Acyl and alkoxy substituted quinolines

• US 5,378,694 A
• Filed: 03/01/1993
• Issued: 01/03/1995
• Est. Priority Date: 09/07/1990
• Status: Expired due to Fees

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Rosenblum, Stuart B., Weinstein, Jay, Afonso, Adriano, Gentles, Margaret J.
• Primary Examiner(s): Daus, Donald G.
• Application Number:
  US07/983,519
• Time in Patent Office: 673 Days
• Field of Search: 514/63, 514/312, 514/82, 546/14, 546/25, 546/155, 546/156
• US Class Current: 514/82
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 311/16 substituted in position 7
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 9/60 Quinoline or hydrogenated quinoline ring systems

Abstract

Compounds useful as antiviral agents against DNA-containing viruses, such as herpes group viruses, are disclosed. The compounds are are represented by compounds of Formula 1.0: ##STR1## and their pharmaceutically acceptable salts and solvates. Pharmaceutical compositions containing compounds represented by Formula 1.0 and methods of treating a viral infection using compounds represented by Formula 1.0 are disclosed.

Also disclosed are compounds useful as antihypertensive agents and methods of treating hypertension using such compounds. The antihypertensive agents are compounds represented by Formula 1.0 wherein R⁴ is selected from the group consisting of alkyl and aminoalkyl. Preferably R¹ is H.

Claims

1. A compound of Formula 1.0:

##STR27## and the pharmaceutically acceptable salts and solvates thereof wherein;

(B) R³ is selected from the group consisting of;

(1) alkyl;

(2) --CH₂ -phenyl;

(3) phenyl;

(4) substituted phenyl;

(7) 3-(2-chloro-4-methoxyphenoxypropyloxymethyl;

(8) --(CH₂)_a R¹¹ wherein a is an integer of 1 to 6 and R¹¹ is selected from the group consisting of --C(O)OR¹², --OR¹², R¹², and --N(R¹²)₂, wherein each R¹² can be the same or different and is selected from the group consisting of alkyl, alkenyl and H; and

(9) --OR¹³ wherein R¹³ is selected from the group consisting of H, alkyl- which may be substituted with OH, SH, NH₂ and/or halogen -, alkenyl;

(C) R¹ is

(1) H;

(2) alkyl;

(5) alkenyl;

(D) Each R² for each m is independently selected from the group consisting of;

(1) alkyl;

(2) alkoxy;

(3) phenoxy;

(4) phenyl

(5) --O--CH₂ -phenyl;

(6) halogen atoms selected from the group consisting of F, Cl, Br and I;

(7) --O--CO--R⁶ wherein R⁶ is alkyl- which may be substituted with OH, SH, NH₂ and/or halogen -;

phenyl; and

alkenyl;

(8) --N(R⁷)₂ wherein each R⁷ is independently selected from the group consisting of H, alkyl, phenyl, and R⁶ C(O)-- wherein R⁶ is as above defined;

(9) --OH;

(10) --CH₂ OH;

(11) --COOH;

(12) --COOR⁸, wherein R⁸ is selected from the group consisting of alkyl and phenyl;

(13) --SO₃ H;

(14) --SO₂ NHR⁹, wherein R⁹ is selected from the group consisting of alkyl, phenyl, and H;

(15) --PO₃ H;

(16) --PO(OR¹⁰)₂, wherein R¹⁰ is selected from the group consisting of alkyl and phenyl;

(17) --OPO₃ H;

(18) --OP(OR¹⁰)₂ wherein R¹⁰ is as above defined; and

(19) --CF₃ ;

