WO2006040650A1 - 4-methoxyacridine-1-carboxamide derivatives and the phenazine and oxanthrene analogs as pde4-inhibitors for the treatment of asthma and chronic pulmonary disease (copd) - Google Patents

Abstract

The present invention relates to new Phosphodiesterase type 4 (PDE4) inhibitors of the formula (1) for treatment of asthma: Ar is a substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; each occurrence of L is O, S or NR3; X and A are independently -CRaRb -, -CRa-, -C(=B)-, O, S(O)m, N or NR3; each occurrence of m is 0, 1, or 2; n is 0-4; p is 0-2; Y is -C(=B)C(=D)NR4 or -C(=B)NR4 B is O, S or NRa; D is O, S or NRa; The other substituents are defined in the claims.

Description

4-METHOXYACRIDINE-1-CARBOXAMIDE DERIVATIVES AND THE PHENAZINE AND OXANTHRENE ANALOGS AS PDE4-INHIBITORS FOR THE TREATMENT OF ASTHMA AND CHRONIC PULMONARY DISEASE (COPD)

This application claims the benefit of U.S. Provisional Application No. 60/618,193, filed October 12, 2004, which is hereby incorporated by reference.

0 Field of the Invention

The present invention relates to novel tricyclic phosphodiesterase type 4 (PDE4) inhibitors and analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs,- pharmaceutically acceptable salts, appropriate N-oxides, and pharmaceutically acceptable solvates thereof, pharmaceutical compositions 5 containing them, and their use for treating conditions mediated by PDE-IV inhibition, such as asthma and chronic obstructive pulmonary disease (COPD).

Background of the Invention

Airway inflammation characterizes a number of severe lung diseases including 0 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 5 of asthmatic reactions is correlated with the number of eosinophils present in the lungs.

The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When 0 activated, they synthesize and release inflammatory cytokines such as IL-I, IL-3, TNF-α and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and broncho-constriction. Tumor necrosis factor (TNF-α) was also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states. It has been well demonstrated that TNF-α production in pro- inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3 ',5 '-monophosphate (cAMP). This second messenger is regulated by the phosphodiesterase (PDE) family of enzymes. The phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and/or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophilis are believed to be a critical proinflammatory target for asthma, identification of the expression of the PDE 4 gene family in eosinophils led to PDE 4 as a potential therapeutic target for asthma [Rogers, D. F., Giembycz, M. A., Trends Pharmacol. ScL, 19, 160-164(1998); Barnes, P.J., Trends Pharmacol. ScL, 19, 415-423 (1998) which is herein incorporated by reference in its entirety].

The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [Soderling, S.H., Bayuga, S.J., and Beavo, J.A., Proc. Natl. Acad. ScL, USA, 96,7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J. Biol. Chem., 7JA_> 18438-18445 (1999) which are herein incorporated by reference in their entireties]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes.

Phosphodiesterase type 4 (PDE4) is an enzyme which regulates activities in cells which lead to inflammation in the lungs. PDE4, a cAMP-specific and Ca⁺²- independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes. The association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors [Trophy,T.J., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) which is herein incorporated by reference in its entirety]. Excessive or unregulated TNF-α production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions, septic shock, endotoxic shock, respiratory distress syndrome and bone resorption diseases. Since TNF-α also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, I, 211- 214 (1995) and ibid., 244-248 which are herein incorporated by reference in their entireties].

Strong interest in drugs capable of selective inhibition of PDE 4 is due to several factors. Tissue distribution of PDE-4 suggests that pathologies related to the central nervous and immune systems could be treated with selective PDE-4 inhibitors. In addition, the increase in intracellular cAMP concentration, the obvious biochemical consequence of PDE-4 inhibition, has been well characterized in immuno-competent cells where it acts as a deactivating signal.

Recently the PDE4 family has grown to include four subtypes - PDE4A to PDE4D, each encoded by a distinct gene {British Journal of Pharmacology; 1999; v.128; p.l 393-1398), which is herein incorporated by reference in its entirety. It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF-α. Since eosinophilis are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE-4 gene family in eosinophils led to the PDE-4 as a potential therapeutic target for asthma.

The usefulness of several PDE-4 inhibitors, unfortunately, is limited due to their undesirable side effect profile which include nausea and emesis (due to action on PDE-4 in the central nervous system) and gastric acid secretion due to action on PDE- 4 in parietal cells in the gut. Barnette, M.S., Grous, M., Cieslinsky, L.B., Burman, M., Christensen, S.B., Trophy, T J., J. Pharmacol. Exp. Ther., 273,1396-1402 (1995) which is herein incorporated by reference in its entirety. One of the earliest PDE-4 inhibitors, Rolipram™, was withdrawn from clinical development because of their severe unacceptable side effect profile. Zeller E. et. al., Pharmacopsychiatry j/7, 188- 190 (1984) which is herein incorporated by reference in their entirety. The cause of severe side effects of several PDE-4 inhibitor molecules in human clinical trials has recently become apparent. There exist two binding sites on mammalian PDE-4 at which inhibitor molecules may bind. Also PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and Low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M.M., Livi, G.P., Burman, M., Trophy, T.J., MoI. Pharmaco., 50, 891-899 (1996) which is herein incorporated by reference in its entirety]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE-4L inhibition. It was also found that human recombinant PDE-4 exists in 4 isoforms A, B, C and D [Muller, T., Engels, P., Fozard, J.R., Trends Pharmacol. Sd., V∑, 294-298 (1996) which is herein incorporated by reference in its entirety]. Accordingly, compounds displaying more PDE-4D isoenzyme selectivity over the A, B or C are found to have fewer side effects than Rolipram [Hughes. B et.al., Br. J. Pharmacol. 1996, 118, 1183-1191 which is herein incorporated by reference in its entirety]. Therefore, selective inhibitors of PDE-4 isozymes may have therapeutic efficacy in the treatment of inflammatory diseases, such as asthma and other respiratory diseases, without the undesirable side effects of prior non-selective PDE-4 inhibitors.

Although several research groups all over the world are working to find highly selective PDE-4 isozyme inhibitors, so far success has been limited. Various compounds have shown PDE-4 inhibition.

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

During the course of our research aimed at the development of novel anti¬ asthmatic compounds having potential PDE4 inhibitory activity, we have filed two PCT applications, which published as International Publication Nos. WO 2004/037805 and WO 2004/089940, both of which are herein incorporated by reference in their entireties, for a novel series of tricyclic compounds useful for the treatment of inflammatory and allergic disorders. SUMMARY OF THE INVENTION

The present invention relates to new heterocyclic compounds which inhibit PDE-4 having the formula below:

(1) wherein: each occurrence of R¹ _, R² and R³ may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -NR⁵R⁶, -C(=L)-R⁵, -C(O)-R³, -C(O)O- R^a, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, nitro, -OH, cyano, formyl, acetyl, halogen, -OR^a, -SR^a, or a protecting group or when two R³ substitutents are ortho to each other, they may be joined to form a C₃-C₈ saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; each occurrence of R⁵ and R⁶ may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, halo, -OH, cyano, -C(O)-R³, -C(O)O-R³, -C(O)NR³R*³, -S(O)_m-R^a, -S(O)_m-NR^aR^b, - C(=NR³)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b, -C(=S)-R^a, -N=C(R^aR^b), -NR^aR^b, - OR^a, -SR^a, or a protecting group or R⁵ and R⁶, when attached to a nitrogen atom, may be joined to form an optionally substituted C₃-C₈ saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S; each occurrence of R^a and R^b may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano, formyl, acetyl, halogen, a protecting group, -C(O)-R^a, -C(O)O-R³, - C(O)NR³R^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, -0R^a, or -SR^a; Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; each occurrence of L is O, S or NR³;

X and A are independently -CR^aR^b-, -CR^a-, -C(=B)-, O, S(O)_m, N or NR³; each occurrence of m is O, 1 or 2; n is 0-4; p is 0-2;

Y is -C(=B)C(=D)NR⁴ or -C(=B)NR⁴

B is O, S or NR^a; D is O, S or NR^a;

R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -0R^a, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring; each dotted line [ — ] in the central ring represents an optional double bond; and analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, N-oxides, and pharmaceutically acceptable solvates thereof. These compounds may also be included in pharmaceutical compositions. Preferably, Ar is an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the optional substituents (one or more) may be same or different and are independently selected from hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino.

Preferred is a compound of formula (I) where R¹ is alkyl or substituted alkyl. Further preferred is a compound of formula (I) where R¹ is methyl.

Further preferred is a compound of formula (I) where R¹ is difluromethyl.

Further preferred is a compound of formula (I) where Y is -C(=B)NR⁴.

Further preferred is a compound of formula (I) where B is O and R⁴ is hydrogen. Further preferred is a compound of formula (I) where Y is -C(O)-NH-.

Further preferred is a compound of formula (I) where A is N and X is CH and both dotted lines represent a bond.

Further preferred is a compound of formula (I) where A is N and X is N and both dotted lines represent a bond. Further preferred is a compound of formula (I) where A is O and X is O and both dotted lines are absent.

