US 4,933,351 AGrant

Benzofuran 2-Carbox Amides Useful as Inhibitors of Leukoriene Biosynthesis

Issue Date:1990-06-12

•5 Claims

Abstract

Compounds of the Formula I: ##STR1## and pharmaceutically acceptable salts thereof are inhibitors of leukotriene biosynthesis. These compounds inhibit the mammalian 5-lipoxygenase enzyme, thus preventing the metabolism of arachidonic acid to the leukotrienes. These compounds are thus useful in the treatment of asthma, allergic disorders, inflammation, skin diseases and certain cardiovascular disorders.

Metadata

Assignee

Merck Frosst Canada, Inc.

Inventors

Joseph G. Atkinson
Yvan Guindon
Cheuk K. Lau

Application Information

Application Number:US 3037843

Filing Date:1989-01-30

Priority Date:1983-10-31

Art Unit:121

Classifications

IPC:

A61K 3134C07D30785

Field of Search:

549546548514467;435196;269251337;382;466;469;320

Patent Drawings

This patent does not have any drawings.

Description

One embodiment of the present invention is a pharmaceutical composition containing a compound of the Formula I and an acceptable pharmaceutical carrier: ##STR2## wherein: Z is a bond, CR.sub.14 .dbd.CR.sub.15 or CHR.sub.14 --CHR.sub.15 ;

X is O, S, SO, or SO.sub.2 ;

R.sub.2 is H, OH, C.sub.1 to C.sub.20 alkoxy, including straight chain or branched chain, cycloalkyl, bicycloalkyl, tricycloalkyl or tetracycloalkyl;

Ar.sub.1 --C.sub.1 to C.sub.3 alkoxy;

NR.sub.8 Ar.sub.1, wherein R.sub.8 and Ar.sub.1 can optionally be joined to form a heterocyclic ring having 5 to 8 atoms;

--NR.sub.8 Het;

--N(R.sub.8)CH.sub.2 Ar.sub.1 ;

--N(R.sub.13)--N(R.sub.13).sub.2 wherein each R.sub.13 is independently hydrogen, R.sub.8, R.sub.9, Ar.sub.1 or Het;

--NH--CH.dbd.C(Ar.sub.1).sub.2 ;

--O(CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 2 to 4;

--Z--Ar.sub.1 ; ##STR3## lower acyloxy-lower alkoxy ##STR4## --CH.sub.2 OH; --(CH.sub.2).sub.n Ar.sub.1 wherein n is 0 to 3;

--(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 6;

C.sub.1 to C.sub.20 alkyl; Ar.sub.1 ; Het; (CH.sub.2).sub.n NR.sub.8 R.sub.9

wherein n is 1 to 3; or

Het; ##STR5## and R.sub.1, R.sub.3, R.sub.4, T and V are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH.sub.2).sub.n M wherein n is 0 to 6 except when X is S and M is OR.sub.5, in which case n is 1 to 6 and

M is

(a) --OR.sub.5 ;

(b) halogen;

(d) --SR.sub.5 ;

(e) Ar.sub.1 ;

(f) --COOR.sub.6 ;

(g) ##STR6## wherein R.sub.12 is H, C.sub.1 to C.sub.6 alkyl, or Ar.sub.1 ; (h) tetrazole; ##STR7## (m) --NR.sub.8 R.sub.9 ; (n) --NHSO.sub.2 R.sub.10 wherein R.sub.10 is OH, C.sub.1 to C.sub.6 alkyl, CF.sub.3, C.sub.1 to C.sub.6 -alkoxy, or Ar.sub.1 ; ##STR8## (p) --SOR.sub.5 ; (q) --CONR.sub.8 R.sub.9 ;

(r) --SO.sub.2 NR.sub.8 R.sub.9 ;

(s) --SO.sub.2 R.sub.5 ;

