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WO2004069831A1 - Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes - Google Patents

Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes Download PDF

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Publication number
WO2004069831A1
WO2004069831A1 PCT/IB2004/000330 IB2004000330W WO2004069831A1 WO 2004069831 A1 WO2004069831 A1 WO 2004069831A1 IB 2004000330 W IB2004000330 W IB 2004000330W WO 2004069831 A1 WO2004069831 A1 WO 2004069831A1
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substituted
unsubstituted
group
compound according
pharmaceutically acceptable
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Gopalan Balasubramanian
Laxmikant Atmaram Gharat
Aftab Dawoodbhai Lakdawala
Sarika Suhas Bedekar
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Glenmark Pharmaceuticals Ltd
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Glenmark Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastreomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them.
  • the present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the formula (1), their analogs, their tautomers, their enantiomers, their diasteromers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate oxides, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.
  • PDE4 Phosphodiesterase type 4
  • R 1 , R 2 and R 3 may be same or different and are independently selected for each occurrence from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -CCOJ-R 1 , -C(0)0-R 1 , -C(0) R 1 R 1 , - S(0) m -R 1 ,
  • OR 1 , -SR1 protecting groups or when two R substitutents ortho to each other, may be joined to a form a ring, which may optionally include up to two heteroatoms selected from O, NR 1 or S;
  • X is selected from the group consisting of consisting of O, S(0) m ,NH , and
  • Y is selected from the group consisting of-C(0)NR 4 , -NR 4 S0 2 , -S0 2 NR 4 or -NR 4 C(0); wherein P is chosen from O or S; wherein b represents 0, 1, 2, 3, 4 or 5; wherein n represents 1,2 or 3; wherein m is 0, 1 or 2;
  • Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted and unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;
  • Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents one ore more may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino
  • R 4 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR 1 , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring ;
  • R 5 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -C(0)-R', -CCOJO-R 1 , -C(0)NR 1 R 1 , - S(0) m -R , -S(0) m -NR 1 R 1 , nitro, hydroxy, cyan
  • the compounds of general formula (1) more particularly, down regulate or inhibit the production of TNF- ⁇ as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • the compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • the airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component.
  • the magnitude of asthmatic reactions is correlated with the number of eosinophils present in lungs.
  • the accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues.
  • TNF- ⁇ Tumor necrosis factor
  • This second messenger is regulated by the phosphodiesterase (PDE) family of enzymes.
  • PDE phosphodiesterase
  • the phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their • inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophilis are believed to be a critical proinflammatory target for asthma, identification of the expression of the PDE 4 gene family in eosinophils led to PDE 4 as potential therapeutic target for asthma [Rogers, D.F., Giembycz, M.A., Trends Pharmacol. Sci, 19, 160-164(1998); Barnes, P.J., Trends Pharmacol. Sci., 19, 415-423 (1998) herein incorporated by reference in their entirety].
  • PDEs The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [Soderling, S.H., Bayuga, S.J., and Beavo, J.A., Proc. Natl. Acad. Sci., USA, 96, 7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J. Biol. Chem., 274, 18438-18445 (1999) herein incorporated by reference in their entirety]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes.
  • Phosphodiesterase type 4 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 [Tro ⁇ hy,TJ., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated by reference in their entirety].
  • TNF- ⁇ 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- ⁇ 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 herein incorporated by reference in their entirety]. Strong interest in drugs capable of selective inhibition of PDE 4 is due to several factors.
  • Tissue distribution of PDE-4 suggests that pathologies related to the central nervous and immune systems could be treated with selective PDE-4 inhibitors.
  • 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.
  • PDE4 family has grown to include four subtypes - PDE4A to PDE4D, each encoded by a distinct gene (British Journal of Pharmacology; 1999; v.128; p.1393-1398), herein incorporated by reference in its entirety.
  • PDE-4 there exist two binding sites on mammalian PDE-4 at which inhibitor molecules may bind. Also PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M.M., Livi, G.P., Burman, M., Trophy, T.J., Mol. Pliarmaco., 50, 891-899 (1996) herein incorporated by reference in their entirety]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE-4L inhibition.
