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Claims for Patent: 5,565,473

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Claims for Patent: 5,565,473

Title: Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists
Abstract:Compounds having the formula I: ##STR1## are leukotriene antagonists and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.
Inventor(s): Belley; Michel L. (Pierrefonds, CA), Leger; Serge (Dollard des Ormeaux, CA), Labelle; Marc (Ville d'Ile Perrot, CA), Roy; Patrick (Pierrefonds, CA), Xiang; Yi B. (Pierrefonds, CA), Guay; Daniel (Montreal, CA)
Assignee: Merck Frosst Canada, Inc. (Kirkland, CA)
Application Number:08/392,592
Patent Claims: 1. A compound of the formula: ##STR15## wherein: R.sup.1 is H, halogen, --CF.sub.3, --CN, --NO.sub.2, or N.sub.3 ;

R.sup.2 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, --CH.sub.2 F, --CHF.sub.2, CH.sub.2 CF.sub.3, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or two R.sup.2 groups joined to the same carbon to form a carbocyclic ring of up to 8 members;

R.sup.3 is H or R.sup.2 ;

R.sup.4 is halogen, --NO.sub.2, --CN, --OR.sup.3, --SR.sup.3, NR.sup.3 R.sup.3, NR.sup.3 C(O)R.sup.7 or R.sup.3 ;

R.sup.5 is H, halogen, --NO.sub.2, --N.sub.3, --CN, --SR.sup.2, --NR.sup.3 R.sup.3, --OR.sup.3, lower alkyl, or --C(O)R.sup.3 ;

R.sup.6 is --(CH.sub.2).sub.s --C(R.sup.7 R.sup.7)--(CH.sub.2).sub.S --R.sup.8 or --CH.sub.2 C(O)NR.sup.12 R.sup.12 ;

R.sup.7 is H or C.sub.1 -C.sub.4 alkyl;

R.sup.8 is the radical W--R.sup.9 ;

R.sup.9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclic or monocyclic carboxylic acid;

R.sup.11 is lower alkyl, --C(O)R.sup.14, unsubstituted phenyl, or unsubstituted benzyl;

R.sup.12 is H, or R.sup.11 ;

R.sup.13 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

R.sup.14 is H or R.sup.13 ;

R.sup.16 is H, C.sub.1 -C.sub.4 alkyl, or OH;

R.sup.17 is lower alkyl, lower alkenyl, lower alkynyl, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

R.sup.18 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

R.sup.19 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3 or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

R.sup.21 is H or R.sup.17 ;

R.sup.22 is R.sup.4, CHR.sup.7 OR.sup.3, or CHR.sup.7 SR.sup.2 ;

m is 0-8;

m' is 2 or 3;

n and n' are independently 0 or 1,

p and p' are independently 0-8;

m+n+p is 1-10 when r is 1 and X.sup.2 is O, S, S(O), or S(O).sub.2 ;

m+n+p is 0-10 when r is 1 and X.sup.2 is CR.sup.3 R.sup.16 ;

m+n+p is 0-10 when r is 0;

m'+n'+p' is 2-10;

r and r' are independently 0 or 1;

s is 0-3;

Q.sup.1 is --C(O)OR.sup.3, 1H (or 2H)-tetrazol-5-yl, --C(O)OR.sup.6, --C(O)NHS(O).sub.2 R.sup.13, --CN, --C(O)NR.sup.12 R.sup.12, NR.sup.21 S(O).sub.2 R.sup.13, --NR.sup.12 C(O)NR.sup.12 R.sup.12, --NR.sup.21 C(O)R.sup.18, --OC(O)NR.sup.12 R.sup.12, --C(O)R.sup.19, --S(O)R.sup.18, --S(O).sub.2 R.sup.18, --S(O).sub.2 NR.sup.12 R.sup.12, --NO.sub.2, --NR.sup.21 C(O)OR.sup.17, --C(NR.sup.12 R.sup.12).dbd.NR.sup.12, --C(R.sup.13).dbd.NOH;

Q.sup.2 is OH;

W is O, S, or NR.sup.3 ;

X.sup.2 and X.sup.3 are independently O, S, S(O), S(O).sub.2, or CR.sup.3 R.sup.16 ; with the proviso that at least one is S or SO.sub.2 ;

Y is --CR.sup.3 .dbd.CR.sup.3 --

Z.sup.1 and Z.sup.2 are independently --HET(--R.sup.3 --R.sup.5)--;

HET is the diradical of a benzene, a pyridine, a furan, or a thiophene;

and the pharmaceutically acceptable salts thereof.

