Method to reduce an inflammatory response from arthritis
The present invention provides a therapeutic method for treating an inflammatory response caused by autoimmune stimulation, comprising the administration to a patient in need thereof of an antiinflammatory amount amount of an A 2A adenosine receptor agonist. The autoimmune stimulation can be caused by arthritis, particularly rheumatoid arthritis. Optionally, the method includes administration of a type IV PDE inhibitor.
1. A therapeutic method for treating an inflammatory response caused by autoimmune stimulation, comprising the administration to a patient in need thereof of an antiinflammatory amount of an A 2A adenosine receptor agonist, wherein the A 2A adenosine receptor agonist is a compound having formula (I):
wherein
Z is CR 3 R 4 R 5 ;
each R 1 is independently hydrogen;
each R 2 is independently hydrogen;
R 4 and R 5 together with the atoms to which they are attached form a saturated mono- or bicyclic cycloalkyl ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms wherein the cycloalkyl optionally comprises 1-2 N, O, or S;
wherein any ring comprising R 4 and R 5 is substituted with from 1 to 3 R 6 groups; wherein each R 6 is independently (C 1 -C 6 )alkyl, CH 2 OH, —CO 2 R a , R a C(═O)O—, or R b R c NC (═O);
R 3 is hydrogen;
each R 7 is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, phenyl or phenyl (C 1 -C 6 )alkylene;
X is CH 2 OH, —CO 2 R a , —CH 2 OC(O)R a , or —C(O)NR b R c ;
wherein any alkyl group of R 6 is optionally substituted on carbon with one or more substituents selected from the group consisting of CH 2 OH, —CO 2 R a , R a C(═O)O—, R a C(═O)—, and R b R c NC(═O)—;
wherein each R a , R b and R c is independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with 1-3(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkylthio, aryl, or aryl(C 1 -C 6 )alkylene;
m is 0 to 6; or
a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the ring comprising R 4 , R 5 and the atom to which they are connected is cyclopentane, cyclohexane, piperidine, piperazine, decaline, hexahydro-pyrimidine, imidazolidine, or pyrazolidine.
3. The method of claim 2 , wherein the ring comprising R 4 , R 5 and the atom to which they are connected is cyclopentane, cyclohexane, piperidine, pyridine, hexahydro-pyrimidine, imidazolidine, or pyrazolidine.
4. The method of claim 3 , wherein the ring comprising R 4 and R 5 and the atom to which they are connected is cyclohexane, piperidine or piperazine.
5. The method of claim 1 , wherein R a and R b are independently hydrogen, methyl or ethyl, phenyl or benzyl.
6. The method of claim 1 , wherein R a is (C 1 -C 6 )alkyl.
7. The method of claim 1 , wherein R a is methyl, ethyl, propyl or butyl.
8. The method of claim 1 , wherein R a is, methyl, ethyl, i-propyl, i-butyl or tert-butyl.
9. The method of claim 1 , wherein R 7 is hydrogen, (C 1 -C 6 )alkyl, phenyl or phenyl(C 1 -C 6 )alkylene.
10. The method of claim 9 , wherein R 7 is hydrogen, methyl or ethyl, phenyl or benzyl.
11. The method of claim 10 , wherein R 7 is H, or methyl.
12. The method of claim 11 , wherein N(R 7 ) 2 is amino, methylamino, dimethylamino, ethylamino, pentylamino, diethylamino or benzylamino.
13. The method of claim 12 , wherein —N(R 7 ) 2 is amino, methylamino, dimethylamino, ethylamino, diethylamino or benzylamino.
14. The method of claim 13 , wherein N(R 7 ) 2 is amino, or methylamino.
15. The method of claim 1 , wherein X is, CH 2 OH, —CO 2 R a , —CH 2 OC(O)R a , or —C(O)NR b R c .
16. The method of claim 15 , wherein X is CH 2 OH or —C(O)NR b R c .
17. The method of claim 16 , wherein X is —CH 2 OH, or —C(O)NHCH 2 CH 3 .
18. The method of claim 1 , wherein m is 0, 1, or 2.
19. The method of claim 1 , wherein the rings comprising R 4 , R 5 and the atom to which they are connected are selected from the group consisting of:
where m is from 1 to 3.
20. The method of claim 1 , wherein the rings comprising R 4 , R 5 and the atom to which they are connected are selected from the group consisting of:
21. The method of claim 1 , wherein the ring comprising R 4 and R 5 is 2-methylcyclohexane, 2,2-dimethylcyclohexane, 2-ethylcyclohexane, 2,2-diethylcyclohexane, 2-tert-butylcyclohexane, 3-methylcyclohexane, 3,3-dimethylcyclohexane, 4-methylcyclohexane, 4-ethylcyclohexane, 4-tert-butylcyclohexane, 4-carboxymethyl cyclohexane, 4-carboxyethyl cyclohexane, 3,3,5,5-tetramethyl cyclohexane, 2,4-dimethyl cyclopentane, 4-cyclohexanecarboxylic acid, or 4-cyclohexanecarboxylic acid esters.
22. The method of claim 1 , wherein the ring comprising R 4 and R 5 is 4-piperidine, 4-piperidene-1-carboxylic acid, 4-piperidine-1-carboxylic acid methyl ester, 4-piperidine-1-carboxylic acid ethyl ester, 4-piperidine-1-carboxylic acid propyl ester, 4-piperidine-1-carboxylic acid tert-butyl ester, 3-piperidine, 3-piperidene-1-carboxylic acid, 3-piperidine-1-carboxylic acid methyl ester, or 3-piperidine-1-carboxylic acid tert-butyl ester.
23. The method of claim 1 , wherein the compound has the formula:
24. The method of claim 1 , wherein the A 2A adenosine receptor agonist is
25. The method of claim 1 , wherein the A 2A adenosine receptor agonist is administered orally or transdermally.
26. The method of claim 1 , wherein autoimmune stimulation is caused by arthritis.
27. The method of claim 1 , wherein autoimmune stimulation is caused by rheumatoid arthritis.