Further preferred is a compound of formula (I) where Ar is an optionally substituted pyridyl or optionally substituted pyridyl-N-oxide.

Further preferred is a compound of formula (I) where Ar is an optionally substituted with Halogen, most preferably chloro.

Further preferred is a compound of formula (I) where Ar is

Further preferred is a compound of formula (I) where p is 0. Further preferred is a compound of formula (I) where n is 0. Representative compounds according to the present invention are specified below, but the invention should not construed to be limited thereto:

1. N 1 -(3 , 5 -dichloropyridin-4-yl)-4-methoxyacridine- 1 -carboxamide;

2. Nl -(pyridin-4-yl)-4-methoxyacridine- 1 -carboxamide; 3. N l-(pyridin-3-yl)-4-methoxyacridine-l -carboxamide;

4. Nl -(3, 5-dichloro-4-pyridyl)-4-methoxy-l-phenazinecarboxarnide;

5. N-(3,5-dichloropyridin-4-yl)-4-methoxyoxanthrene-l -carboxamide;

6. 7V-(pyridin-4-yl)-4-methoxyoxanthrene- 1 -carboxamide;

7. N-(pyridin-3-yl)-4-methoxyoxanthrene- 1 -carboxamide; 8. N-(pyridin-3-yl)-4-methoxy-7-nitrooxanthrene-l -carboxamide;

9. Νl-(3,5-dichloropyridin-4-yl)-4-difluoromethoxyacridine-l -carboxamide; and pharmaceutically acceptable salts of the foregoing where applicable.

DETAILED DESCRIPTION OF THE INVENTION

Definitions The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as a Ci_-6 alkyl, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1 -dimethyl ethyl (t-butyl). The term "C_1-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms.

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

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

The term "alkoxycarbonyl" denotes an alkoxy group as defined above attached via a carbonyl linkage to the rest of the molecule. Representative examples of such groups are -C(O)-OCH₃, and -C(O)-OC₂H₅.

The term "alkylcarbonyloxy" denotes an alkylcarbonyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -0-C(O)CH₃, and -0-C(O)C₂H₅. The term "alkylamino" denotes an alkyl group as defined above attached via an amino linkage to the rest of the molecule. Representative examples of such groups are -NH₂CH₃, -NH(CH₃)₂ , and -N(CH₃)₃.

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

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

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

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

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

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

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

The term "heterocyclyl" refers to a heterocylic ring radical as defined above. The heterocylcyl 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 an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term "cyclic ring" refers to a cyclic ring containing 3-10 carbon atoms. The term "protecting group" includes, but is not limited to, carbobenzyloxy (CBZ) and tert-butyloxy carbonyl (BOC).

The term "halogen" refers to radicals of fluorine, chlorine, bromine and iodine.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, and the like; salts of chiral bases such as alkylphenylamine, glycinol, phenyl glycinol and the like; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, and the like; quaternary ammonium salts of the compounds of invention with alkyl halides or alkyl sulphates such as MeI, (Me)₂SO₄ and the like; salts of non-natural amino acids such as D- isomers or substituted amino acids; salts of guanidine or substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl or alkynyl; ammonium or substituted ammonium salts; and aluminum salts. Other salts include acid addition salts where appropriate, such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.

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

"Treating" or "treatment" of a state, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition;

(2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or

(3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of their clinical or subclinical symptoms.

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

Methods of Treatment Another aspect of the invention is a method of treating inflammatory diseases, disorders and conditions characterized by or associated with an undesirable inflammatory immune response and diseases and conditions induced by or associated with an excessive secretion of TNF-α and PDE-4 which comprises administering to a subject a therapeutically effective amount of a compound according to formula 1. Another aspect of the invention is a method of treating inflammatory conditions and immune disorders in a . subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to formula 1.

Preferred inflammatory conditions and immune disorders include, but are not limited to, asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uveitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis and chronic inflammation. Further preferred are allergic inflammatory conditions.

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

Further preferred are inflammatory conditions chosen from asthma and chronic obstructive pulmonary disease.

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

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

Preferred diseases of the central nervous system include, but are not limited to, depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease. Another aspect of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to Formula 1.

The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. The classic symptoms of acute inflammation are redness, elevated temperature, swelling, and pain in the affected area, and loss of function of the affected organ.

Symptoms and signs of inflammation associated with specific conditions include: • rheumatoid arthritis- pain, swelling, warmth and tenderness of the involved joints, generalized and morning stiffness; • insulin-dependent diabetes mellitus- insulitis; this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy, coronary artery disease, peripheral vascular disease, and cerebrovascular disease; • autoimmune thyroiditis- weakness, constipation, shortness of breath, puffmess of the face, hands and feet, peripheral edema, and bradycardia;

• multiple sclerosis- spasticity, blurry vision, vertigo, limb weakness, paresthesias;

• uveoretinitis- decreased night vision, loss of peripheral vision; • lupus erythematosus- joint pain, rash, photosensitivity, fever, muscle pain, puffiness of the hands and feet, abnormal urinalysis (hematuria, cylinduria, proteinuria), glomerulonephritis, cognitive dysfunction, vessel thrombosis, pericarditis;

• scleroderma- Raynaud's disease; swelling of the hands, arms, legs and face; skin thickening; pain, swelling and stiffness of the fingers and knees, gastrointestinal dysfunction, restrictive lung disease; pericarditis,; renal failure;

• other arthritic conditions having an inflammatory component such as rheumatoid spondylitis, osteoarthritis, septic arthritis and polyarthritis- fever, pain, swelling, tenderness;

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

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

• inflammatory skin disorders, such as , eczema, other dermatites (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sun rays and similar UV sources)- erythema, pain, scaling, swelling, tenderness;

• inflammatory bowel disease, such as Crohn's disease, ulcerative colitis- pain, diarrhea, constipation, rectal bleeding, fever, arthritis;

• asthma- shortness of breath, wheezing; • other allergy disorders, such as allergic rhinitis- sneezing, itching, runny nose

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

• heart tissue injury due to myocardial ischemia- pain, shortness of breath; • lung injury such as that which occurs in adult respiratory distress syndrome- shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates;

• inflammation accompanying infection, such as sepsis, septic shock, toxic shock syndrome- fever, respiratory failure, tachycardia, hypotension, leukocytosis;

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

• inflamed appendix- fever, pain, tenderness, leukocytosis;

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

• inflamed gall bladder- abdominal pain and tenderness, fever, nausea, leukocytosis;

• chronic obstructive pulmonary disease- shortness of breath, wheezing; • congestive heart failure- shortness of breath, rales, peripheral edema;

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

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

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

Dosage Forms

The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used. A most preferable dosage is about 0.5 mg to about 250 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.

Generally, the compounds of the present invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.

Methods of Preparation

The compounds of formula (I) may be prepared by the following processes.

In one embodiment the compounds of formula (1) wherein Y is -CONR⁴, X is -CR^a-, and A is N or N-oxide, can be prepared by the process described in the general scheme I.

GENERAL SCHEME I:

In the above general scheme I, Ar, R¹, R², and R³ have the meanings as described above in formula I. Intermediate (14) can be synthesized by reduction of either intermediate (12) or (13) using the appropriate reducing conditions, such as hydrogenation in the presence of palladium on carbon, dissolving metal reductions (such as sodium in alcohol), or metal hydride reductions. The intermediates of formula (12) and (13) can be obtained by cyclization of the intermediate of formula (11) using, for example, phosphorus oxychloride, aluminum chloride, or sulphuric acid. The intermediate of formula (11) in turn, can be obtained by reacting an appropriately substituted alkoxy aniline of formula (10) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted o-halobenzoic acid under appropriate basic conditions, such as with potassium carbonate in DMF in the presence of copper powder. Alternatively, the intermediate of formula (11) can be synthesized by reacting an appropriately substituted alkoxy aniline of formula (10) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted diphenyl iodonium carboxylate, for example, in the presence of copper (II) acetate in DMF. Intermediate (14) can be aromatized to intermediate (15) using oxidizing agents, such as DDQ or nitric acid. The functional group (FG) on intermediate (15) can be then converted to the carboxylic acid intermediate (16) using known methods in the literature. (For example if FG in intermediate (15) is an ester, it can be hydrolysed to the carboxylic acid; if FG is methyl then the methyl group can be oxidized using manganese or chromium reagents to the carboxylic acid group; if FG is a cyano group then the cyano group can be hydrolysed to the carboxylic acid; if FG is bromine then it can be transformed to carboxylic acid via lithiation followed by treatment with carbon dioxide.) The intermediate of formula (16) can then be converted to the desired compounds of formula (1) by reacting the acid halide, the mixed anhydride, or an active ester of the intermediate of formula (16) with an appropriate amine of the formula ArNHR⁴ using standard conditions known in the literature such as sodium hydride in DMF, diisopropylethyl amine in THF and the like. The desired compounds of formula (1) obtained can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of formula (1) obtained can then be converted into the free compounds.

In another embodiment, the compounds of formula (1) wherein Y is -CONR⁴, X is -N or N-oxide and A is -CR^a- , can be prepared by the process described in the general scheme Ia.

