, 2 or 3;

In yet another embodiment the present invention relates to compounds represented by general formula (I) wherein ring B represents but not limited to substituted or unsubstituted moieties selected from



Wherein X is as defined above;

In yet another embodiment, the representative compounds of the present invention are listed below without limiting the scope the invention

(4-Difluoromethoxy-8-nitro-dibenzofuran-1-yl)-(2, 3-dihydro-pyrrolo [3, 2-c]pyridin-1-yl)-methanone

N-[6-Difluoromethoxy-9-(2, 3-dihydro-pyrrolo [3, 2-c]pyridine-1-carbonyl) -dibenzofuran-2-yl]-methanesulfonamide

N-[9-(2, 3-Dihydro-pyrrolo [3, 2-c]pyridine-1-carbonyl)-6-methoxy-dibenzofuran-2-yl]-methanesulfonamide

N-[5-(2, 3-Dihydro-pyrrolo[3,2-c]pyridine-1-carbonyl)-8-methoxy-9-methyl-9H-carbazol-3-yl]- methanesulfonamide

(7-Bromo-2, 3-dihydro-pyrrolo [3, 2-c]pyridin-1-yl)-(4-difluoromethoxy-8-nitro-dibenzofuran -1-yl)-methanone

Present invention also relates to a process for the preparation of the novel heterocyclic compounds of general formula (I).

The compounds of the present invention may inhibit or regulate the TNF alpha production and are useful in the treatment of allergic and inflammatory diseases including asthma, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease allergic rhinitis endotoxic shock and adult respiratory distress syndrome. The compounds of present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Detailed description of the invention:

Definitions:

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon that may be substituted or unsubstituted. Examples of "Alkyl" include but are not limited to methyl,ethyl,n-propyl,isopropyl,n-butyl,t-butyl,n-pentyl,isobutyl and the like.

The term "alkenyl" used herein, either alone or in combination with other radicals, denotes a straight or branched C2-C6 aliphatic hydrocarbon chain containing one or more carbon to carbon double bonds that may be optionally substituted with multiple degrees of substitution being allowed. The term "alkenyl" includes dienes and trienes of straight and branched chains and are selected form Vinyl allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl The term "alkynyl" used herein, either alone or in combination with other radicals, denotes a straight or branched chain aliphatic hydrocarbon containing two to eight carbons with one or more triple bonds which may be substituted or unsubstituted. The term "alkynyl" includes di-and tri-ynes. such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.

The term "Acyl" refers to the group-C(0)Rd where Rdis Alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl each as herein defined and examples of which include acetoyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, benzoyl and the like, which may be substituted or unsubstitutted.

"Alkoxy" refers to a group -ORc where Rc is alkyl as herein defined. Representative examples include but are not limited to methoxy, ethoxy and like "Alkylamino" refers to the group - N(RC)2 where one Rc is alkyl and the other Rc independently is H or alkyl as herein defined "Alkylhalo" refers to the group 'Rc-halogen' where Rc is alkyl defined as above and halogen is selected from Fluorine, Chlorine, Bromine and Iodine and it can be haloalkyl, dihaloalkyl or trihaloalkyl or polyhaloalkyl like methylene chloride,CF3,CHF2,CF2-CF3 etc.,

"Halogen" refers to Fluorine, Chlorine, Bromine or Iodine
"Alkylhydroxy or hydroxyalkyl" refer to the group RcOH where Rc is alkyl as herein defined and the representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, hydroxy propyl and like

"Aryl" refers to optionally substituted aromatic ring system having the carbon atoms in the range of five to ten carbon atoms and they may be monocyclic, bicyclic or polycyclic and unsaturated or partially saturated and one or more carbons may optionally be replaced by one or more heteroatoms selected from N, O and S. Exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and like.

