US 4,870,084 AGranted

Bicyclic benzo fused pyran compounds used for nausea treatment and prevention

AssigneePfizer Inc.

InventorsJames F. Eggler, Michael R. Johnson, Lawrence S. Melvin, Jr.

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Abstract

Bicyclic fused benzenoid compounds of the formula ##STR1## and pharmaceutically acceptable cationic and acid addition salts thereof, where M is O, CH.sub.2 or NR.sub.6 ; R.sub.6 is hydrogen, formyl, carbobenzyloxy or certain carboalkoxyalkyl, alkanoyl, alkyl, aralkyl or aralkylcarbonyl groups; A' is: (1) A where one of A and B is hydrogen such that when A is hydrogen, B is C(R.sub.2 R.sub.3)(CH.sub.2).sub.f Q and f is 1 or 2; when B is hydrogen, A is C(R.sub.2 R.sub.3)(CH.sub.2).sub.f Q and f is 0 or 1, when taken together A and OR.sub.1 form a lactone or certain derivatives thereof; (2) A' is ##STR2## (3) A' is Q.sub.3 ; Q is CO.sub.2 R.sub.7, COR.sub.8, C(OH)R.sub.8 R.sub.9, CN, CONR.sub.12 R.sub.13, CH.sub.2 NR.sub.12 R.sub.13, CH.sub.2 NHCOR.sub.14, CH.sub.2 NHSO.sub.2 R.sub.17 or 5-tetrazoyl; Q.sub.3 is ##STR3## 5-tetrazolyl, CH.sub.2 CONHCOR.sub.7, COOH or certain ester, amide, carboximido or sulfonimido derivatives thereof, CONHOH, CONHCONH.sub.2, or COCH.sub.2 Q.sub.4 where Q.sub.4 is CN or COOH or certain esters thereof; R.sub.1 is hydrogen, benzyl or certain acyl groups; R.sub.4 is hydrogen, certain alkyl or certain aralkyl groups; R.sub.5 is hydrogen or certain alkyl groups; Z is (C.sub.1 -C.sub.9) alkylene, optionally interrupted by O, S, SO or SO.sub.2 ; and W is hydrogen, methyl, certain aryl or cycloalkyl groups; useful in mammals as analgesics, tranquilizers, antiemetic agents, diuretics, anticonvulsants, antidiarrheals, antitussives, in treatment of glaucoma, and intermediates therefore.

Claims14

Dependent claims

A method for prevention and treatment of nausea in a mammal subject to said nausea which comprises orally or parenterally administering to said mammal a nausea preventing effective amount of a compound of the formula ##STR127## and pharmaceutically acceptable cationic and acid addition salts thereof;

wherein Q.sub.3 is COOR.sub.7, CONHOH, CONHCONH.sub.2, CONR.sub.12 R.sub.13, CONHCOR.sub.19, CONHSO.sub.2 R.sub.17, CH.sub.2 CONHCOR.sub.19 or COCH.sub.2 Q.sub.4 where
Q.sub.4 is CN or COOR.sub.5 ;
M is O;
R.sub.1 is a member selected from the group consisting of hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms and --CO--(CH.sub.2).sub.p --NR.sub.15 R.sub.16 wherein p is 0 or an integer from 1 to 4;
each of R.sub.15 and R.sub.16 when taken individually is selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms;
R.sub.15 and R.sub.16 when taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring selected the group consisting of piperidino, pyrrolo and pyrrolidino;
R.sub.4 is hydrogen, alkyl having from 1 to 6 atoms or --(CH.sub.2).sub.z --C.sub.6 H.sub.5 wherein z is an integer from 1 to 4;
R.sub.5 is hydrogen, methyl or ethyl;
R.sub.7 is hydrogen, alkyl having from one to four carbon atoms or benzyl;
R.sub.12 and R.sub.13 are each hydrogen, alkyl having from one to six carbon atoms, phenyl or benzyl;
R.sub.17 is alkyl having from one to six carbon atoms, benzyl or R.sub.18 C.sub.6 H.sub.4,
where R.sub.18 is H, NH.sub.2, F, Cl, Br, CH.sub.3, or OCH.sub.3 ;
R.sub.19 is R.sub.7, phenyl or phenethyl;
and
Z is selected from the group consisting of
(a) alkylene having from one to nine carbon atoms;
and
(b) --(alk.sub.1).sub.m --x--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not greater than nine;
each of m and n is 0 or 1;
X is selected from the group consisting of O, S, SO and SO.sub.2 ;
and W is selected from the group consisting of hydrogen, methyl, ##STR128## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR129## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR130## a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5;
with the proviso that the sum of a and b is not greater than 5.

