Phenyl derivatives and methods of use
View Patent ↗Novel phenyl compounds, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the compounds are agonists and/or ligands of cannabinoid receptors and may be useful, inter alia, for treating and/or preventing pain, gastrointestinal disorders, genitourinary disorders, inflammation, glaucoma, auto-immune diseases, ischemic conditions, immune-related disorders, and neurodegenerative diseases, for providing cardioprotection against ischemic and reperfusion effects, for inducing apoptosis in malignant cells, and as an appetite stimulant.
1. A compound of formula I:
wherein:
R 1 , R 2 , R 3 , and R 4 are each independently H, alkyl, —OR 9a , —N(R 10 )(R 11 ), —C(═O)N(R 12 )(R 13 ), —C(═O)—OR 9b , —OP(═O)(OR 9c )(OR 9d ), —CN, or
R 5 and R 6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring, wherein 1 to 3 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, or —N(R 9e )—;
R 7 is H, alkyl, halogen, or —OR 9f ;
each R 8 is independently H or alkyl;
A, B, D, and E are each independently N, CR 14a , C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 , or C—[C(R 15b )(R 16b )] p —OC(═O)—N(R 18a )(R 18b );
J is N or CR 14b , provided that no more than two of A, B, D, E, and J are N;
each G 1 is independently —S(═O) 2 R 19 , —S(═O) 2 N(R 20a )(R 20b ), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R 18c )(R 18d ), —C(═CHNO 2 )—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f );
G 2 is acyl;
each R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f is independently H or alkyl;
each R 10 , R 11 , R 12 , and R 13 is independently H, alkyl, alkenyl, aryl, or heteroaryl, or each R 10 and R 11 or R 12 and R 13 , taken together with the nitrogen atom to which they are attached, independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(alkyl)-, —N(C(═O)—R 9a )—, or —N(S(═O) 2 —R 9a )—;
each R 14a and R 14b is independently H, halogen, alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN, —(CH 2 ) r- OH, or —(CH 2 ) r —O-alkyl;
each R 18a , R 18b , R 18c , R 18d , R 18e , R 18f , R 20a , and R 20b is independently H, alkyl, alkenyl, or aryl, or each R 18a and R 18b or R 18c and R 18d or R 20a and R 20b , taken together with the nitrogen atom to which they are attached independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O) 2 —, —NH—, —N(alkyl)-, —N(C(═O)—R 9a )—, or —N(S(═O) 2 —R 9a ) —;
each R 19 is independently H, alkyl, aryl, OH, or —O-alkyl;
W is a single bond;
X is —N(R 21 )—;
each R 15a , R 15b , R 16a , R 16b , R 17 , and R 21 is independently H or alkyl; or R 17 and R 18c , taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(alkyl)-, —N(C(═O)—R 9a )—, or —N(S(═O) 2 —R 9a )—;
m is 1;
n is 2;
each p is independently an integer from 0 to 5; and
each r is independently an integer from 0 to 4;
with the proviso that:
at least one of A, B, D, and E is C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 or C—[C(R 15b )(R 16b )] p —OC(═O)—N(R 18a )(R 18b );
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R 1 is —OR 9a or —N(R 10 )(R 11 ).
3. A compound according to claim 2 , wherein R 1 is —OR 9a .
4. A compound according to claim 3 , wherein R 1 is —OH.
5. A compound according to claim 1 , wherein R 3 and R 4 are each independently H or alkyl.
6. A compound according to claim 5 , wherein R 3 and R 4 are each H.
7. A compound according to claim 1 , wherein R 5 and R 6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring, wherein one of the ring carbon atoms may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, or —N(R 9e )—.
8. A compound according to claim 7 , wherein R 5 and R 6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring, wherein one of the ring carbon atoms may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, or —N(R 9e )—.