(t) --NO.sub.2 ; or

(u) --CN;

or any two of R.sub.3, R.sub.4, T and V may be joined to form a saturated ring having 5 or 6 ring atoms, said ring atoms comprising 0, 1 or 2 atoms selected from oxygen and sulfur, the remaining ring atoms being carbon;

each R.sub.5 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, Ar.sub.1, perfluoro-C.sub.1 to C.sub.4 alkyl, CH.sub.2 --R.sub.11 wherein R.sub.11 is C.sub.1 to C.sub.5 alkyldimethylamino, hydroxy-C.sub.2 to C.sub.5 alkyl, CH.sub.2 COOR.sub.6, or CH.sub.2 CO--R.sub.7 ;

each R.sub.6 is independently H or C.sub.1 to C.sub.6 alkyl;

each R.sub.7 is independently C.sub.1 to C.sub.6 alkyl, benzyl, Ar.sub.1, NR.sub.8 R.sub.9, NHAr.sub.1, or O--C.sub.1 to C.sub.4 alkyl;

each R.sub.8 and each R.sub.9 is independently H or C.sub.1 to C.sub.4 alkyl, or R.sub.8 and R.sub.9 may be joined through the N to which they are attached to form a heterocycloalkyl ring having 5 to 8 ring atoms;

each Het is independently an aromatic heterocyclic ring having 5 or 6 ring atoms, one or more of which are selected from N, O and S;

each Ar.sub.1 is independently 1- or 2- naphthyl, phenyl or mono- or disubstituted phenyl, wherein the substituents on the phenyl are independently selected from C.sub.1 to C.sub.3 alkyl, I, Br, Cl, F, COOR.sub.6, (CH.sub.2).sub.n --NR.sub.8 R.sub.9 wherein n is 0 to 2, methylenedioxy, C.sub.1 to C.sub.3 alkoxy, OH, CN, NO.sub.2, CF.sub.3, C.sub.1 to C.sub.4 acyl, NR.sub.8 R.sub.9, S-C.sub.1 to C.sub.6 alkyl, SO-C.sub.1 to C.sub.6 alkyl, and SO.sub.2 --C.sub.1 to C.sub.6 alkyl; and

R.sub.14 and R.sub.15 are each independently H or C.sub.1 to C.sub.6 alkyl;

or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treatment for disease states caused by the synthesis of the Leukotriences C.sub.4, D.sub.4, E.sub.4 and F.sub.4, as well as Leukotriene B.sub.4, in mannals especially in a human subject. This method comprises administering to said subject an effective amount of a compound of Formula I combined with an appropriate pharmaceutical carrier.

The compounds of Formula I may be used to treat or prevent mammalian (especially human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosion; hepatic ischemia; noxious agent induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl.sub.4 and D-galactsoamine; ischemic rental failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced rental failure.

Finally, this invention also provides novel compounds within the Formula I that act as inhibitors of the mammalian 5-lipoxygenase enzyme system, thus preventing the biosynthesis of the Leukotrienes C.sub.4, D.sub.4 and E.sub.4 and also Leukotriene B.sub.4.

Claims

What is claimed is:

1. A compound of the Formula: ##STR9## wherein the substituents for compound are selected from the following groups: Compound R.sub.1 R.sub.2 ______________________________________ 162 CH.sub.3 ##STR10## 163 CH.sub.3 NHPh 164 CH.sub.3 NHPh-p-NO.sub.2 165 CH.sub.3 NHPh-p-OMe 166 CH.sub.3 NHPh-p-OMe 167 CH.sub.3 NHPh-p-NO.sub.2 168 CH.sub.3 NHPh-p-OMe 169 CH.sub.3 NHPh-p-NO.sub.2 170 CH.sub.3 ##STR11## 171 CH.sub.3 NHPh 173 CH.sub.3 NHCH.sub.2 Ph 174 CH.sub.3 NHPh-p-Cl 175 CH.sub.3 ##STR12## 176 CH.sub.3 ##STR13## 177 Pr NHPh-p-Cl 178 Ph NHPh-p-Cl 181 CH.sub.3 ##STR14## 182 Ph NHPh-p-Cl 183 CH.sub.3 NMePh 184 CH.sub.3 ##STR15## 185 CH.sub.3 NMePh 186 CH.sub.3 NHPh-p-OMe 187 CH.sub.3 ##STR16## 188 Pr NHPh-p-Cl 189 CH.sub.3 NHPh-p-Cl 190 CH.sub.3 NHPh-p-Cl 191 CH.sub.3 NHPh-p-OMe 192 CH.sub.3 NHPh-p-Cl 193 Pr NHPh-p-Cl 278 CH.sub.3 ##STR17## ______________________________________ Compound R.sub.3 R.sub.4 ______________________________________ 162 4-OH H 163 4-OH H 164 6-OH H 165 6-OH H 166 4-OH H 167 4-OAc H 168 4-OAc H 169 4-OH H 170 4-OH H 171 4-OAc H 173 4-OAc H 174 4-OAc H 175 4-OAc H 176 4-OH H 177 6-OH H 178 6-OAc H 181 5-OH H 182 6-OH H 183 4-OAc H 184 4-OH H 185 4-OH H 186 4-OH 5-Pr 187 4-OAc H 188 6-OAc H 189 4-OH H 190 ##STR18## 5-CH.sub.2 CHCH.sub.2 191 ##STR19## 5-Pr 192 5-OH H 193 ##STR20## H 278 4-OH H ______________________________________

2. A method of inhibiting mammalian leukotriene biosynthesis or action which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of claim 1.

