US2010168108A1PendingUtilityA1
Phenyl derivatives and methods of use
Est. expiryOct 5, 2024(expired)· nominal 20-yr term from priority
A61P 3/10A61P 37/02A61P 9/12A61P 9/10A61P 37/08A61P 9/06A61P 37/06A61P 43/00A61P 25/04A61P 25/14A61P 29/00A61P 27/06A61P 25/00A61P 25/16A61P 25/28C07C 311/04A61P 1/04C07D 213/89A61P 15/00A61P 21/00C07C 275/32C07D 285/06C07D 307/24A61P 13/10C07D 295/096A61P 13/00A61P 11/06C07C 311/08C07D 231/14C07D 207/28C07D 213/82A61P 17/06A61P 1/12C07D 261/18C07D 333/38A61P 21/04C07D 295/185A61P 1/14A61P 11/00C07D 307/68C07C 275/24A61P 19/10C07D 207/34A61P 19/02C07D 241/24A61P 1/08A61P 1/02A61P 13/12
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . 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 )—;
each R 7 and R 8 is independently H, alkyl, halogen, or —OR 9f ;
A, B, D, and E are each independently N, CR 14a , C-[C(R15a)(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 alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —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(═O)—OR 9b , —C(═CHNO 2 O)—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f );
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, —O—, —S—, —CH 2 —, —CF 2 —, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R 7 and R 8 is independently H or alkyl;
X is a single bond, —CH═CH—, —O—, or —N(R 21 )—, provided that when X is —O—, G 2 is other than —C(═N—CN)—N(R 18e )(R 18f ); and provided that when X is —O— or —N(R 21 )—, then R 8 is H or alkyl; and provided that when G 2 is —C(═CHNO 2 )—N(R 18c )(R 18d ), then X is —N(R 21 )—; and
provided that when G 2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
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 )—; or R 18c and R 21 , 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 -alkyl)-;
m and n are each independently an integer from 1 to 5;
each p is independently an integer from 0 to 5; and
each r is independently an integer from 0 to 4;
with the provisos that:
(1) 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 ); and
(2) when each R 8 is independently H or alkyl, W is a single bond, X is —N(R 21 ), m is 1, and n is 2, then G 2 is other than acyl;
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 G 2 is —S(═O) 2 R 19 , —S(═O) 2 N(R 20a )(R 20b ), —C(═O)—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f ).
23 . A compound according to claim 1 , wherein G 2 is alkyl or —C(═O)—N(R 18c )(R 18d ).
24 . A compound according to claim 23 , wherein G 2 is —C(═O)—N(R 18c )(R 18d ).
25 . A compound according to claim 24 wherein X is ——N(R 21 )—, and R 18c and R 21 , 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(acyl)-, or —N(S(═O) 2 -alkyl)-.
26 . A compound according to claim 24 , wherein X is a single bond, —CH═CH—, —O—, —N(H)— or —N(alkyl)-
27 . A compound according to claim 1 wherein R 9a is H.
28 . A compound according to claim 1 , wherein R 14a is H.
29 . A compound according to claim 1 , wherein R 14b is H.
30 . 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.
31 . 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)-.
32 . A compound according to claim 31 wherein each R 18c and R 18d is independently H or alkyl optionally substituted with alkoxycarbonyl.
33 . A compound according to claim 32 , wherein at least one of R 18c and R 18d is alkyl substituted with C 1 -C 3 alkoxycarbonyl.
34 . A compound according to claim 33 , wherein at least one of R 18c and R 18d is —CH 2 C(═O)—OCH 2 CH 3 .
35 . A compound according to claim 31 , wherein one of R 18c and R 18d is optionally substituted aryl.
36 . A compound according to claim 35 , wherein one of R 18c and R 18d is phenyl substituted with alkoxy, cyano, or dialkylamino.
37 . A compound according to claim 36 , 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.
38 . A compound according to claim 1 , wherein W is —O— or —CH 2 —.
39 . A compound according to claim 1 , wherein X is a single bond or —N(R 21 )—.
40 . A compound according to claim 1 , wherein at least one of R 15a , R 16a , and R 21 is H.