"Aminosulfonyl" refers to -NH-SO2-; "Carboxy" refers to -COO-; "Carbamoyl" refers to the group -C(O)NH2; "Sulfonyl" Refer to the group -S(O)2-; "Sulfinyl" Refer to the group -S(O)-"Thio" refers to "-S-"; "Sulfamido" refers to a group -S(O)2NH2; "Carboxamido" refers to group -CO-NH2; "Guanidyl" refers to a group -NH-C (=NH)-NH2; "Ureido or uredyl" group refers to -NH-C(O)-NH2;

The term "cycloalkyl" used herein, either alone or in combination with other radicals, denotes mono, bicyclic or polycyclic saturated, partially saturated hydrocarbon ring system of about 3 to 12 carbon atoms which may be substituted or unsubstituted. Exemplary "cycloalkyl" groups include but are not limited to cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, perhydronapthyl, adamantyl, noradamantyl or spirobicyclic groups such as spiro (4,4)non-2-yl.

The term "cycloalkylalkyl" refers to a cycloalkyl ring containing 3 to 12 carbon atoms directly attached to an alkyl group which is then attched to the main structure at any carbon atom in the alkyl group that results in a stable structure such as cyclopropylmethyl, cyclobutylmethyl and the like.

"Heteroaryl "refers to monocyclic aromatic ring system or a fused bicyclic aromatic ring systems comprising two or more aromatic rings preferably two to three ring systems. These heteroaryl rings contain one or more nitrogen, sulfur and or oxygen atoms where N-oxides sulfur oxides and dioxides are permissible heteroatom substitutions The term includes ring(s) optionally substituted with halogens, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyl, hydroxy, and alkyl. Examples of heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, chromanyl, iso chromanyl and the like.

"Heterocyclyl" refers to a stable 3 to 15 membered ring that is either saturated or has one or more degrees of unsaturation or unsaturated. These heterocyclic rings contain one or more heteroatoms selected from the group consisting of nitrogen sulfur and/or oxygen atoms where N-oxides, sulfur oxides and dioxides are permissible heteroatom substitutions. Such a ring may be optionally fused to one or more of another heterocyclic ring(s), aryl ring(s) or cycloalkyl ring(s). Examples of such groups may be selected from the group comprising azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphonilyl, pyridazinyl, indolyl, isoindolyl, quinolinyl, chromanyl and like..

"Heterocyclylalkyl" refers to a heterocyclic ring radical defined above directly bonded to an 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.

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 alkenyi, 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, -COOR5, -C(O)R5, -C(S)R5, -C(O)NR5R6, - C(O)ONR6R7, -NR5CONR6R7, -N(R5)SOR6, -N(R5)SO2R6, -(=N-N(R5)R6), -NR5C(O)OR6, -NR5R6, -NR5C(O)R6, -NR5C(S)R6, -NR5C(S)NR6R7, -SONR5R6, - SO2NR5R6, -OR5, -OR5C(O)NR6R7, -OR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, - R5NR6C(O)R7, -R5OR6, -R5C(O)OR6, -R5C(O)NR6R7, -R5C(O)R6, -R5OC(O)R5, -SR5, - SOR5, -SO2R5, and -ONO2l wherein R5, Re and R7 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 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. Alternately R6 and R7 together along with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted. 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"

"Stereoisomers" refers to certain compounds described here in contain one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers. Scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers such as purified enantiomers/diastereomers or enantiomerically / diastereomerically enriched mixtures.

"Bioisosteres" refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity. Bioisostereic compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.

"Pharmaceutically acceptable salts" forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, 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, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates and the like.

"Pharmaceutically acceptable solvates" may be hydrates or comprising other solvents of crystallization such as alcohols.

"Compounds of the invention" or "present invention" refers to the compounds of the present invention represented by general formula (I) as here in defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides .their pharmaceutically acceptable salts , their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

The compounds of the present invention may inhibit or regulate the TNF alpha production and are useful in the treatment of allergic and inflammatory diseases including asthma, inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease allergic rhinitis endotoxic shock and adult respiratory distress syndrome. The compounds of present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Another embodiment of the present invention is a method of treating an inflammatory disease, disorder or condition associated with undesirable inflammatory immune response or a disease or condition induced by or associated with an excessive secretion of TNF-a and PDE-4 in humans. The method includes administering to the human a therapeutically effective amount of a compound according to the general formula (I). "Method of treating" includes preventing or delaying the appearance of clinical symptoms, inhibiting the state disorder or condition, relieving the disease causing regression of the disease.