  • R 1 , R 2 and R3 may be same or different and are independently selected for each occurrence from the groups consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -(-(OJ-R 1 - -C(0)NR 1 R 1 , - S(0) m -R , -S(0) m
  • Y is selected from the group consisting of-C(0)NR 4 , -NR 4 S0 2 , -S0 2 NR 4 and
  • Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring;
  • Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents one ore more may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino '
  • R 4 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR 1 , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring ;
  • R 5 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl., substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , -C(0)-R 1 , -C(0)NR 1 R 1 , - S(0) m -R 1 , -S(0) m -NR 1 R 1 , nitro, hydroxy, cyano, amino, formy
  • the present invention also relates to a process for the preparation of the above said novel heterocyclic compounds of the formula (1) as defined above.
  • the compounds of general formula (1) more particularly, down regulate or inhibit the production of TNF- ⁇ as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • the compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • substituents in the 'substituted alkyl' 'substituted alkoxy' 'substituted alkenyl' 'substituted alkynyl' 'substituted cycloalkyl' 'substituted cycloalkylalkyl' 'substituted cyclocalkenyl' 'substituted arylalkyl' 'substituted aryl' 'substituted heterocyclic ring', 'substituted heteroaryl ring,' 'substituted heteroarylalkyl', 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl', 'substituted cyclic ring' 'substituted alkylcarbonyl', 'substituted alkyl
  • R 1 is unsubstituted alkyl. Further prefered is where R 1 is methyl. Further prefered is where R 1 is substituted alkyl. Further prefered is where R 1 is -CHF 2 . Further prefered is where P is O.
  • X is selected from the group consisting of O, NH, N- R 5 and S.
  • Y is -C (O) NH.
  • Ar is selected from the group consisting of substituted or unsubstituted 4-pyridyl; substituted or unsubstituted 4-pyridyl-N-oxide; substituted or unsubstituted 3 -pyridyl;
  • Ar is selected from the group consisting of
  • alkyl' refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like .
  • Alkenyl refers to aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms in the e.g., ethenyl, 1-propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
  • Alkynyl refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl. propynyl, butnyl and the like.
  • Alkoxy denotes alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH 3 , -OC 2 H 5 and the like
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicycic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms directly attached to alkyl group which then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure, such as cyclopropylmethyl, cyclobuylethyl, cyclopentylethyl, and the like.
  • cycloalkenyl refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms with atleast one carbon- carbon double bond such as cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
  • aryl refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 , -C 2 H 5 C 6 H 5 and the like.
  • Heterocyclic ring refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • 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.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic.
  • 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.
  • Heteroaryl refers to heterocyclic ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • Heteroarylalkyl refers to heteroaryl ring radical as defined above directly bonded to alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
  • Heterocyclyl refers to a heterocylic ring radical as defined above.
  • the heterocylyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • Heterocyclylalkyl refers to a heterocylic ring radical as defined above directly bonded to alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
  • Carbocyclic refers to a cyclic group containing 3-10 carbon atoms
  • protecting group refers to CBZ or BOC and the like
  • Halogen refers to radicals of Fluorine, Chlorine, Bromine, Iodine.
  • the substituents in the 'substituted alkyl 5 may be the same or different which one or more selected
  • salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, mo ⁇ holine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'- diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydro
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, fumarates,maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
  • Another object of the invention is a method of treating inflammatory diseases, disorders and conditions characterized by or associated with an undesirable inflammatory immune response and all disease and conditions induced by or associated with an excessive secretion of TNF-c- and PDE-4 which comprises administering to a subject a therapeutically effective amount of a compound according to Formula 1.
  • Another object of the invention is a method of treating inflammatory conditions and immune disorders in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula 1.
  • Preferred inflammatory conditions and immune disorders are chosen from the group consisting of asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uteltis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis and chronic inflammation. Further preferred are allergic inflammatory conditions.
  • inflammatory conditions and immune disorders selected from the group consisting of inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin and heart.
  • inflammatory conditions chosen from the group consisting of bronchial asthma, nepritis, and allergic rhinitis.
  • Another object of the invention is a method for abating inflammation in an affected organ or tissue including delivering to the organ or tissue a therapeutically effective amount of a compound represented by a compound according to Formula 1.
  • Another object of the invention is a method of treating diseases of the central nervous system in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound accordmg to Formula 1.
