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Details for Patent: 5,856,322

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Details for Patent: 5,856,322

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. (St. Laurent, CA), Leger; Serge (Dollard des Ormeaux, CA), Roy; Patrick (Pierrefonds, CA), Labelle; Marc (Ville d'Ile Perrot, CA), Xiang; Yi Bin (Pierrefonds, CA), Guay; Daniel (Montreal, CA)
Assignee: Merck Frosst Canada, Inc. (Kirkland, CA)
Filing Date:Feb 08, 1996
Application Number:08/598,758
Claims:1. A pharmaceutical composition comprising an effective amount of a H.sub.1 -receptor antagonist and an effective amount of a second compound of the formula: ##STR11## 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 may form a ring of up to 8 members containing 0-2 heteroatoms chosen from O, S, and N;

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 A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S or O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or B) 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 containing not more than 1 heteroatom in the ring;

R.sup.10 is --SR.sup.11, OR.sup.12, or --NR.sup.12 R.sup.12 ;

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

R.sup.12 is H.sub.1 R.sup.11, or two R.sup.12 groups joined to the same N may form a ring of 5 or 6 members containing 1-2 heteroatoms chosen from O, S, and N;

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.20 is H, C.sub.1 -C.sub.4 alkyl, substituted or unsubstituted phenyl, benzyl, phenethyl, or pyridinyl or two R.sup.20 groups joined to the same N may form a saturated ring of 5 or 6 members containing 1-2 heteroatoms chosen from O, S, and N;

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 and m' are independently 0-8;

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 0-10;

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; or if Q.sup.1 is --C(O)OH and R.sup.22 is --OH, --SH, --CHR.sup.7 OH or --NHR.sup.3, then Q.sup.1 and R.sup.22 and the carbons through which they are attached may form a heterocyclic ring by loss of water;

Q.sup.2 is OH or NR.sup.2 OR.sup.20 ;

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 ;

Y is --CR.sup.3 .dbd.CR.sup.3 -- or --C.tbd.C;

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;

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition 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 may form a ring of up to 6 carbons;

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

CR.sup.3 R.sup.22 may be the radical of a standard amino acid;

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)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 A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S or O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or B) 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.10 is --SR.sup.11, --OR.sup.12, or --NR.sup.12 R.sup.12 ;

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

R.sup.12 is H, R.sup.11, or two R.sup.12 groups joined to the same N may form a ring of 5 or 6 members containing 1-2 heteroatoms chosen from O, S, and N;

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 and m' are independently 0-4;

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 1-9;

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 ; or if Q.sup.1 is C(O)OH and R.sup.22 is --OH, --SH, --CH.sub.2 OH or --NHR.sup.3 then Q.sup.1 and R.sup.22 and the carbons through which they are attached may form a heterocyclic ring by loss of water;

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 ;

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;

or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition 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. The pharmaceutical composition of claim 1 wherein the second compound has Formula Ia: ##STR12## 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 2or 3;

p' is 0 or 1;

m+p is 1-5;

or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4 wherein p' is 0.

6. The pharmaceutical composition of claim 4 wherein the carbon .alpha. to Q.sup.1 is lower alkyl-substituted.

7. The pharmaceutical composition of claim 4 wherein the second compound has Formula Ib: ##STR13## 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 0, 2 or 3;

p is 0 or 1;

p' is 1-4;

m+p is 0-4;

and the pharmaceutically acceptable salts thereof.

8. The pharmaceutical composition of claim 1 wherein the second compound has Formula I.sup.1 ##STR14## wherein the substiutents are as follows:

9. The pharmaceutical composition of claim 8 wherein the second compound is the R-enantiomer,

R1 is 7-Cl, Y is --CH.dbd.CH--, A is SCH.sub.2 (1,1-C-Pr)CH.sub.2 CO.sub.2 H and

B is (CH.sub.2).sub.2 (1,2-phe)CMe.sub.2 OH.

10. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 7, either concurrently in separate formulations or combined as claimed in claim 7.

11. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second nd defined in claim 2, either concurrently in separate formulations or combined as claimed in claim 2.

12. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 3, either concurrently in separate formulations or combined as claimed in claim 3.

13. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 4, either concurrently in separate formulations or combined as claimed in claim 4.

14. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 5, either concurrently in separate formulations or combined as claimed in claim 5.

15. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 6, either concurrently in separate formulations or combined as claimed in claim 6.

16. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 7, either concurrently in separate formulations or combined as claimed in claim 7.

17. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 8, either concurrently in separate formulations or combined as claimed in claim 8.

18. A method of treating asthma, allergy and inflammation in a patient in need of such treatment by the administration of an effective amount of a H.sub.1 -receptor and an effective amount of a second compound defined in claim 9, either concurrently in separate formulations or combined as claimed in claim 9.
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