2-carbocyclic and 2-heterocyclic quinoline-4-carboxylic acids and salts thereof useful as immunosuppressive agents

• US 5,578,609 A
• Filed: 08/03/1995
• Issued: 11/26/1996
• Est. Priority Date: 03/25/1994
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: The Dupont Merck Pharmaceutical Company
• Inventors: Batt, Douglas G., Petraitis, Joseph J., Sherk, Susan R.
• Primary Examiner(s): Springer, David B.
• Application Number:
  US08/510,933
• Time in Patent Office: 481 Days
• Field of Search: 546/167, 546/170, 514/314, 514/311
• US Class Current: 514/314
• CPC Class Codes: C07D 215/52 with aryl radicals attached in position 2
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention relates to 2-carbocyclic and 2-heterocyclic quinoline-4-carbocyclic acid compounds, and salts thereof, to pharmaceutical compositions comprising such compounds, and to methods of using such compounds for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal.

Claims

1. A compound of Formula I ##STR27## or pharmaceutically acceptable salts or prodrug forms thereof wherein:

A is selected from;

##STR28## X is --N(R⁷)--, --O--, --S--, or --CH═

CH--;

Y is --N-- or --C(R⁸)--;

Z is --C(R⁸)(R⁹)--;

R¹ and R² are independently selected from H, Cl, Br, F, CF₃, or C₁ -C₄ alkyl;

R³ is selected from hydrogen, C₁ -C₃ alkyl, --CN, --NR⁸ R⁹, --OR⁸, --SR⁸, --CF₃, --OCF₃, --SCF₃ ;

R⁴ is selected from hydrogen, Cl, F, C₁ -C₃ alkyl, --OR^8a, --CF₃, --OCF₃, --SR^8a, --SCF₃, --NR⁸ R⁹ ;

R⁵ is an aryl or heteroaryl selected from phenyl, thienyl, furyl, pyridinyl, thiazolyl, or oxazolyl, said aryl or heteroaryl being optionally substituted with 0-2 R¹¹ ;

R⁶ and R^6a are independently selected from hydrogen or C₁ -C₃ alkyl;

R⁷, R⁸, and R⁹ are independently selected from hydrogen or C₁ -C₃ alkyl;

R^8a is C₁ -C₃ alkyl;

R⁸ and R⁹ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂ CH₂ N(R¹⁰)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R¹⁰ is hydrogen or methyl;

R¹¹ is selected from hydrogen, Cl, F, C₁ -C₃ alkyl, --OR^8a, --CF₃, --OCF₃, --SR^8a, --SCF₃, --NR⁸ R⁹.

6. A method of treating a skin or muco-epithelial disease in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of claim 1.

7. A topical pharmaceutical composition comprising a carrier suitable for topical formulation and a therapeutically effective amount of a compound of claim 1.

8. A method of treating a tumor or a leukemia in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of claim 1.

2. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to a mammal in need of such treatment using a therapeutically effective amount of a compound of Formula I:

##STR29## or pharmaceutically acceptable salts or prodrug forms thereof wherein;

A is selected from;

##STR30## X is --N(R⁷)--, --O--, --S--, or --CH═

CH--;

Y is --N-- or --C(R⁸)--;

Z is --C(R⁸)(R⁹)--;

R¹ and R² are independently selected from H, Cl, Br, F, CF₃, or C₁ -C₄ alkyl;

R³ is selected from hydrogen, C₁ -C₃ alkyl, --CN, --NR⁸ R⁹, --OR⁸, --SR⁸, --CF₃, --OCF₃, --SCF₃ ;

R⁴ is selected from hydrogen, Cl, F, C₁ -C₃ alkyl, --OR^8a, --CF₃, --OCF₃, --SR^8a, --SCF₃, --NR⁸ R⁹ ;

R⁵ is an aryl or heteroaryl selected from phenyl, thienyl, furyl, pyridinyl, thiazolyl, or oxazolyl, said aryl or heteroaryl being optionally substituted with 0-2 R¹¹ ;

R₆ and R^6a are independently selected from hydrogen or C₁ -C₃ alkyl;

R⁷, R⁸, and R⁹ are independently selected from hydrogen or C₁ -C₃ alkyl;

R^8a is C₁ -C₃ alkyl;

R⁸ and R⁹ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂ CH₂ N(R¹⁰)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R¹⁰ is hydrogen or methyl;

R¹¹ is selected from hydrogen, Cl, F, C₁ -C₃ alkyl, --OR^8a, --CF₃, --OCF₃, --SR^8a, --SCF₃, --NR⁸ R⁹.

3. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Formula II:

##STR31## or a pharmaceutically acceptable salt form thereof, wherein;

X is --NR⁷ -- or --CH═

CH--;

Y is --C(R⁸)-- or --N--;

Z is --C(R⁸)(R⁹)--

R₁ is F or CF₃ ;

R₃ is hydrogen or methyl;

R₄ is hydrogen;

R⁵ is phenyl substituted with 0-2 R¹¹ ;

R₆ and R^6a are both hydrogen;

R₈ is H or CH₃ ;

R¹¹ is hydrogen, methyl, --OCH₃, --F or --CF₃.

4. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of ##STR32## or a pharmaceutically acceptable salt form thereof, wherein:

A is selected from;

##STR33## X is --NR⁷ -- or --CH═

CH--;

Y is --C(R⁸)-- or --N--;

Z is --C(R⁸)(R⁹)--

R¹ is F or CF₃ ;

R³ is hydrogen or methyl;

R⁴ is hydrogen;

R⁵ is phenyl, 2-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl;

R⁶ and R^6a are both hydrogen;

R⁸ is H or CH₃ ;

R¹¹ is hydrogen, methyl, --OCH₃, --F or --CF₃.

5. A method of treating organ transplantation rejection, graft versus host disease, psoriasis, rheumatoid arthritis, autoimmune diseases, or chronic inflammatory diseases in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound selected from the following:

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-2-[4-(2-fluorophenyl)-1-indolinyl]-3-methylquinoline-4-carboxylic acid, sodium salt,

6-fluoro-[4-(2-methoxyphenyl)-1-indolinyl]-3-methylquinoline-4-carboxylic acid, sodium salt,

6-fluoro-3-methyl-2-[4-(2-methylphenyl)-1-indolinyl]-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-[4-(3-methoxyphenyl)-1-indolinyl]-3-methylquinoline-4-carboxylic acid, sodium salt,

6-fluoro-3-methyl-2-[4-(3-trifluoromethylphenyl)-1-indolinyl]-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-2-[4-(2-methylphenyl)-1-indolinyl]-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-2-[4-(3-trifluoromethylphenyl)-1-indolinyl]-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolyl)-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, diethanolamine salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, N-methyl-D-glucamine salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, procaine salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, lysine salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, choline salt,

6-fluoro-3-methyl-2-(4-phenyl-1-indolinyl)-quinoline-4-carboxylic acid, tris-(hydroxymethyl)aminomethane salt,

6-fluoro-3-methyl-2-(5-phenyl-1-naphthyl)-quinoline-4-carboxylic acid, sodium salt,

6-fluoro-3-methyl-2-(7-phenyl-1-methyl-3-indolyl)-quinoline-4-carboxylic acid, sodium salt,

3-methyl-2-(7-phenyl-1-methyl-3-indolyl)-6-trifluoromethylquinoline-4-carboxylic acid, sodium salt,

6-fluoro-3-methyl-2-(6-fluoro-4-phenyl-1-benzimidazolyl)-quinoline-4-carboxylic acid.