US2014121258A1PendingUtilityA1
Compounds act at multiple prostaglandin receptors giving a general anti-inflammatory response
Est. expiryJul 1, 2030(~4 yrs left)· nominal 20-yr term from priority
A61P 9/10A61P 7/02A61P 35/00A61P 37/08A61P 37/00A61P 37/06A61P 3/10A61P 29/00A61P 27/02A61P 3/04A61P 25/28A61P 33/00A61P 25/00A61P 11/06A61P 1/16A61P 1/04A61P 21/00A61P 11/02A61P 13/12A61P 17/00A61P 19/02A61P 17/04A61P 15/00A61P 11/00A61P 17/06C07D 231/12A61K 31/415
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Claims
Abstract
The present invention provides a compound, that is a 1-[(2-{[(alkyl or aryl)methyl]oxyl}halo or haloalkyl substituted-phenyl)alkyl]-5-hydrocarbyl or substituted hydrocarbyl-1H-pyrazole carboxylic acid or alkylenylcarboxylic acid or a hydrocarbyl or substituted hydrocarbyl sulfonamide of said carboxylic acid or said alkylenylcarboxylic acid, provided however said compound is not a 3-carboxylic acid, a sulfonamide thereof, or a 3-methylenylcarboxylic acid. The compound may be represented by the following formula (I). Wherein R1, R2, R3, R4, R5, R6, X, W, X and Y are as defined in the specification. The compounds may be administered to treat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases or conditions.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound, that is a 1-[(2-{[(alkyl or aryl)methyl]oxy}halo or haloalkyl substituted-phenyl)alkyl]-5-hydrocarbyl or substituted hydrocarbyl-1H-pyrazole carboxylic acid or alkylenylcarboxylic acid or a hydrocarbyl or substituted hydrocarbyl sulfonamide of said carboxylic acid or said alkylenylcarboxylic acid, provided however said compound is not a 3-carboxylic acid, a sulfonamide thereof, or a 3-methylenylcarboxylic acid.
2 . A compound according to claim 1 wherein said 5-hydrocarbyl is 5-methyl.
3 . A compound according to claim 2 wherein said halo or haloalkyl substituted-phenylalkyl is halo or haloalkyl substituted-phenyl)methyl.
4 . A compound according to claim 3 , that is a 1-[(2-{[(alkyl)methyl]oxy}halo or haloalkyl-substituted phenyl)methyl]-5-methyl-1H-pyrazole-3-ethylenylcarboxylic acid, wherein said halo is selected from the group consisting of fluoro, chloro and bromo.
5 . A compound according to claim 3 , that is a 1-[(2-{[(aryl)methyl]oxy}halo or haloalkyl-substituted phenyl)methyl]-5-methyl-1H-pyrazole-3-carboxylic acid fluoro-substituted alkylsulfonamide or alkylenylcarboxylic acid fluoro-substituted alkylsulfonamide, wherein said halo is selected from the group consisting of fluoro, chloro and bromo.
6 . The compound of claim 4 wherein said halo or haloalkyl-substituted phenyl is selected from the group consisting of trifluoromethylphenyl, chlorophenyl and bromophenyl.
7 . The compound of claim 3 wherein said halo or haloalkyl-substituted phenyl is selected from the group consisting of trifluoromethylphenyl, chlorophenyl and bromophenyl.
8 . The compound of claim 1 wherein said compound is a trifluoromethylsulfonamide and said aryl is chlorophenyl.
9 . The compound of claim 6 wherein said alkyl is 3-pentyl.
10 . The compound of claim 6 wherein said alkyl is cyclopentyl.
11 . A compound having the following formula
wherein R 1 is selected from the group consisting of OR 7 , N(R 7 ) 2 , and N(R 7 )SO 2 R 7 wherein R 7 is selected from the group consisting of H, alkyl and aryl, wherein said alkyl and aryl may be substituted with fluoro;
R 2 is selected from the group consisting of H and alkyl;
R 3 is selected from the group consisting of H and alkyl; wherein R 2 and R 3 , individually or together, can form a cycloalkyl ring;
X is (CH 2 ) n wherein n is 0 or an integer of from 1 to 3; provided however that when n is 0 or 1, R 1 is not OR 7 or NR 2 ;
R 4 is selected from the group consisting of H, alkyl and fluoroalkyl;
R 5 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R 6 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy and aryloxy;
Z is (CH 2 ) m wherein m is 0 or an integer of from 1 to 3;
Y is selected from the group consisting of O, S, SO, SO 2 and (CH 2 ) p , wherein p is 0 or an integer of from 1 to 3; and
W is selected from the group consisting of alkyl and aryl.
12 . The compound of claim 11 wherein R 1 is selected from the group consisting of OH and NHSO 2 CF 3 .
13 . The compound of claim 12 wherein R 2 and R 3 are H.
14 . The compound of claim 13 wherein R 4 is alkyl.
15 . The compound of claim 14 wherein R 4 is methyl.
16 . The compound of claim 12 wherein R 5 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy, aryloxy and R 6 is H.
17 . The compound of claim 16 wherein R 5 is selected from the group consisting of H, alkyl, alkoxy, halogen and fluorinated alkyl and alkoxy.
18 . The compound of claim 17 wherein R 5 is selected from the group consisting of chloro, bromo and trifluoromethyl.
19 . The compound of claim 12 wherein Z is (CH 2 ).
20 . The compound of claim 12 wherein Y is O.