General method of preparation

The compounds of general formula (I) can be synthesized by the scheme illustrated below:

The compound of general formula a (wherein ring A and X are as defined in the specification) is oxidized using suitable oxidizing agents such as potassium permanganate, sodium chlorite, potassium dichromate, potassium chromate, pyridinium dichlorochromate, pyridinium chlorochromate, Jone's reagent (solution of chromium trioxide in concentrated sulfuric acid) and the like in the presence of suitable solvents such as acetone, acetone-water, sulfamic acid, glacial acetic acid, water, DCM, chloroform, EDC and the like to form the compound of general formula ab. The compound of general formula ab is then converted to either acid chloride or ester using suitable chlorinating agents such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride or suitable reagents such as DCC/p-Nitrophenol in the
presence of suitable solvents such as benzene, dimethylformide (DMF), tetrahydrofuran (THF), ethyl acetate, dichloromethane, chloroform and the like. The acid chloride or ester thus formed is
then reacted with suitable substituted or unsubstituted group represented by ring B in presence of suitable bases such as N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), sodium
methoxide, sodium hydride, potassium tertiary.butoxide, sodium hydroxide and the like in the presence of suitable solvents such as tetrahydrofuran, dimethylformamide (DMF), acetonitrile,
water and the like to obtain the compound of general formula 1. Alternately compound of general formula ab can be converted to compound of general formula 1 via mixed anhydride method using suitable reagent such as alkyl chloroformate or aryl chloroformate in the presence of suitable solvents such as tetrahydrofuran (THF), dioxane, chloroform, ethylene dichloride (EDC), ethyl acetate and the like. Also the compound of general formula ab is converted to
compound of general formula ac using coupling reagent such as 1-ethyl-(3,3'- dimethylaminopropyO-carbodiimide (EDCI), 1,1'-carbonyldiimidazole (CDI), N,N'-dicylohexylcarbodiimide (DCC), 1- hydroxyl-benzotriazole (HOBt) and the like tetrahydrofuran, dichloromethane, chloroform, ethyl acetate and the like.

The stereo isomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.

Different polymorphs of a compound of general formula (I) of present invention may be prepared by crystallization of the compound of formula (I) under different conditions .For example making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, by exposing to room temp, by heating or melting the compound followed by gradual cooling and the like. The presence of polymorphs may be determined by one or more methods like solid probe NMR spectroscopy, DSC, TGA, Powder X-Ray diffraction and IR.

The present invention also provides pharmaceutical compositions containing the compounds of invention as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their polymorphs .their enantiomers, their diastereomers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the suitable pharmaceutically acceptable carriers, diluents. The pharmaceutical compositions according to the present invention are useful for the treatment of allergic and inflammatory diseases including asthma , inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease allergic rhinitis endotoxic shock and adult respiratory distress syndrome and related diseases. The pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays and like and may contain flavorants, sweeteners etc., in a suitable solid or liquid carriers or diluents or in a suitable sterile media to form injectable solutions or suspensions.

It is understood that in any of the above schemes any reactive group in the substrate molecule may be protected according to any conventional procedure known in the priorart. Suitable protecting groups comprises N-Boc, N-Cbz, N-Fmoc, alkyl, benzophenoneimine for protection of amino group, acetal protection for aldehyde, ketal protection for ketone.

The invention also encompasses prodrugs of compounds of the invention , which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances, In general such prodrugs will be functional derivatives of compounds of invention, which are readily convertible in vivo into compounds of the invention.

The invention also encompasses the active metabolites of the compounds of the present invention of general formula (I).

Experimental data

Preparation of Intermediate:

Procedure: Prepared according to the procedure reported in US 2007/0105855.


Procedure: Prepared according to the procedure reported in WO 2008/005955.

Procedure: Prepared according to the procedure reported in US 2007/0105855.

Procedure: Prepared according to the procedure reported in WO 2008/005955.

