Oxindole derivatives carrying a piperidyl-substituted azetidinyl substituent and use thereof for treating vasopressine-related diseases

Patent metadata

Field	Value
Publication number	US-9840495-B2
Application number	US-201415106670-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 20, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present invention relates to novel substituted oxindole derivatives of formula (I) wherein the variables are as defined in the claims and description; to pharmaceutical compositions comprising them, and to their use for treatment of vasopressin-related disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
X 1 is N or CH;
X 2 is C—R 1 or N;
R 1 and R 2 , independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy;
R 3 is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy;
R 4 is C 1 -C 3 -alkoxy;
R 5 is selected from the group consisting of hydrogen and C 1 -C 3 -alkoxy;
R 6 is selected from the group consisting of cyano and halogen;
R 7 is selected from the group consisting of hydrogen, halogen and cyano;
R 8 is selected from the group consisting of hydrogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxy-C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -halocycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
R 9 is selected from the group consisting of C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 7 -cycloalkoxy, C 3 -C 7 -halocycloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -haloalkylsulfinyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -haloalkylsulfonyl, phenoxy, wherein the phenyl moiety may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO 2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; or
R 8 and R 9 , together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, wherein the heterocyclic ring may contain 1 or 2 further heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO 2 as ring members, and wherein the heterocyclic ring may carry 1 or 2 substituents R 12 and/or 1 or 2 substituents R 13 ; wherein in case that the heterocyclic ring does not contain 1 or 2 further heteroatoms or heteroatom groups as ring members, the heterocyclic ring carries 1 or 2 substituents R 12 and optionally 1 or 2 substituents R 13 ;
R 10 and R 11 , independently of each other and independently of each occurrence, are selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, with the proviso that R 10 and R 11 are not halogen, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy if they are bound to a carbon atom in α-position to a nitrogen ring atom; or
two non-geminal radicals R 10 form together a group —(CH 2 ) n —, wherein n is 1, 2, 3 or 4, wherein 1 or 2 hydrogen atoms in this group may be replaced a methyl group; or
two non-geminal radicals R 11 form together a group —(CH 2 ) n —, wherein n is 1, 2, 3 or 4, wherein 1 or 2 hydrogen atoms in this group may be replaced a methyl group;

each R 12 is independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 7 -cycloalkoxy, C 3 -C 7 -halocycloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -haloalkylsulfinyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -haloalkylsulfonyl, phenoxy, benzyloxy, wherein the phenyl moiety in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO 2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
or
two radicals R 12 , together with the atom(s) they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO 2 as ring members, wherein the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;

each R 13 is independently selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxy-C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -halocycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 7 -cycloalkoxy, C 3 -C 7 -halocycloalkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -haloalkylsulfinyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -haloalkylsulfonyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, phenyl, phenoxy and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, N, S, NO, SO and SO 2 as ring members, wherein the phenyl moieties or the heterocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
a is 0, 1 or 2; and
b is 0, 1, 2, 3 or 4;
or a N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof; or the above compound, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.

2. The compound of claim 1 , wherein at least one hydrogen atom has been replaced by a deuterium atom.

3. The compound of claim 1 , wherein X 2 is C—R 1 and R 1 , R 2 and R 3 , independently of each other, are selected from the group consisting of hydrogen, halogen, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy.

4. The compound of claim 3 , wherein R 1 , R 2 and R 3 , independently of each other, are selected from the group consisting of hydrogen, fluorine and methoxy.

5. The compound of claim 4 , wherein R 1 is selected from the group consisting of hydrogen, fluorine and methoxy.

6. The compound of claim 4 , wherein R 2 is selected from the group consisting of hydrogen, fluorine and methoxy.

7. The compound of claim 4 , wherein R 3 is hydrogen or fluorine.

8. The compound of claim 1 , wherein X 2 is N and R 2 and R 3 , independently of each other, are selected from the group consisting of hydrogen, halogen, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alko

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Geneste Hervé
• Hornberger Wilfried
• Hutchins Charles W
• Jantos Katja
• Kling Andreas
• Laplanche Loic
• Van Gaalen Marcel

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title