# US 5,350,744 A · Phenylnaphthalene lactones as inhibitors of leukotriene biosynthesis

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- Number: US 5,350,744 A
- Document ID: US5350744A
- Status: Granted
- Kind: A
- Application number: 07/937,078
- Filed: 1992-08-27
- Granted: 1994-09-27
- Earliest claimed: 1992-08-27
- Assignees: Merck Frosst Canada, Inc.
- Inventors: Yves Girard; Pierre Hamel
- Web page: https://patentgrep.com/patent/US5350744A

## CPC

- C07D 405/14: containing three or more hetero rings
- A61K 31/365: Lactones
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 493/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Compounds having the formula I: ##STR1## are 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 and in preventing the formation of atherosclerotic plaques.

## Claims

### Claim 1

A compound of the formula: ##STR17## wherein: R.sup.1,R.sup.5, and R.sup.11 is each independently H, OH, lower alkyl, or lower alkoxy;
R.sup.2 is H, lower alkyl, or together with R.sup.1 forms a double bonded oxygen (.dbd.O);
R.sup.3 is H, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, or is joined to R.sup.1 to form a carbon bridge of 2 or 3 carbon atoms or a mono-oxa carbon bridge of 1 or 2 carbon atoms, said bridge optionally containing a double bond;
R.sup.4, R.sup.12, and R.sup.14 is each independently H or lower alkyl;
R.sup.6 is H or lower alkyl, or two R.sup.6 groups on the same or adjacent carbons can form a saturated ring of 3 to 8 members;
R.sup.7 is H, OH, lower alkyl, lower alkoxy, lower alkylthio, or lower alkylcarbonyloxy;
R.sup.8 is H, halogen, lower alkyl, lower alkoxy, CF.sub.3, CN, COR.sup.14, or a non-bonded electron pair;
R.sup.9 and R.sup.10 is each independently H, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylthio lower alkylcarbonyl, (R.sup.8)2-phenylthio lower alkyl, halogen, CN, NO.sub.2, CF.sub.3, N.sub.3, N(R.sup.13).sub.2, NR.sup.13 COR.sup.14, NR.sup.13 CON(R.sup.13).sub.2, SR.sup.15, S(O)R.sup.15, S(O).sub.2 R.sup.15, S(O).sub.2 N(R.sup.13).sub.2, COR.sup.14, CON(R.sup.13).sub.2, CO.sub.2 R.sup.14, C(R.sup.14).sub.2 OC(R.sup.14).sub.2 -CO.sub.2 R.sup.14, or C(R.sup.14).sub.2 CN;
R.sup.10 is attached to either ring of the naphthalene ring system; R.sup.13 is H, or lower alkyl, or two R.sup.13 groups attached to the same nitrogen may form a saturated ring of 5 or 6 members, optionally containing a second heteroatom chosen from O, S or NR.sup.4 ;
R.sup.15 is lower alkyl, phenyl-(R.sup.8).sub.2, or CF.sub.3 ;
X.sup.1 is O;
X.sup.2 is C(R.sup.6).sub.2 ;
X.sup.3 is C(R.sup.6).sub.2 O;
Ar is phenyl(R.sup.9).sub.2 ;
Het is pyridyl-(R.sup.8).sub.2 and
m is 1;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1 of the formula: ##STR18## or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound of claim 1 of the formula: ##STR19## wherein: R.sup.1 is H, Me, or OMe;
R.sup.3 is H or Me;
R.sup.1 and R.sup.3 together are --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, --OCH.sub.2 --, or --CH.sub.2 O--;
R.sup.7 is OH or OMe; and
Het is 5,3-Pye; 6,2-Pye; 4,2-Pye, or 2,4-Pye;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

A compound of claim 3 of the formula: ##STR20## wherein the substituents are as follows:
______________________________________ EX R.sup.1 R.sup.3 R.sup.7 Het ______________________________________ 1 H H OH 5,3-Pye 2 H H OMe 5,3-Pye 3 H H OH 6,2-Pye 4 H H OMe 6,2-Pye 5 H H OH 4,2-Pye 6 H H OMe 4,2-Pye 7 --CH.sub.2 O-- OH 5,3-Pye 8 --CH.sub.2 O-- OMe 5,3-Pye 9 --CH.sub.2 O-- OH 6,2-Pye 10 --CH.sub.2 O-- OMe 6,2-Pye 11 --CH.sub.2 O-- OH 2,4-Pye 12 --CH.sub.2 O-- OMe 2,4-Pye ______________________________________

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 5)

A pharmaceutical composition of claim 5 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steriodal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; H.sub.1 - or H.sub.2 -receptor antagonists; antihistaminic agents; prostaglandin antagonists; thromboxane antagonists; thromboxane synthetase inhibitors; and ACE antagonists.

### Claim 7 (depends on 6)

A pharmaceutical composition of claim 6, wherein the second active ingredient is a non-steriodal anti-inflammatory drug.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, an effective amount of a second active ingredient which is a non-steriodal anti-inflammatory drug, and a pharmaceutically acceptable carrier, wherein the weight ratio of said compound of claim 1 to said second active ingredient ranges from about 1000:1 to 1:1000.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 9)

A method of claim 9 wherein the mammal is man.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 1)

A method of treating inflammatory diseases 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.

### Claim 13 (depends on 12)

The method of claim 12 wherein the mammal is man.