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- Nachgewiesen in: USPTO Patent Grants
- Sprachen: English
- Patent Number: 8,604,053
- Publication Date: December 10, 2013
- Appl. No: 12/579821
- Application Filed: October 15, 2009
- Assignees: AbbVie Inc. (North Chicago, IL, US)
- Claim: 1. A compound having formula (I-i) or a pharmaceutically acceptable thereof, [chemical expression included] wherein R A is methyl, NH 2 , or Cl; p is 0 or 1; R x , at each occurrence, represents optional substituent(s) on any substitutable position of the bicyclic ring selected from the group consisting of alkyl, halogen, haloalkyl, OH, O(alkyl), O(haloalkyl), NH 2 , N(H)(alkyl), and N(alkyl) 2 ; R 2 and R 3 are the same or different, and are each independently hydrogen, C 1 -C 5 alkyl, or haloalkyl; or R 2 and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6 monocyclic cycloalkyl ring, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halogen; R 4 , at each occurrence, represents optional substituent(s) on any substitutable position of the bicyclic ring selected from the group consisting of alkyl, halogen, haloalkyl, O(alkyl), O(haloalkyl), and SCF 3 ; and m and n are each independently 0, 1, 2, or 3; with the proviso that the compound is other than N-(7-tert-butyl-3,4-dihydro-2H-chromen-4-yl)-N′-(3-methylisoquinolin-5-yl)urea; N-(6-fluoro-3,4-dihydro-2H-chromen-4-yl)-N′-(3-methylisoquinolin-5-yl)urea; or N-(6-methyl-3,4-dihydro-2H-chromen-4-yl)-N′-(3-methylisoquinolin-5-yl)urea.
- Claim: 2. The compound of claim 1 having formula (I-i) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; R x is alkyl or halogen; and R 4 is alkyl, halogen, haloalkyl, or O(haloalkyl).
- Claim: 3. The compound of claim 1 having formula (I-i) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same or different, and are each independently C 1 -C 5 alkyl or haloalkyl.
- Claim: 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound exhibits a limited transient temperature effect on core body temperature of a mammal.
- Claim: 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound alters core body temperature of a mammal by less than about +0.5° C.
- Claim: 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound alters core body temperature of a mammal from about −2.5° C. to less than about +0.5° C.
- Claim: 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound alters core body temperature of a mammal from about −0.5° C. to less than about +0.5° C.
- Claim: 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound alters core body temperature of a mammal from about −0.3° C. to about +0.3° C.
- Claim: 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound at concentration of 3 μM blocks at least about 95% calcium flux caused by activation of human TRPV1 by addition of 1 μM capsaicin, and blocks less than about 95% calcium flux caused by activation of human TPRV1 at pH 5.5.
- Claim: 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound at concentration of 3 μM blocks at least about 95% calcium flux caused by activation of human TRPV1 by addition of 1 μM capsaicin.
- Claim: 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound exhibits about 0% inhibition to about 49% inhibition at 2.2 μM against CYP2C9, CYP2D6, and CYP3A4.
- Claim: 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound modify the mean arterial pressure or heart beat in a mammal by less than or equal to about 15% when administered intravenously.
- Claim: 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said compound has at least two of the following properties: a) alters core body temperature of a mammal from about −2.5° C. to less than about +0.5° C., b) at concentration of 3 μM blocks at least about 95% calcium flux caused by activation of human TRPV1 by addition of 1 μM capsaicin, c) exhibits about 0% inhibition to about 49% inhibition at 2.2 μM against CYP2C9, CYP2D6, and CYP3A4.
- Claim: 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof wherein said compound modify the mean arterial pressure or heart beat in a mammal by less than or equal to about 15% when administered intravenously.
- Claim: 15. The compound according to any one of claim 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , or 14 , or a pharmaceutically acceptable salt thereof wherein R 2 and R 3 the same or different, and are each independently hydrogen, C 1 -C 5 alkyl, or haloalkyl.
- Claim: 16. The compound according to claim 15 , or a pharmaceutically acceptable salt thereof wherein R 2 and R 3 are the same or different, and are each independently C 1 -C 5 alkyl or haloalkyl.
- Claim: 17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof wherein m is 0, 1, or 2; and R 4 is alkyl, halogen, haloalkyl, or O(haloalkyl).
- Claim: 18. The compound according to any one of claim 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , or 14 , or a pharmaceutically acceptable salt thereof wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a C 3 -C 6 monocyclic cycloalkyl ring, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halogen.
- Claim: 19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof wherein m is 0, 1 or 2; and R 4 is alkyl, halogen, haloalkyl, or O(haloalkyl).
- Claim: 20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-[(4R)-2,2-diethyl-6-fluoro-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-2,2-diethyl-8-fluoro-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-6-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-(3-methylisoquinolin-5-yl)-N′-[(4R)-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]urea; N-[(4R)-8-fluoro-2,2-dipropyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-chloro-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-(3-chloroisoquinolin-5-yl)-N′-[(4R)-2,2-diethyl-8-fluoro-3,4-dihydro-2H-chromen-4-yl]urea; N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-2,2-bis(fluoromethyl)-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-8-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-2,2-dimethyl-8-(trifluoromethoxy)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-6,8-difluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-bromo-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-(3-aminoisoquinolin-5-yl)-N′-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]urea; N-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-fluoro-2,2,8-trimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7,8-difluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-2,2-dimethyl-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-8-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-6,8-difluoro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(2R,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(2S,4R)-7-chloro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(4R)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-N′-(6-fluoro-3-methylisoquinolin-5-yl)urea; N-[(2S,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; N-[(2R,4R)-8-fluoro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea; and N-[(2S,4R)-8-fluoro-2-(fluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea.
- Claim: 21. The compound or salt according to claim 1 , wherein the compound is N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea.
- Claim: 22. The compound according to claim 21 that is N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea.
- Claim: 23. The salt of claim 21 that is a pharmaceutically acceptable salt of N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea.
- Claim: 24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , or 20 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
- Claim: 25. The pharmaceutical composition according to claim 24 further comprising one or more analgesic or one or more nonsteroidal anti-inflammatory drug, or a combination thereof.
- Claim: 26. The pharmaceutical composition according to claim 24 , wherein the composition comprises N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea, or a pharmaceutically acceptable salt thereof.
- Claim: 27. A method for treating pain comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , or 20 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
- Claim: 28. The method according to claim 27 further comprising the step of co-administering with one or more analgesics, or with one or more nonsteroidal anti-inflammatory drug, or combination thereof.
- Claim: 29. The method according to claim 28 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.
- Claim: 30. A method for treating incontinence, micturition disorder, renal colic, cystitis, stroke, acute cerebral ischemia, ischemia, multiple sclerosis, asthma, cough, chronic obstructive pulmonary disease (COPD), broncho-constriction, gastroesophageal reflux disease (GERD), dysphagia, ulcer, urinary incontinence, bladder overactivity, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, Crohn's disease, cancer chemotherapy-induced emesis, or obesity, comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , or 20 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
- Claim: 31. A method for treating inflammatory states, comprising burns, rheumatoid arthritis and osteoarthritis comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , or 20 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
- Claim: 32. The method for treating pain according to claim 27 , wherein the method comprises administering a therapeutically effective amount of N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-N′-(3-methylisoquinolin-5-yl)urea, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
- Current U.S. Class: 514/310
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- Primary Examiner: Davis, Zinna Northington
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