Octahydropyrano[3,4-C]Pyrrole Tachykinin Receptor Antagonists
The present invention is directed to certain hydropyranopyrrolidine 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:
wherein:
R 1 is selected from the group consisting of:
(1) aryl, selected from phenyl and naphthyl,
(2) heteroaryl, wherein the heteroaryl is an aromatic monocyclic of 5 or 6 atoms having 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O,
(3) heterocyclic ring, wherein the heterocycle is a non-aromatic ring of 5 or 6 atoms having 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O,
(4) cyclohexane,
(5) cyclohexenone,
(5) —C(O)-aryl,
(6) —C(O)-heteroaryl,
(7) —C(O)-heterocycle,
(8) —C(O)-cyclohexane,
(9) —C(O)-cyclohexenone,
(10) —C(O)CH 2 —OH,
(11) —S(O) 2 —C 1-3 alkyl,
(12) —C(O)—O—C 1-3 alkyl, and
(13) —C(O)—CH 2 —O—C(O)—CH 3 ,
wherein choices (1) through (9) are optionally substituted with 1 or 2 groups selected from
(1) oxo,
(2) CH 3 ,
(3) OH
(4) —OCH 3
(5) —C(O)—O—C 1-3 alkyl,
(6) —C(O)—OH,
(7) CH 2 —OH, and
(8) Benzyl;
X, Y and Z are independently selected from the group consisting of:
(1) hydrogen,
(2) halo, and
(3) methyl;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
2 . The compound of claim 1 of the formula Ia:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
3 . A compound of claim 1 wherein
the cyclohexane or cyclohexenone ring of R 1 is selected from the group consisting of
4 . A compound of claim 1 wherein
the heterocycle of R 1 is selected from the group consisting of
5 . A compound of claim 1 wherein
the of R 1 is heteroaryl selected from the group consisting of
6 . The compound of claim 1 wherein X is fluorine, Y is hydrogen, and Z is hydrogen.
7 . The compound of claim 1 wherein X is methyl, Y is hydrogen, and Z is hydrogen.
8 . A compound of claim 1 wherein
R 1 is selected from the group consisting of:
(1) aryl, selected from phenyl and naphthyl,
(2) heteroaryl, wherein the heteroaryl is an aromatic monocyclic of 5 or 6 atoms having 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O,
(3) heterocyclic ring, wherein the heterocycle is a non-aromatic ring of 5 or 6 atoms having 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O,
(4) cyclohexane,
(5) —C(O)-heterocycle,
wherein choices (1) through (5) are optionally substituted with 1 or 2 groups selected from
(1) oxo,
(2) CH 3 ,
(3) OH
(4) —OCH 3
(5) —(O)—O—C 1-3 alkyl,
(6) —C(O)—OH,
(7) —CH 2 —OH, and
(8) Benzyl.
9 . A compound of claim 1 wherein
R 1 is selected from the group consisting of:
(1) heterocyclic ring, wherein the heterocycle is a non-aromatic ring of 5 or 6 atoms having 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O,
(2) cyclohexane,
(3) —C(O)-heterocycle,
wherein choices (1) through (3) are optionally substituted with 1 or 2 groups selected from
(1) oxo,
(2) CH 3 ,
(3) OH
(4) —OCH 3
(5) C(O)—O—C 1-3 alkyl,
(6) —C(O)—OH,
(7) —CH 2 —OH, and
(8) Benzyl.
10 . A compound which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
11 . A compound already to claim 1 selected from the group consisting of
12 . A compound already to claim 1 of the formula
Ex
R 1
X
34
4-F
35
4-F
36
4-F
37
4-F
38
4-F
39
4-F
40
4-F
13 . A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
14 . 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.
15 . 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.