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  Quinoline derivatives as crth2 antagonistsUSPTO Application #: 20070197587Title: Quinoline derivatives as crth2 antagonists Abstract: wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the description, their use as medicament, pharmaceutical compositions containing them and processes for their preparation.
The invention relates to compounds of formula (I) (end of abstract)
Agent: Pfizer Inc. - Groton, CT, US Inventors: Mohamed M. Ali Awad, Marc J. Bazin, Frederic Feru, Steven W. Goldstein, Cyrille F. Kuhn USPTO Applicaton #: 20070197587 - Class: 514312000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Quinolines (including Hydrogenated), The Patent Description & Claims data below is from USPTO Patent Application 20070197587. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The invention relates to quinoline derivatives, pharmaceutical compositions containing them, processes for their preparation and their use as medicament. BACKGROUND OF THE INVENTION [0002] In 1999, Nagata et al identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), a novel G protein-coupled receptor (GPCR) belonging to the leucocyte chemoattractant receptor family. [0003] The CRTH2 receptor is selectively expressed from a wide variety of tissues including the brain, lung and lymphoid organs in mouse (Abe et al., Gene (1999) 227 (1):71-7). With respect to expression from immune system cells, it is reported that CRTH2 receptor is selectively expressed on Th2 cells, eosinophils and basophils, but not Th1 cells, B cells and NK cells in human (Nagata et al., FEBS Letters (1999) 459 (2): 195-9). [0004] Bauer et al., (see EP 1170594A2) identified Prostaglandine D.sub.2 (PGD.sub.2) as the endogenous ligand of CRTH2. PGD.sub.2 is released from immunologically stimulated mast cells and Th2 cells. [0005] Interaction of CRTH2 with PGD.sub.2 plays a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. In addition, CRTH2 mediates PGD.sub.2 dependent cell migration of blood eosinophils and basophils. [0006] Allergic asthma and allergic rhinitis are diseases that currently affect about 10% of the population, and that number appears to be increasing (Bush, R. K. a. G., John W., Handbook of asthma and rhinitis. 1st ed. (1991), Abingdon: Blackwell Science. 270). Currently numerous classes of pharmaceutical agents are widely used to treat these diseases, for example, antihistamines, decongestants, .beta.2 agonists, anticholinergics, methylxanthines, cromolyns, corticosteroids, and leukotriene modulators. Generally however, the usefulness of these agents is limited by side effects and low efficacy. Accordingly, there is a critical medical need to identify pharmaceutically active compounds that interfere with key steps of the inflammatory and immunological processes that contribute to these disease states, and other inflammatory conditions. [0007] EP 987251 discloses cholesteryl ester transfer protein of formula for use in the treatment of diseases affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides such as atherosclerosis and cardiovascular diseases. [0008] WO91/05549 discloses compounds of formula for use as vasodilator, hypotensive agent, water diuretics and platelet agglutination inhibitor. [0009] U.S. Pat. No. 4,521,607 discloses compounds of formula for use as antihypertensives. [0010] WO 02/079165 discloses compounds of formula as STAT6 signaling pathway modulators. SUMMARY OF THE INVENTION [0011] The invention relates to quinoline derivatives of general formula (I) wherein, [0012] R.sup.1 represents H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl or (CH.sub.2).sub.m --R'.sup.1, in which [0013] R'.sup.1 is selected from aromatic heterocycle, phenyl and (C.sub.3-C.sub.6)cycloalkyl wherein the phenyl, the heterocycle and the cycloalkyl groups are unsubstituted or substituted by one or several groups, preferably 1 to 3, selected from [0014] Q.sup.1, and, [0015] --(C.sub.1-C.sub.4)alkyl optionally substituted with one or several, preferably 1 to 3, groups which are the same or different and which are selected from Q.sup.1, wherein Q.sup.1 is selected from halogen, NO.sub.2, CN, SO.sub.2CH.sub.3, SO.sub.2NR.sup.9R.sup.10, OR.sup.9, COOR.sup.9, C(.dbd.O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9SO.sub.2R.sup.10, NR.sup.9C(.dbd.O)R.sup.10 and C(.dbd.O)R.sup.9 wherein R.sup.9 and R.sup.10 are the same or different and are selected from H and (C.sub.1-C.sub.4)alkyl; [0016] m is an