9. A compound according to claim 8 , wherein R 5 and R 6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring.
10. A compound according to claim 9 , wherein R 5 and R 6 are each independently H or alkyl.
11. A compound according to claim 10 wherein R 5 and R 6 are methyl.
12. A compound according to claim 1 , wherein R 7 and R 8 are each independently H or alkyl.
13. A compound according to claim 12 , wherein R 7 and R 8 are H.
14. A compound according to claim 1 , wherein A, B, D, and E are each independently CR 14a , C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 , or C—[C(R 15b )(R 16b )] p —OC(═O)—N(R 18a )(R 18b ).
15. A compound according to claim 14 , wherein A, B, D, and E are each independently CR 14a or C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 .
16. A compound according to claim 15 , wherein G 1 is —C(═O)—N(R 18c )(R 18d ) and R 17 and R 18c , taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(alkyl)-.
17. A compound according to claim 15 , wherein R 17 is H or alkyl.
18. A compound according to claim 15 , wherein two or three of A, B, D, and E are each independently CR 14a .
19. A compound according to claim 1 , wherein J is CR 14b .
20. A compound according to claim 1 , wherein each G 1 is independently —S(═O) 2 R 19 , —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, or —C(═O)—N(R 18c )(R 18d ).
21. A compound according to claim 20 , wherein each G 1 is —C(═O)-heteroaryl or —C(═O)—N(R 18c )(R 18d ).
22. A compound according to claim 1 wherein R 9a is H.
23. A compound according to claim 1 , wherein R 14a is H.
24. A compound according to claim 1 , wherein R 14b is H.
25. A compound according to claim 1 , wherein at least one of R 14a and R 14b is —(CH 2 ) r —OH or —(CH 2 ) r —O-alkyl.
26. A compound according to claim 1 wherein each R 18c and R 18d is independently H, alkyl, or aryl, or each R 18c and R 18d , taken together with the nitrogen atom to which they are attached independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, or —N(alkyl)-.
27. A compound according to claim 26 wherein each R 18c and R 18d is independently H or alkyl optionally substituted with alkoxycarbonyl.
28. A compound according to claim 27 , wherein at least one of R 18c and R 18d is alkyl substituted with C 1 -C 3 alkoxycarbonyl.
29. A compound according to claim 28 , wherein at least one of R 18c and R 18d is —CH 2 C(═O)—OCH 2 CH 3 .
30. A compound according to claim 26 , wherein one of R 18c and R 18d is optionally substituted aryl.
31. A compound according to claim 30 , wherein one of R 18c and R 18d is phenyl substituted with alkoxy, cyano, or dialkylamino.
32. A compound according to claim 31 , wherein one of R 18c and R 18d is phenyl substituted with meta-alkoxy, meta-cyano, meta-dialkylamino, para-alkoxy, para-cyano, or para-dialkylamino.
33. A compound according to claim 1 , wherein at least one of R 15a , R 16a , and R 21 is H.
34. A compound according to claim 33 , wherein R 15a , R 16a , and R 21 are each H.
35. A compound according to claim 1 , wherein at least one of R 17 and R 18c is H.
36. A compound according to claim 1 , wherein p is 1.
37. A compound according to claim 1 , wherein r is 1 or 2.
38. A compound according to claim 1 , wherein one of A and D is C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 or one of B and E is C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 .
39. A compound according to claim 38 , wherein R 17 is H.
40. A compound according to claim 39 , wherein R 1 is —OR 9a .
41. A compound according to claim 40 wherein R 2 , R 3 , and R 4 are each H.
42. A compound according to claim 41 , wherein R 5 and R 6 are each alkyl.
43. A compound according to claim 42 , wherein R 5 and R 6 are each independently C 1 -C 3 alkyl.
44. A compound according to claim 43 , wherein R 5 and R 6 are each methyl.
45. A compound according to claim 44 , wherein R 7 and R 8 are each H.
46. A compound according to claim 45 , wherein J is CR 14b , one of D and E is C—[C(R 15a )(R 16a )] p —N(R 17 )-G 1 , and A and B and the other of D and E are each independently CR 14a .