3. A method of claim 2 wherein the mammal is a human.

4. A method of treating pulmonary conditions, inflammation, allergies, pain, cardiovascular conditions, or skin conditions which comprises administering to a human in need of such treatment a pharmaceutically effective amount of a compound of claim 1.

5. A pharmaceutical composiiton useful for inhibiting the ibosynthesis of mammalian leukotrienes comprising a pharmaceuticlaly acceptable carrier and an effective amount of a compound of claim 1.

Patent Citations (38)

Patent	Date	Inventor
US3557152	1971-11-01	Zergenzi et al.
US3574208	1971-04-01	Zergenzi et al.
US3627785	1971-12-01	Zergenzi et al.
US3646047	1972-02-01	Wright et al.
US3651094	1972-03-01	Libis et al.
US3665074	1972-05-01	Brandstrom et al.
US3674810	1972-07-01	Zergenzi et al.
US3723619	1973-03-01	Zergenizi et al.
US3830929	1974-08-01	Nordmann et al.
US3915687	1975-10-01	Braunling et al.
US4055117	1977-10-01	Munday
US4085117	1978-04-01	Cragoe Jr. et al.
US4100294	1978-07-01	Cragoe, Jr. et al.
US4213998	1980-07-01	Witiak
US4221793	1980-09-01	Weber et al.
US4229467	1980-11-01	Parker
US4424231	1984-01-01	Bantick et al.
BEX671060	1966-04-01
EPX19955	1980-12-01
EPX45473	1982-02-01
EPX73663	1983-03-01
EPX69521	1983-11-01
EPX123543	1984-10-01
DEX1212984	1966-03-01
DEX2909754	1980-09-01
FRX2231372	1974-02-01
JPX50-35310	1975-04-01
JPX50-049270	1975-05-01
JPX56039015	1979-09-01
JPX57-040479	1982-03-01
CHX500966	1971-02-01
CHX540900	1973-08-01
SUX399106	1973-09-01
GBX1008260
GBX2118552
GBX1233268	1971-05-01
GBX1464242	1977-02-01
GBX2007973	1979-05-01

Non-Patent Literature (11)

Die Pharmazie 35, No. 9, pp. 517-539 (Sep. 1980).
Rene Rober et al., Eur, J. Med. Chem. Chimica Therapeutica, Mar.-Apr., 1974-9 No. 2 pp. 136-145.
W. B. Whalley, J. Chem. Soc., pp. 3229-3235 (1951).
Fujiwara et al., J. Org. Chem., 46, 851 (1981).
Chem. Abstracts, 65, 18546h.
Chem. Abstracts, 58, 13881c.
Chem. Ber., 99 (6), 2063-2065 (1966).
Rodighiero and Fornasiero, GAZZ. Chim. Ital., 91, 90-102 (1961).
Eur. J. Med. Chem.-Chim. Ther. 17, 577-580 (1982).
Grimev et al., C.A. 93:26184h.
Gaevai, V. P., C.A. 96:79444m.

Abstract

Description

X is O, S, SO, or SO.sub.2 ;

R.sub.2 is H, OH, C.sub.1 to C.sub.20 alkoxy, including straight chain or branched chain, cycloalkyl, bicycloalkyl, tricycloalkyl or tetracycloalkyl;

Ar.sub.1 --C.sub.1 to C.sub.3 alkoxy;

NR.sub.8 Ar.sub.1, wherein R.sub.8 and Ar.sub.1 can optionally be joined to form a heterocyclic ring having 5 to 8 atoms;

--NR.sub.8 Het;

--N(R.sub.8)CH.sub.2 Ar.sub.1 ;

--N(R.sub.13)--N(R.sub.13).sub.2 wherein each R.sub.13 is independently hydrogen, R.sub.8, R.sub.9, Ar.sub.1 or Het;

--NH--CH.dbd.C(Ar.sub.1).sub.2 ;

--O(CH.sub.2).sub.n NR.sub.8 R.sub.9 wherein n is 2 to 4;