41 . A compound according to claim 40 , wherein R 15a , R 16a , and R 21 are each H.
42 . A compound according to claim 1 , wherein at least one of R 17 and R 18c is H.
43 . A compound according to claim 1 , wherein m is 1.
44 . A compound according to claim 1 , wherein n is 1 or 2.
45 . A compound according to claim 1 , wherein p is 1.
46 . A compound according to claim 1 , wherein r is 1 or 2.
47 . 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 .
48 . A compound according to claim 47 , wherein R 17 is H.
49 . A compound according to claim 48 , wherein R 1 is —OR 9a .
50 . A compound according to claim 49 wherein R 2 , R 3 , and R 4 are each H.
51 . A compound according to claim 50 , wherein R 5 and R 6 are each alkyl.
52 . A compound according to claim 51 , wherein R 5 and R 6 are each independently C 1 -C 3 alkyl.
53 . A compound according to claim 52 , wherein R 5 and R 6 are each methyl.
54 . A compound according to claim 53 , wherein R 7 and R 8 are each H.
55 . A compound according to claim 54 , 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 .
56 . A compound according to claim 55 , of formula IIa or IIb:
57 . A compound according to claim 56 of formula IIa or IIb, wherein W is a single bond, —O—, or —CH 2 —.
58 . A compound according to claim 57 , wherein W is —O— or —CH 2 —.
59 . A compound according to claim 58 , wherein n is 1 or 2.
60 . A compound according to claim 59 , wherein n is 2.
61 . A compound according to claim 59 , wherein X is a single bond, —CH═CH—, or —N(R 21 )—.
62 . A compound according to claim 61 , wherein X is a single bond or —N(R 21 )—.
63 . A compound according to claim 61 , wherein G 2 is alkyl, acyl, or —C(═O)—N(R 18c )(R 18d ).
64 . A compound according to claim 63 wherein G 2 is C 1 -C 3 alkyl.
65 . A compound according to claim 63 wherein G 2 is —C(═O)—C 1 -C 6 alkyl.
66 . A compound according to claim 63 , wherein G 2 is —C(═O)—N(R 18c )(R 18d ).
67 . A compound according to claim 63 , wherein G 1 is —C(═O)—N(R 18c )(R 18d ).
68 . A compound according to claim 67 , wherein G 1 is —C(═O)—NH(C 1 -C 3 alkyl).
69 . A compound according to claim 63 , wherein G 1 is —C(═O)-heterocycloalkyl.
70 . A compound according to claim 69 , wherein G 1 is:
71 . A compound according to claim 63 , wherein G 1 is —S(═O) 2 -alkyl.
72 . A compound according to claim 71 , wherein G 1 is —S(═O) 2 —CH 3 .
73 . A compound according to claim 68 of formula IIa, wherein G 1 is —C(═O)—N(H)CH 2 CH 3 , G 2 is
X is a single bond, n is 2, p is 1, W is —O—, and R 9a , R 15a , and R 16a are each H.
74 . A compound according to claim 68 of formula IIa, wherein G 1 is C(═O)—N(H)CH 2 CH 3 , G 2 is —C(═O)—C(CH 3 ) 3 , X is —NH—, n and p are each 1, W is —CH 2 —, and R 9a , R 15a , and R 16a are each H.
75 . A compound according to claim 68 of formula IIa, wherein G 1 is C(═O)—N(H)CH 2 CH 3 , G 2 is
X is a —NH—, n and p are each 1, W is —CH 2 —, and R 9a , R 15a , and R 16a are each H.
76 . A compound according to claim 68 of formula IIa, wherein G 1 is —C(═O)—N(H)CH 3 , G 2 is
X is a single bond, n is 2, p is 1, W is —CH 2 —, and R 9a , R 15a , and R 16a are each H.
77 . A compound according to claim 68 of formula IIa, wherein G 1 is —C(═O)—N(H)CH 2 CH 3 , G 2 is
X is a single bond, n is 2, p is 1, W is —CH 2 —, and R 9a , R 15a , and R 16a are each H.
78 . A compound according to claim 68 of formula IIa, wherein G 1 is —C(═O)—N(H)CH(CH 3 ) 2 , G 2 is
X is a single bond, n is 2, p is 1, W is —CH 2 —, and R 9a , R 15a , and R 16a are each H.