integer selected from 0, 1 and 2; [0017] R.sup.2 represents (C.sub.1-C.sub.4)alkyl, wherein the alkyl group may be substituted with one or several, substituents, preferably 1 to 3, selected from halogen, OR.sup.9, NR.sup.9R.sup.10, COOR.sup.9, C(.dbd.O)NR.sup.9R.sup.10, NHSO.sub.2R.sup.9 and C(.dbd.O)(C.sub.1-C.sub.4)alkyl wherein R.sup.9 and R.sup.10 are the same or different and are selected from H and (C.sub.1-C.sub.4)alkyl; [0018] R.sup.3 represents (C.sub.3-C.sub.6)cycloalkyl or -A-R'.sup.3, wherein [0019] A represents a bond, straight or branched (C.sub.1-C.sub.3)alkylene, or (C.sub.2-C.sub.3)alkenylene; [0020] R'.sup.3 represents (C.sub.6-C.sub.12)aryl or an heterocycle, optionally aromatic, having from 5 to 10 atoms in the cycle, wherein the aryl and the heterocycle groups are unsubstituted or substituted by one or several substituents, preferably 1 to 3, selected from, [0021] (C.sub.6-C.sub.12)aryl, an aromatic heterocycle, [0022] Q.sup.2, and, [0023] (C.sub.1-C.sub.4)alkyl optionally substituted with one or several, preferably 1 to 3, groups which are the same or different and which are selected from Q.sup.2, wherein Q.sup.2 is selected from halogen, NO.sub.2, CN, SO.sub.2CH.sub.3, SO.sub.2NR.sup.9R.sup.10, OR.sup.9, SR.sup.9, OCH.sub.2CF.sub.3, COOR.sup.9, C(.dbd.O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9SO.sub.2R.sup.10, NR.sup.9C(.dbd.O)R.sup.10 and C(.dbd.O)R.sup.9 wherein R.sup.9 and R.sup.10 are the same or different and are selected from H and (C.sub.1-C.sub.4)alkyl; [0024] R.sup.4 represents H or (C.sub.1-C.sub.4)-alkyl; [0025] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are the same or different and are selected from [0026] H, Q.sup.3, and, [0027] (C.sub.1-C.sub.4)alkyl optionally substituted with one or several groups, preferably 1 to 3, which are the same or different and which are selected from Q.sup.3, wherein Q.sup.3 is selected from halogen, NO.sub.2, CN, SO.sub.2CH.sub.3, SO.sub.2NR.sup.9R.sup.10, OR.sup.9, SR.sup.9COOR.sup.9, C(.dbd.O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9SO.sub.2R.sup.10, NR.sup.9C(.dbd.O)R.sup.10 and C(.dbd.O)R.sup.9 wherein R.sup.9 and R.sup.10 are the same or different and are selected from H and (C.sub.1-C.sub.4)alkyl; their optical isomers, as well as their N-oxides and pharmaceutically acceptable salts and their use as medicament. [0028] The invention further concerns the use of a compound of formula (I) for the preparation of a medicament for the prevention or the treatment of disorders for which therapy by a CRTH2 antagonist is relevant. [0029] The invention also provides a method for the treatment of a disorder for which therapy by a CRTH2 antagonist is relevant, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I). [0030] The invention also concerns a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier, excipient, diluent or delivery system. [0031] The invention further relates to processes for the preparation of compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION [0032] The invention relates to quinoline derivatives of formula (I) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined in the summary of the invention. their optical isomers, as well as their N-oxides and pharmaceutically acceptable salts and their use as CRTH2 antagonist and as medicament. [0033] These compounds are selective CRTH2 antagonists. In man, CRTH2 is selectively expressed on immune system cells, and in particular on Th2 cells, eosinophils and basophils. CRTH2 plays a critical role in the recruitment of these cells. The compounds of the invention are useful for the prevention or treatment of diseases states involving Th2 cells, eosinophils and/or basophils. In particular, the compounds of the invention are useful in the prevention and treatment of disease states involving inflammatory components, including, without limitation, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, Crohn's disease, colitis ulcerosa, inflammatory bowel disease; disorders of the skin including psoriasis, eczema, erythema, pruritis, and acne; systemic lupus erythematous, chronic obstructive pulmonary disease, angioedema, stroke, any disease marked by reperfusion injury, graft rejection, and autoimmune diseases, allergic diseases, such as allergic asthma, atopic dermatitis, and allergic rhinitis. [0034] The compounds of the invention are also useful as research tools that can be used to antagonize the CRTH2 receptor. For example, to determine the signaling pathway of a