GENERAL SCHEME Ia:

In the above general scheme Ia, wherein Ar, R¹, R², and R³ have the meanings as described in the above general formula (1). Intermediate (21) can be synthesized by reduction of either intermediate (19) or (20) using the appropriate reducing conditions, such as hydrogenation (e.g., in the presence of palladium on carbon and the like), dissolving metal reductions (such as sodium in alcohol and the like), or metal hydride reduction. The intermediates of formulas (19) and (20) can be obtained by cyclization of intermediate (18) using, for example, phosphorus oxychloride, aluminum chloride, or sulphuric acid. The intermediate of formula (18) in turn can be obtained by reacting an appropriately substituted alkoxy aniline of formula (17) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted o-halobenzoic acid under appropriate basic conditions, such as potassium carbonate in DMF in the presence of copper powder. Alternatively, the intermediate of formula (18) can be synthesized by reacting an appropriately substituted alkoxy aniline of formula (17) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted diphenyl iodonium carboxylate, for example, in the presence of copper (II) acetate in DMF. Intermediate (21) can be aromatized to intermediate (22) using oxidizing agents, such as DDQ or nitric acid. The functional group (FG) on intermediate (22) can then be converted to the carboxylic acid intermediate (23) using known methods in the literature. (For example, if FG in intermediate (22) is an ester, it can be hydrolysed to the carboxylic acid; if FG is methyl then the methyl group can be oxidized using, for example, manganese or chromium reagents to the carboxylic acid group; if FG is a cyano group then the cyano group can be hydrolysed to the carboxylic acid; if FG is bromine then it can be transformed to carboxylic acid via lithiation followed by treatment with carbon dioxide.) The intermediate of the formula (22) can then be converted to the desired compounds of formula (1) by reacting the acid halide, the mixed anhydride, or an active ester of the intermediate of formula (22) with an appropriate amine of the formula ArNHR⁴ using standard conditions known in the literature, such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.

The desired compounds of formula (1) obtained can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of formula (1) obtained can then be converted into the free compounds.

In yet another embodiment, the compounds of formula (1) wherein Y is -

CONR > ⁴4⁴,, A A i iss O O,, S S,, o orr N NRR³³ a anndd X is C=O or -CR³R -, can be prepared by the process described in general scheme II.

GENERAL SCHEME U:

In the above general scheme II, wherein Ar, R¹, R², and R³ have the meanings described above, intermediate (25) can be synthesized by reacting an appropriately substituted aromatic group of formula (24) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group and Z is OH, SH or NHR³) with an appropriately substituted o-halobenzoic acid under appropriate basic conditions, such as potassium carbonate in DMF in the presence of copper powder. The intermediate of formula (25) can be further cyclized to the intermediate of formula (26) or (28). The functional group (FG) on intermediate (26) or (28) can then be converted to a carboxylic acid group to obtain an intermediate of formula (27) or (29), respectively, using known methods in the literature. (For example, if FG in intermediates (26) and (28) is an ester, it can be hydrolysed to the carboxylic acid; if FG is methyl then the methyl group can be oxidized using, for example, manganese or chromium reagents to the carboxylic acid group; if FG is a cyano group then the cyano group can be hydrolysed to the carboxylic acid; if FG is bromine then it can be transformed to carboxylic acid via lithiation followed by treatment with carbon dioxide.) The intermediate of formula (27) or (29) can then be converted to the desired compound of formula (1) by reacting the corresponding acid halide, the mixed anhydride, or an active ester of the intermediate of the formula (27) or (29) with an appropriate amine of the formula ArNHR⁴ using standard conditions known in the literature, such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.

In yet another embodiment, the compounds of formula (1) wherein Y is - CONR⁴, X = A = N or N-oxide, can be prepared by the process described in general scheme III.

GENERAL SCHEME III:

33

In the above general scheme III, the appropriately functionalized nitroaromatic group of the general formula (30) (wherein FG is methyl, formyl, acetyl, cyano or an ester) can be reacted with appropriately substituted aniline of the formula (31), for example, in the presence of a base such as potassium hydroxide sodium hydroxide, to obtain the intermediate phenazine of formula (32). The functional group FG in the intermediate of formula (32) can be converted to a carboxylic acid using standard processes (if FG is methyl, then it can be oxidized using oxidizing agents, such as chromium trioxide or potassium persulfate; if FG is an ester then it can be hydrolyzed, for example, using aqueous sodium hydroxide) to obtain the intermediate (33). The intermediate of formula (33) can be converted to the desired compound of formula (1) by reacting the corresponding acid halide, the mixed anhydride, or an active ester of the intermediate of formula (33) with an appropriate amine of the formula ArNHR⁴ using standard conditions known in the literature such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.

In yet another embodiment, the compounds of formula (1) wherein Y is - CONR⁴, X = A = O, and the dotted lines in the central ring are absent, can be prepared by the process described in general scheme IV. GENERAL SCHEME IV:

38

In the above general scheme IV, the appropriately functionalized catechol of the formula (34) can be reacted with an appropriately substituted halonitrobenzene of the formula (35), for example, in the presence of base such as potassium hydroxide, sodium hydroxide, or potassium carbonate, to obtain the tricyclic intermediate of the formula (36). Formylation using standard conditions, such as dichloromethylmethylether in the presence of tin (IV) chloride or phosphorus oxychloride in N,N-dimethylformamide, can provide the intermediate (37). This can be oxidized using oxidizing agents, such as sodium chlorite or potassium permanganate, to obtain the carboxylic acid intermediate (38). The intermediate of formula (38) can be converted to the desired compound of formula (1) by reacting the corresponding acid halide, the mixed anhydride, or an active ester of the intermediate of the formula (38) with an appropriate amine of the formula ArNHR using standard conditions known in the literature, such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.

The desired compound of formula (1) obtained can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of formula (1) obtained can then be converted into the free compounds. The N-oxidation can be carried out in a manner likewise familiar to the person of ordinary skill in the art, e.g., with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. The substances according to the invention can be isolated and purified by any method known in the art, 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, reprecipitating, 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 formula (1) are selected from diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like. The chlorinated solvent which may be employed may be selected from dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride and the like. The aromatic solvents which may be employed may be selected from benzene and toluene. The alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert-butanol and the like. The aprotic solvents which may be employed may be selected from N, N-dimethylformamide, dimethyl sulfoxide and the like.

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

The present invention provides new heterocyclic compounds of the general Formula 1, their analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastreomers, polymorphs, pharmaceutically acceptable salts, appropriate N-oxides and pharmaceutically acceptable solvates and pharmaceutically acceptable salts of the preceeding.

The present invention also provides pharmaceutical compositions, containing compounds of general formula (1) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, enantiomers, diasteromers, or their pharmaceutically acceptable solvates and pharmaceutically acceptable salts of the preceeding 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 general formula (1) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in the compounds of general formula (1) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures. The invention may also contain E and Z geometrical isomers wherever possible in the compounds of general formula (1) which includes the single isomer or mixture of both the isomers

The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The active compounds of formula (1) will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds of formula (1) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds of the formula (1) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of formula (1) The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. The compounds can also be administered by inhalation when application within the respiratory tract is intended. Formulation of the present compounds is especially significant for respiratory inhalation, wherein the compound of Formula (1) is to be delivered in the form of an aerosol under pressure. It is preferred to micronize the compound of Formula (1) after it has been homogenised, e.g., in lactose, glucose, higher fatty acids, sodium salt of dioctylsulfosuccinic acid or, most preferably, in carboxymethyl cellulose, in order to achieve a microparticle size of 5 μm or less for the majority of particles. For the inhalation formulation, the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substance. An inhaler or atomizer or nebulizer may be used. Such devices are known. See, e.g., Newman et al., Thorax, 1985, 40:61-676; Berenberg, M., J. Asthma USA, 1985, 22:87-92; incorporated herein by reference in their entirety. A Bird nebulizer can also be used. See also U.S. Patents 6,402,733; 6,273,086; and 6,228,346, incorporated herein by reference in their entirety. The compound of the structure (1) for inhalation is preferably formulated in the form of a dry powder with micronized particles. The compounds of the invention may also be used in a metered dose inhaler using methods disclosed in U.S. Patent 6, 131,566, incorporated herein by reference in their entirety. In addition to the compounds of formula (1) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful therapeutic agents.

The following intermediates have been used to synthesize the representative examples of the compounds of the invention.

INTERMEDIATE 1 4-methoxy-acridine-l-carboxyIic acid

STEP 1: Methyl-(3-amino-4-methoxy) benzoate

Methyl (4-methoxy-3-nitro)benzoate (4.2 g, 0.019 mol) (Lancaster) was dissolved in DMF (65 ml) and hydrogenated in the presence of Raney nickel (2.1 g) for 5 h at 50 psi. The reaction mixture was filtered through celite. Water (100 ml) was added to the filtrate to precipitate the product. The precipitated product was extracted in dichloromethane, dried over anhydrous sodium sulphate, and concentrated in vacuo to obtain the product as a buff color solid (3.4 g).