  • Preferred diseases of the central nervous system are chosen from the group consisting of depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.
  • Another object of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound accordmg to Formula 1.
  • Treating or “treatment” of a state, disorder or condition includes:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • the four classic symptoms of acute inflammation are redness, elevated temperature, swelling, and pain in the affected area, and loss of function of the affected organ.
  • Symptoms and signs of inflammation associated with specific conditions include: o rheumatoid arthritis- pain, swelling, warmth and tenderness of the involved joints; generalized and morning stiffness; o insulin-dependent diabetes mellitus- insulitis; this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease, and cerebrovascular disease; • autoimmune thyroiditis- weakness, constipation, shortness of breath, puffiness of the face, hands and feet, peripheral edema, bradycardia;
  • 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; o asthma- shortness of breath, wheezing; o other allergy disorders, such as allergic rhinitis- sneezing, itching, runny nose o 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;
  • nephritis e.g., glomerulonephritis
  • oliguria e.g., urinalysis
  • 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.
  • Delivery a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished , e.g., by local or by systemic administration of the active ingredient to the host.
  • a subject or "a patient” or “a host” refers to mammalian animals, preferably human.
  • the compounds according to the present invention may be prepared by the following processes.
  • the symbols P, X, Y, Ar, R 1 , R 2 , R 3 , R 4 when used in the formulae below are to be understood to present those groups described above in relation to fo ⁇ nula (1) unless otherwise indicated.
  • a compound of the general formula 2 is reacted with a compound of the general formula 3 under standard basic conditions such as K 2 C0 3) NaH and the like to obtain a compound of the general formula (4).
  • the intermediate of the general formula 4 can then be cyclized under standard acidic conditions such polyphosphoric acid or H 2 S0 4 and the like to obtain the tricylic intermediate of the general formula 5 which further can be formylated using (SnClJTiC in the presence of Dichloro methylmethyl ether) standard literature methods to give the intermediate of the general formula 6.
  • the intermediate of the general formula 6 is further oxidized using KMn0 4 or NaOCl 2 to obtain a intermediate of the general formula 7.
  • the intermediate of the general formula 7 can then be transformed into the desired compounds of the general formula (1) by reacting the suitably activated carboxylic acid of intermediate 7 with the optionally substituted aryl or heteroaryl amines (ArNHR ) under basic conditions such as NaH or trieth lamine and the like.
  • the heteroatom, in cases where Ar is a heteroaryl ring can be also converted to its oxide by using appropriate oxidizing agents such as m-chloroperbenzoic acid or hydrogen peroxide as permitted by the synthetic scheme.
  • the heteroatom, in cases where Ar is a heteroaryl ring can also be converted to its oxide by using appropriate oxidizing agents such as m-chloroperbenzoic acid or hydrogen peroxide as permitted by the synthetic scheme.
  • the heteroatom, in cases where Ar is a heteroaryl ring can also be converted to its oxide by using appropriate oxidizing agents such as m-chloroperbenzoic acid or hydrogen peroxide as permitted by the synthetic scheme.
  • the desired compounds of the formula (1) obtained are then converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula (1) obtained are then converted into the free form.
  • N-oxidation is 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 are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customaiy 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.
  • 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, reprecepitating, 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.
  • the ethereal solvents used in the above described processes for the preparation of compounds of the formula (1) are selected from diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like.
  • the , chlorinated solvent which may be employed may be selected from dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride and the like.
  • the aromatic solvents which may be employed may be selected from benzene and toluene.
  • the alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert-butanol and the like.
  • the aprotic solvents which may be employed may be selected from N, N-dimethylformamide, dimethyl sulfoxide and the like.
  • 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 (petether), chloroform, ethyl acetate, acetone, methanol or their combinations.
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethan
  • polymo ⁇ hs 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. Polymo ⁇ hs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymo ⁇ hs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention provides novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastreomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their appropriate N-oxides and their pharmaceutically acceptable solvates.
  • the present invention also provides pharmaceutical compositions, containing compounds of general formula (1) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymo ⁇ hs, their enantiomers, their diasteromers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders. ⁇
  • 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.
  • 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.
  • the compounds of the formula (1) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • 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 ⁇ m or less for the majority of particles.
