Compounds affecting gap junction activity
This invention relates to novel quinoline compounds which affect gap junction activity. Also provided are methods of using such compounds and compositions containing the compounds to treat gap junction disorders.
1. A compound having the following formula:
where Ar is o-, m- or p-C 6 H 4 CF 3 ;
R A and R B are independently selected from the group consisting of: hydrogen, —(CH 2 ) n —(X) m —Y, where n is an integer from 0-6; m is an integer from 0-2; X is independently —O—, —C(═O)—, —C(═NH)—, —S—, —S(═O)—, —SO 2 —; and Y is selected from the group consisting of: hydrogen, C1-C6 alkyl groups and nitrogen containing groups comprising —NH 2 ; —NO 2 ; —CN; phthalimide; imidazole; pyrazole; pyridine; pyrimidine; pyrazine; and pyridazine, provided that R A and R B are not both hydrogen.
2. A compound having the formula:
where R Z , R M and R D are independently selected from the group consisting of:
hydrogen, halogen, aldehyde, ketone, alcohol, optionally substituted C1-C6 straight chain or branched alkyl or alkoxy, nitro, amine, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, arylsulfanyl, arylsulfinyl, and arylsulfonyl , where the optional substituents are independently halogen, nitro, amine, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, arylsulfanyl, arylsulfinyl, and arylsulfonyl;
R E and R F are hydrogen, R G is o-, p-, or m-CF 3 ;
R A and R B are independently selectecd from the group consisting of: hydrogen, —(CH 2 ) n —(X) m —Y, where n is an integer from 0-3;m is an integer from 0-2; X is independently —O—, —C(═O)—, —C(═NH)—, —S—, —S(═O)—,—SO 2 —; and Y is selected from the group consisting of: hydrogen, C1-C3straight chain or branched alkyl or alkoxy, and nitrogen containing groups including —NH 2 , —NO 2 , —CN, phthalimide imidazole, pyrazole, pyridine, pyrimidine, pyrazine, and pyridazine and pharmaceutically acceptable salts thereof, provided that R A and R B are not both hydrogen.
3. The compound of claim 2 , wherein R M is OMe.
4. The compound of claim 1 , wherein R A is hydrogen and R B is —(CH 2 ) n —(X) m —Y, where m is 0, and Y is selected from the group consisting of —NH 2 ; —NO 2 ; —CN; phthalimide; imidazole; and pyrazole.
5. The compound of claim 4 , wherein R A is hydrogen and R B is —(CH 2 ) n —(X) m —Y, where m is 0, and Y is a nitrogen-containing group.
6. The compound of claim 1 , having formula:
where Ar is o-, p-, or m-C 6 H 4 CF 3 .
7. The compound of claim 1 , having formula:
8. The compound of claim 1 , wherein Ar is o-, p-, or m-C 6 H 4 CF 3 ; R A is hydrogen and R B is —(CH 2 ) n —(X) m —Y, where n is 1; m is 0; and Y is imidazole.
9. A compound of claim 2 which affects gap junction activity.
10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
11. A method for treating a gap junction disorder, wherein the disorder is selected from ischemia, cancer, or parasitic infections, comprising administering an effective amount of the compound of claim 2 .
12. A method for treating a gap junction disorder, wherein the disorder is selected from ischemia, cancer, or parasitic infections, comprising administering an effective amount of the compound of claim 1 to a patient.
13. The method of claim 12 , wherein R A is hydrogen and R B is —(CH 2 ) n —(X) m —Y, where m is 0, and Y is selected from the group consisting of —NH 2 ; —NR 2 , where R is C1-C6 alkyl; —NO 2 ; —CN; phthalimide; imidazole; and pyrazole.
14. The method of claim 12 , where the gap junction disorder is cancer and the compound is
15. The method of claim 12 , wherein R A is hydrogen and R B is —(CH 2 ) n —(X) m —Y, where m is 0, and Y is selected from the group consisting of —NH 2 ; —NO 2 ; —CN; phthalimide; imidazole; and pyrazole.
16. The method of claim 12 , wherein the compound of claim 1 has the formula:
17. The method of claim 12 , wherein Ar is m-C 6 H 4 CF 3 ;
R A is hydrogen and R B is —(CH 2 ) n —(X) m —Y, where n is 1; m is 0; and Y is imidazole.