IR (KBr): 3297, 2949, 2846, 1710, 1600, 1517, 1440, 1310, 1219, 1198, 1106, 1021, 876, 761 cm^"1. H*-NMR (300 MHz, DMSOd₆) δ 3.76 (s, 3 H), 3.82 (s, 3 H), 4.99 (brs, 2 H, exchanges with D₂O), 6.87 (d, 1 H, J = 8.4 Hz), 7.21 (d, 1 H, J = 8.2 Hz), 7.26 (s, IH).

STEP 2: 2-{[2-methoxy-5-(methoxycarbonyl)phenyl]amino} benzoic acid To a solution of Methyl-(3-amino-4-methoxy) benzoate (2.5 g, 0.013 mol) in DMF (50 ml) was added Diphenyl iodonium carboxylate (DPIC) (4.4 g, 0.013 mol) and copper (II) acetate (100 mg) and stirred at 100⁰C for 2 h. The reaction mixture was cooled to room temperature, concentrated to dryness and diluted with aqueous ethyl acetate (75 %). The organic layer was separated, washed with IN hydrochloric acid (20 ml) followed by treatment aqueous ammonia (2 x 20 ml). The aqueous layer was neutralized with 6N hydrochloric acid to precipitate the product which was filtered, washed with water and dried to obtain a pale yellow solid (2.5 g). IR (KBr): 3307, 2951, 1713, 1702, 1676, 1599, 1583, 1538, 1500, 1453, 1442, 1271, 1133, 1102, 1024, 896, 763 cm^"1. H'-NMR (300 MHz, DMSOd₆) δ 3.81 (s, 3H), 3.92 (s, 3H), 6.84 (t, IH, J= 6.9 Hz), 7.19 (d, IH, J = 8.4 Hz), 7.27 (d, IH, J = 8.4 Hz), 7.45 (t, IH, 6.9 Hz), 7.66 (d, IH, J = 8.4 Hz), 7.93 (d, 2H), 9.85 (brs, IH, exchanges with D₂O), 13.1 (brs, IH, exchanges with D₂O) STEP 3: Methyl 9-chloro-4-methoxy acridine-1-carboxylate 2-{[2-methoxy-5-(methoxycarbonyl)phenyl]amino} benzoic acid (1.0 g) was refluxed in phosphorus oxychloride (10 ml) for 24 h. The phosphorus oxychloride was distilled off the residue was diluted with ice water (30 ml). The solution was neutralized with aqueous ammonia to pH 8 to obtain the product as a pale green solid (1.0 g) which is filtered and dried. IR (KBr): 2949, 2839, 1720, 1528, 1286, 1272, 1124, 1101, 98, 768 cm^"1.

H'-NMR (300 MHz, DMSO-d₆) δ 3.91 (s, 3H), 4.09 (s, 3H), 7.25 (d, IH, J= 8.1 Hz), 7.81 (d, IH, J= 8.1 Hz), 7.86 (t, IH, J= 7.8 Hz), 7.98 (t, IH, J= 7.5 Hz), 8.28 (d, IH, J= 8.7 Hz), 8.44 (d, IH, J= 9.0 Hz). STEP 4: Methyl-4-methoxy-4a, 9, 9a, lO-tetrahydroacridine-l-carboxylate Methyl 9-chloro-4-methoxy acridine-1-carboxylate (1.0 g) was hydrogenated in the presence of 10% Pd/C (0.5 g) and triethylamine (1.0 ml) in methanol (25 ml) at 80 psi for 2 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using 20 % ethyl acetate in petroleum ether as the eluent to obtain the product as viscous oil (500 mg). H'-NMR (300 MHz, DMSO-d₆) δ 3.88 (s, 3H), 3.94 (s, 3H), 4.51 (s, 2H), 6.54 (brs, IH, exchanges with D₂O), 6.64 (t, IH, J = 7.5 Hz), 6.70 (d, 2H), 7.04-7.14 (m, 2H), 7.53(d, IH, J= 8.7 Hz).

STEP 5: Methyl-4-methoxy-acridine-l-carboxylate Methyl -4-methoxy-4a, 9, 9a, 10-tetrahydroacridine-l-carboxylate (500 mg) was oxidized using 70% nitric acid (10 ml) at room temperature for 2 h. The reaction mixture was diluted with water, stirred for Ih and then neutralized using aqueous ammonia to precipitate the product which was filtered and dried (490 mg). IR (KBr): 3000, 2951, 2846, 1697, 1610, 1526, 1265, 1219, 1149, 1121, 1100, 1022,

971, 774, 742 cm^"1.

H'-NMR (300 MHz, DMSO-d₆) δ 4.03 (s, 3H), 4.24 (s, 3H), 7.05 (d, IH, J= 8.4 Hz),

7.61 (t, IH, J= 7.5 Hz), 7.83 (t, IH, J= 7.5 Hz), 8.09 (d, IH, J= 8.1 Hz), 8.39 (d, 2H, J= 8.1 Hz), 10.18 (s, IH).

STEP 6: 4-methoxy-acridine-l-carboxylic acid

MethyM-methoxy-acridine-l-carboxylate (480 mg, 1.81 mmol) was dissolved in methanol (15 ml). To this solution was added IN NaOH (1.0 ml) and stirred for 12 h at room temperature. The methanol was evaporated and the residue was diluted with water (20 ml), washed with ethyl acetate. The aqueous layer was neutralized to pH 4-

5 using 50 % aqueous acetic acid and then extracted with ethyl acetate (50 x 3 ml).

The organic layer was dried over anhydrous sodium sulphate, concentrated in vacuo to obtain the product as a red solid (390 mg).

IR (KBr): 3436, 2934, 2563, 1696, 1611, 1529, 1248, 1229, 1103, 978, 729 cm^"1. H^!-NMR (300 MHz, DMSO-d₆) δ 4.12 (s, 3H), 7.26 (d, IH, J= 8.4 Hz), 7.68 (t, IH, J

= 7.1Hz), 7.89 (t, IH, J= 7.5 Hz), 8.22 (t, 2H), 8.37 (d, 2H, J= 8.1 Hz), 10.14 (s,

IH).

INTERMEDIATE 2 4-Nitrophenyl 4-methoxy-acridine-l-carboxylate

A suspension of 4-methoxy-acridine-l-carboxylic acid (intermediate 1) (25 mg, 0.098 mmol), p-nitro phenol (16. 3 mg, 0.117 mmol), EDCI (23.5 mg, 0.122 mmol), DMAP (1.19 mg, 0.009 mmol), in dry dichloromethane (2 ml) was stirred at room temperature for 2 h. Dichloromethane was distilled off, water (8 ml) was added to the residue and extracted with ethyl acetate (30 x 3 ml). The organic layer was dried over anhydrous sodium sulphate, concentrated in vacuo to obtain the product as a yellow solid (20 mg). INTERMEDIATE 3 4-Nitrophenyl 4-methoxy-l-phenazine carboxylate

Step 1: 4-Methyl-2-nitrophenol

Cone. H₂SO₄ (2 equivalent) was carefully added in a thin stream to 15 ml of water with cooling. Solid KNO₃ (1.2 equivalent) was then carefully added and the resulting mixture was cooled at 0 to -1O⁰C with constant stirring. To this, 5.4 ml of/?-cresol (1 equivalent) was added drop wise with vigorous stirring and the reaction was continued at -1O⁰C for 2h. The reaction mixture was poured onto water and resulting mixture was extracted with CHCl₃. The organic layer was collected and washed with water, brine and dried over anhydrous Na₂SO₄ The solvent was removed by distillation under vacuum to yield the crude product which was column chromatographed using 20 % ethyl acetate in petroleum ether to give yellow oil. Yield: 50%

IR(KBr): 3085,2950,2855, 1695, 1680, 1540, 1354, 1200,954, 833,740

¹H NMR (300 MHz, DMSO): 2.265 (s, 3H), 7.029 (d, IH, J= 8.7 Hz), 7.38 (dd, IH, J

= 8.1 Hz), 7.701 (s, IH), 10.683 (s, IH, exchanges with D₂O)

M⁺¹: 154 Step 2: 4-Methyl-2-nitrophenol methyl ether

4-Methyl-2-nitrophenol (1 equivalent) was dissolved in a solution of NaOH (1.5 equivalent) in water (10 times) to form the sodium salt. Tetrabutyl ammonium bromide (0.05 equivalents) and dichloromethane (10 times) were then added and the resulting mixture was cooled at 1O⁰C. To this, dimethyl sulfate (1.2 equivalent) was added was drop wise and the resulting reaction mixture was stirred at 25⁰C for 10- 12h. After completion, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic extracts were combined and washed with water, brine and dried over anhydrous Na₂SO₄. The solvent was removed by distillation under vacuum to yield the crude product which was column chromatographed using 20 % ethyl acetate in petroleum ether to give yellow oil. Yield: 90%

IR (KBr): 2965, 2846, 2878, 1728, 1623, 1529, 1462, 1350, 1261, 1200, 1158, 1061, 1020, 921, 883, 852, 810, 766, 672, 593.