Preparation of (4-Difluoromethoxy-8-nitro-dibenzofuran-1-yl)-(2, 3-dihydro-pyrrolo [3, 2-c]py ridin-1 -yl)-methanone

To a solution of 4-difluoromethoxy-8-nitro-dibenzofuran-1-carboxylic acid (200 mg, 0.6173 mmol) in toluene(3ml) was added thionyl chloride (0.460ml, 6.191mmol) and mixture was stirred at reflux temperature for about 3 hours, cooled the reaction mixture to room temperature and toluene was evaporated under vacuum. Repeated for 4 to 5 times to remove excess thionyl chloride. The above acid chloride was dissolved in tetrahydrofuran and added N, N-diisopropyl-N-ethyl amine (1ml) followed by 2, 3-dihydro-1 H-pyrrolo [3, 2-c]-pyridine (80 mg, 0.6167 mmol) at room temperature. The reaction mass was stirred at room temperature for 4 hours. Added water and the product was extracted with 10% MeOH/CHCI3 which was concentrated under vacuum and purified with column chromatography to afford the titled compound (160 mg, 61% yield).

1H NMR (300 MHz, CDCI3) 6 3.25-3.31 (t, 2H), 4.25 (br s, 2H), 6.66-7.14 (t, 1 H, J = 72.3 Hz), 7.47-7.56 (m, 2 H), 7.54-7.78 (d, 1H, J = 9.09 Hz), 8.34-8.48 (m, 3H), 8.83 (d, 1H, J = 1.9 Hz). MS m/z[M+1] 426.1.

Preparation of N-[6-Difluoromethoxy-9-(2, 3-dihydro-pyrrolo [3, 2-c]pyridine-1-carbonyl) -dibenzofuran-2-yl]-methanesulfonamide
To the clear solution of example 1 (160 mg, 0.388 mmol) in a mixture of solvent (EtOH: THF: H20 :: 2:1:0.5, 15 ml) at 85 °C was added ammonium chloride (75 mg) and iron powder (75 mg). The reaction mixture was stirred at the same temperature for 1 hour. The reaction mass was cooled to room temperature and filtered through celite bed. To the filtrate added 20 ml saturated brine and then extracted with 10% MeOH/CHCI3 which was dried with anhydrous sodium sulphate and concentrated under vacuum to afford crude amine (150 mg). The crude amine was dissolved in a mixture of dichloromethane (3.5 ml) and THF (3.5 ml) and cooled to 0 to 5 °C. To this mixture was added a mixture of methanesulphonyl chloride, pyridine and the above solvent at the same temperature and stirred for 45 min. The reaction mass was quench with water and extracted with 20% MeOH/CHCI3 which was dried with anhydrous sodium sulphate and concentrated under vacuum and purified by column chromatography to afford the titled compound (46 mg, 20 % yield) as off-white solid. HPLC Purity: 93.09 %.

IR (KBr) cm'1 3413, 3068, 2853, 1659, 1595, 1484, 1464, 1439, 1391, 1377, 1317, 1290, 1153, 1111.

1H NMR (300 MHz, DMSO-d6) 5 2.82 (s, 3 H), 3.16 (s, 2H), 4.03 (br s, 2H), 7.31 (s, 0.3 H), 7.43-7.45 (m, 1.3 H), 7.56 -7.65 (m, 4.4 H), 7.81-7.84 (m, 2 H), 8.43 (s, 1H), 9.89 (brs, 1 H). MS m/z[M+1] 474.1.

Step 1: Preparation of (2,3-Dihydro-pyrrolo[3, 2-c]pyridin-1-yl)-(4-methoxy-8-nitro-dibenzofuran-1 -yl)-methanone

To a solution of 4-methoxy-8-nitro-dibenzofuran-1-carboxylic acid (500 mg, 1.639 mmol), prepared according to the procedure described in US 2007/0105855, in benzene (10 ml) was added thionyl chloride (5 ml) and cat. amount of dimethylformamide. The mixture was stirred at reflux temperature for about two and half hours. Cooled the reaction mixture to room temperature and benzene was evaporated under vacuum with repeating it for 4 to 5 times to remove excess thionyl chloride. The above acid chloride was dissolved in tetrahydrofuran (15 ml) and to this was added N, N-diisopropyl-N-ethyl amine (1ml) at room temperature followed by 2, 3-dihydro-1H-pyrrolo[3,2-c]pyridine (238 mg, 1.967 mmol). The reaction mass was stirred at room temperature for 16 hours. Added water and the tetrahydrofuran was removed under vacuum and the precipitated solid was filtered and dried to afford the titled compound (480 mg, 76% yield) as off-white solid.