21 . The compound of claim 12 wherein W is selected from the group consisting of alkyl, benzylyl and halogen-substituted benzyl.
22 . The compound of claim 21 wherein W is selected from the group consisting of alkyls having from 4 to 7 carbon atoms.
23 . The compound of claim 22 wherein W is cyclopentyl.
24 . The compound of claim 11 , wherein said compound is selected from the group consisting of N-(3-{1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-C,C,C-trifluoromethanesulfonamide,
3-{1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, 3-[1-(5-Bromo-2-cyclopentylmethoxybenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid, and, 3-[1-(2-Cyclopentylmethoxy-5-trifluoromethylbenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid.
25 . The compound of claim 11 wherein the compound is selected from the group consisting of
26 . A method for decreasing the secretion of cytokines from a macrophage comprising administering a compound having the following formula
Wherein R 1 is selected from the group consisting of OR 7 , N(R 7 ) 2 , and N(R 7 )SO 2 R 7 wherein R 7 is selected from the group consisting of H, alkyl and aryl, wherein said alkyl and aryl may be substituted with fluoro;
R 2 is selected from the group consisting of H and alkyl;
R 3 is selected from the group consisting of H and alkyl; wherein R 2 and R 3 , individually or together, can form a cycloalkyl ring;
X is (CH 2 ) n wherein n is 0 or an integer of from 1 to 3, provided however that when n is 0 or 1, R 1 is not OR 7 . or NR 2 ;
R 4 is selected from the group consisting of H, alkyl and fluoroalkyl;
R 5 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R 6 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy and aryloxy;
Z is (CH 2 ) m wherein m is 0 or an integer of from 1 to 3;
Y is selected from the group consisting of O, S, SO, SO 2 and (CH 2 ) p , wherein p is 0 or an integer of from 1 to 3; and
W is selected from the group consisting of alkyl and aryl.
27 . The method of claim 26 wherein said compound is administered to treat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases or conditions.
28 . A method for decreasing the secretion of a cytokine selected from the group consisting of VEGF, IL-8, MCP-1, TNFα, IL-1α, MDC and RANTES in a patient in need thereof comprising administering to a patient an effective amount of a compound according to formula
Wherein R 1 is selected from the group consisting of OR 7 , N(R 7 ) 2 , and N(R 7 )SO 2 R 7 wherein R 7 is selected from the group consisting of H, alkyl and aryl, wherein said alkyl and aryl may be substituted with fluoro;
R 2 is selected from the group consisting of H and alkyl;
R 3 is selected from the group consisting of H and alkyl; wherein R 2 and R 3 , individually or together, can form a cycloalkyl ring;
X is (CH 2 ) n wherein n is 0 or an integer of from 1 to 3, provided however that when n is 0 or 1, R 1 is not OR 7 . or NR 2 ;
R 4 is selected from the group consisting of H, alkyl and fluoroalkyl;
R 5 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R 6 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy and aryloxy;
Z is (CH 2 ) m wherein m is 0 or an integer of from 1 to 3;
Y is selected from the group consisting of O, S, SO, SO 2 and (CH 2 ) p , wherein p is 0 or an integer of from 1 to 3; and
W is selected from the group consisting of alkyl and aryl.
29 . A method according to claim 28 wherein said cytokine is IL-8 and said compound is administered for treating rheumatoid arthritis.
30 . A method according to claim 28 wherein said cytokine is MCP-1 and said compound is administered for treating inflammatory diseases characterized by monocytic infiltration, such as RA rheumatoid arthritis, psoriasis, and atherosclerosis; atopic dermatitis, renal disease; pleurisy; allergy and asthma; colitis; endometriosis; polymyositis and dermatomyositis; uveitis; restenosis; brain inflammation and obesity; diabetes and diabetes-induced atherosclerosis and MCP-1/CCR2-mediated multiple inflammatory diseases.
31 . A method according to claim 28 wherein said cytokine is MDC and said compound is administered for treating rheumatoid arthritis, inflammation, thrombosis and atherosclerosis, chronic renal failure, chronic liver diseases, Alzheimer's disease and systemic sclerosis.
32 . A method according to claim 28 wherein said cytokine is RANTES and said compound is administered for treating rheumatoid arthritis, inflammation, thrombosis and atherosclerosis, asthma, including allergic lung inflammation, lung leukocyte infiltration, bronchial hyper-responsiveness, and the recruitment of eosinophils in the pathogenesis of asthma, and allergic rhinitis, multiple sclerosis, CNS disorders, parasitic disease, cancer, autoimmune and heart diseases.
33 . A method according to claim 28 wherein said cytokine is TNFα and said compound is administered for treating diseases resulting from the stimulation of the production of proinflammatory cytokines/chemokines, collagenases, metalloproteinases, and other inflammatory mediators; activation of endothelial cells and neutrophils; promotion T- and B-cell growth, as well as stimulation of bone resorption, the production of local and systemic proinflammatory cytokines/chemokines and serum MMP-3, nitric oxide synthase activity, VEGF release, and angiogenesis in inflamed joints.
34 . A method according to claim 26 wherein said macrophage is a human macrophage.
35 . A method for treating inflammation in a human patient which comprises administering to a patient in need thereof an effective amount of a compound selected from the group consisting of
36 . A method for treating uveitis in a human patient which comprises administering to a patient in need thereof an effective amount of a compound selected from the group consisting of
37 . A method for treating allergic conjunctivitis in a human patient which comprises administering to a patient in need thereof an effective amount of a compound selected from the group consisting ofCited by (0)
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