¹H NMR (300 MHz, DMSO): 2.307 (s, 3H), 3.88 (s, 3H), 7.257 (d, IH, J - 8.4Hz), 7.492 (d, IH, J= 8.7 Hz), 7.693 (s, IH) M⁺¹: 168

Step 3: l-Methoxy-4-methyl pheπazine

4-Methyl-2-nitrophenol methyl ether (1 equivalent), aniline (1 equivalent) and KOH- pellets (excess) were suspended in toluene (10 times) and the resulting mixture was heated at 12O⁰C for 4h. After completion, the reaction mixture was filtered hot to remove inorganic solid and the filtrate obtained was concentrated to remove excess of solvent to give brown oil as crude product. Purification was done by column chromatography using 20 % ethyl acetate in petroleum ether to give pure product as yellow solid. Yield: 50%

IR(KBr): 3053, 3019, 2913, 2837, 1821, 1604, 1626, 1575, 1530, 1462, 1448, 1483, 1384, 1338, 1316, 1279, 1248, 1231, 1117, 1099, 809,756,630 ¹H NMR (300 MHz, DMSO): 2.736 (s, 3H), 4.044 (s, 3H), 7.17 (d, IH,J= 7.8 Hz), 7.687(d, IH,7.8Hz),7.946(m,2H),8.279(m,2H) M⁺¹: 225

Step 4: 4-Methoxy phenazine -1-carboxylic acid

l-Methoxy-4-methyl phenazine (1 equivalent) was dissolved in a mixture of acetic acid-water and to this, chromium trioxide (8.5 equivalent) was added and the resulting mixture was heated at 12O⁰C for 2h. After completion, the distillation of excess of acetic acid and water under reduced pressure followed by addition of water yielded the product as yellow colored crystalline solid.

Yield: 6%

IR(KBr): 3400-3210(broad), 3011,2924,2850, 1747, 1680, 1557, 1439, 1382, 1288,

1210, 1102,765 ¹HNMR(300MHz,DMSO):4.194(s,3H),7.486(d, IH,J=8.4Hz), 8.107(m,2H),

8.423 (m,2H), 8.734(d, IH,J=8.4Hz), 14.904(IH,exchangeswithD₂O)

M⁺¹: 255

Step 5: 4-Nitrophenyl 4-methoxy-l-phenazine carboxylate

4-Methoxy phenazine -1-carboxylic acid (1 equivalent), />-nitro phenol (1.2 equivalent), EDCI (1.25 equivalent) and N, N-dimethyl amino pyridine (0.1 equivalent) were mixed together and dissolved in dry dichloromethane under nitrogen atmosphere. The resulting reaction mixture was heated at 40-45⁰C for 5-6h and the reaction mixture was then cooled and extracted with 0.5N NaOH solution. The organic layer was washed with water and brine and dried over anhydrous Na₂SO₄. The solvent was removed by distillation under reduced pressure to yield p- nitrophenyl-4-methoxy-l -phenazine carboxylate as yellow solid which was directly used in the next step

INTERMEDIATE 4 4-methoxy oxanthrene- 1-carboxylic acid

Step 1: 8-Nitrooxanthren-l-ol

Synthesized form pyrogallol (.0209 moles) and l-Flouro-2,4-dinitrobenzene (.0268 moles) and K₂CO₃ in DMF as a solvent at reflux temperature for 1-2 hrs. Cooled reaction mass was poured in ice cold water. Filtered the solid and dried.

H'-NMR (300 MHz, DMSO-d₆) 6.48 (dd, IH, J = 1.2 and 1.5 Hz), 6.61 (dd, IH, J= 1.2 and 1.5 Hz), 6.82 (t, IH, J= 8.1 Hz), 7.19 (d, IH, J= 8.7 Hz), 7.73 (d, IH J= 2 Hz),

7.89(dd, IH,J=8.8Hz), 10.03 (s, IH), LR(KBr): 3421,3090, 1625, 1589, 1521, 1510, 1483, 1342, 1264, 1245, 1200, 1126,

1075, 1029,952, 866,849,979,740,706,539,447cm^"1,

Step 2: l-methoxy-8-nitrooxanthrene

2-Nitrooxanthrene (4.8 mmoles) and K₂CO₃ (8.1 mmoles) was taken in DMF as solvent at room temperature. Add methyl iodide (8.1 mmoles) in above reaction mixture at room temperature. Heat the reaction mass at 70-80 ⁰C for 2-3 hrs. Cool the reaction mass and pour in ice cold water. Filtered the solid and dried.

H'-NMR (300 MHz, DMSO-d₆) 3.91 (s, 3H), 6.52 (d, IH, J = 1.2 Hz), 6.54 (d, IH, J

= 1.5 Hz), 6.62 (d, IH, J= 1.5 Hz), 6.64 (d, IH, J= 1.5 Hz), 6.87 (s, IH), 6.92 (m,

IH), LR (KBr) : 2925, 1625, 1582, 1530, 1501, 1017, 833, 821, 768, 742, 554, cm^'1

Step 3: 9-Methoxyoxanthren-2-amine

Compound was dissolved in methanol and 5 % Pd/C was added at room temperature.

Put reaction mass under hydrogen at 60 psi pressure in Parr apparatus for 2-3 hrs.

Filter through celite bed and evaporate solvent up to compound dryness. H'-NMR (300 MHz, DMSO-d₆) 3.91 (s, 3H), 6.52 (d, IH, J = 1.2 Hz), 6.54 (d, IH, J

= 1.5 Hz), 6.62 (d, IH, J= 1.5 Hz), 6.64 (d, IH₅ J= 1.5 Hz), 6.87 (s, IH), 6.92 (m,

IH,)

Step 4: 1-methoxyoxanthrene

To a cold solution of (320 micro liter) rectified spirit and (43 micro liter) cone. sulphuric acid add solution of crude amine (from step 3) (0.43 mmoles). Cool to 5⁰C.

Then add slowly a solution of (0.69 mmoles) of pure NaNO₂ in water. Cool to 1O⁰C for 20 minutes after all the nitrite solution has been added in order to complete the diazotization. Add (0.21mmoles) Cu powder to diazotized solution and cool it in ice bath. Warm the flask on water bath until vigorous evolution of gas commences. When reaction subsided again warm the flask gently and finally heat on boiling water bath for 10 minutes. At the end of the reaction the color was changes from reddish to brown to yellow. Cool the reaction mass and extract with ethyl acetate evaporate solvent up to dryness and purify the compound by column chromatography. H^!-NMR (300 MHz, DMSOd₆) 3.89 (s, 3H), 6.50 (dd, IH, J = 8.2 Hz), 6.54 (d, IH, J= 8.4 Hz), 6.96 (m, 5H,). Step 4: 4-methoxyoxanthrene-l-carbaldehyde

To stirred solution of 1 -methoxyoxanthrene (0.46 mmoles) in dichloromethane at - 15°C, SnCl₄ (0.79 mmoles) was added in one lot. After stirring for 15 minutes (0.46 mmoles) 1.1, dichloromethyl -methyl ether was added to it. Reaction was stirred for 30 minutes and monitored by TLC. Poured the reaction mass on crushed ice and filtered the solid and dried.

H'-NMR (300 MHz, DMSOd₆) 6.66 (d, IH, J= 9 Hz), 6.96 (m, 4H,), 7.49 (d, IH, J

= 9 Hz), 10.30 (s, 3H).

Step 5: 4-methoxyoxanthrene-l-carboxylic acid

To a solution of acetone water) 4-methoxyoxanthrene-l-carbaldehyde (0.35 mmoles) and NH₂SO₃H (0.52 mmoles) was dissolved at 0-10 ⁰C under stirring. Slowly a solution OfNaO₂Cl in water (0.52 mmoles) was added at 0- 10⁰C. Reaction monitored by TLC. Reaction completed within in 1-2 hrs. Acetone was distilled out and water was poured in reaction mass. The precipitated solid was filtered and dried. H'-NMR (300 MHz, DMSO-d₆) 3.84 (s, 3H), 7.13 (m, 4H,), 6.89 (d, IH, J= 9 Hz), 7.70 (d, IH, J= 9 Hz), 12.50 (bs, IH, D₂O Exchangeable).

INTERMEDIATE 5 4-methoxy-7-nitrooxanthrene-l-carboxylic acid

Step 1: 4-methoxy-7-nitrooxanthrene-l-carbaldehyde

To stirred solution of l-methoxy-7- nitrooxanthrene (3.8 mmoles) (from step 3 of intermediate 4) in DCM at -15°C, SnCl₄ (6.5 mmoles) was added in one lot. After stirring for 15 minutes (3.8 mmoles) 1.1, dichloromethyl-methyl ether was added to it. Reaction was stirred for 30 minutes and monitored by TLC. Pour the reaction mass on crushed ice. Filter the solid, dry and purify by column chromatography. H'-NMR (300 MHz, DMSO-d₆) 3.91 (s, 3H,), 6.53 (dd, 2H, J= 2.7 Hz), 6.79 (m, 2H,), 7.85 (m, 2H,) 10.25 (s, IH) Step 2: 4-methoxy-7-nitrooxanthrene-l-carboxylic acid To a solution of acetone water Methoxy-7-nitrooxanthrene- 1 -carbaldehyde (3.1 mmoles) and NH₂SO₃H (4.7 mmoles) was dissolved at 0-10 ⁰C under stirring. Slowly a solution OfNaO₂Cl in water (4.7 mmoles) was added at 0- 10 ⁰C. Reaction completed within in 1-2 hrs. Acetone was distilled out and water was poured in reaction mass. The precipitated solid was filtered and dried.