1H NMR (300 MHz, CDCI3) 5 3.36 (br s, 2H), 4.15 (s, 3H), 4.37 (br s, 2H), 7.14-7.16 (m, 1H), 7.38 (m, 1H), 7.56-7.59 (m, 1H), 7.73-7.76 (d, 1H, J = 9.3 Hz), 8.31 (m, 1H), 8.41-8.49 (m, 2H), 8.88 (d, 1H, J = 1.9 Hz). MS m/z [M+1] 390.2.

Step2: Preparation of N-[9-(2, 3-Dihydro-pyrrolo [3, 2-c]pyridine-1-carbonyl)-6-methoxy-dibenzofuran-2-yl]-methanesulfonamide
To the clear solution of (2, 3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-(4-methoxy-8-nitro-dibenzofuran-1-yl)-methanone (300 mg ) in a mixture of solvent (EtOH: THF: H20:: 2:1:0.5) at 85 °C was added ammonium chloride (150 mg) and iron powder (150 mg). The reaction mixture was stirred at the same temperature for 1hour. The reaction mass was cooled to room temperature and filtered through celite bed. To the filtrate added 20 ml saturated brine and then extracted with 10% MeOH/CHCI3 which was dried with anhydrous sodium sulphate and concentrated under vacuum to afford crude amine (160 mg). The crude amine was dissolved in tetrahydrofuran (5 ml) and cooled to 0-5 °C. To this mixture was added a mixture of methanesulphonyl chloride (0.091ml, 1.114 mmol), pyridine (0.212ml, 2.674 mmol) and the above solvent at the same temperature and stirred for 45 min. The reaction mass was quenched with water and extracted with 20% MeOH/CHCI3 which was dried with anhydrous sodium sulphate and concentrated under vacuum and purified by column chromatography to afford the titled compound (70 mg, 36 % yield) as off-white solid. mp: 258.6-259.6 °C. HPLC Purity: 95.81 %.

IR (KBr) cm"1 3431, 3025, 2926, 2851, 1674, 1636, 1607, 1482, 1410, 1325, 1289, 1152, 1104, 822.

1H NMR (300 MHz, DMSO-de) 6 2.88 (s, 3H), 3.25-3.41 (t, 2H), 4.08 (s, 3H), 4.18-4.24 (t, 2H), 7.33 (d, 1 H, J = 8.1 Hz), 7.42 (d, 1 H, J = 8.4 Hz), 7.64 (d, 1 H, J = 8.4 Hz), 7.73-7.86 (m, 3 H,), 8.59 (d, 1 H, J = 6.6 Hz), 8.68 (s, 1 H), 9.81 (s, 1 H). MS m/z [M+1] 438.2.

Step 1: Preparation of (2, 3-Dihydro-pyrrolo [3, 2-c]pyridin-1-yl)-(1-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-methanone

To the suspension of 1-methoxy-9-methyl-6-nitro-9H-carbazole-4-carboxylic acid (prepared as per the procedure mentioned in US20070105855), (400 mg, 1.33 mmol) in benzene (15 ml) was
added thionyl chloride (5 ml) and refluxed for 4 hours. The reaction mixture was concentrated under vacuum completely. Added benzene (10 ml) and removed under vacuum. This process
was repeated again three times. The crude acid chloride was suspended in tetrahydrofuran (15 ml) and cooled to 0 °C and added N, N-diisopropyl-N-ethyl amine (0.35 ml) followed by 2, 3- Dihydro-1H-pyrrolo[3,2-c]pyridine (192 mg, 1.59 mmol). The reaction mass was stirred overnight at room temperature. The reaction mass was concentrated under vacuum completely and then
water was added, stirred for about one hour. The precipitated solid was filtered and washed with water and dried under vacuum to afford the titled compound (350 mg, 65% yield) as off-white solid.