  • 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; inco ⁇ orated 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, inco ⁇ orated 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, inco ⁇ orated herein by reference in its entirety.
  • 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.
  • Step 1 2-(2-metl ⁇ oxyphenoxy)-l-cyclohexanone ;
  • a stirred suspension of potassium carbonate (16.68 gm, 0.1209 mol) in dry DMF (30 ml) was added a solution of 2-methoxy phenol (guaicol) (5.0 gm, 0.0404 mol) in DMF (10 ml).
  • the reaction contents were heated at 140°C for 1-2 h.
  • 2-bromocyclohexanone (14.26 gm, 0.0806 mol) in DMF (5 ml) was added to the above suspension and the reaction mixture was stirred at room temperature for 24 h.
  • Step 2 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan; 2-(2-methoxyphenoxy)-l- cyclohexanone (0.384 gm, 0.00174 mol) was added as fine powder at room temperature to viscous polyphosphoric acid [prepared from o-phosphoric acid (2.13 gm, 0.0217 mol) and phosphorus pentoxide (3.2 gm, 0.0112 mol)] and stirred with a glass rod manually to homogeneity for 15 min. Ice (10 gm) was added to the above reaction mass and stirred for 15 min. followed by extraction with ethyl acetate (25 ml x 3). The organic layer was washed with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulphate. The organic layer was concentrated under vaccuo to give the crude product as a pale yellow oil which was taken to the next step without purification.
  • Step 3 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan-9-carbaldehyde; 6- methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan (obtained from step 2) was dissolved in dichloromethane (5 ml) and the solution was cooled to -10°C. To this solution was added tin (IV) chloride (0.29 gm, 0.0018 mol) all at once at -10°C under nitrogen atmosphere followed by dropwise addition of a solution of dichloromethyl methyl ether (0.125 gm, 0.001 mol) in dichloromethane (5 ml) at -10°C.
  • tin (IV) chloride (0.29 gm, 0.0018 mol
  • the reaction mixture was allowed to attain room temperature under stirring for 30 min.
  • Cold water (20 ml) was added to the reaction mixture and extracted with ethyl acetate (25 ml x 3).
  • the organic layer was washed with water and dried over anhydrous sodium sulphate.
  • the organic layer was concentrated under vaccuo to give the crude product as greenish oil which was purified by silica gel column chromatography using 20 % ethyl acetate in petroleum ether as the eluent.
  • the product was obtained as a white solid (35 mg). mp 83-89°C.
  • Step 4 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]f ⁇ ran-9-carboxylic acid; To a solution of 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan-9-carbaldehyde (35 mg, 0.152 mmol) in acetone ( 4 ml) was added sulfamic acid (22 mg, 0.227 mmol) while stirring at 0°C. A solution of 80% sodium chlorite (19 mg, 0.212 mmol) in water (2.0mL) was added drop wise to the above reaction mixture over a period of 10 min. and was allowed to stir at 0°C for additional 30 min. Water (40 ml) was added to obtain a precipitate which was filtered, washed with water and air dried to give 40 mg of the product as white solid, mp 210-214°C.
  • IR (KBr): 2934, 2854, 2633, 1682, 1624, 1562, 1508, 1417, 1284, 1215, 1151, 1097, 1008, 911, 780 cm -1 .
  • Step 5 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan-9-carboxylic acid chloride;
  • Step 1 2-(2-methoxyphenoxy)-5-methyl cyclohexanone ;
  • a stirred suspension of potassium carbonate (16.68 gm, 0.1209 mol) in dry DMF (30 ml) was added a solution of guaicol (5.0 gm, 0.0404 mol) in DMF (10 ml).
  • the reaction contents were heated at 140°C for 1-2 h.
  • 2-bromo-4-methylcyclohexanone (14.26 gm, 0.0806 mol) in DMF (5 ml) was added to the above suspension and the reaction mixture was stirred at room temperature for 24 h.
  • the reaction were poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3).
