Allosteric adenosine receptor modulators
View Patent ↗The present invention relates to compounds of formula (IA): the preparation thereof, pharmaceutical formulations thereof, and their use in medicine as allosteric adenosine receptor modulators for uses including protection against hypoxia and ischemia induced injury and treatment of adenosine-sensitive cardiac arrhythmias.
1. A method for providing pain management, comprising administering to a patient in need of treatment thereof an effective amount to treat the disorder of a compound of formula IA:
wherein:
R 1 is
wherein R 2 is H, C(═O)R 8 ;
R 8 is H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl;
R 3 and R 4 are independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, alkoxy, alkylthio, or arylthio;
or if R 3 and R 4 are both alkoxy or alkylthio, may form a 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, or 1,3-dithian-2-yl group;
or together R 3 and R 4 may form a carbonyl oxygen; R 5 , R 6 , and R 7 are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, hydroxy, nitro, amino, substituted amino, disubstituted amino, alkoxy, aryloxy, alkylthio, arylthio, sulfonamido, or substituted sulfonamido;
and wherein together R 5 and R 6 or R 6 and R 7 are CH═CH—CH═CH, such that they form a fused aromatic ring;
A and B are each a carbon-carbon single bond;
m and n are independently 0, 1, 2, or 3;
m plus n equals 3; and
X is CH═CH.
2. The method of claim 1 , wherein the pain management involves the treatment of diabetic neuropathy, post herpetic neuralgia or other forms of neuropathic pain.
3. The method of claim 2 wherein the treatment involves acute intravenous injection, chronic oral administration or chronic intravenous injection.
4. The method of claim 1 wherein the compound is selected from the group consisting of:
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-1-yl-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-iodonaphthalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]-thiophen-3-yl)-(4-methoxynaph-thalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chloronaphthalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-bromonaphthalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-2-yl-methanone;
(2-Amino-6-benzyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-2-yl- methanone;
(2-Amino-6-benzyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl]-naphthalen-2-yl-methanone; and
[2-Amino-6-(4-nitrobenzyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl]-naphthalen-2-yl-methanone.
5. The method of claim 1 , wherein the compound is selected from the group consisting of:
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-1-yl-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-iodonaphthalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-methoxynaphthalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chloronaphthalen-1-yl)-methanone;
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-bromonaphthalen-1-yl)-methanone; and
(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-2-yl-methanone.
6. The method of claim 5 , wherein the compound is (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-1-yl-methanone.
7. The method of claim 5 , wherein the compound is (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chloronaphthalen-1-yl)-methanone.
8. The method of claim 5 , wherein the compound is (2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-naphthalen-2-yl-methanone.