1H NMR (300 MHz, CDCI3) 5 3.26-3.32 (t, 2H), 4.09 (s, 3H), 4.27 (s, 3H), 4.29-4.35 (m, 2H), 6.91-6.94 (m, 1H), 7.04-7.07 (d, 1H, J = 8.1 Hz), 7.33-7.35 (d, 1 H, J = 8.1 Hz), 7.41-7.44 (d, 1
H, J = 9.0 Hz), 8.33-8.40 (m, 3H), 8.83 (d, 1 H, J = 1.8 Hz). MS m/z [M+1] 403.3.

Step 2: N-[5-(2, 3-Dihydro-pyrrolo[3,2-c]pyridine-1-carbonyl)-8-methoxy-9-methy l-9H-carbazol-3-yl]-methanesulfonamide

To the suspention of (2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-(1-methoxy-9-methyl-6-nitro-9H- carbazol-4-yl)-methanone (390 mg, 0.969 mmol) in EtOH:THF:H20 (2:1:0.5, 11 ml) was added
ammonium chloride (390 mg) and iron powder (390 mg)and refluxed for about two and half hours. The reaction mass was cooled to room temperature, filter through celite bed and washed with chloroform. The filtrate was concentrated under vacuum and the resulted mass was dissolved in ethyl acetate which was washed with brine, dried with anhydrous sodium sulphate and concentrated under vacuum to afford crude amine (295 mg). The crude amine was dissolved in mixture of dichloromethane and tetrahydrofuran (1:1, 15 ml). To this a mixture of pyridine (0.34 ml) and methanesulphonyl chloride (0.131 ml) in tetrahydrofuran (2 ml) was added at 0 °C and stirred at the same temperature for 1 hour. The reaction mass was diluted with water and extracted with ethyl acetate which was washed with brine, dried with anhydrous sodium sulphate and concentrated under vacuum and purified by column chromatography eluted with 3 % MeOH/CHCI3 to afford the titled compound (130 mg, 30 % yield) as off-white solid, mp (DSC): 270.75 °C. HPLC Purity: 99.05 %.

IR (KBr) cm_1 3431, 2936, 2835, 2695, 1664, 1597, 1575, 1497, 1454, 1435, 1380, 1329, 1304, 1276, 1258, 1151.

1H NMR (300 MHz, DMSO-d«) 5 2.69 (s, 3H), 3.12 (m, 2H), 3.92- 4.04 (br s, 5H), 4.16 (s, 3H), 7.13-7.22 (m, 2H), 7.32-7.35 (dd, 1H, J = 1.8, 8.8 Hz), 7.58-7.63 (m, 2H), 8.14-8.35 (m, 2H), 9.48 (s, 1H). MS m/z [M+1] 451.3, [M+Na1] 473.3.

Step 1: 2, 3-Dihydro-pyrrolo [3,2-c]pyridine-1-carboxylic acid tert-butyl ester

Procedure: Prepared according to the procedure reported in J. Org. Chem. 64, 9430-9443 (1999).

Step 2: 2, 3-Dihydro-1H-pyrrolo [3, 2-c]pyridine


The mixture of 2, 3-Dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (2.2 g, 0.01 mol) in 1, 2-dimethoxyethane (10 ml) and cone. HCI (5 ml) was stirred at 50-55 °C for 30 min.

Cooled to room temperature, basified with saturated sodium bicarbonate and extracted with chloroform which was dried with anhydrous sodium sulphate and concentrated under vacuum to afford the titled compound (670 mg, 60% yield).

1H NMR (300 MHz, DMSO-d6) 5 2.94 (t, 2H), 3.51 (t, 2H), 6.40 (d, 1H, J = 5.4 Hz), 6.51 (s, 1H), 7.89-7.95 (m, 2H).