  • Step 2 ( ⁇ ) 6-methoxy-3-methyl-l,2,3,4-tetrahydrodibenzo[b,rf]furan; 2-(2- methoxyphenoxy)-5-methyl cyclohexanone (0.384 gm, 0.00174 mol) was added as fine powder at room temperature to viscous polyphosphoric acid [prepared from o- phosphoric acid (2.13 gm, 0.0217 mol) and phosphorus pentoxide (3.2 gm, 0.0112 mol)] and stirred with a glass rod manually to homogeneity for 15 min. Ice (10 gm) was added to the above reaction mass and stirred for 15 min. followed by extraction with ethyl acetate (25 ml x 3). The organic layer was washed with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulphate. The organic layer was concentrated under vaccuo to give the crude product as a pale yellow oil which was taken to the next step without purification.
  • Step 3 ( ⁇ ) 6-methoxy-3-methyl-l,2,3,4-tetrahydrodibenzo[6, ⁇ -]f ⁇ ran-9- carbaldehyde; ⁇ 6-methoxy-3-methyl-l,2,3,4-tetrahydrodibenzo[b, ⁇ 5?]furan (obtained from step 2) was dissolved in dichloromethane (5 ml) and the solution was cooled to - 10°C.
  • Step 4 ( ⁇ ) 6-methoxy-3-methyl-l,2,3,4-tetrahydrodibenzo[b,rf]furan-9-carboxylic acid; To a solution of ⁇ 6-methoxy-3-methyl-l,2,3,4-tet ahydrodibenzo[b,- ]furan-9- carbaldehyde (35 mg, 0.152 mmol) in acetone ( 4 ml) was added sulfamic acid (22 mg, 0.227 mmol) while stirring at 0°C. A solution of 80% sodium chlorite (19 mg, 0.212 mmol) in water (2.0mL) was added drop wise to the above reaction mixture over a period of 10 min.
  • Step 2 6-difluoromethoxy-l,2,3,4-tetrahydrodibenzo[b, ⁇ flfuran-9-carboxylic acid: To a well stirred solution of compound 3 (270mg, 1.01 mmol) in acetone (10ml) and cooled to 0°C was added a solution of sulphamic acid (150mg, 1.52 mmol) in water (2.5ml). Then after a solution of sodium chlorite (HOmg, 1.21mmol) was added drop wise at 0-5°C and stirred at this temperature for 2.0 hours. Reaction mixture was diluted with water (100 ml) and extracted with chloroform (3x50ml).
  • Step 3 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan-9-carboxylic acid chloride;
  • Step 1 6-cylopropylmethoxy-l,2,3,4-tetrahydrodibenzo[6,rf]furan-9- carbaldehyde
  • Step 2 6-cylopropylmethoxy-l,2,3,4-tetrahydrodibenzo [b,rf]furan-9-carboxylic acid
  • Step 3 6-cyclopropyImethoxy-l,2,3,4-tetrahydrodibenzo[b,rf]furan-9-carboxylic acid chloride;
  • Step 3 6-ethoxy-l,2,3,4-tetrahydrodibenzo[b-./]furan-9-carboxylic acid chloride;
  • Step 1 6-isoproyIoxy-l,2,3,4-tetrahydrodibenzo[b, ⁇ /
  • Step 3 6-isopropylo-sy-l,2-3,4-tetrahydrodiben__o[b,rf]furan-9-carboxylic acid chloride;
  • Step 1 6-cyclopentyloxy-l,2,3,4-tetrahydrodibenzo[b, ⁇ /]furan-9-carbaldehyde
  • Step 3 6-cyclopentyloxy-l,2,3-4-tetrahydrodiben_-o[b, «
  • Step 3 4-methoxy-7,8,9,10-tetrahydro-6H-benzo [b] cyclohepta[ ⁇ fl furan:
  • Step 4 4-methoxy-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[ ⁇ f
  • Step 5 4-methoxy-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[rf]furan-l- carboxylic acid
  • acetone 15 ml
  • water 2ml
  • sulfamic acid 268 mg, 0.002766 mol
  • a solution of sodium chlorite 233 mg, 0.002582 mol
  • water 2.0mL
  • Water 150 ml was added to obtain a precipitate which filtered and dried under vacuum ( 245mg ) m.p- 140- 145°C.
  • Step 6 4-methoxy-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[rf]furan-l- carboxylic acid chloride:
  • Step 1 2-(2-methoxythiophenoxy)-l-cyclohexanone: To a sti ⁇ ed suspension of potassium carbonate ( 2.76 gm, 0.0206 mol ) in dry DMF (30 ml ) was added a solution of thioanisole (1.4 gm, 0.0103 mol ) in DMF (10 ml ). The reaction contents were heated at 80°C for 1-2 hr. 2-bromocyclohexanone ( 3.54 gm, 0.0206 mol ) in DMF ( 10 ml ) was added to the above suspension and the reaction mixture was sti ⁇ ed at room temperature for 24 hr.