EXAMPLE 1 Nl-(3,5-dichloropyridin-4-yl)-4-methoxyacridine-l-carboxamide

4-Nitrophenyl 4-methoxy-acridine-l-carboxylate (intermediate 2) (20 mg, 0.053 mmol), 3,5-dichloro-4-aminoρyridine (Lancaster) (17.2 mg, 0.106 mmol) was dissolved in DMF (3 ml), cooled to O⁰C and sodium hydride (60% dispersion) (3.8 mg, 0.096 mmol) was added slowly to the reaction mixture. The reaction mixture was stirred 12 h at room temperature and then quenched with water (10 ml) and then extracted with dichloromethane (30 x 3 ml). The organic layer was washed with saturated sodium bicarbonate (10 ml), dried over anhydrous sodium sulphate, concentrated in vacuo and the residue was purified by silica gel column chromatography using 90 % ethyl acetate in petroleum ether as the eluent to obtain the product as pale yellow solid (3.0 mg). H '-NMR (300 MHz, DMSO-d₆) δ 4.13 (s, 3H), 7.33 (d, IH, J = 8.1 Hz), 7.68 (t, IH, J = 7.2 Hz), 7.90 (t, IH, J = 7.5 Hz), 8.10 (d, IH, J= 7.8 Hz), 8.22 (d, 2H, J= 8.1 Hz), 8.81 (s, 2H), 9.57 (s, IH, exchanges with D₂O), 10.91 (s, IH).

EXAMPLE 2 Nl-(pyridin-4-yl)-4-methoxyacridine-l-carboxamide

A suspension of 4-methoxy-acridine-l-carboxylic acid (intermediate 1) (35 mg, 0.138 mmol), 4-aminopyridine (Lancaster) (19.5 mg, 0.207 mmol), EDCI (33.0 mg, 0.172 mmol), DMAP (1.70 mg, 0.013 mmol) and triethylamine, in dry DMF (2 ml) was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 x 3 ml). The organic layer was dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by silica gel column chromatography using 4.0 % methanol in dichloromethane as the eluent to obtain the product as pale yellow solid (3.0 mg). H'-NMR (300 MHz, DMSO-d₆) δ 4.13 (s, 3H), 7.29 (d, IH, J = 8.1 Hz), 7.67 (t, IH, J = 7.2 Hz), 7.82 (d, 2H, J = 5.7 Hz), 7.89 (t, IH, J = 7.5 Hz), 7.99 (d, IH, J= 7.8 Hz), 8.23 (d, 2H), 8.52 (d, 2H, J = 6.3 Hz), 9.49 (s, IH, exchanges with D₂O), 10.95 (s, IH).

EXAMPLE 3 Nl-(pyridin-3-yl)-4-methoxyacridine-l-carboxamide

A suspension of 4-methoxy-acridine-l-carboxylic acid (intermediate 1) (50 mg, 0.197 mmol), 3-aminopyridine (28 mg, 0.296 mmol), EDCI (47.2 mg, 0.246 mmol), DMAP (2.4 mg, 0.019 mmol), triethylamine (30 mg, 0.295 mmol) was stirred in 2 ml DMF at room temperature for 17 hrs. Reaction mass was diluted with water (10 ml) and extracted with ethyl acetate (30 x 3 ml), dried over anhydrous sodium sulphate and concentrate. Product was purified by column chromatography using 1 % methanol in dichloromethane to obtained product as solid. (18 mg). Melting Point : 201⁰C IR (KBr) : 3437, 3246, 2929, 1930, 1678, 1609, 1583, 1541, 1528, 1418, 1330, 1297, 1275, 1210, 1096, 833, 722, 468 cm^"1. ¹H NMR (CDCl₃) δ 4.08 (s, 3H), 6.40 (t, IH), 7.44 (t,lH), 7.57 (dd, 2H), 7.79 (t, IH), 7.88 (d, IH, J= 7.7Hz), 8.24 (d, IH J= 8.7Hz), 8.50 (dd, 2H), 8.78 (S, IH,), 8.97 (s, IH,), 9.26 (s, IH Exchange with D₂O).

Example 4 Nl-(3, 5-dichloro-4-pyridyl)-4-methoxy-l-phenazinecarboxamide

/>-nitrophenyl-4-methoxy-l-phenazine carboxylate (1 equivalent) (intermediate 3), was dissolved in dry DMF under nitrogen atmosphere. 3, 5-dichloro-4-aminopyridine (1 equivalent), dissolved in dry THF was added to the reaction mixture and resulting mixture was cooled at -3O⁰C. To this, pre-washed suspension of 60% NaH (2 equivalent) was added at O⁰C with vigorous stirring and the reaction mixture was stirred at O⁰C for 2h and then at 25⁰C for 48h. After completion, the reaction mixture was poured onto brine and extracted with CHCl₃. The organic layer was washed with IN NaOH solution, water and brine and dried over anhydrous Na₂SO₄. The solvent was removed by distillation under reduced pressure to give crude compound which was column chromatographed using 20 % acetone in chloroform to give yellow solid. Yield: 35% IR (KBr):3368, 3014, 2924, 2854, 1747, 1701, 1557, 1439, 1382, 1288, 1216, 1102, 760

¹H NMR (300 MHz, DMSO): 4.203 (s, 3H), 7.51 (d, IH, J = 8.7 Hz), 8.095 (m, 2H), 8.39 (d, IH, J= 8.1 Hz), 8.50 (d, IH, J = 8.3 Hz), 8.793 (s, 2H), 8.879 (d, IH, J= 8.4 Hz), 13.078 (s, IH, exchanges with D₂O), M⁺¹: 399

Example 5 7V-(3,5-dichloropyridin-4-yl)-4-methoxyoxanthrene-l-carboxamide

The 4-methoxyoxanthrene-l-carboxylic acid (intermediate 4) (0.110 mmoles) was taken in CCl₄ solvent slowly SOCl₂ (2 ml.) was added to the above reaction mass. Heat the reaction mass at reflux temperature for 1-2 hrs. Excess thionyl chloride was distilled out under nitrogen. Above reaction mass was dissolved in dry THF at room temperature. A solution of 4-amino-3,5-dichloropyridine in THF (0.340 mmoles) was added at 0-10 ⁰C. Slowly 60 % NaH (0.340 mmoles) was added at 0-10 ⁰C. Reaction was completed within 1-2 hrs and then quenched with water and extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure to give crude compound which was column chromatography. H'-NMR (300 MHz, DMSO-d₆) 3.97 (s, 3H), 6.70 (dd, IH, J= 9 Hz) 7.00 (m, 4H), 7.90 (d, IH, J= 9 Hz), 8.73 (bs, 2H), 9.15 (s, IH, D2O Exchangeable),

LR-(KBr): (CM^"1)3248,2960,2925,2852,2347,2177, 1725, 1663, 1629, 1548, 1514, 1416, 1465, 1401, 1309, 1256, 1107, 1090, 1029, 1071,901,891,882,812, 791,751,619.

Example6 iV-(pyridin-4-yl)-4-methoxyoxanthrene-l-carboxamide

To a solution of 4-methoxyoxanthrene-l-carboxylic acid (intermediate 4) (0.38 mmoles) in DMF, EDCI. (7.7 mmoles), p-amino pyridine (0.58 mmoles), HOBT (0.19 mmoles) was added at R.T. then cool at 0-10⁰C and add slowly triethylamine (7.7 mmoles). Reaction was completed with in 2-3 hrs. Compound purified by column chromatography.

H'-NMR (300 MHz, DMSO-dβ) 3.89 (s, 3H), 6.99 (m, 5H,) 7.29 (d, IH, J= 8.7), 7.83 (d, 2H, J= 6.6 Hz), 8.55 (d, 2H J= 6.6), 10.77 (s, IH, D2O Exchangeable), 1.R-(KBr) : (CM^"1) 3358, 3058, 2844, 1666, 1627, 1586, 1595, 1497, 1447, 1461, 1462, 1412, 1330, 1289, 1256, 1211, 1180, 1087, 997, 937, 873, 821, 789, 757, 704, 636.

Example 7 7V-(pyridin-3-yl)-4-methoxyoxanthrene-l-carboxamide

To a solution of 4-methoxyoxanthrene-l-carboxylic acid (intermediate 4) (0.77 mmoles) in DMF, EDCI. (1.55 mmoles), 3-aminopyridine (.1.10 mmoles), HOBT (.38 mmoles) was added at R.T. then cool at 0-10⁰C. Add slowly triethylamine (1.5 mmoles) at above temperature. Reaction was completed with in 2-3 hrs. Compound purified by column chromatography.