47. A compound according to claim 46 , of formula IIa or IIb:
48. A compound according to claim 47 wherein G 2 is —C(═O)—C 1 -C 6 alkyl.
49. A compound according to claim 47 , wherein G 1 is —C(═O)—N(R 18c )(R 18d ).
50. A compound according to claim 49 , wherein G 1 is —C(═O)—NH(C 1 -C 3 alkyl).
51. A compound according to claim 47 , wherein G 1 is —C(═O)-heterocycloalkyl.
52. A compound according to claim 51 , wherein G 1 is:
53. A compound according to claim 47 , wherein G 1 is —S(═O) 2 -alkyl.
54. A compound according to claim 53 , wherein G 1 is —S(═O) 2 —CH 3 .
55. A compound according to claim 1 which exhibits activity toward the cannabinoid receptors.
56. A compound according to claim 1 selected from the group consisting of:
N-(4-{3′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-2,2-dimethylpropionamide;
2-amino-N-(4-(3′-((3-ethylureido)methyl)-2-hydroxybiphenyl-4-yl)-4-methylpentyl)-2-methylpropanamide;
N-(4-(3′-((3-ethylureido)-methyl)-2-methoxybiphenyl-4-yl)-4-methylpentyl)-pivalamide;
or a pharmaceutically acceptable salt thereof.
57. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .
58. A pharmaceutical composition according to claim 57 , further comprising at least one cannabinoid.
59. A pharmaceutical composition according to claim 58 , wherein the cannabinoid is Δ 9 -tetrahydrocannabinol or cannabidiol.
60. A pharmaceutical composition according to claim 57 , further comprising at least one opioid.
61. A pharmaceutical composition according to claim 60 , wherein said opioid is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil and tramadol, and mixtures thereof.
62. A pharmaceutical composition according to claim 57 , further comprising at least one analgesic.
63. A pharmaceutical composition according to claim 62 ,
wherein the analgesic is a COX2 inhibitor, aspirin, acetaminophen, ibuprophen, or naproxen, or a mixture thereof.
64. A pharmaceutical composition according to claim 57 , further comprising at least one agent selected from the group consisting of an anti seizure agent, an anti-depressant, an NMDA receptor antagonist, an ion channel antagonist, a nicotinic receptor agonist, an anti-Parkinson's agent, and mixtures thereof.
65. A pharmaceutical composition according to claim 64 wherein said anti-seizure agent is carbamazepine, gabapentin, lamotrigine, or phenytoin, or a mixture thereof.
66. A pharmaceutical composition according to claim 64 wherein said anti-depressant is amitryptiline.
67. A pharmaceutical composition according to claim 64 , wherein said antiParkinson's agent is deprenyl, amantadine, levodopa, or carbidopa, or a mixture thereof.
68. A compound according to claim 1 , wherein each G 1 is independently —S(═O) 2 R 19 , —S(═O) 2 N(R 20a )(R 20b ), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f ).
69. A compound according to claim 1 , each R 17 is independently H or alkyl.
70. A compound according to claim 1 , R 21 is H or lower alkyl.
71. A compound according to claim 56 which is N-(4-{3′- [(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl }-4-methylpentyl)-2,2-dimethylpropionamide or a pharmaceutically acceptable salt thereof.
72. A compound according to claim 56 which is 2-amino-N-(4-(3′-((3-ethylureido)methyl)-2-hydroxybiphenyl-4-yl)-4-methylpentyl)-2-methylpropanamide or a pharmaceutically acceptable salt thereof.
73. A compound according to claim 56 which is N-(4-(3′-((3-ethylureido)-methyl)-2-methoxybiphenyl-4-yl)-4-methylpentyl)-pivalamide or a pharmaceutically acceptable salt thereof.