Hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists
View Patent ↗The present invention is directed to certain hydroxymethyl ether hydroisoindoline 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, LUTS, depression, and anxiety.
1. A compound of the formula I:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof wherein: R 1 is
X is independently selected from the group consisting of:
(1) hydrogen, and
(2) fluorine;
Y is independently selected from the group consisting of:
(1) hydrogen, and
(2) methyl; and
Z is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(3) —(CO)—C 1-6 alkyl,
(4) —(CO)-Aryl
(5) —(CO)O—C 1-6 alkyl,
(6) —(CO)—NH 2 ,
(7) —(CO)—NHC 1-6 alkyl, and
(8) —(CO)—N(C 1-6 alkyl)(C 1-6 alkyl).
2. The compound of claim 1 of the formula Ia or Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 2 of the formula Ia:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
4. The compound of claim 2 of the formula Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
5. The compound of claim 1 wherein Z is selected from the group consisting of
(1) hydrogen,
(2) C 1-3 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(3) —(CO)-phenyl, and
(4) —(CO)O-methyl.
6. The compound of claim 1 wherein X is hydrogen.
7. The compound of claim 1 wherein X is fluorine.
8. The compound of claim 1 wherein Y is hydrogen.
9. The compound of claim 1 wherein Y is methyl.
10. The compound of claim 1 wherein Z is hydrogen.
11. The compound of claim 1 wherein Z is methyl.
12. The compound of claim 1 of the formula Ia or Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof wherein
R 1 is
X is independently selected from the group consisting of:
(1) hydrogen, and
(2) fluorine;
Y is independently selected from the group consisting of:
(1) hydrogen, and
(2) methyl; and
Z is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(3) —(CO)—C 1-6 alkyl,
(4) —(CO)-Aryl
(5) —(CO)O—C 1-6 alkyl, and
(6) —(CO)—NH 2 .
13. A compound of claim 12 wherein Z is selected from the group consisting of
(1) hydrogen,
(2) C 1-3 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(3) —(CO)-phenyl, and
(4) —(CO)O-methyl.
14. A compound of claim 12 wherein Z is selected from hydrogen and methyl.
15. A compound which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 .
17. A method for the treatment of pain or inflammation, migraine, emesis, post-therapeutic neuralgia, depression, anxiety or urinary incontinence, and LUTS which method comprises administration to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .
18. A method according to claim 17 for the treatment of urinary incontinence or LUTS.
19. A method of antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a patient in need thereof comprising administration to said patient a therapeutically effective amount of the compound of claim 1 .