H'-NMR (300 MHz, DMSO-d₆) 3.88 (s, 3H), 6.89 (d, IH J= 8.7), 7.02 (m, 4H), 7.29 (d, 2H, J= 3.6 Hz), 7.40 (m, IH), 8.18 (d, IH, J= 8.1 Hz) 8.3 l(d, 1H, J=3.6), 8.88 (s, IH) 10.33 (s, IH D₂O Exchangeable)

LR-(KBr)(CM^"1)3351, 3053,2932,2844, 1654, 1625, 1595, 1499, 1462, 1482, 1447,

1408, 1333, 1309, 1271, 1218, 1230, 1192, 1180, 1156, 1111, 1025,991,936, 871,

819,798,788,755,629.

Example 8 N-(pyridin-3-yl)-4-methoxy-7-nitrooxanthrene-l-carboxamide

To a solution of 4-methoxy-7-nitrooxanthrene-l-carboxylic acid (intermediate 5) (0.60 mmoles) in DMF, EDCI (1.30 mmoles), 4-aminopyridine (0.90 mmoles), HOBT (.30 mmoles) was added at R.T. then cool at 0-10⁰C. Add slowly triethylamine (1.3 mmoles) at above temperature. Reaction was completed with in 2-3 hrs. Compound purified by column chromatography. H '-NMR (300 MHz, DMSO-d₆) 3.92 (s, 3H), 6.99 (d, IH J= 8.7), 7.21(dd, 2H, J= 9 Hz), 7.33 (dd, IH J= 8.7 Hz), 7.70 (dd, 2H, J= 4.8 Hz), 7.90 (m, 2H), 8.49 (d, 1 H, J= 2.4 Hz), 10.58 (b, IH D₂O Exchangeable.

1.R-(KBr) (CM^"1) 3102, 2994, 2840, 2658, 2365, 2016, 1618,1633, 1616, 1591, 1522, 1506, 1446, 1416, 1318, 1344, 1296, 1264, 1279, 1215, 1139, 1094, 1074, 992, 828, 798.

EXAMPLE 9 Nl-(3,5-dichloropyridin-4-yl)-4-difluoromethoxyacridine-l-carboxamide

Step 1: Methyl 4-hydroxyacridine-l-carboxylate

To a solution of 4-methyl benzene thiol (0.935 g, 7.4 mmol), in toluene (20 ml) was added NaOH (0.296 g, 7.4 mmol) and resulting reaction mass was refluxed under azeotropic distillation for 2 h then HMPA (1.34 g, 7.4 mmol), and Methyl-4-methoxy- acridine-1-carboxylate (from step 5 of intermediate 1) (1 g, 3.7 mmol) and resulting reaction mass was refluxed for 2 h. Toluene was distilled out added water (40 ml) extracted with ethyl acetate (40 x 3 ml), dried over sodium sulfate and concentrate. Product was purified using silica gel column chromatography to get yellow solid (674 mg).

¹H NMR -.(CDCl₃) δ (in ppm): 10.2 (s, IH), 8.43 (d, IH, J= 7.8Hz), 8.21 (d, IH, J = 8.7 Hz), 8.12 (d, IH, J= 9Hz), 7.83 (t, IH) ,7.62 (t, IH) 7.18 (d, IH, J= 7.8Hz), 4.02 (s, 3H) Step 2: Methyl 4-(difluoromethoxy) acridine-1-carboxylate

To a solution of Methyl 4-hydroxyacridinecarboxylate (0.650 g, 2.58 mmol), in DMF (25ml), was added potassium carbonate (0.715 g, 5.17 mmol) and heated up to 90- 100⁰C and difluorochloromethane gas was bubbled through reaction mass for 2 hrs. Reaction mass was quenched in water solid precipitated out was filtered dried to get 0.725 g of the product as white solid.

¹H NMR :(CDC1₃) δ (in ppm):-10.14 (s, IH), 8.33 (t, 2H), 8.11 (d, IH, J= 8.4Hz), 7.86 (t, IH), 7.62 (dd, 2H), 7.55 (d, IH, J= 7.8Hz), 7.41 (t, IH) ,4.036 (s, 3H) Step 3: 4-(difluoromethoxy) acridine-1-carboxylic acid To a solution of Methyl 4-(difluoromethoxy) acridine-1-carboxylate (700 mg, 2.32 mmol) in methanol (15 ml) was added a of IN solution of NaOH (5 ml) and heated at 70-80⁰C for 3 h. Reaction mass was concentrated to dryness and added water (5ml) and neutralized with IN HCl up to pH 5 The precipitate was filtered and dried to get red solid (560mg) ¹H NMR : (CDCl₃) δ (in ppm), 10.13 (S, IH), 8.31 (m, 2H), 8.23 (d, IH, J= 8.7Hz) 7.96 (m IH), 7.68 (m, IH) 7.65 (d, IH, J= 8.1Hz), 7.49 (t, IH) IR (KBr, cm.^"1):- 3434, 3078, 2518, 1937, 1688, 1534, 1478, 1271, 1219, 1034, 737, 623. Step 4: 4-nitrophenyl 4-(difluoromethoxy) acridine-1-carboxylate

A mixture of 4-(difluoromethoxy) acridine-1-carboxylic acid (250 mg,0.988 mmol) , para nitrophenol (145 mg, 1.04 mmol) EDCI (200.13mg, 1.04 mmol ) DMAP (17.06 mg, 0.139 mmol) in dry THF (15 ml) was stirred at room temperature for 3 h. Reaction mass was quenched in water slowly to get yellow solid which was filtered and dried on vacuum.(190 mg) .

¹H NMR :(DMSO-d⁶) δ (in ppm):-10.07 (s, IH), 8.70 (d, IH, J= 8.4Hz), 8.43 (d, 2H,

J= 8.7Hz), 8.30 (dd, 2H), 7.99 (t, IH), 7.77 (m, 4H), 7.84 (t, IH).

IR (KBr, cm/¹)- 3086, 1730, 1617, 1525, 1356, 1262, 1149, 1142, 1047, 964, 861,

741.

Step 5: 7V-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) acridine-1-carboxamide 4-nitrophenyl 4-(difluoromethoxy) acridine-1-carboxylate (150 mg, 0.367 mmol) and p-amino-3, 5, dichloropyridine (88.7 mg, 0.554 mmol) was dissolved in dry DMF and cooled to O⁰C. Sodium hydride (44.1 mg, 1.83 mmol) was added slowly and allowed to come at room temperature (30 min.) Reaction mass was quenched in water (20 ml), neutralized with IN HCl aqueous layer was extracted with dichloromethane (40 x 3ml) washed with brine (20ml) dried and concentrated. Product was purified by silica gel column chromatography, to get product as yellow solid (65 mg) Melting point- above 25O⁰C ¹H NMR :-(DMSO-d⁶) δ (in ppm):- 11.14 (s, IH exchanges with D₂O), 9.57 (s, IH) , 8.83 (s, 2H) , 8.28 (t, 2H), 8.07 ( d, IH, J= 7.8Hz) 7.98 (t, IH), 7.75 (m, 2H), 7.50 (t, IH).

IR(KBr,cm.^"1):3197,3043,2724, 1658, 1555, 1494, 1284, 1273, 1207, 1148, 1065, 1024,736. In vitro Studies

Inhibition of Phosphodiesterase Enzymes (PDE4)

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

The assay was performed with modification of the method of Thompson and Appleman (Biochemistry; 1971; 10; 311-316) and Schwartz and Passoneau (Proc. Natl. Acad. Sci. U.S.A. 1974; 71; 3844-3848), both references incorporated herein by reference in their entirety, at 34⁰C. In a 200 ul total reaction mixture, the reaction mixture contained 12.5mM of Tris, 5 mM MgCl₂, 1 μM cAMP (cold) and ³H cAMP (0.1 uCi), (Amersham). Stock solutions of the compounds to be investigated were prepared in DMSO in concentrations such that the DMSO content in the test samples did not exceed 0.05 % by volume to avoid affecting the PDE4 activity. Drug samples were then added in the reaction mixture (25 μl/tube). The assay was initiated by addition of enzyme mix (75 μl) and the mixture was incubated for 20 minutes at 34⁰C. The reaction was stopped by boiling the tubes for 2 mins at 100⁰C in a water bath. After cooling on ice for 5 minutes and addition of 50 ug/reaction of 5'- nucleotidase snake venom from Crotalus atrox (Sigma) incubation was carried out again for 20 min. at 34⁰C. The unreacted substrate was separated from (³H) Adenosine by addition of Dowex AG 1-X8 ( Biorad Lab), (400 ul) which was prequilibrated (1:1 :1) in water and ethanol. Reaction mixture was then thoroughly mixed, placed on ice for 15 minutes, vortexed and centrifuged at 14,000 r.p.m. for 2 mins. After centrifugation, a sample of the supernatant was taken and added in 24 well optiplates containing Scintillant (1 ml) and mixed well. The samples in the plates were then determined for radioactivity in a Top Counter and the PDE4 activity was estimated. PDE4 enzyme was present in quantities that yield <30% total hydrolysis of substrate (linear assay conditions). Results were expressed as percent inhibition (IC₅o) in Nm concentrations. The IC₅₀ values were determined from the concentration curves by nonlinear regression analysis. :

