Spiro-oxazolones

Patent metadata

Field	Value
Publication number	US-9828385-B2
Application number	US-201615240705-A
Country	US
Kind code	B2
Filing date	Aug 18, 2016
Priority date	Feb 20, 2014
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

The present invention provides spiro-oxazolones, which act as V1a receptor modulators, and in particular as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The present compounds are useful as therapeutics acting peripherally and centrally in the conditions of inappropriate secretion of vasopressin, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, aggressive behavior and phase shift sleep disorders, in particular jetlag.

First claim

The invention claimed is:

1. A compound of formula I,

wherein
X 1 , X 2 , X 3 and X 4 are C—R 1 ;
Y is O or S(O) m ;
m is 0, 1 or 2;
R 1 each separately is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 -alkyl- and C 1-6 -alkoxy-;
R 2 is selected from the group consisting of H and C 1-6 -alkyl-;
R 3 is selected from the group consisting of H and C 1-6 -alkyl-;
or R 2 and R 3 together are ═O;
R 4 is selected from the group consisting of
i) aryl-C 1-6 -alkyl-, wherein the aryl moiety can be optionally substituted by halogen,
ii) C 1-6 -alkoxy-CH 2 —,
iii) C 1-6 -alkyl-,
iv) C 2-6 -alkenyl-CH 2 —,
v) C 2-6 -alkynyl-CH 2 —,
vi) halogen-C 1-6 -alkyl-,
vii) halogen-C 2-6 -alkenyl-CH 2 —, and
viii) hydrogen;

R 5 is selected from the group consisting of
i) aryl-,
ii) aryl-C 1-6 -alkyl-, wherein
the aryl moiety can be optionally substituted by C 1-6 -alkyl, halogen-C 1-6 -alkyl or halogen, and
the C 1-6 -alkyl moiety can optionally be substituted by C 1-6 -alkyl-COO—, halogen or hydroxy,

iii) C 3-10 -cycloalkyl-C 1-6 -alkyl,
iv) halogen-C 1-6 -alkyl-,
v) heteroaryl-C 1-6 -alkyl-, wherein the heteroaryl moiety can be optionally substituted by halogen,
vi) heterocycloalkyl-C 1-6 -alkyl-,
vii) C 1-6 -alkyl-,
viii) C 2-6 -alkenyl-CH 2 — that is optionally substituted by halogen, (C 1-6 -alkyl) 3 SiO—, C 1-6 -alkyl-COO— or C 1-6 -alkyl-OOC—,
ix) C 1-6 -alkoxy-CH 2 —, and
x) C 2-6 -alkynyl-CH 2 —;

or R 4 and R 5 together are selected from the group consisting of
i) C 3-10 -cycloalkyl that is optionally substituted by C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OOC—, halogen, halogen-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl or oxo;
ii) heterocycloalkyl that is optionally substituted by benzyl, C 1-6 -alkyl, C 1-6 -alkyl-OOC—, halogen-C 1-6 -alkyl or oxo;
iii) C 3-10 -cycloalkenyl that is optionally substituted by C 1-6 -alkyl, C 1-6 -alkyl-OOC—, halogen-C 1-6 -alkyl, (C 1-6 -alkyl) 3 SiO—C 1-6 -alkyl- or hydroxy-C 1-6 -alkyl, and
iv) indanyl when Y is SO 2 ;
or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein
Y is O;
R 4 is selected from the group consisting of
i) aryl-C 1-6 -alkyl-, wherein the aryl moiety can be optionally substituted by halogen,
ii) C 1-6 -alkyl-,
iii) C 2-6 -alkenyl-CH 2 —,
iv) C 2-6 -alkynyl-CH 2 —,
v) halogen-C 2-6 -alkenyl-CH 2 —, and
vi) hydrogen;

