Methotrexate derivatives

• US 6,559,149 B1
• Filed: 07/12/1994
• Issued: 05/06/2003
• Est. Priority Date: 01/27/1992
• Status: Expired due to Fees

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Maruyama, Noriaki, Kuroki, Toshio, Nakagomi, Kazuya, Tsuji, Keiichiro, Suzuki, Hiroshi, Matsuoka, Hiroharu, Kato, Nobuaki
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/256,441
• Time in Patent Office: 3,220 Days
• Field of Search: 514/258, 514/249, 544/260
• US Class Current: 514/249
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 475/08 with a nitrogen atom directly attached in position 2

Abstract

Antirheumatic agent containing as an active ingredient a compound resented by the following general formula (II):

Claims

1. Compound represented by the formula (I)

wherein W is represented by

where R₁ is a straight chain lower alkyl group having 1-4 carbon atoms;

R₂ is a straight chain lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group;

R₃ is a hydrogen atom, a straight chain lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group;

R₄ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms;

R₅ is represented by the formula COOR₆ where R₆ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms, or R₅ is represented by the formula SO₃H; and

n is 3;

or

W is represented by

where R₁₅ is a lower alkyl group having 1-4 carbon atoms;

R₁₆ is a lower alkyl group having 1-4 carbon atoms, and K is 3.

2. A compound according to claim 1 wherein W is

3. A compound selected from the group consisting of:

Dimethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3-methyl}benzoyl-L-2-aminoadipate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3-methyl}benzoyl-L-2-aminoadipic acid;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3-trifluoromethyl}benzoyl-L-2-aminoadipic acid;

Dimethyl N-{1-[2,4-diamino-6-pteridinyl)methyl]-7-methylindoline-5-carbonyl}-L-2-aminoadipate;

N-{1-[2,4-diamino-6-pteridinyl)methyl]-7-methylindoline-5-carbonyl}-L-2-aminoadipic acid;

N-{1-[2,4-diamino-6-pteridinyl)methyl]indole-5-carbonyl}-L-2-aminoadipic acid;

N-{1-[2,4-diamino-6-pteridinyl)methyl]indole-5-carbonyl}-L-homocysteic acid ammonium salt;

N-{1-[2,4-diamino-6-pteridinyl)methyl]indole-5-carbonyl}-L-glutamic acid;

N-{1-[2,4-diamino-6-pteridinyl)methyl]7-methylindole-5-carbonyl}-L-2-aminoadipic acid;

Dimethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)

Dimethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl) methylamino]-3-methyl)benzoyl-L-2-aminoadipate; and

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methylamino]-3-methyl)benzoyl-L-2-aminoadipic acid.

4. A compound according to claim 3, selected from the group consisting of:

5. A method for treating rheumatism comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound represented by formula (II)

wherein W is represented by

where R₁ is a straight chain lower alkyl group having 1-4 carbon atoms;

R₂ is a straight chain lower alkyl group having 1-4 carbon atoms or a trifluoromethyl group;

R₃ is having 1-4 carbon atoms or a trifluoromethyl group;

R₄ is a hydrogen atoms or a lower alkyl group having 1-4 carbon atoms;

R₅ is a group represented by formula COOR₆ where R₅ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms or R₅ is a group represented by the formula SO₃H; and

n is an integer of 1-4, or W is represented by;

where R₇ is a lower alkyl group having 1-4 carbon atoms;

R₈ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms;

R₉ is a group represented by the formula COOR₁₀ where R₁₀ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms, or R₆ is a group represented by the formula SO₃H; and

m is an integer of 1-4, or W is represented by

where R₁₁ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms;

R₁₂ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms;

R₁₃ is a group represented by the formula COOR₁₄ where R₁₄ is a hydrogen atoms or a lower alkyl group having 1-4 carbon atoms, or R₁₃ is a group represented by the formula SO₃H and 1 is an integer of 1-4 or W is represented by

where R₁₅ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms;

R₁₆ is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; and

k is an integer of 2 or 3.

6. The method for treating rheumatism according to claim 5 with the proviso that, in said compound, R₁ is not lower alkyl when R₂ and R₃ are methyl, R₄ is hydrogen, n is 2 and R is COOH;

and R₁ is not lower alkyl when R₂ is methyl, R₃ and R₄ are each hydrogen, n is 2 and R₅ is COOH.

7. The method for treating rheumatism according to claim 5, wherein said compound is selected from the group consisting of:

Diethyl N-4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

methylamino]-3-methylbenzoyl-L-glutamate;

Dimethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3-methyl}benzoyl-L-2-aminoadipate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]3-methylbenzoyl}-L-glutamic acid;

Diethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-ethylamino]3-methylbenzoyl}-L-glutamate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

ethylamino]-3-methylbenzoyl}-L-glutamic acid;

Diethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-ethylamino]3-methylbenzoyl}-L-glutamate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-ethylamino]-3-methyl}benzoyl-L-glutamic acid;

Dimethyl N-}4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]3-methylbenzoyl}-L-2-aminoadipate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3-methyl}benzoyl-L-2-aminoadipic acid;

N-(4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

methylamino]-3-methylbenzoyl}-L-homocysteic acid ammonium salt;

Diethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]3-ethylbenzoyl}-L-glutamate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3-ethylbenzoyl}-L-glutamic acid;

Diethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3,5-dimethylbenzoyl}-L-glutamate;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

-methylamino]-3,5-dimethylbenzoyl}-L-glutamic acid;

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-N′

methylamino]-3-trifluoromethylbenzoyl}-L-2-aminoadipic acid;

Dimethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methyl-7-methylindoline-5′

carbonyl}-L-2-aminoadipate;

N-{1-[N′

-(2,4-diamino-6-pteridinyl)methyl-7-methylindoline-5′

carbonyl}-L-2-aminoadipic acid;

N-{1-[2,4-diamino-6-pteridinyl)methyl]indole-5-carbonyl}-L-aminoadipic acid;

N-{1-[2,4-diamino-6-pteridinyl)methyl]indole-5-carbonyl}-L-2-aminoadipic acid;

N-{1-[2,4-diamino-6-pteridinyl)methyl]indole-5′

carbonyl}-L-homocysteic acid ammonium salt;

N-{1-[(2,4-diamino-6-pteridinyl)methyl]indole-5′

carbonyl}-L-glutamic acid;

N-{1-[(2,4-diamino-6-pteridinyl)methyl-7-methylindole-5′

carbonyl}-L-2-aminoadipic acid;

Diethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methylamino]3-methyl}benzoyl-L-glutamate;

Dimethyl N-{4-[N′

-(2,4-diamino-6-pteridinyl)methylamino]-3-methyl}benzoyl-L-2-aminoadipate; and

N-{4-[N′

-(2,4-diamino-6-pteridinyl)methylamino]-3-methyl)benzoyl-L-2-aminoadipic acid.

8. A method for treating rheumatism according to claim 5 wherein said compound is selected from the group consisting of: