Methods and compositions for treating rheumatoid arthritis

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;
• R2 is selected from the group consisting of lower alkyl, lower alkenyl, and lower alkylenecycloalkyl;
• R1 and R3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;
• and pharmaceutically acceptable salts thereof.

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;
• R2 is —CH2—R′ where R′ is selected from the group consisting of hydrogen, methyl or —CH═CH2;
• R1 and R3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;
• and pharmaceutically acceptable salts thereof.

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;
• R1 and R3 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;
• R2 is lower alkynyl;
• and pharmaceutically acceptable salts thereof.

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;
• R2 is lower alkynyl;
• R1 and R3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;
• and pharmaceutically acceptable salts thereof.

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;
• R2 is lower alkynyl;
• R1 and R3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;
• and pharmaceutically acceptable salts thereof.

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;
• R1 and R3 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;
• R2 is selected from the group consisting of lower alkyl lower alkenyl, and lower alkylenecycloalkyl;
• and pharmaceutically acceptable salts thereof.

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;
• R1 and R3 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;
• R2 is lower alkynyl;
• and pharmaceutically acceptable salts thereof.

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;
• R2 is lower alkynyl;
• R1 and R3 together with the nitrogen atom to which they are bound form an azetidinyl, pyrrolidinyl, or piperidinyl group;
• and pharmaceutically acceptable salts thereof.