Hexahydro-3H-Pyrrolizin-3-Ones Useful as Tachykinin Receptor Antagonists
The present invention is directed to certain hexahydrpyrrolidinone compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.
1 . A compound of the formula I, II or III:
wherein:
R 1 and R 1a are each hydrogen or together with the carbon atom to which they are attached form a carbonyl;
Each R 2 is selected from the group consisting of:
(1) hydrogen,
(2) NH 2 , and
(3) CH 3 ;
R 3 are each independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxyl,
(3) NH 2 ,
(4) N(CH 3 ) 2 ;
(5) NH—C(O)—C(CH 3 ) 2 —NH 2 ,
(6) NH—C(O)—CF 3 ,
(7) C 1-6 alkyl,
(8) C 1-6 alkyl-O—C 1-6 alkyl, and
(9) -A1, wherein A1 is a heteroaryl or heterocycle of 5 or 6 atoms wherein the heteroaryl or heterocyle contains 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, and wherein the heteroaryl or heterocylce is optionally substituted with a group selected from methyl, oxo and hydroxyl,
(10) —NH-A1
(11) —NH—CH 2 -A1,
(12) CO 2 Me; and
(13) CO 2 H;
R 4 and R 5 are each independently selected from a group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) hydroxyC 1-3 alkyl,
(4) C 1-3 alkyl,
(5) —C(O)—O—CH 3 ,
(6) NH 2 ,
(7) aminoC 1-3 alkyl,
(8) N(R 9 )(R 10 ),
(9) A2, wherein A2 is selected from the group consisting of
wherein A2 is optionally substituted with a group selected from hydroxyl, methyl, COOH, —COO—C 1-4 alkyl and
(10) A3, wherein A3 is a heteraromatic or heterocyclic ring of 5 or 6 atoms, wherein 1, 2, or 3 of the atoms is a heteroatom selected from N, S or O, and wherein at least one of the heteroatoms is a N, and wherein the heteroaryl or heterocycle is optionally substituted with a group selected from methyl, oxo, hydroxyl, —CH 3 —NH 2 and —CH 3 —N(CH 3 ) 2 ,
(11) C 1-3 -A2,
(12) C 1-3 -A3, and
or R 4 and R 5 together with the carbon to which they are attached form a carbonyl;
R 6 and R 7 are each independently selected from a group consisting of:
(1) hydrogen,
(2) halo, and
(3) methyl;
R 9 and R 10 are each selected from the group consisting of
(1) hydrogen,
(2) methyl,
(3) A4, wherein A4 is a heteroaryl or heterocycle of 5 or 6 atoms wherein the heteroaryl or heterocyle contains 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, and wherein the heteroaryl or heterocycle is optionally substituted with a group selected from methyl, oxo, hydroxyl, —CH 3 —NH 2 and —CH 3 —N(CH 3 ) 2 , and
(4) —C 1-3 alkyl-A4,
or a pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
2 . A compound according to claim 1 of formula II
3 . A compound according to claim 1 wherein
A1 is selected from the group consisting of
4 . A compound according to claim 1 wherein
R 3 is selected from the group consisting of
(1) NH 2 , and
(2) —NH-A1, wherein A1 is selected from the group consisting of
and A1 is optionally substituted with a group selected from methyl, oxo and hydroxyl.
5 . A compound according to claim 1 wherein A3 and A4 are each selected from the group consisting of
wherein A4 is optionally substituted with a substituent selected from the group consisting of hydroxyl, oxo, methyl, —CH 3 —NH 2 and CH 3 —N(CH 3 ) 2 .
6 . A compound according to claim 1 wherein
R 4 and R 5 are each independently selected from a group consisting of:
(1) hydroxy,
(2) NH 2 , and
(3) N(R 9 )(R 10 ).
7 . A compound according to claim 1 wherein
R 6 and R 7 are each independently selected from a group consisting of:
(1) hydrogen,
(2) fluoro, and
(3) methyl.