MS m/z[M+1] 121.3.
Step 3: 2,3-Dihydro-1H-pyrrolo [3,2-c]pyridine hydrochloride

To the solution of 2, 3-dihydro-pyrrolo [3, 2-c]pyridine-1-carboxylic acid tert-butyl ester 5.2 g, 0.0236 mol) in dichloromethane (30 ml) and ethyl acetate (60 ml) was added dry HCI in ethyl acetate (20 ml) at room temperature and stirred for 2 hours. The precipitated solid was filtered and washed with ethyl acetate and dried under vacuum to afford titled compound (2.2 g, 55.5 % yield) as off-white solid which is hygroscopic.

1H NMR (300 MHz, DMSO-d6) 5 3.11 (t, 2H), 3.80 (t, 2H), 6.62 (d, 1H, J = 6.7 Hz), 7.95-8.00 (m, 2H), 8.78 (s, 1H, D20 exchangeable), 13.29 (br s, 1H, D20 exchangeable).

MS m/z[M+1] 121.1.

Step 4:7-Bromo-2, 3-dihydro-1H-pyrrolo [3,2-c]pyridine

To the solution of 2, 3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (500 mg, 3.205 mmol) in dry dimethylformamide (10 ml) was added N-bromosuccinimide (599 mg) and stirred overnight at room temperature. The reaction mixture was diluted with water and basified with sodium bicarbonate and extracted with ethyl acetate which was dried with anhydrous sodium sulphate, concentrated under vacuum and purified by column chromatography eluted with 50 % ethyl acetate in hexane to afford the titled compound (200 mg, 31 % yield).

IR (KBr) cm _1 3202, 3167, 2908, 1705, 1609, 1503, 1476, 1438, 1311, 1257, 1152, 1103, 1031, 883.

1H NMR (300 MHz, DMSO-d6) 5 3.07 (t, 2H), 3.57 (t, 2H), 6.65 (s, 1H, DzO exchangeable), 7.91 (s, 1H), 8.03 (s, 1H). MS m/z [M+] 198.9, [M+2] 200.9.
Step 5: (7-Bromo-2, 3-dihydro-pyrrolo [3,2-c]pyridin-1-yl)-(4-difluoromethoxy-8- nitro-dibenzofuran-1-yl)-methanone

To a solution of 4-difluoromethoxy-8-nitro-dibenzofuran-1-carboxylic acid (200mg, 0.6191 mmol) in toluene (3ml) was added thionyl chloride (0.460ml, 6.191mmol) and catalytic amount of DMF. The mixture was stirred at 90 °C for about two and half hours, cooled to room temperature and toluene was evaporated under vacuum with repeating it for 4 to 5 times to remove excess thionyl chloride. The above acid chloride was dissolved in tetrahydrofuran and to this was added N, N-diisopropyl-N-ethyl amine (0.128 ml) at room temperature followed by 7-bromo-2, 3-dihydro-1H-pyrrolo[3,2-c]pyridine (123 mg, 0.6191 mmol). The reaction mass was stirred at room temperature for 48 hours. Added water and the product was extracted with CHCI3 which was concentrated under vacuum and purified with column chromatography to afford the titled compound (40 mg, 30% yield). HPLC Purity: 95.65 %.

1H NMR (300 MHz, DMSO-d6) 5 3.06-3.17 (m, 2H), 3.56-3.62 (t, 2H), 7.36-7.85 (t, 1H, J = 72.6 Hz), 7.61-7.63 (m, 1 H), 7.92 (s, 1H), 8.07-8.15 (m, 3 H), 8.51-8.54 (m, 1H), 9.82 (s, 1H).