  • Step2 6-methoxy-l,2,3,4-tetrahydrodibenzo[b, ⁇ flthiophene: 2-(2-methoxythio phenoxy)- 1 -cyclohexanone ( 1.4 gm, 0.0060 mol ) was added as thick liquid at ice temperature to viscous polyphosphoric acid [ prepared from o-phosphoric acid ( 7.35 gm, 0.075 mol ) and phosphorus pentoxide ( 5.49 gm, 0.039 mol )] and sti ⁇ ed with a glass rod manually to homogeneity for 15 min.
  • Step3 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,-
  • Step 4 6-methoxy-l,2,3,4-tetrahydrodibenzo[b,rf]thiophene-9-carboxylic acid; To a solution of l-methoxy-5,6,7,8-tetrahydrodibenzo[b,fi ]thiophene-4-carbaldehyde ( 70 mg, 0.30 mmol ) in acetone ( 4 ml ) was added sulfamic acid ( 43 mg, 0.45 mmol ) while stirring at 0°C.
  • Step 5 6-methoxy-l-2,3,4-tetrahydrodiben_-o[6,-i ⁇ thiophene-9-carbosylic acid chloride: A suspension of 6-methoxy-l,2,3,4-tefrahydrodibenzo[b, J]thiophene-9- carboxylic acid ( 100 mg, 0.387 mmol ) in freshly distilled thionyl chloride ( 2.5 ml ) was heated to reflux temperature for 3-4 hr. The excess thionyl chloride was removed under vacuum to get the co ⁇ esponding acid chloride which was subjected the next reaction as such.
  • Step 2 Preparation of Methyl 8-methoxy-2,3,4,9-tetrahydro-lH-5-carba_-ole carboxylate:
  • Methyl 3-hydrazino-4-methoxybenzoate hydrochloride 1 (0.5 g, 2.1 mmols) was dissolved in absolute ethanol (20 ml) and cyclohexanone (0.21 g, 2.1 mmols) was added to it. The reaction mixture was refluxed for 2 hrs. The reaction mixture cooled to room temperature and ethanol was removed to get the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate and petroleum ether gradient. Yield: 0.40 g
  • Step 3 Preparation of 8-methoxy-2,3,4,9-tetrahydro-lH-5-carbazolecarboxylic acid: Above methyl ester 2 (0.6 g, 2.3 mmols) was dissolved in methanol (40 ml) and a solution of sodium hydroxide (1 g, 25 mmols) in water (25 ml) was added to it and reaction mixture for refluxed for 24 hrs till the completion of reaction. Methanol was removed under vacuo and residue diluted with water and acidified with 1 N hydrochloric acid which gave a precipitate which was filtered, washed with water and dried to get pure product. Yield: 0.4 g ( light yellow solid)
  • Step 1 Methyl 9-cyclohesylmethyl-8-methosy-2,3,4,9-tetrahdro-lH-5-carba--ole carboxylate
  • Step 2 9-cyclohexylmethyl-8-methoxy-2,3,4,9-tetrahdro-lH-5- carbazolecarboxylic acid
  • Step 1 Methyl 9-(4-fluorobenzyl)-8-methoxy-2,3,4,9-tetrahdrolH-5-carbazole carboxylate was prepared by using a similar method as described for the preparation of
  • Step 2 9-(4-fluorobenzyl)-8-methoxy-2,3,4,9-tetrahdro-lH-5- carbazolecarboxylic acid
  • Step 1 Methyl 4-methoxy-5,6,7,8,9,10-hexahydro cyclohepta [b] indole -1- carboxylate
  • Step 1 Methyl 5-methoxy-l,2,3,4-tetrahydrocyclopenta[b] indole -8-carboxylate
  • Step 2 5-methoxy-l,2,3,4-tetrahydrocyclopenta[b] indole -8-carboxalic acid, 20.