20 more elements

A pharmaceutical composition suitable for use in prevention and treatment of nausea which comprises a pharmaceutically-acceptable carrier and a nausea preventing effective amount of a compound of the formula ##STR131## and pharmaceutically acceptable cationic and acid addition salts thereof;

wherein Q.sub.3 is COOR.sub.7, CONHOH, CONHCONH.sub.2, CONR.sub.12 R.sub.13, CONHCOR.sub.19, CONHSO.sub.2 R.sub.17, CH.sub.2 CONHCOR.sub.19 or COCH.sub.2 Q.sub.4 where
Q.sub.4 is CN or COOR.sub.5 ;
M is O;
R.sub.1 is a member selected from the group consisting of hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms and --CO--(CH.sub.2).sub.p --NR.sub.15 R.sub.16 wherein p is 0 or an integer from 1 to 4;
each of R.sub.15 and R.sub.16 when taken individually is selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms;
R.sub.15 and R.sub.16 when taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo and pyrrolidino;
R.sub.4 is hydrogen, alkyl having from 1 to 6 carbon atoms or --(CH.sub.2).sub.z --C.sub.6 H.sub.5 wherein z is an integer from 1 to 4;
R.sub.5 is hydrogen, methyl, or ethyl;
R.sub.7 is hydrogen, alkyl having from one to four carbon atoms or benzyl;
R.sub.12 and R.sub.13 are each hydrogen, alkyl having from one to six carbon atoms, phenyl or benzyl;
R.sub.17 is alkyl having from one to six carbon atoms, benzyl or R.sub.18 C.sub.6 H.sub.4,
where R.sub.18 is H, NH.sub.2, F, Cl, Br, CH.sub.3 or OCH.sub.3 ;
R.sub.19 is R.sub.7, phenyl or phenethyl;
and
Z is selected from the group consisting of
(a) alkylene having from one to nine carbon atoms;
and
(b) --(alk.sub.1).sub.m --x--(alk.sub.2).sub.n -- wherein each of (alk.sub.1) and (alk.sub.2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk.sub.1) plus (alk.sub.2) is not greater than nine;
each of m and n is 0 or 1;
X is selected from the group consisting of O, S, SO and SO.sub.2 ;
and W is selected from the group consisting of hydrogen, methyl, ##STR132## wherein W.sub.1 is selected from the group consisting of hydrogen, fluoro and chloro;
and ##STR133## wherein W.sub.2 is selected from the group consisting of hydrogen and ##STR134## a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5;
with the proviso that the sum of a and b is not greater than 5.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/278,635Filed 1 Dec 1988 · division
Priority: 16 Mar 1982
Granted: 26 Sep 1989
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07C 37/055
By replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis: the substituted group being bound to…
C07C 39/08
Monocyclic with no unsaturation outside the aromatic ring: dihydroxy benzenes; Alkylated derivatives thereof
C07C 41/30
By reactions not forming ether-oxygen bonds: by increasing the number of carbon atoms, e.g. by oligomerisation

Family

Serial358,751Parent of this continuation-in-part · filed 16 Mar 1982
Serial457,171Parent of this division · filed 13 Jan 1983
Serial639,038Parent of this division · filed 9 Aug 1984
US 4,486,428 AParent of this division
US 4,870,084 AThis patent

From the US filing history. Foreign family members aren’t listed.