79 . A compound according to claim 1 which exhibits activity toward the cannabinoid receptors.
80 . 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 ).
81 . A compound according to claim 1 , wherein each R 17 is independently H or alkyl.
82 . A compound according to claim 1 , wherein each G 2 is alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —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(═O)—OR 9b , or —C(═N—CN)—N(R 18e )(R 18f ).
83 . A compound according to claim 1 , wherein R 21 is H or alkyl.
84 . A compound according to claim 1 selected from the group consisting of:
1-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-2-yl]-3-ethyl-urea; N-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-2-yl]-methanesulfonamide; N-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-3-yl]-methanesulfonamide; 6-(2-hydroxy-3′-methanesulfonylaminobiphenyl-4-yl)-6-methylheptanoic acid methyl ester; 1-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-{2-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-2-yl]-ethyl }-3-ethyl-urea; N-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-3-ylmethyl]methanesulfonamide; N-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-2-ylmethyll-methanesulfonamide; N-{2-[4′-(1,1-dimethylheptyl)-2′-hydroxybiphenyl-2-yl]-ethyl}-methanesulfonamide; 1-{4′-[1,1-dimethyl-2-(3-morpholin-4-yl-3-oxo-propoxy)-ethyl]-2′-hydroxybiphenyl-3-ylmethyl}-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-propyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-propyl-urea; 1-ethyl-3-{2′-hydroxy-4′-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-biphenyl-2ylmethyl}-urea; 1-ethyl-3-{2′-hydroxy-4′-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-biphenyl-3ylmethyl}-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hex-4-enyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-isopropyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-(4-methoxyphenyl)-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-ureido}-acetic acid ethyl ester; 1-(4-dimethylaminophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-urea; 1-(3-cyanophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-(3-methoxyphenyl)-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-isopropyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-(4-methoxyphenyl)-urea; {3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-ureido}-acetic acid ethyl ester; 1-(4-dimethylaminophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-urea; 1-(3-cyanophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-(3-methoxyphenyl)-urea; 1-(4-{2′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-3-isopropylurea; 1-(4-{3′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-3-isopropylurea; ethylcarbamic acid 4-{3′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl ester; ethylcarbamic acid 4-{2′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl ester; morpholine-4-carboxylic acid (4-{3′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-amide; tetrahydrofuran-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; furan-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; furan-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; isoxazole-5-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; 2,5-dimethylfuran-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; N-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-nicotinamide; pyrazine-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; 1-methyl-1H-pyrrole-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; 5-methylisoxazole-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; thiophene-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; 5-oxo-pyrrolidine-2-carboxylic acid[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; [1,2,3]-thiadiazole-4-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; 5-methylpyrazine-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; N-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-1-hydroxyisonicotinamide N-oxide; 1,5-dimethyl-1H-pyrazole-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; tetrahydrofuran-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide furan-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; furan-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; isoxazole-5-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; 2,5-dimethylfuran-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; N-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-nicotinamide; pyrazine-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; 1-methyl-1H-pyrrole-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; 5-methylisoxazole-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; thiophene-3-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; 5-oxopyrrolidine-2-carboxylic acid[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; [1,2,3]-thiadiazole-4-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; 5-methylpyrazine-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-amide; tetrahydrofuran-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; furan-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; 4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-methanesulfonamide; 4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-methanesulfonamide; N-(4-(3′-((3-ethylureido)-methyl)-2-hydroxybiphenyl-4-yl)-4-methylpentyl)-nicotinamide; 1-ethyl-3-((2′-methoxy-4′-(2-methyl-7-morpholino-7-oxoheptan-2-yl)-biphenyl-3-yl)methyl)urea; 1-ethyl-3-((2′-hydroxy-4′-(2-methyl-7-morpholinoheptan-2-yl)-biphenyl-3-yl)methyl)-urea; and 1-ethyl-3-((2′-hydroxy-4′-(2-methyl-5-(neopentylamino)-pentan-2-yl)biphenyl-3-yl)-methyl)urea; or a pharmaceutically acceptable salt thereof.
