Pharmaceutically active compounds and methods of use thereof
The present invention relates to dihydrofolate reductase inhibitors having an aromatic group and a heteroaromatic group linked by a methylene group; and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such dihydrofolate reductase inhibitors.
1. A compound according to Formula I:
wherein:
R A is Independently selected at each occurrence of R A from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, chloro, fluoro, C 1-4 fluoroalkyl, amino, mono and di(C 1-6 alkyl)amino, nitrile, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylamino, optionally substituted heteroarylamino, C 1-6 alkylthio, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted aryl acetoxy or optionally substituted heteroaryl acetoxy;
R 1 and R 2 are independently selected at each occurrence or R 1 , and R 2 in Formula I from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, chloro, fluoro, C 1-6 fluoroalkyl, C 1-6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylamino, optionally substituted heteroarylamino, C 1-6 alkylthio, optionally substituted arylthio, optionally substituted heteroarylthio;
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 fluoroalkyl:
W is hydroxyl, alkoxy, amino, carboxylate, C 1-6 alkylcarbonyloxy, sulfonate or carhoxamide;
i is an integer from 0 to 3; and
n Is an integer from about 1 to about 12.
2. A compound according to claim 1 wherein R A is hydrogen at each occurrence of R A , in Formula I.
3. A compound according to claim 1 of the Fomiula II:
wherein
W is hydroxy or carboxylate;
R 3 is a C 1-4 alkyl group; and
n is an integer from 3 to 8.
4. A compound of any one of claims 1 through 3 where W is carboxylate.
5. A compound according to Formula III:
wherein:
R A is independently selected at each occurrence of R A from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, C 1-4 fluoroalkyl, amino, mono and di(C 1-6 alkyl)amino, nitrile, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylamino, optionally substituted heteroarylamino, C 1-6 alkylthio, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted aryl acetoxy or optionally substituted heteroaryl acetoxy;
R 1 , R 2 , and R 4 are independently selected at each occurrence of R 1 , R 2 , and R 4 in Formula III from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, chioro, fluoro, C 1-6 fluoroalkyl, C 1-6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylamino, optionally substituted heteroarylamino, C 1-6 alkylthio, optionally substituted arylthio, optionally substituted heteroarylthio;
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-5 alkynyl, and C 1-6 fluoroalkyl;
W is hydroxy, alkoxy, amino, carboxylate, C 1-6 alkylcarbonyloxy or carboxamide;
Z is N or CH;
i is an integer from 0 to 5; and
n is an integer from 1 to 12.
6. A compound according to claim 5 , wherein R A is hydrogen at each occurrence of R A i n Formula III.
7. A compound according to claim 5 , of the Formula IV
wherein
W is hydroxy or carboxylate;
R 3 is a C 1-4 alkyl group;
R 4 is hydrogen, chloro, methoxy or methyl; and
n is an integer from 3 to 8.
8. A compound according to claim 5 , of the Formula V
wherein
W is hydroxy or carboxylate;
R 3 is a C 1-4 alkyl group;
R 4 is hydrogen, chloro, methoxy or methyl; and
n is an Integer from 3 to 8.
9. A compound of any one of claims 5 through 8 where W is carboxylate.
10. A compound of claim 1 or claim 5 , wherein the compound has an IC 50 of 50 μM or less against a DHFR enzyme of an organism selected from the group consisting of organisms causing malaria, trypanosomiasis, leprosy, toxoplasmosis, and pneumocystis carinii pneumonia.
11. A compound of claim 10 , wherein the organism is selected from the group consisting of Pneumocystis carinii, Toxoplasma gondii , and Mycobacterium avium.
12. A compound according to claim 1 or claim 5 , wherein a binding selectivity of the compound is about 1, wherein the binding selectivity is a ratio of the compound's IC 50 for binding mammalian DHFR enzymes to the compound's IC 50 for binding to a DHFR enzyme of an organism selected from the group consisting of organisms causing malaria, trypanosomiasis, leprosy, toxoplasmosis, and pneumocystis carinii pneumonia.
13. A compound according to claim 12 , where the binding selectivity of the compound is about 2.
14. A compound according to claim 12 , where the binding selectivity of the compound is about 4.
15. A compound according to claim 12 , where the binding selectivity of the compound is about 8.
16. A compound according to claim 12 , where the binding selectivity of the compound is about 16.
17. A compound according to claim 12 , where the binding selectivity of the compound is about 20.
18. A compound according to claim 12 , where the binding selectivity of the compound is about 50.
19. A pharmaceutical composition comprising a compound of claim 1 or claim 5 , and a pharmaceutically acceptable carrier.
20. A method for treating a mammal suffering or susceptible to an infection or disorder selected from the group consisting of trypanosomiasis, toxoplasmosis, and pneumocystis carinii pneumonia, comprising administering to the mammal an effective amount of a compound or composition of claim 1 or claim 5 .
21. A method of claim 20 wherein the mammal is immuno-compromised.
22. The method of claim 20 , wherein the mammal is a HIV-positive human.
23. The method of claim 20 , wherein the mammal is suffering from an acquired immune deficiency disorder.
24. The method of claim 20 , wherein the mammal is suffering from an autoimmune disorder or disease.
25. The method of claim 20 , wherein the infection is a Pneumocystis carinii (Pc), Toxoplasma gondii or Mycobacterium avium infection.
26. A compound of claim 10 , wherein the compound has an IC 50 of 25 μM or less against the DHFR enzyme.
27. A compound of claim 10 , wherein the compound has an IC 50 of 10 μM or less against the DHFR enzyme.
28. A compound of claim 10 , wherein the compound has an IC 50 of 5 μM or less against the DHFR enzyme.
29. A compound of claim 10 , wherein the compound has an IC 50 of 1 μM or less against the DHFR enzyme.
30. A compound of claim 10 , wherein the compound has an IC 50 of 0.5 μM or less against the DHFR enzyme.