--Z--Ar.sub.1 ; ##STR3## lower acyloxy-lower alkoxy ##STR4## --CH.sub.2 OH; --(CH.sub.2).sub.n Ar.sub.1 wherein n is 0 to 3;

--(CH.sub.2).sub.n COOR.sub.6 wherein n is 0 to 6;

C.sub.1 to C.sub.20 alkyl; Ar.sub.1 ; Het; (CH.sub.2).sub.n NR.sub.8 R.sub.9

wherein n is 1 to 3; or

Het; ##STR5## and R.sub.1, R.sub.3, R.sub.4, T and V are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH.sub.2).sub.n M wherein n is 0 to 6 except when X is S and M is OR.sub.5, in which case n is 1 to 6 and

M is

(a) --OR.sub.5 ;

(b) halogen;

(d) --SR.sub.5 ;

(e) Ar.sub.1 ;

(f) --COOR.sub.6 ;

(r) --SO.sub.2 NR.sub.8 R.sub.9 ;

(s) --SO.sub.2 R.sub.5 ;

(t) --NO.sub.2 ; or

(u) --CN;

each R.sub.6 is independently H or C.sub.1 to C.sub.6 alkyl;

each R.sub.7 is independently C.sub.1 to C.sub.6 alkyl, benzyl, Ar.sub.1, NR.sub.8 R.sub.9, NHAr.sub.1, or O--C.sub.1 to C.sub.4 alkyl;

each Het is independently an aromatic heterocyclic ring having 5 or 6 ring atoms, one or more of which are selected from N, O and S;

R.sub.14 and R.sub.15 are each independently H or C.sub.1 to C.sub.6 alkyl;

or a pharmaceutically acceptable salt thereof.

Claims

What is claimed is:

3. A method of claim 2 wherein the mammal is a human.

5. A pharmaceutical composiiton useful for inhibiting the ibosynthesis of mammalian leukotrienes comprising a pharmaceuticlaly acceptable carrier and an effective amount of a compound of claim 1.

Patent Citations (38)

Patent	Date	Inventor
US3557152	1971-11-01	Zergenzi et al.
US3574208	1971-04-01	Zergenzi et al.
US3627785	1971-12-01	Zergenzi et al.
US3646047	1972-02-01	Wright et al.
US3651094	1972-03-01	Libis et al.
US3665074	1972-05-01	Brandstrom et al.
US3674810	1972-07-01	Zergenzi et al.
US3723619	1973-03-01	Zergenizi et al.
US3830929	1974-08-01	Nordmann et al.
US3915687	1975-10-01	Braunling et al.
US4055117	1977-10-01	Munday
US4085117	1978-04-01	Cragoe Jr. et al.
US4100294	1978-07-01	Cragoe, Jr. et al.
US4213998	1980-07-01	Witiak
US4221793	1980-09-01	Weber et al.
US4229467	1980-11-01	Parker
US4424231	1984-01-01	Bantick et al.
BEX671060	1966-04-01
EPX19955	1980-12-01
EPX45473	1982-02-01
EPX73663	1983-03-01
EPX69521	1983-11-01
EPX123543	1984-10-01
DEX1212984	1966-03-01
DEX2909754	1980-09-01
FRX2231372	1974-02-01
JPX50-35310	1975-04-01
JPX50-049270	1975-05-01
JPX56039015	1979-09-01
JPX57-040479	1982-03-01
CHX500966	1971-02-01
CHX540900	1973-08-01
SUX399106	1973-09-01
GBX1008260
GBX2118552
GBX1233268	1971-05-01
GBX1464242	1977-02-01
GBX2007973	1979-05-01

Non-Patent Literature (11)

Die Pharmazie 35, No. 9, pp. 517-539 (Sep. 1980).

Rene Rober et al., Eur, J. Med. Chem. Chimica Therapeutica, Mar.-Apr., 1974-9 No. 2 pp. 136-145.

W. B. Whalley, J. Chem. Soc., pp. 3229-3235 (1951).

Fujiwara et al., J. Org. Chem., 46, 851 (1981).

Chem. Abstracts, 65, 18546h.

Chem. Abstracts, 58, 13881c.

Chem. Ber., 99 (6), 2063-2065 (1966).

Rodighiero and Fornasiero, GAZZ. Chim. Ital., 91, 90-102 (1961).

Eur. J. Med. Chem.-Chim. Ther. 17, 577-580 (1982).

Grimev et al., C.A. 93:26184h.

Gaevai, V. P., C.A. 96:79444m.