85 . A compound according to claim 84 selected from the group consisting of:
1-{4′-[1,1-dimethyl-2-(3-morpholin-4-yl-3-oxo-propoxy)-ethyl]-2′-hydroxybiphenyl-3-ylmethyl}-3-ethyl-urea; morpholine-4-carboxylic acid (4-{3′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-amide; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-isopropyl-urea; 1-(4-{3′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-3-isopropyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hex-4-enyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-isopropyl-urea; tetrahydrofuran-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; N-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-methanesulfonamide; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-propyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-propyl-urea; 1-ethyl-3-{2′-hydroxy-4′-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-biphenyl-2-ylmethyl}-urea; 1-ethyl-3-{2′-hydroxy-4′-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-biphenyl-3-ylmethyl}-urea; 1-[4′-(1,1-dimethyl-heptyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-(4-{2′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-3-isopropyl-urea; ethylcarbamic acid 4-13′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl ester; ethylcarbamic acid 4-12′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl ester; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-(4-methoxyphenyl)-urea; {3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-ureido}-acetic acid ethyl ester; 1-(4-dimethylaminophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-urea; 1-(3-cyanophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-(3-methoxyphenyl)-urea;
1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-(4-methoxyphenyl)-urea;
{3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-ureido}-acetic acid ethyl ester;
1-(4-dimethylaminophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-urea;
1-(3-cyanophenyl)-3-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-urea; and
1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-(3-methoxyphenyl)-urea;
or a pharmaceutically acceptable salt thereof.
86 . A compound according to claim 85 selected from the group consisting of:
1-{4′-[1,1-dimethyl-2-(3-morpholin-4-yl-3-oxo-propoxy)-ethyl]-2′-hydroxybiphenyl-3-ylmethyl}-3-ethyl-urea; morpholine-4-carboxylic acid (4-13′-[(3-ethylureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-amide; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-isopropyl-urea; 1-(4-{3′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-3-isopropyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2’-hydroxybiphenyl-2-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(41,1-dimethyl-6-morpholin-4-yl-6-oxo-hex-4-enyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-isopropyl-urea; tetrahydrofuran-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; N-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-methanesulfonamide; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-propyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(2-butoxy-1,1-dimethylethyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-propyl-urea; 1-ethyl-3-{2′-hydroxy-4′-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-biphenyl-2-ylmethyl}-urea; and 1-ethyl-3-{2′-hydroxy-4′-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-biphenyl-3-ylmethyl}-urea; or a pharmaceutically acceptable salt thereof.
87 . A compound according to claim 86 selected from the group consisting of:
1-{4′-[1,1-dimethyl-2-(3-morpholin-4-yl-3-oxo-propoxy)-ethyl]-2′-hydroxybiphenyl-3-ylmethyl}-3-ethyl-urea; morpholine-4-carboxylic acid (4-{3′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-amide; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-isopropyl-urea; 1-(4-{3′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-3-isopropyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hex-4-enyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-ethyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-2-ylmethyl]-3-isopropyl-urea; tetrahydrofuran-2-carboxylic acid [4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-amide; and N-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-methanesulfonamide; or a pharmaceutically acceptable salt thereof.
88 . A compound according to claim 87 selected from the group consisting of:
1-{4′-[1,1-dimethyl-2-(3-morpholin-4-yl-3-oxo-propoxy)-ethyl]-2′-hydroxybiphenyl-3-ylmethyl}-3-ethyl-urea; morpholine-4-carboxylic acid (4-{3′-[(3-ethyl-ureido)-methyl]-2-hydroxybiphenyl-4-yl}-4-methylpentyl)-amide; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-methyl-urea; 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-ethyl-urea; and 1-[4′-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2′-hydroxybiphenyl-3-ylmethyl]-3-urea; or a pharmaceutically acceptable salt thereof.
89 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .
90 . A pharmaceutical composition according to claim 89 , further comprising at least one cannabinoid.
91 . A pharmaceutical composition according to claim 90 , wherein the cannabinoid is Δ 9 -tetrahydrocannabinol or cannabidiol.
92 . A pharmaceutical composition according to claim 89 , further comprising at least one opioid.