PGD.sub.2 mediated effect, it is essential to find out which PGD.sub.2 receptor is involved in said pathway. This can be achieved only if selective antagonists are available for each of the PGD.sub.2 receptors. The compounds of the invention, which are selective CRTH2 antagonists can be used for that purpose. [0035] Preferred compounds of the invention are compounds of formula (I) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined in the summary of the invention with the exclusion of: [0036] N-(1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolyl)-acetanilide, [0037] N-(1-benzoyl-6-chloro-1,2,3,4-tetrahydro-2-methyl-4-quinolyl)-ace- tanilide, [0038] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(4-methoxyphenyl- )-2-methyl-propanamide, [0039] N-[1-(4-fluorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl- -butanamide, [0040] N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl- ]-pentanamide, [0041] N-[1-[(4-fluorophenyl)acetyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N- -phenyl-propanamide, [0042] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-2,2-dimethyl-N-phe- nyl-propanamide, [0043] N-(1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-p- entanamide, [0044] N-[1-(2-furanylcarbonyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phen- yl-acetamide, [0045] 2-methyl-N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-q- uinolinyl]-propanamide, [0046] 2,2,2-trifluoro-N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-met- hyl-4-quinolinyl]-acetamide, [0047] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(3-methoxyphenyl- )-acetamide, [0048] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(4-methylphenyl)- -acetamide, [0049] N-[1-(4-chloro-3-nitrobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-- N-phenyl-acetamide, [0050] N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(3-nitrobenzoyl)-4-quinolinyl]-- acetamide, [0051] N-phenyl-N-[1,2,3,4-tetrahydro-1-[3-(4-methoxyphenyl)-1-oxo-2-propenyl]-2- -methyl-4-quinolinyl]-acetamide, [0052] N-[1-(3-chlorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl- -acetamide, [0053] N-[1-(3-fluorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl- -acetamide, [0054] N-[1-[4-(1,1-dimethylethyl)benzoyl]-1,2,3,4-tetrahydro-2-methyl-4-quinoli- nyl]-N-phenyl-acetamide, [0055] N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxo-3-phenyl-2-propenyl)-4-q- uinolinyl]-acetamide, [0056] N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(2-thienylcarbonyl)-4-quinoliny- l]-acetamide, [0057] N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl- ]-acetamide, [0058] N-[1-(3,5-dinitrobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phe- nyl-acetamide, [0059] N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(4-nitrobenzoyl)-4-quinolinyl]-- acetamide, [0060] N-phenyl-N-[1,2,3,4-tetrahydro-1-(2-iodobenzoyl)-2-methyl-4-quinolinyl]-a- cetamide, [0061] N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl- ]-acetamide, [0062] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-pentanami- de, [0063] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-butanamid- e, [0064] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl- -propanamide, [0065] 1-benzoyl-1,2,3,4-tetrahydro-4-(N-phenylacetamido)-quinaldine, [0066] N-[(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2-methyl-N-phenyl propanamide; [0067] N-[1-(4-bromobenzoyl)-1,2,3,4-tetrahydro-2,6-dimethyl-4-quinolinyl]-aceta- mide; [0068] N-(1-benzoyl-1,2,3,4-tetrahydro-2,6-dimethyl-4-quinolinyl)-acetamide; and, [0069] N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-acetamide. [0070] A further preferred group of compounds are cis-isomers of formula (Ia) and (Ib), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5R.sup.6R.sup.7 and R.sup.8 are as defined in compound of formula (I) the summary of the invention and R.sup.4 is (C.sub.1-C.sub.4)alkyl, with the exclusion of the following compounds, [0071] N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2-methyl-N- -phenyl propanamide; [0072] N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2,2-dimeth- yl-N-phenyl-propanamide; [0073] N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl butanamide; [0074] N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl acetamide, [0075] N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-p- entanamide and, [0076] N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-acetamide. Continue reading... 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