8 . A compound according to claim 1 wherein
R 9 and R 10 are each selected from the group consisting of
(1) hydrogen, and
(2) -A4, wherein A4 is selected from the group consisting of
wherein A4 is optionally substituted with a substituent selected from the group consisting of hydroxyl, oxo, methyl, —CH 3 —NH 2 and —CH 3 —N(CH 3 ) 2 .
9 . A compound according to claim 1 wherein
Each R 2 is selected from the group consisting of:
(1) hydrogen, and
(2) CH 3 .
10 . A compound according to claim 1 wherein
R 6 is fluoro and R 7 is methyl.
11 . A compound according to claim 2 wherein
R 1 and R 1a are each hydrogen or together with the carbon atom to which they are attached form a carbonyl;
each R 2 is selected from the group consisting of:
(1) hydrogen, and
(2) CH 3 ;
R 3 is selected from the group consisting of
(1) NH 2 , and
(2) —NH-A1, wherein A1 is selected from the group consisting of
and A1 is optionally substituted with a group selected from methyl, oxo and hydroxyl;
R3 is selected from the group consisting of
(1) NH 2 , and
(2) —NH-A1, wherein A1 is selected from the group consisting of
and A1 is optionally substituted with a group selected from methyl, oxo and hydroxyl;
R 4 and R 5 are each independently selected from a group consisting of:
(1) hydroxy,
(2) NH 2 , and
(3) N(R 9 )(R 10 ).
R 6 and R 7 are each independently selected from a group consisting of:
(1) hydrogen,
(2) fluoro, and
(3) methyl;
R 9 and R 10 are each selected from the group consisting of
(1) hydrogen,
(2) methyl, and
(3) A4, wherein A1 is a heteroaryl or heterocycle of 5 or 6 atoms wherein the heteroaryl or heterocyle contains 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, and wherein the heteroaryl or heterocylce is optionally substituted with a group selected from methyl, oxo, hydroxyl, —CH 3 —NH 2 and —CH 3 —N(CH 3 ) 2 ,
(4) —C 1-3 alkyl-A4,
or a pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
12 . A compound according to claim 1 of formula I or III
13 . A compound according to claim 12 wherein
R 1 and R 1a are each hydrogen or together with the carbon atom to which they are attached form a carbonyl;
Each R 2 is selected from the group consisting of:
(1) hydrogen, and
(2) CH 3 ;
R 3 are each independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxyl,
(3) C 1-6 alkyl, and
(4) C 1-6 alkyl-O—C 1-6 alkyl;
R 4 and R 5 are each independently selected from a group consisting of:
(1) hydroxy,
(2) NH 2 , and
(3) N(R 9 )(R 10 ).
R 6 and R 7 are each independently selected from a group consisting of:
(1) hydrogen,
(2) fluoro, and
(3) methyl;
R 9 and R 10 are each selected from the group consisting of
(1) hydrogen,
(2) methyl, and
(3) A4, wherein A1 is a heteroaryl or heterocycle of 5 or 6 atoms wherein the heteroaryl or heterocyle contains 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, and wherein the heteroaryl or heterocylce is optionally substituted with a group selected from methyl, oxo, hydroxyl, —CH 3 —NH 2 and CH 3 —N(CH 3 ) 2 ,
(4) —C 1-3 alkyl-A4,
or a pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
14 . A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15 . A compound according to claim 1 of the formula
wherein
R 9 and R 10 are
or a pharmaceutically acceptable salt thereof.
16 . A compound according to claim 1 of the formula
wherein
R 11 is
or a pharmaceutically acceptable salt thereof.
17 . A compound according to claim 1 of the formula
wherein
R 12 is
or a pharmaceutically acceptable salt thereof.
18 . A compound according to claim 1 of formula
R 12 is
or a pharmaceutically acceptable salt thereof.
19 . A compound according to claim 1 of formula
wherein
R 13 is
or a pharmaceutically acceptable salt theory
20 . A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
21 . A method for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal comprising combining a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier or diluent.
22 . A method for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins in a mammal comprising combining a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier or diluent.