Bicyclic cannabinoid agonists for the cannabinoid receptor
Novel polycyclic cannabinoid analogs are presented which have preferentially high affinities for the cannabinoid CB2 receptor sites. The improved receptor affinity makes these analogs therapeutically useful as medications in individuals and animals for treatment of pain, glaucoma, epilepsy, nausea associated with chemotherapy.
1. A compound of the formula
and physiologically acceptable salts of the compound, wherein:
R 1 is selected from OH; H; OCH 3 ; N 3 ; NH 2 ; O(CH 2 ) n N(CH 3 ) 2 and
where n is an integer from 1-3;
R 3 is selected from H; OH; OCH 3 ; N 3 and O(CH 2 ) n OH; where n is an integer from 1-5; and
R 2 is selected from (CH 2 ) n C≡CH where n is an integer from 3-5, C≡C(CH 2 ) n CH 3 where n is an integer from 2-4,
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5,
where R is (CH 2 ) n CH 3 and n is a maximum of 7, C(CH 3 ) 2 (CH 2 ) n CH 3 , where n is an integer from 3-5, and (CH 2 ) n CH 3 , where n is an integer from 4-6; with the provisos that:
R2 cannot be C(CH 3 ) 2 (CH 2 ) n CH 3 , where n is an integer from 3-5 when R 1 and R 3 are both OH,
R2 cannot be (CH 2 ) n CH 3 , where n is an integer from 4-6 when one of R 1 or R 3 is H and the other of R 1 or R 3 is OCH 3 , and
R2 cannot be (CH 2 ) n CH 3 , where n is an integer from 4-6 when R 1 and R 3 are both OH.
2. The compound of claim wherein 1 wherein R 2 is selected from (CH 2 ) n C≡CH where n is an integer from 3-5, C≡C(CH 2 ) n CH 3 where n is an integer from 2-4,
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5, and
where R is H or (CH 2 ) n CH 3 and n is a maximum of 7.
3. The compound of claim 1 wherein R 1 and R 3 are each OH and R 2 is selected from (CH 2 ) n C≡CH where n is an integer from 3-5, C≡C(CH 2 ) n CH 3 where n is an integer from 2-4,
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5, and
where R is H or (CH 2 ) n CH 3 and n is a maximum of 7.
4. The compound of claim 1 wherein:
R 1 is selected from OH; NH 2 ; O(CH 2 ) n N(CH 3 ) 2 and
where n is an integer from 1-3;
R 2 is selected from C(CH 3 ) 2 (CH 2 ) n CH 3 , where n is an integer from 3-5;
where each X is independently selected from CH 2 O, S and NH and n is an integer from 3-5; and
and where R is H, (CH 2 ) n CH 3 , and n is a maximum of 7; and
R 3 is selected from H; OH; OCH 3 N 3 and O(CH 2 ) n OH; where n is an integer from 1-5.
5. A method of preferentially stimulating the CB2 receptors in an individual or animal comprising administering to the individual or animal a therapeutically effective amount of a compound having the formula:
and physiologically acceptable salts of the compound, wherein R 1 is selected from OH; H; OCH 3 ; N 3 ; NH 2 ; O(CH 2 ) n N(CH 3 ) 2 and
where n is an integer from 1-3;
R 2 is selected from (CH 2 ) n CH 3 , where n is an integer from 4-6; C(CH 3 ) 2 (CH 2 ) n CH 3 , where n is an integer from 3-5;
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5; (CH 2 ) n C≡CH where n is an integer from 3-5; C≡C(CH 2 ) n CH 3 where n is an integer from 2-4 and
where R is (CH 2 ) n CH 3 ,
and n is a maximum of 7; and
R 3 is selected from H; OH; OCH 3 ; N 3 and O(CH 2 ) n OH; where n is an integer from 1-5.
6. The method of claim 5 wherein R 1 and R 3 are each OH and R 2 is 1,1-dimethylheptyl.
7. The method of claim 5 wherein:
R 1 is selected from OH; NH 2 ; O(CH 2 ) n N(CH 3 ) 2 and
where n is an integer from 1-3;
R 2 is selected from C(CH 3 ) 2 (CH 2 ) n CH 3 , where n is an integer from 3-5;
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5; and
where R is H, (CH 2 ) n CH 3 , and n is a maximum of 7; and
R 3 is selected from H; OH; OCH; N 3 and O(CH 2 ) n OH; where n is an integer from 1-5.
8. The method of claim 5 wherein R 2 is selected from (CH 2 ) n C≡CH where n is an integer from 3-5, C≡C(CH 2 ) n CH 3 where n is an integer from 2-4,
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5, and
where R is H or (CH 2 ) n CH 3 and n is a maximum of 7.
9. A pharmaceutical composition containing a therapeutically effective amount of a compound having the formula:
and physiologically acceptable salts of the compound, wherein R 1 is selected from OH; H; OCH 3 ; N 3 ; NH 2 ; O(CH 2 ) n N(CH 3 ) 2 and
where n is an integer from 1-3;
R 2 is selected from (CH 2 ) n CH 3 , where n is an integer from 4-6; (CH 3 ) 2 (CH 2 ) n CH 3 , where n is an integer from 3-5;
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5; (CH 2 ) n C≡CH where n is an integer from 3-5; C≡C(CH 2 ) n CH 3 where n is an integer from 2-4 and
where R is H, (CH 2 ) n CH 3 , and
n is a maximum of 7; and
R 3 is selected from H; OH; OCH 3 ; N 3 and O(CH 2 ) n OH; where n is an integer from 1-5.
10. The pharmaceutical composition of claim 9 wherein:
R 1 is selected from OH; NH 2 ; O(CH 2 ) n N(CH 3 ) 2 and
where n is an integer from 1-3;
R 2 is selected from C(CH 3 ) 2 (CH 2 ),CH 3 , where n is an integer from 3-5;
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5; and
where R is H, (CH 2 ) n CH 3 , and n is a maximum of 7; and
R 3 is selected from H; OH; OCH 3 ; N 3 and O(CH 2 ) n OH; where n is an integer from 1-5.
11. The pharmaceutical composition of claim 9 wherein R 2 is selected from (CH 2 ) n C≡CH where n is an integer from 3-5, C≡C(CH 2 ) n CH 3 where n is an integer from 2-4,
where each X is independently selected from CH 2 , O, S and NH and n is an integer from 3-5, and
where R is H or (CH 2 ) n CH 3 and n is a maximum of 7.