R 5 is selected from the group consisting of
i) aryl-,
ii) aryl-C 1-6 -alkyl-, wherein
the aryl moiety can be optionally substituted by C 1-6 -alkyl, halogen-C 1-6 -alkyl or halogen, and
the C 1-6 -alkyl moiety can optionally be substituted by C 1-6 -alkyl-COO—, halogen or hydroxy,

iii) C 3-10 -cycloalkyl-C 1-6 -alkyl-,
iv) heteroaryl-C 1-6 -alkyl-, wherein the heteroaryl moiety can be optionally substituted by halogen,
v) heterocycloalkyl-C 1-6 -alkyl-,
vi) C 1-6 -alkyl-,
vii) C 2-6 -alkenyl-CH 2 — that is optionally substituted by halogen, (C 1-6 -alkyl) 3 SiO—, C 1-6 -alkyl-COO— or C 1-6 -alkyl-OOC—,
viii) C 1-6 -alkoxy-CH 2 —, and
ix) C 2-6 -alkynyl-CH 2 —;

or R 4 and R 5 together are selected from the group consisting of
i) C 3-10 -cycloalkyl that is optionally substituted by C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OOC—, C 1-6 -alkyl-COO—, halogen, halogen-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl or oxo;
ii) heterocycloalkyl that is optionally substituted by benzyl, C 1-6 -alkyl, C 1-6 -alkyl-OOC—, halogen-C 1-6 -alkyl or oxo; and
iii) C 3-10 -cycloalkenyl that is optionally substituted by C 1-6 -alkyl, C 1-6 -alkyl-OOC—, halogen-C 1-6 -alkyl, (C 1-6 -alkyl) 3 SiO—C 1-6 -alkyl- or hydroxy-C 1-6 -alkyl.

3. The compound of claim 1 , wherein each R 1 is separately is selected from the group consisting of hydrogen, halogen, and C 1-6 -alkoxy.

4. The compound of claim 1 , wherein R 1 is hydrogen.

5. The compound of claim 1 , wherein Y is O.

6. The compound of claim 1 , wherein Y is SO 2 .

7. The compound of claim 1 , wherein R 2 is hydrogen.

8. The compound of claim 1 , wherein R 3 is hydrogen.

9. The compound of claim 1 , wherein R 2 and R 3 are ═O.

10. The compound of claim 1 , wherein R 4 is hydrogen or C 1-6 -alkyl.

11. The compound of claim 1 , wherein R 5 is benzyl or C 3-10 -cycloalkyl-C 1-6 -alkyl.

12. The compound of claim 1 , wherein R 4 and R 5 together are
i) C 3-10 -cycloalkyl that is optionally substituted by halogen;
ii) heterocycloalkyl that is optionally substituted by C 1-6 -alkyl;
iii) C 3-10 -cycloalkenyl that is optionally substituted by halogen-C 1-6 -alkyl, and
iv) indanyl when Y is SO 2 .

13. The compound of claim 1 , selected from the group consisting of
(−)-(5S)-5-Benzyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-(Cyclopentylmethyl)-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-(Ethoxymethyl)-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(−)-5-[(4-Chlorophenyl)(hydroxy)methyl]-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one diastereomer a,
(+)-5-[(4-Chlorophenyl)(hydroxy)methyl]-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one diastereomer b,
(+)-5-[(5-Chlorothiophen-2-yl)methyl]-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(−)-5-[(6-Chloropyridin-3-yl)methyl]-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(−)-5-Benzyl-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(−)-5-Butyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(−)-5-Butyl-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(−)-5-Methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-oxazol-4(5H)-one diastereomer a,
(−)-5-Methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-oxazol-4(5H)-one diastereomer b,
(+)-5-Methyl-5-(1-phenylethyl)-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one diastereomer a,
(+)-5-Methyl-5-(1-phenylethyl)-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one diastereomer b,
(+)-(5R)-5-Benzyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-(Cyclopentylmethyl)-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-(Ethoxymethyl)-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-[(4-Chlorophenyl)(hydroxy)methyl]-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one diastereomer a,
(+)-5-[(4-Chlorophenyl)(hydroxy)methyl]-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one diastereomer b,
(+)-5-[(5-Chlorothiophen-2-yl)methyl]-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-[(6-Chloropyridin-3-yl)methyl]-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-Benzyl-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-Butyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-Butyl-5-methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-1,3-oxazol-4(5H)-one,
(+)-5-Methyl-2-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-5-(tetrahydro-2H-pyran-3-ylmet

Assignees

• Hoffmann La Roche

Inventors

• Dolente Cosimo
• Fasching Bernhard
• Runtz-Schmitt Valerie
• Schnider Patrick

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/12

  for decreasing, blocking or antagonising the activity of the posterior pituitary hormones · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title