We claim

1. The compound of formula

their analogues, derivatives, tautomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable solvates, N-oxides and bioisosteres

Wherein

Z is selected from C(O), NR1, S(O)m, C(O)NR1, NR1(CO), CR2R3, CR2R3C(O), CR2R30 CR2R3, C(O)CR2R3, CR2R3C(O)C(O), C(O)C(O)CR2R3, NR1C(S), C(S)NR1, CR2R3S(O)m, S(O)mCR2R3, S(O)mNR1, NR1S(O)m, NR1S(O)mNR1;

R1 is selected from hydrogen or substituted or unsubstituted alkyl;
R2 and R3 are independently selected from hydrogen, d-C6 straight or branched alkyl, dialkyl, C2-C6 straight or branched alkenyl, alkylamino, alkyl halo, alkyl hydroxy, acyl, alkoxy; or
R2 and R3 together with the carbon they are attached form a C3 to C5 substituted or unsubstituted spiro ring;

m represents an integer ranging from 0,1 or 2;

Hy represents substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;

2. A compound according to claim 1, wherein Z is -C(O)-

3. A compound according to claim 1, wherein Z is -NH-

4. A compound according to claim 1, wherein Z is -CH2NH-

5. A compound according to claim 1, wherein Z is S(O)m wherein m represents an integer ranging from 0,1, or 2

6. A compound according to claim 1, wherein Hy is substituted carbazole

7. A compound according to claim 1, wherein Hy is substituted dibenzofuran

8. A compound according to claim 1, wherein Hy is substituted dihydro pyrrolo pyridine

9. A compound according to claim 1, wherein the compound is selected from (4-Difluoromethoxy-8-nitro-dibenzofuran-1-yl)-(2, 3-dihydro-pyrrolo [3, 2-c]pyridin-1-yl)- methanone

N-[6-Difluoromethoxy-9-(2, 3-dihydro-pyrrolo [3, 2-c]pyridine-1-carbonyl) -dibenzofuran-2-yl]-methanesulfonamide

N-[9-(2, 3-Dihydro-pyirolo [3, 2-c]pyridine-1-carbonyl)-6-methoxy-dibenzofuran-2-yl]-methanesulfonamide

N-[5-(2, 3-Dihydro-pyrrolo[3,2-c]pyridine-1-carbonyl)-8-methoxy-9-methyl-9H-carbazol-3-yl]- methanesulfonamide

(7-Bromo-2, 3-dihydro-pyrrolo [3, 2-c]pyridin-1-yl)-(4-difluoromethoxy-8-nitro-dibenzofuran -1-yl)-methanone

10.. A process for preparing a compound according to claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enaontiomer, diastereiomer or N-oxide thereof, comprising at least one of the steps of

a) oxidising the compound of formula ac

using suitable oxidizing agents such as potassium permanganate, sodium chlorite. potassium chromate and the like to obtain the compound of formula ab
COOH

b) chlorinating the compound of formula ab using conventional chlorinating agents such as thionyl chloride, phosphorous trichloride, phosphorous oxychloride and the like to obtain the corresponding acid chloride

c) alternately, reacting the compound of formula ab with para nitro phenol in the presence of DCC to obtain the corresponding ester

d) reacting the acid chloride or the ester formed above with ring B in the presence of a suitable base such as sodium hydride, and the like to obtain the compound of formula 1

General Formula 1

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition according to claim 11, or a pharmaceutically acceptable salt thereof for use as a Phosphodiesterase 4 (PDEIV) inhibitor.

13. A method for treating an inflammatory disease, disorder or condition characterized by or associated with an excessive secretion of TNF-a and Phosphodiesterase 4 (PDE IV), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1

14. The method according to claim 13, wherein said inflammatory conditions and disorders are chosen from the group comprising asthma, COPD, allergic rhinitis, allergic conjunctivitis, respiratory distress syndrome, chronic bronchitis, nephritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, eosinophilic granuloma, psoriasis, rheumatoid septic shock, ulcerative colitis, multiple sclerosis, chronic inflammation, Crohn's syndrome and central nervous system(CNS) disorders

15. The Use of the compound according to claims 1 to 9, in a medicament for the treatment of inflammatory conditions and disorders are chosen from the group comprising asthma, COPD, allergic rhinitis, allergic conjunctivitis, respiratory distress syndrome, chronic bronchitis, nephritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, eosinophilic granuloma, psoriasis, rheumatoid septic shock, ulcerative colitis, multiple sclerosis, chronic inflammation, Crohn's syndrome and , central nervous system(CNS) disorders.