  • Step 1 To a dry DMF (5 ml) solution of intermediate 11 (0.2 g, 0.8 mmol) was added N,N'-carbonyldiimidazole (0.145 g, 0.89 mmol) and the reaction mixture was sti ⁇ ed 3 hrs at room temperature under nitrogen atmosphere.
  • Step 2 In another round bottomed flask to a dry DMF (3ml) solution of 4-amino-3, 5- dichloropyridine (0.146 g, 0.89 mmol) was added slowly NaH (0.89 mmol, 0.047 mg of 50 % dispersion in oil) at 0°C and it was sti ⁇ ed for 30 min. To this reaction mixture, reaction mixture obtained from step 1 solution was added drop wise. After addition the reaction mixture was sti ⁇ ed fir nearly 60 hrs at room temperature. The reaction mixture was diluted with water, neutralized with IN hydrochloric acid which gave a precipitate. The precipitate was filtered washed with water, 10% aqueous sodium hydroxide, water and dried to get the crude product which was crystallized from chlorofonn and petroleum ether. Yield: 0.025 g white solid
  • Example 27 N5-(3,5-dichloro-4-pyridyI)-9-cyclohexyImethyl-8-methoxy-2,3,4,9-tetrahdro-lH-
  • Step 1 Preparation of 4-nitrophenyl 9-(4-fluorobenzyl)-8-methoxy-2,3,4,9- tetrahdrolH-5-carbazolecarboxylate: To a solution of 9-(4-fluorobenzyl)-8- methoxy-2,3,4,9-tetrahdro-lH-5-carbazolecarboxylic acid, (intermediate 13) (O.lg, 0.283 mmol) in dry dichloromethane (5 ml) was added 4-nitrophenol (0.039g, 0.283 mmol), EDCI (0.081 g, 0.425 mmol), DMAP (0.003g, 0.028 mmol) and triethylamine (0.06 ml, 0.453 mmol) respectively at room temperature and the reaction mixture was continue to sti ⁇ ed overnight under N 2 atmosphere.
  • 4-nitrophenol 0.039g, 0.283 mmol
  • EDCI 0.081 g, 0.425
  • Step 2 To a solution of 4-ammo-3,5-dichloropyridine (0.02g, 0.123 mmol) in dry DMF (3 ml) was added 4-nitrophenyl 9-(4-fluorobenzyl)-8-methoxy-2,3,4,9- tetrahdrolH-5-carbazolecarboxylate (0.06g, 0.123 mmol) (from above step 1) and NaH (0.255 mmol, 0.01 lg of 50 % dispersed in oil) at room temperature under N 2 atmosphere and the reaction mixture was sti ⁇ ed for overnight. The reaction mixture was added to cooled 1 N hydrochloric acid (10 ml) which gave a precipitate of the product which was filtered and washed with water. The crude product was crystallized from ethyl acetate to get pure product. Yield: 0.015 g, as off-white solid m.p.: 229-231 °C
  • PDE4 enzyme converts [ 3 H] cAMP to the co ⁇ esponding [ 3 H] 5'- AMP in proportion to the amount of PDE4 present.
  • the [ 3 H] 5 '-AMP then was quantitatively converted to free [ 3 H] adenosine and phosphate by the action of snake venom 5'-nucleotidase.
  • the amount of [ 3 H] 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 inco ⁇ orated herein by reference in their entirety, at 34°C.
  • the reaction mixture contained 12.5mM of Tris, 5 mM MgCl 2 , 1 ⁇ M cAMP (cold) and 3 H cAMP (0.1 uCi), (Amersham).
  • the umeacted substrate was separated from ( 3 H) 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).
  • Phosphodiesterase enzymes namely, PDE l(Ca.sup.2+/calmodulin-dependent), PDE 2(cGP-stimulated), PDE 3 (cGP-inhibited), PDE 5 (cGP-specific) and PDE 6 (cGP- specific, photoreceptor).
  • Results were expressed as percent inhibition (IC 50 ) in nM concentrations.
  • the IC 50 values were determined from the concentration curves by nonlinear regression analysis.