93 . A pharmaceutical composition according to claim 92 , 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.
94 . A pharmaceutical composition according to claim 89 , further comprising at least one analgesic.
95 . A pharmaceutical composition according to claim 94 ,
wherein the analgesic is a COX2 inhibitor, aspirin, acetaminophen, ibuprophen, or naproxen, or a mixture thereof.
96 . A pharmaceutical composition according to claim 89 , 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.
97 . A pharmaceutical composition according to claim 96 wherein said anti-seizure agent is carbamazepine, gabapentin, lamotrigine, or phenytoin, or a mixture thereof.
98 . A pharmaceutical composition according to claim 96 wherein said anti-depressant is amitryptiline.
99 . A pharmaceutical composition according to claim 96 , wherein said antiParkinson's agent is deprenyl, amantadine, levodopa, or carbidopa, or a mixture thereof.
100 . A method of binding cannabinoid receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of 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 )—;
each R 7 and R 8 is independently H, alkyl, halogen, or —OR 9f ;
A, B, D, and E are each independently N, CR 14a , C—[C(R 15 a)(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 alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —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(═O)—OR 9b , —C(═CHNO 2 )—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f );
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, —O—, —S—, —CH 2 —, —CF 2 —, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R 7 and R 8 is independently H or alkyl;
X is a single bond, —CH═CH—, —O—, or —N(R 21 )—, provided that when X is —O—, G 2 is other than —C(═N—CN)—N(R 18e )(R 18f ); and provided that when X is —O— or —N(R 21 )—, then R 8 is H or alkyl; and provided that when G 2 is —C(═CHNO 2 )—N(R 18c )(R 18d ), then X is —N(R 21 )—; and
provided that when G 2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
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 )—; or R 18c and R 21 , 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 -alkyl)-;
m and n are each independently an integer from 1 to 5;
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.
101 . A method according to claim 100 , wherein said cannabinoid receptors are selected from the group consisting of CB1 and CB2 cannabinoid receptors.
102 . A method according to claim 100 , wherein said cannabinoid receptors are located in the central nervous system.
103 . A method according to claim 100 , wherein said cannabinoid receptors are located peripherally to the central nervous system.
104 . A method according to claim 101 , wherein said compound selectively binds the CB2 cannabinoid receptors relative to the CB1 cannabinoid receptors.
105 . A method according to claim 101 , wherein said compound selectively binds the CB1 cannabinoid receptors relative to the CB2 cannabinoid receptors.
106 . A method according to claim 100 , wherein the binding agonizes the activity of the cannabinoid receptors.
107 . A method according to claim 100 , wherein said compound does not substantially cross the blood-brain barrier.
108 . A method according to claim 100 , further comprising administering to said patient an effective amount of at least one cannabinoid.
109 . A method according to claim 108 , wherein said cannabinoid is Δ 9 -tetrahydrocannabinol or cannabidiol.
110 . A method according to claim 100 , further comprising administering to said patient an effective amount of at least one opioid.
111 . A method according to claim 110 , wherein said opioid is selected from 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.
112 . A method according to claim 100 wherein said patient is in need of treatment or prevention of a disease or disorder selected from the group consisting of pain, a gastrointestinal disorder, a genitourinary disorder, inflammation, glaucoma, an auto-immune disease, an ischemic condition, an immune-related disorder, a neurodegenerative disease, and combinations thereof.
113 . A method according to claim 112 , wherein the disease or disorder is pain.
114 . A method according to claim 112 , wherein said pain is inflammatory pain, neuropathic pain, visceral pain, surgical pain, post-surgical pain, cancer related pain or a combination thereof.
115 . A method according to claim 113 , wherein said compound of formula I is administered intravenously.
116 . A method according to claim 112 , wherein said gastrointestinal disorder is nausea, vomiting, loss of appetite, cachexia, diarrhea, inflammatory bowel disease, irritable bowel syndrome or a combination thereof.
117 . A method according to claim 112 , wherein said genitourinary disorder is bladder dysfunction, nephritis or a combination thereof.
118 . A method according to claim 112 , wherein said auto-immune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, myasthenia gravis, diabetes mellitus type I, osteoporosis, or a combination thereof.
