Methods and compositions for treating rheumatoid arthritis

1. A method for treating rheumatoid arthritis in a mammal in need thereof comprising administering in therapeutically effective amounts a combination therapy comprising methotrexate and a compound of Formula X below:

wherein each X is independently fluoro, chloro or bromo;

p is an integer from 0 to 3;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, pyrrolyl, 2,5-dihydopyrrol-1-yl, piperidinyl, or 1,2,3,6-tetrahydro-pyridin-1-yl;

R 2 is selected from the group consisting of lower alkyl, lower alkenyl, and lower alkylenecycloalkyl;

and pharmaceutically acceptable salts thereof.

2. A method for treating rheumatoid arthritis in a mammal in need thereof comprising administering in therapeutically effective amounts a combination therapy comprising methotrexate and a compound of Formula XI below:

wherein each X is independently selected from the group consisting of fluoro and chloro;

m is an integer equal to 1 or 2;

R 2 is selected from the group consisting of lower alkyl, lower alkenyl, and lower alkylenecycloalkyl;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;

and pharmaceutically acceptable salts thereof.

3. A method for treating rheumatoid arthritis in a mammal in need thereof comprising administering in therapeutically effective amounts a combination therapy comprising methotrexate and a compound of Formula XII below:

wherein each X is independently fluoro or chloro;

n is zero or one;

R 2 is —CH 2 —R′ where R′ is selected from the group consisting of hydrogen, methyl or —CH═CH 2;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;

and pharmaceutically acceptable salts thereof.

4. The method according to claim 3 , wherein the compound of Formula XII is the compound of Formula P below:

5. The method according to claim 1 , wherein R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group.

6. The method according to any one of claims 1 , 2 , or 3 , wherein R 2 is CH 3 .

7. The method according to claim 3 , wherein X is F or Cl and n is 0.

8. The method according to claim 1 , wherein the compound of Formula X is selected from the group consisting of:

N-(2-[N′,N′-diethylamino]-5-[N″-(4-chlorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine ELN;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-chlorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(piperidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″(4-fluorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(piperidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-chlorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-chlorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(2,4-difluorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(2,4-difluorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(2,4-difluorophenylsulfonyl)-N″-methylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(2,4-difluorophenylsulfonyl)-N″-ethylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine; and

pharmaceutically acceptable salts thereof.

9. A method for treating rheumatoid arthritis in a mammal in need thereof comprising administering in therapeutically effective amounts a combination therapy comprising methotrexate and a compound of Formula XIII below:

wherein each X is independently fluoro, chloro or bromo;

p is an integer from 0 to 3;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, pyrrolyl, 2,5-dihydopyrrol-1-yl, piperidinyl, or 1,2,3,6-tetrahydropyridin-1-yl;

R 2 is lower alkynyl;

and pharmaceutically acceptable salts thereof.

10. A method for treating rheumatoid arthritis in a mammal in need thereof comprising administering in therapeutically effective amounts a combination therapy comprising methotrexate and a compound of Formula XIV below:

wherein each X is independently selected from the group consisting of fluoro and chloro;

m is an integer equal to 1 or 2;

R 2 is lower alkynyl;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;

and pharmaceutically acceptable salts thereof.

11. A method for treating rheumatoid arthritis in a mammal in need thereof comprising administering in therapeutically effective amounts a combination therapy comprising methotrexate and a compound of Formula XV below:

wherein each X is independently fluoro or chloro;

n is zero or one;

R 2 is lower alkynyl;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;

and pharmaceutically acceptable salts thereof.

12. The method according to claim 9 , wherein R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group.

13. The method according to any one of claims 9 , 10 , or 11 , wherein R 2 is propargyl.

14. The method according to claim 12 , wherein X is F or Cl and n is 0.

15. The method according to claim 12 , wherein the compound of Formula XIII is the compound of Formula Q below:

16. The method according to claim 9 , wherein the compound of Formula XIII is selected from the group consisting of:

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-propargylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(2,4-difluorophenylsulfonyl)-N″-propargylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(2,4-difluorophenylsulfonyl)-N″-propargylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-fluorophenylsulfonyl)-N″-propargylamino]pyrimidin-4-yl)-4′-(azetidin-1-ylcarbonyloxy)-L-phenylalanine;

N-(2-[N′,N′-diethylamino]-5-[N″-(4-chlorophenylsulfonyl)-N″-propargylamino]pyrimidin-4-yl)-4′-(pyrrolidin-1-ylcarbonyloxy)-L-phenylalanine; and

pharmaceutically acceptable salts thereof.

17. A regimen for the treatment of rheumatoid arthritis which comprises administering to a subject in need thereof about 2 mg to about 20 mg of methotrexate and about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a compound of formula X, wherein the amount of methotrexate administered per week does not exceed 20 mg, wherein the compound of formula X is as below:

wherein each X is independently fluoro, chloro or bromo;

p is an integer from 0 to 3;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, pyrrolyl, 2,5-dihydopyrrol-1-yl, piperidinyl, or 1,2,3,6-tetrahydro-pyridin-1-yl;

R 2 is selected from the group consisting of lower alkyl lower alkenyl, and lower alkylenecycloalkyl;

and pharmaceutically acceptable salts thereof.

18. A regimen for the treatment of rheumatoid arthritis which comprises administering to a subject in need thereof about 2 mg to about 20 mg of methotrexate and about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a compound of formula XIII, wherein the amount of methotrexate administered per week does not exceed 20 mg, wherein the compound of formula XIII is as below:

wherein each X is independently fluoro, chloro or bromo;

p is an integer from 0 to 3;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, pyrrolyl, 2,5-dihydopyrrol-1-yl, piperidinyl, or 1,2,3,6-tetrahydropyridin-1-yl;

R 2 is lower alkynyl;

and pharmaceutically acceptable salts thereof.

19. A regimen for the treatment of rheumatoid arthritis which comprises administering to a subject in need thereof about 2 mg to about 20 mg of methotrexate and about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a compound of formula XIV, wherein the amount of methotrexate administered per week does not exceed 20 mg, wherein the compound of formula XIV is as below:

wherein each X is independently selected from the group consisting of fluoro and chloro;

m is an integer equal to 1 or 2;

R 2 is lower alkynyl;

R 1 and R 3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;

and pharmaceutically acceptable salts thereof.