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Abstract

L'invention concerne de nouveaux composés hétérocycliques ainsi que leurs analogues, tautomères, régio-isomères, stéréo-isomères, énantiomères, diastéréomères, polymorphes, sels pharmaceutiquement acceptables, oxydes appropriés, solvates pharmaceutiquement acceptables et des compositions pharmaceutiques les contenant. L'invention concerne plus particulièrement de nouveaux inhibiteurs de la phosphodiestérase de type 4 (PDE4) ainsi que leurs analogues, tautomères, énantiomères, diastéréomères, régio-isomères, stéréo-isomères, polymorphes, sels pharmaceutiquement acceptables, oxydes appropriés, solvates pharmaceutiquement acceptables et des compositions pharmaceutiques les contenant.
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WO2006064355A3 (fr) * 2004-12-17 2006-08-03 Glenmark Pharmaceuticals Sa Nouveaux composes heterocycliques utiles pour le traitement de troubles inflammatoires et allergiques
WO2008026687A1 (fr) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé
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US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
US8076353B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Inhibition of VEGF translation
US8076352B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Administration of carboline derivatives useful in the treatment of cancer and other diseases
CN102850266A (zh) * 2012-08-24 2013-01-02 郑州明泽医药科技有限公司 罗氟司特的制备方法
WO2013177241A1 (fr) * 2012-05-22 2013-11-28 Trustees Of Dartmouth College Procédé permettant de synthétiser des cycloalcanyl[b]indoles, des cycloalcanyl[b]benzofuranes, des cycloalcanyl[b]benzothiophènes, composés et procédés d'utilisation
US8940896B2 (en) 2004-03-15 2015-01-27 Ptc Therapeutics, Inc. Tetra-cyclic carboline derivatives useful in the inhibition of angiogenesis
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WO2002072567A2 (fr) * 2001-03-13 2002-09-19 Glenmark Pharmaceuticals Limited Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant

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US8076353B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Inhibition of VEGF translation
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WO2006065480A3 (fr) * 2004-11-23 2006-08-03 Ptc Therapeutics Inc Tetrahydrocarbazoles en tant qu'agents actifs permettant d'inhiber la production de vegf par regulation de la traduction
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JP2008520741A (ja) * 2004-11-23 2008-06-19 ピーティーシー セラピューティクス， インコーポレイテッド 翻訳制御によるｖｅｇｆ生成を阻害するための活性因子としてのテトラヒドロカルバゾール
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US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
WO2006064355A3 (fr) * 2004-12-17 2006-08-03 Glenmark Pharmaceuticals Sa Nouveaux composes heterocycliques utiles pour le traitement de troubles inflammatoires et allergiques
EA014956B1 (ru) * 2004-12-17 2011-04-29 ГЛЕНМАРК ФАРМАСЬЮТИКАЛС Эс.Эй. Гетероциклические соединения, применяемые для лечения воспалительных и аллергических нарушений
JP2008524201A (ja) * 2004-12-17 2008-07-10 グレンマーク・ファーマシューティカルズ・エスエー 炎症性障害およびアレルギー障害の治療に有用な新規な複素環式化合物
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
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US7511150B2 (en) 2006-07-06 2009-03-31 Forest Laboratories Holdings Limited Synthesis of heterocyclic compounds
US7601856B2 (en) 2006-07-27 2009-10-13 Wyeth Benzofurans as potassium ion channel modulators
WO2008026687A1 (fr) 2006-09-01 2008-03-06 Kyorin Pharmaceutical Co., Ltd. Dérivé de pyrazolopyridine carboxamide et inhibiteur de phosphodiestérase (pde) comprenant le dérivé
WO2013177241A1 (fr) * 2012-05-22 2013-11-28 Trustees Of Dartmouth College Procédé permettant de synthétiser des cycloalcanyl[b]indoles, des cycloalcanyl[b]benzofuranes, des cycloalcanyl[b]benzothiophènes, composés et procédés d'utilisation
JP2015517577A (ja) * 2012-05-22 2015-06-22 トラスティーズ・オブ・ダートマウス・カレッジ シクロアルカニル［ｂ］インドール、シクロアルカニル［ｂ］ベンゾフラン、シクロアルカニル［ｂ］ベンゾチオフェンを合成するための方法、化合物および使用の方法
US9598365B2 (en) 2012-05-22 2017-03-21 Trustees Of Dartmouth College Method for synthesizing cycloalkanyl[b]indoles, cycloalkanyl[b]benzofurans, cycloalkanyl[b]benzothiophenes, compounds and methods of use
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