119 . A method according to claim 112 , wherein said ischemic condition is renal ischemia, cerebral stroke, cerebral ischemia, or a combination thereof.
120 . A method according to claim 112 , wherein said immune-related disorder is asthma, chronic pulmonary obstructive disorder, emphysema, bronchitis, allergy, tissue rejection in organ transplants, celiac disease, Sjogren's syndrome, or a combination thereof.
121 . A method according to claim 112 , wherein said neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or a combination thereof.
122 . A method according to claim 121 , further comprising administering to said patient deprenyl, amantadine, levodopa, or carbidopa.
123 . A method according to claim 115 , further comprising administering to said patient codeine, carbamazepine, gabapentin, lamotrigine, phenytoin, amitryptiline, an NMDA receptor antagonist, an ion channel antagonist, a nicotinic receptor agonist, or a mixture thereof.
124 . A method of providing cardioprotection against ischemic and reperfusion effects in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of 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 )—;
each R 7 and R 8 is independently H, alkyl, halogen, or —OR 9f ;
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 201 ), —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 alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —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(═O)—OR 9b , —C(═CHNO 2 )—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f );
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 ), —OH, or —(CH 2 ), —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, —O—, —S—, —CH 2 —, —CF 2 —, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R 7 and R 8 is independently H or alkyl;
X is a single bond, —CH═CH—, —O—, or —N(R 21 )—, provided that when X is —O—, G 2 is other than —C(═N—CN)—N(R 18e )(R 18f ); and provided that when X is —O— or —N(R 21 )—, then R 8 is H or alkyl; and provided that when G 2 is —C(═CHNO 2 )—N(R 18c )(R 18d ), then X is —N(R 21 )—; and provided that when G 2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
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 )—; or R 18c and R 21 , 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 -alkyl)-;
m and n are each independently an integer from 1 to 5;
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.
125 . A method according to claim 124 , wherein the ischemic or reperfusion effect is arrhythmia or hypertension.
126 . A method of inducing apoptosis in malignant cells, comprising the step of:
contacting said cells with an effective amount of 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 )—;
each R 7 and R 8 is independently H, alkyl, halogen, or —OR 9f ;
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 alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —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(═O)—OR 9b , —C(═CHNO 2 )—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f );
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, —O—, —S—, —CH 2 —, —CF 2 —, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R 7 and R 8 is independently H or alkyl;
X is a single bond, —CH═CH—, —O—, or —N(R 21 )—, provided that when X is —O—, G 2 is other than —C(═N—CN)—N(R 18e )(R 18f ); and provided that when X is —O— or —N(R 21 )—, then R 8 is H or alkyl; and provided that when G 2 is —C(═CHNO 2 )—N(R 18c )(R 18d ), then X is —N(R 21 )—; and provided that when G 2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
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 )—; or R 18c and R 21 , 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 -alkyl)-;
m and n are each independently an integer from 1 to 5;
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.
127 . A method according to claim 126 , wherein said apoptosis occurs in vitro.
128 . A method according to claim 127 , wherein said apoptosis occurs in vivo.
129 . A method for modulating appetite, comprising the step of:
administering to said patient an effective amount of 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 )—;
each R 7 and R 8 is independently H, alkyl, halogen, or —OR 9f ;
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 alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —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(═O)—OR 9b , —C(═CHNO 2 )—N(R 18c )(R 18d ), or —C(═N—CN)—N(R 18e )(R 18f );
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, —O—, —S—, —CH 2 —, —CF 2 —, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R 7 and R 8 is independently H or alkyl;
X is a single bond, —CH═CH—, —O—, or —N(R 21 )—, provided that when X is —O—, G 2 is other than —C(═N—CN)—N(R 18e )(R 18f ); and provided that when X is —O— or —N(R 21 )—, then R 8 is H or alkyl; and provided that when G 2 is —C(═CHNO 2 )—N(R 18c )(R 18d ), then X is —N(R 21 )—; and
provided that when G 2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
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 )—; or R 18c and R 21 , 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 -alkyl)-;
m and n are each independently an integer from 1 to 5;
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.Join the waitlist — get patent alerts
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