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

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

Claims

Claims:

1. A compound of general formula (I)

(1) wherein: each occurrence of R , R and R may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstiruted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstiruted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -NR⁵R⁶, -C(=L)-R⁵, -C(O)-R³, -C(O)O- R^a, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, nitro, -OH, cyano, formyl, acetyl, halogen, -OR^a, -SR^a, or a protecting group or when two R³ substitutents are ortho to each other, they may be joined to form a C₃-C₈ saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR¹ or S; each occurrence of R⁵ and R⁶ may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, halo, -OH, cyano, -C(O)-R^a, -C(O)O-R^a, -C(O)NR a³rR> b⁰, -S(O)₀₁-R³, -S(O)_1n-NR >a³τR> b", - C(=NR^a)-R^b, -C(=NR^a)-NR^aR^b, -C(=S)-NR^aR^b, -C(=S)-R^a, -N=C(R^aR^b), -NR^aR^b, - OR^a, -SR^a, or a protecting group or R⁵ and R⁶, when attached to a nitrogen atom, may be joined to form an optionally substituted C₃-C₈ saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR^a or S; each occurrence of R^a and R^b may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro,

-OH, cyano, formyl, acetyl, halogen, a protecting group, -C(O)-R^a, -C(O)O-R^a, -

C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, -OR^a, or -SR^a;

Ar is a substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; each occurrence of L is O, S or NR³;

X and A are independently -CR^aR^b-,-CR^a-,-C(=B)-, O, S(O)_m, N or NR³; each occurrence of m is 0, 1 or 2; n is 0-4; p is 0-2;

Y is -C(=B)C(=D)NR⁴ or -C(=B)NR⁴

B is O, S or NR^a;

D is O, S or NR^a;

R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR^a, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring; and each dotted line [ — ] in the central ring represents an optional double bond; or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer, polymorph, pharmaceutically acceptable salt, N-oxide, pharmaceutically acceptable solvate or a pharmaceutical acceptable salt thereof.

2. The compound according to claim 1, wherein R¹ is substituted or unsubstituted alkyl.

3. The compound according to claim 2, wherein R¹ is methyl.

4. The compound according to claim 2, wherein R¹ is difluromethyl.

5. The compound according to any one of claims 1-3 or 4 where A is N , X is CH and the dotted line represents a bond.

6. The compound according to any one of claims 1-3 or 4 where A is N, X is N and both dotted lines represent a bond.

7. The compound according to any one of claims 1-3 or 4 where A is O, X is O and the dotted lines are absent.

8. The compound according to any one of claims 1-6 or 7, wherein Y is - C (O)-NH- .

9. The compound according to any one of claims 1-7 or 8, wherein Ar is an optionally substituted pyridyl.

10. The compound according to claim 9, wherein said substituent is halogen.

11. The compound according to claim 10, wherein said halogen is chloro.

12. The compound according to claim 9, wherein Ar is

13. The compound according to claim 12 wherein Ar is

14. The compound according to any one of claims 1-12 or 13, wherein p is 0 and n is 0.

15. A compound according to claim 1 selected from: Nl-(3,5-dichloropyridin-4-yl)-4-methoxyacridine-l-carboxamide; Nl-(pyridin-4-yl)-4-methoxyacridine carboxamide; Nl-(pyridin-3-yl)-4-methoxyacridine-l-carboxamide; Nl-(3, 5-dichloro-4-pyridyl)-4-methoxy-l-phenazinecarboxamide; N-(3,5-dichloropyridin-4-yl)-4-methoxyoxanthrene-l-carboxamide; iV-(pyridin-4-yl)-4-methoxyoxanthrene- 1 -carboxamide; N-(pyridin-3-yl)-4-methoxyoxanthrene-l -carboxamide; N-(pyridin-3-yl)-4-methoxy-7-nitrooxanthrene-l -carboxamide; or Nl-(3,5-dichloropyridin-4-yl)-4-difluoromethoxyacridine-l -carboxamide; or a pharmaceutically acceptable salt thereof .

16. A method for the preparation of a compound of claim 1 having formula

(I)

(1) comprising the steps of: a) reacting a compound of formula (10) with a compound of formula (10a)

10 10a wherein W is a halogen and FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group to obtain an intermediate of formula (11)

11 b) cyclising an intermediate of the formula (11) to afford a tricyclic intermediate of the formula (12) or (13)

c) reducing a tricyclic intermediate of the general formula (12) or (13) to obtain an intermediate of formula (14)

d) aromatization of an intermediate of formula (14) to an intermediate of formula (15)

15

e) conversion of FG in the intermediate of formula (15) to a carboxylic acid group to give an intermediate of formula (16)

16

f) conversion of an intermediate of formula (16) to a compound of formula (I)

(I)

g) optionally converting the compound of formula (I) into a corresponding salt or N- oxide.

17. A method for the preparation of a compound according to claim 1 having formula (I)

(1) comprising the steps of: a) reacting a compound of formula (17) with a compound of formula (10a)

17 10a wherein W is a halogen and FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group to obtain an intermediate of the formula (18)

18 b) cyclising an intermediate of formula (18) to obtain a tricyclic intermediate of the general formula (19) or (20)

c) reducing a tricyclic intermediate of formula (19) or (20) to obtain an intermediate of the general formula (21)

d) aromatization of the intermediate of formula (21) to an intermediate of formula (22)

e) converting FG in the intermediate of formula (22) to a carboxylic acid group to give an intermediate of formula (23)

f) converting an intermediate of formula (23) to a compound of formula (I)

(1)

g) optionally converting the compound of formula (1) to a corresponding salt or N- oxide.

18. A method for the preparation of a compound according to claim 1 having formula (I)

comprising the steps of: a) reacting a compound of formula (24) with a compound of formula (10a)

24 10a wherein W is a halogen, FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group, and Z is -OH₅-NHR³ or -SH to obtain an intermediate of formula (25)

b) cyclising an intermediate of formula (25) to form a tricyclic intermediate of formula (26) or (28)

wherein A is O, S(O)_1n or NR³, and X is -CR³R - or C(=B)-; c) converting the FG in the tricyclic intermediate of formula (26) or (28) to give an intermediate of formula (27) or (29), respectively

wherein A is O, S(O)_1n or NR³ and X is -CR^aR^b- or C(=B)-; d) conversion of the intermediate of formula (27) or (29) to a compound of formula (1)

(1) e) optionally converting the compound of formula (1) to a corresponding salt or N- oxide.

19. A method for the preparation of a compound according to claim 1 having formula (I)

(1) comprising the steps of: a) reacting a compound of formula (30) with a compound of formula (31)

30 31 wherein FG is alkyl, acetyl formyl, cyano, or a carboxylic acid ester group to obtain an intermediate of formula (32)

32

b) conversion of FG in the tricyclic intermediate of formula (32) to give an intermediate of formula (33)

33

c) conversion of an intermediate of formula (33) to a compound of formula (1)

(1) d) optionally converting the compound of formula (1) to a corresponding salt or N- oxide.

20. A method for the preparation of according to claim 1 having formula (I)

(1) comprising the steps of: a) reacting a compound of formula (34) with a compound of formula (35)

34 35 wherein W is a halogen, to obtain the intermediate of formula (36)

36

b) formylation of the intermediate of formula (36) to provide an intermediate of formula (37)

37

c) oxidation of the intermediate of formula (37) to give an intermediate of formula (38)

d) conversion of the intermediate of formula (38) to a compound of formula (1)

(1)

e) optionally converting the compound of formula (1) to a corresponding salt or N- oxide.

21. A method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1-14 or 15.

22. A method of treating a disease or condition induced by or associated with excessive secretion of TNF-α and PDE-4 which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1-14 or 15.

23. A method of treating an inflammatory condition or immune disorder which comprises administering to to a subject in need thereof a therapeutically effective amount of a compound according to claim 1-14 or 15.

24. The method according to claim 23 wherein said inflammatory condition or immune disorder is asthma, bronchial asthma chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uveits, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis or chronic inflammation.

25. The method according to claim 24 wherein said inflammatory condition or immune disorder is an allergic inflammatory condition.

26. The method according to claim 25 wherein said inflammatory condition or immune disorder is an inflammatory condition or immune disorder of the lungs, joints, eyes, bowels, skin or heart.

27. The method according to claim 26 wherein said inflammatory condition of the lungs is asthma or chronic obstructive pulmonary disease.

28. A method for abating inflammation in an affected organ or tissue comprising delivering to said organ or tissue a therapeutically effective amount of a compound according to claim 1-14 or 15.

29. A method of treating a disease of the central nervous system in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1-14 or 15.

30. The method according to claim 29 wherein said disease of the central nervous system is depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock or cerebrovascular disease.

31. A method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1-14 or 15.