(E) m is an integer from 0 to 1; and

(F) R⁴ is selected from the group consisting of H, aminoalkyl and hydroxyalkyl

and wherein

acyl represents alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, phenyl-C(O)- or cycloalkenyl-C(O)-;

alkaryl represents an phenyl group, as defined below, in which an alkyl group, as defined below, is substituted for one of the phenyl H atoms;

alkenyl represents straight and branched aliphatic hydrocarbon groups having 1 bond and having from 2 to 6 carbon atoms;

alkoxy represents an alkyl radical attached to a molecule through an oxygen atom (-O-alkyl);

alkyl represents straight or branched saturated hydrocarbon groups which have from 1 to 6 carbon atoms;

aminoalkyl represents NH₂ -alkyl, alkyl-NH₂ -alkyl, (alkyl)₂ NH₂ -alkyl;

cycloalkenyl represents a carbocyclic ring having from 5 to 7 carbon atoms and one carbon-to-carbon double bond in the ring;

cycloalkyl represents a saturated carbocyclic ring having from 3 to 7 carbon atoms;

hydroxyalkyl represents an alkyl group wherein one or two hydroxy groups is substituted for one or two hydrogen atoms; and

substituted alkyl represents an alkyl group, as defined above, wherein one of the alkyl H atoms is replaced with a group selected from the group consisting of alkyl, aryl, heteroaryl,--OH, --O-alkyl, --NH₂, --N(alkyl)₂ wherein each alkyl group is the same or different, --SH, --S-alkyl, --C(O)O-alkyl, --C(O)H, --NHC(;

NH)NH₂, --C(O)NH₂, --OC(O)NH₂, NO₂ and --NHC(O)-alkyl, wherein alkyl, aryl, and heteroaryl are as above defined.

2. A compound of claim 1 wherein R² is selected from the group consisting of:

(1) --CH₃ ;

(2) --OCH₃ ;

(3) --OCOCH₃ ;

(4) --OCH₂ -phenyl;

(5) Cl;

(6) F;

(7) I; and

(8) --CF₃.

3. A compound of claim 1 wherein R³ is selected from the group consisting of:

(1) --CH₃ ;

(2) --C₆ H₁₃ ;

(3) --C₇ H₁₅,

(4) --CH₂ -phenyl;

(6) phenyl;

##STR28## (8) --CH₂ CO₂ CH₂ CH═

CH₂ ; and

(9) --CH₂ CO₂ CH₃.

4. A compound of claim 3 wherein:

(A) X is NR³ ;

(C) R² is selected from the group consisting of;

(1) --CH₃ ;

(2) --OCH₃ ;

(3) --OCOCH₃ ;

(4) --OCH₂ -phenyl;

(5) Cl;

(6) F;

(7) I; and

(8) --CF₃ ; and

m is 0, 1 or 2;

(D) R³ is selected from the group consisting of;

(1) --CH₃ ;

(2) --C₆ H₁₃ ;

(3) --C₇ H₁₅ ;

(4) --CH₂ -phenyl;

(6) phenyl;

##STR29## (8) --CH₂ CO₂ CH₂ CH═

CH₂ ; and

(9) --CH₂ CO₂ CH₃ ; and

R⁴ is --O(CH₂)₂ N(CH₃)₂.

5. The compound of claim 1 wherein R⁴ is an aminoalkyl group.

6. The compound of claim 5 wherein R⁴ is --(CH₂)₂ N(CH₃)₂.

7. The compound of claim 6 R² is alkyl.

8. The compound of claim 7 wherein R² is --CH₃.

11. The compound of claim 1 wherein:

(B) R¹ is selected from the group consisting of H and alkyl;

(C) R² is --CH₃ and m is 0 or 1;

(D) R³ is selected from the group consisting of;

(1) --C₆ H₁₃ ;

(2) --C₇ H₁₅ ; and

(3) --CH₂ -phenyl; and

(E) R⁴ is --O(CH₂)₂ N(CH₃)₂.

12. The maleate salt of a compound of claim 1 wherein R⁴ is --O(CH₂)₂ N(CH₃)₂.

13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method of treating hypertension in a patient in need of such treatment comprising administering to such patient an effective antihypertensive amount of a compound of claim 5.

9. A compound selected from the group consisting of ##STR30##

10. A compound selected from the group consisting of ##STR31##