N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamides

• US 4,738,971 A
• Filed: 04/16/1985
• Issued: 04/19/1988
• Est. Priority Date: 03/03/1981
• Status: Expired due to Term

• Current Assignee: Pharmacia Biosystems AB (Pharmacia Corp.)
• Original Assignee: Aktiebolaset Leo
• Inventors: Stalhandske, Lars J. T., Sandberg, Eva B. M., Eriksoo, Edgar
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US06/723,746
• Time in Patent Office: 1,099 Days
• Field of Search: 546/155, 546/156, 546/157, 546/158, 514/312, 514/291
• US Class Current: 514/312
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: C07D 455/04 containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
• CPC Class Codes: C07D 471/06 Peri-condensed systems

Abstract

This invention relates to novel heterocyclic carboxamides which increase the activity of the immune system and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds and methods of treatment therewith.

Claims

1. A compound having the formula:

##STR11## or a tautomer thereof, wherein the groups A¹ and A² are interchanged and there is a 2,3- rather than a 3,4-double bond;

R¹, R² and R³ are independently

selected from the group consisting of;

hydrogen, lower alkyl, lower alkoxy, halogen, OH, OCOR⁸, NR⁶ R⁷, and NR⁶ COR⁸ ; and

where R¹ and R² or R² and R³ together may also be in the form of a methylenedixoy group; and

where only one of R¹, R², and R³ may be NO₂ ;

where R⁴ is selected from the group consisting of;

lower alkyl, lower alkenyl, cycloalkyl, optionally mono- or disubstituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, OH and OCOR⁸ ; and

phenyl, optionally mono- or disubstituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy and halogen; and

wherein R⁵ is selected from the group consisting of;

##STR12## wherein R⁹, R¹⁰, and R¹¹ are the same or different and selected from the group consisting of;

hydrogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, halogen, CN, SO₂ CH₃, OH, OCOR⁸, NR⁶ R⁷, NR⁶ COR⁸, COOR¹², OCH₂ COOR¹², CH₂ COOR¹², COR⁸, and ##STR13## wherein m is four or five; and

where R⁹ and R¹⁰ or R¹⁰ and R¹¹ together also may be in the form of a methylenedioxy group;

wherein A¹ is selected from the group consisting of OR¹², OCOR⁸, NR⁶ R⁷ and NR⁶ COR⁸ and A² is selected from the group consisting of O and NR⁶ ;

wherein R⁶ and R⁷ are selected from the group consisting of hydrogen and lower alkyl;

wherein R⁸ is lower alkyl;

wherein R¹² is selected from the group consisting of lower alkyl and M; and

wherein M is selected from the group consisting of hydrogen and pharmaceutically-acceptable inorganic and organic cations; and

wherein R¹³ is selected from the group consisting of hydrogen, lower alkyl, optionally substituted with a substituent selected from the group consisting of OH, OR⁸ and OCOR⁸, and lower alkenyl;

provided that R¹³ is selected from the group consisting of lower alkyl, optionally substituted with a substituent selected from the group consisting of OH, OR⁸ and OCOR⁸, and lower alkenyl when R⁵ is ##STR14## and R⁹, R¹⁰, and R¹¹ are selected from the group consisting of lower alkyl, lower alkenyl and lower alkoxy; and

addition salts with pharmaceutically-acceptable inorganic or organic acids;

the term "lower" when used herein meaning in each case that the group referred to may be straight or branched and contains one to four carbon atoms, inclusive.

2. A compound according to claim 1 characterized in that R¹³ is selected from the group consisting of lower alkyl optionally substituted or lower alkenyl, A¹ is OH and A² is O, and the R⁴ is lower alkyl.

3. A compound according to claim 1 characterized in that A¹ is selected from the group consisting of NR⁶ R⁷ and NR⁶ COR⁸, A² is O, R⁴ is lower alkyl and where R⁶, R⁷ and R⁸ have the meanings as defined above.

4. A compound according to claim 1 characterized in that R¹³ is hydrogen R⁵ is the group II as defined above wherein R⁹, R¹⁰ and R¹¹ are selected from the group consisting of halogen, OH, OCOR⁸, NR⁶ R⁷, NR⁶ COR⁸, ##STR15## COOR¹², OCH₂ COOR¹² and CH₂ COOR¹², where R⁶, R⁷, R⁸, R¹² and m have the meanings as defined above.

5. A compound according to claim 1 characterized in that at least two of the substituents R¹, R² and R³ are hydrogen and at least one of the substituents R⁹, R¹⁰ and R¹¹ is hydrogen.

6. A compound according to claim 1 selected from the group consisting of:

(a) N-(4-dimethylaminophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(b) N-(4-carboxymethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(c) N-(4-hydroxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(d) N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(e) N-methyl-N-phenyl-4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

(f) N-phenyl-1,2-dihydro-4-hydroxy-2-imino-1-methyl-quinoline-3-carboxamide

(g) N-methyl-N-phenyl-1,2-dihydro-6-dimethylamino-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(h) N-(4-methoxyphenyl)-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(i) N-(4-chlorophenyl)-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

(j) N-(2-hydroxyphenyl)-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

and said compounds (a)-(j) in the form of salts with pharmaceutically-acceptable inorganic or organic cations or addition salts with pharmaceutically-acceptable inorganic or organic acids.

7. A composition of matter suitable for enhancing immunity comprising as an active ingredient an effective immunizing amount of one or more of the compounds having the formula I as defined in claim 1 together with a pharmaceutically-acceptable carrier.

8. The composition of claim 7 wherein the active ingredient is a compound according to claim 6 present in an amount between about 0.05 and 15 percent by weight of the composition.

9. A compound according to claim 1 wherein R⁹, R¹⁰ and R¹¹ are the same or different and are selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxy lower alkylthio, CN, SO₂ CH₃, OH, OCOR⁸, NR⁶ R⁷, NR⁶ COR⁸, COOR¹², OCH₂ COOR¹², CH₂ COOR¹², COR⁸ and ##STR16## wherein m is four or five and where R⁹ and R¹⁰ and R¹⁰ and R¹¹ together also may be in the form of a methylenedioxy group.

10. A compound according to claim 1 selected from the group consisting of

(a) N-(4-dimethylaminophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

(b) N-(4-carboxymethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

(c) N-(4-hydroxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

(d) N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

(e) N-methyl-N-phenyl-4-amino-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

(f) N-phenyl-1,2-dihydro-4-hydroxy-2-imino-1-methyl-quinoline-3-carboxamide,

(g) N-methyl-N-phenyl-1,2-dihydro-6-dimethylamino-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

(h) N-(4-methoxyphenyl)-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

(i) N-(2-hydroxyphenyl)-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

and said compounds (a)-(i) in the form of salts with pharmaceutically-acceptable inorganic or organic cations or addition salts with pharmaceutically-acceptable inorganic or organic acids.

11. N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide.