N-substituted indoles and use as allosteric modulators of cannabinoid receptors
Heteroaromatic compounds are provided which are allosteric modulators of the cannabinoid receptors and which are useful for the treatment of glaucoma, pain, neuropathic pain, post-traumatic stress disorder (PTSD), and neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other diseases where cannabinoid receptors are involved.
1 . A compound having a structure according to Formula I
wherein
X and Y are CH;
Z is (CH 2 ) k , and k is 0 to 4;
A is an unsaturated carbocyclic ring and n is 2;
B is phenyl or a 5 to 6 membered heteroaryl ring;
R 1 is H, OH, ═CH 2 , or C1 to C5 alkyl, linear or branched, optionally substituted with CO 2 H, CONH 2 , or —C═C—;
R 2 is H, halogen, or alkyl;
R 4 is H, halogen, alkoxy, OH, alkyl, haloalkyl, optionally substituted, alkyne, NO 2 , CN, CO 2 R, NR 2 , a deuterated alkyl group, a five- or six-membered heterocyclic ring, a (hetero)aromatic ring, or SO 2 NHR, wherein R is independently H or alkyl, optionally substituted;
R 3 is H;
R 5 is H;
R 6 is CO 2 H; (CHR 7 ) p CO 2 R 7 ; CN; CONH 2 ; alkoxy; CONR 7 R 8 ; aryl; heterocyclic ring; CH═CHCO 2 R 7 ; or (CHR 7 ) y COR 7 ; wherein R 7 and R 8 , including each of R 7 , is independently H or alkyl, optionally substituted, p is 2 to 4 and y is 0 to 4;
* represents a chiral center; and
m is 0 to 5, with the proviso that, when m=0, R 1 and R 6 are bonded to the atom marked with *.
2 . The compound of claim 1 , wherein R 6 is CO 2 H.
3 . The compound of claim 1 , wherein R 6 is CO 2 H and m is 1.
4 . The compound of claim 1 , wherein each of R 1 and R 6 is CO 2 H.
5 . The compound of claim 1 , wherein each of R 1 and R 6 is CO 2 H and m is 1.
6 . The compound of claim 1 , wherein R 1 is CH 2 OH and m is 1.
7 . The compound of claim 1 , wherein each of R 1 and R 6 is CH 2 OH and m is 1.
8 . The compound of claim 1 , wherein R 6 is a heterocyclic ring.
9 . The compound of claim 8 , wherein the heterocyclic ring is tetrazole.
10 . The compound of claim 1 , wherein R 6 is CH 2 COR 7 and R 7 is alkyl and m is 1.
11 . The compound of claim 10 , wherein R 1 is H.
12 . The compound of claim 10 , wherein each of R 1 and R 7 is CH 3 .
13 . A compound of claim 1 having a structure selected from the group consisting of
14 . The compound of claim 1 that binds to a CB1 receptor.
15 . The compound of claim 14 that is a positive allosteric modulator.
16 . The compound of claim 1 that binds to a CB2 receptor.
17 . A compound having a structure selected from the group consisting of
18 . A pharmaceutical composition comprising a compound of claim 1 and one or more excipients.
19 . A method of treating a medical condition selected from the group consisting of glaucoma, post-traumatic stress disorder, epilepsy, pain, neuropathic pain, a neurodegenerative disease, Huntington's disease, Alzheimer's disease, and Parkinson's disease, the method comprising administering the compound of claim 1 to a subject in need thereof.