Methods for synthesis of diarylmethanes
The present invention relates to dihydrofolate reductase inhibitors having an aromatic group and a heteroaromatic group linked by a methylene group; methods of preparation of dihydrofolate reductase inhibitors that include metal mediated cross coupling of an aromatic halide or heteroaromatic halide with an organozinc reagent; 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, and nitrile; or
two adjacent R A groups taken in combination form a group of the formula:
which may be optionally substituted;
R 3 is hydrogen; and
i is an integer from 0 to about 5.
2. A compound of claim 1 wherein R A is independently selected at each occurrence of R A from the group consisting of hydrogen, chloro, and fluoro; or
two adjacent R A groups taken in combination form a group of the formula:
R 3 is hydrogen; and
i is an integer from 0 to about 3.
3. A compound of claim 1 according to Formula I-A:
wherein
two adjacent R A groups taken in combination form a group of the formula:
and
i is 2.
4. A pharmaceutical composition comprising a compound of any one of claims 1 , 2 , or 3 and a pharmaceutically acceptable carrier.
5. A method for treating a mammal suffering from a Pneumocystis carinii infection or a Toxoplasma gondii infection, comprising administering to the mammal an effective amount of a pharmaceutical composition of claim 4 .
6. A method of claim 5 wherein the mammal is immuno-compromised.
7. The method of claim 5 , wherein the mammal is HIV-positive.
8. The method of claim 5 , wherein the mammal is suffering from an acquired immune deficiency disorder.
9. The method of claim 5 , wherein the mammal is suffering from an autoimmune disorder or disease.
10. The method of claim 5 , wherein the mammal is suffering from Toxoplasma gondii infection.
11. The method of claim 5 , wherein the mammal is a human.
12. The method of claim 5 , wherein the mammal is suffering from Pneumocystis carinii infection.
13. A method of forming a compound according to Formula I:
the method comprising the steps of
contacting an aryl halide of the formula:
with at least one molar equivalent of a organozinc reagent, RZnY, and at least a catalytic amount of a palladium catalyst to form a C—C bond by a palladium mediated cross-coupling reaction; and
contacting the product of the cross-coupling reaction with chloroformamidine under dry-fusion conditions to form a compound according to Formula I, wherein
R is a benzyl residue of the formula —CH 2 C 6 H 5-i (R A ) i ;
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, C 1-6 alkylthio, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted aryl acetoxy or optionally substituted heteroaryl acetoxy; or
or
two adjacent R A groups taken in combination form a group of the formula:
which may be optionally substituted;
R 3 is hydrogen; and
i is 0, 1, 2, or 3;
Y is Cl, Br, I, or triflate.