2. A compound of claim 1 wherein:

R.sup.1 is H, halogen, CF.sub.3 or --CN;

R.sup.2 is C.sub.1 -C.sub.4 alkyl, --CF.sub.3, --CHF.sub.2, --CH.sub.2 F, or two R.sup.2 groups joined to the same carbon to form a ring of up to 6 carbons;

R.sup.3 is H or R.sup.2 ;

R.sup.4 is --OR.sup.3, --SR.sup.3, NR.sup.3 R.sup.3, NHC(O)CH.sub.3, or R.sup.3 ;

R.sup.5 is H or halogen;

R.sup.6 is --(CH.sub.2).sub.S --C(R.sup.7 R.sup.7)--(CH.sub.2).sub.S --R.sup.8 or --CH.sub.2 C(O)NR.sup.12 R.sup.12 ;

R.sup.7 is H or C.sub.1 -C.sub.4 alkyl;

R.sup.8 is the radical W--R.sup.9 ;

R.sup.9 contains up to 20 carbon atoms and is (1) an alkyl group or (2) an alkylcarbonyl group;

R.sup.11 is lower alkyl, --C(O)R.sup.14, unsubstituted phenyl, or unsubstituted benzyl;

R.sup.12 is H, or R.sup.11 ;

R.sup.13 is lower alkyl, --CF.sub.3, or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

R.sup.14 is H or R.sup.13 ;

R.sup.16 is H, C.sub.1 -C.sub.4 alkyl, or OH;

R.sup.22 is R.sup.4, --CH.sub.2 OR.sup.3, or --CH.sub.2 SR.sup.2 ;

m is 0-4;

m' is 2 or 3;

n and n' are independently 0 or 1;

p and p' are independently 0-4;

m+n+p is 1-9 when r is 1 and X.sup.2 is O or S;

m+n+p is 0-9 when r is 1 and X.sup.2 is CR.sup.3 R.sup.16 ;

m+n+p is 0-9 when r is 0;

m'+n'+p' is 2-9;

r and r' are independently 0 or 1;

s is 0-3;

Q.sup.1 is --C(O)OR.sup.3, 1H (or 2H)-tetrazol-5-yl, --C(O)OR.sup.6, --C(O)NHS(O).sub.2 R.sup.13, --C(O)NR.sup.12 R.sup.12, --NHS(O).sub.2 R.sup.13 ;

Q.sup.2 is OH;

W is O, S, or NH;

X.sup.2 and X.sup.3 are independently O, S, or CR.sup.3 R.sup.16 ; with the proviso that at least one is S;

Y is (E)--CH.dbd.CH--;

Z.sup.1 and Z.sup.2 are independently --HET(--R.sup.3 --R.sup.5)--;

HET is the diradical of a benzene, pyridine, furan, or thiophene;

and the pharmaceutically acceptable salts thereof.

3. A compound of claim 1 wherein the R.sup.22 .alpha. to Q.sup.1 is lower alkyl, CF.sub.3 or substituted or unsubstituted phenyl.

4. A compound of claim 1 of the Formula Ia: ##STR16## wherein: R.sup.1 is H, halogen, CF.sub.3, or CN;

R.sup.22 is R.sup.3, --CH.sub.2 OR.sup.3, or --CH.sub.2 SR.sup.2 ;

Q.sup.1 is --C(O)OH, 1H (or 2H)-tetrazol-5-yl, --C(O)NHS(O).sub.2 R.sup.13, --C(O)NR.sup.12 R.sup.12, or --NHS(O).sub.2 R.sup.13 ;

m' is 2 or 3;

p' is 0 or 1;

m+p is 1-5;

and the pharmaceutically acceptable salts thereof.

5. A compound of claim 4 wherein the carbon .alpha. to Q.sup.1 is lower alkyl-substituted.

6. A compound of claim 1 of the Formula Ib: ##STR17## wherein: R.sup.1 is H, halogen, CF.sub.3, or CN;

R.sup.22 is R.sup.3, --CH.sub.2 OR.sup.3, or --CH.sub.2 SR.sup.2 ;

Q.sup.1 is --C(O)OH, 1H (or 2H)-tetrazol-5-yl, --C(O)NHS(O).sub.2.sup.R.sup.13, --C(O)NR.sup.12 R.sup.12, or --NHS(O).sub.2 R.sup.13 ;

m is 0, 2 or 3;

p is 0 or 1;

p' is 2-4;

m+p is 0-4;

and the pharmaceutically acceptable salts thereof.

7. A compound of claim 1 of Formula I' ##STR18## wherein the substituents are as follows:

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

9. The pharmaceutical composition of claim 8 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene bisynthesis inhibitors; H.sub.2 -receptor antagonists; antihistaminic agents; prostaglandin antagonists; thromboxane antagonists; thromboxane synthetase inhibitors; and ACE antagonists.

10. A pharmaceutical composition of claim 9, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

11. A pharmaceutical composition of claim 10, wherein the weight ratio of said compound of claim 1 to said second active ingredient ranges from about 1000:1 to 1:1000.

12. A method of preventing the synthesis, the action, or the release of SRS-A or leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of claim 1.

13. The method of claim 12 wherein the mammal is man.

14. A method of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

15. A method of treating inflammatory deseases of the eye in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

16. The method of claim 15 wherein the mammal is man.

17. A compound of Formula I' ##STR19## wherein the substituents are as follows:

18. 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy- 2 -propyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.

19. Sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-p ropyl)phenyl)propyl)thio)methyl) cyclopropaneacetate.

20. A pharmaceutical composition comprising a pharmaceutical carrier and dispersed therein a therapeutically effective amount of a compuond of claim 18 and a pharmaceutically acceptable carrier.

21. A method of preventing the action of leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of claim 18.

22. A method of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective mount of a compound of claim 18.

23. A method of treating inflammatory diseases in the eye in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective mount of a compound of claim 18.
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