Inhibitor compounds of phosphodiesterase type 10A

Patent metadata

Field	Value
Publication number	US-9856220-B2
Application number	US-201615207137-A
Country	US
Kind code	B2
Filing date	Jul 11, 2016
Priority date	Nov 9, 2011
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

The present invention relates to compounds which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders.

wherein
X 1 is CH or N, X 2 is C—R 5 or N, Y is O or S,
R 1 is inter alia C 2 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 8 -cycloalkyl, C 5 -C 8 -cycloalkyl carrying a fused benzene ring, or a moiety Z 1 —Ar 1 ;
R 2 is a radical of the formula CR 21 R 22 R 23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R a ,
R 3 is inter alia hydrogen, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 8 -cycloalkyl, etc, or
R 2 and R 3 together with the nitrogen atom, to which they are bound form an optionally substituted saturated 5- to 7-membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO 2 ;
R 4 is inter alia C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl or Z 4 —Ar 4 ;
R 5 is inter alia hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkoxy, —Z 5 —Ar 5 , —O—Z 5 —Ar 5 , etc;
where Z 1 to Z 5 , Ar 1 to Ar 5 , R a , R 21 , R 22 , and R 23 are as defined in the claims.

First claim

We claim:

1. A compound of formula (I)

wherein
X 1 is CH;
X 2 is C—R 5 ;
Y is O or S;
R 1 is selected from the group consisting of C 2 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 8 -cycloalkyl, C 5 -C 8 -cycloalkyl carrying a fused benzene ring, fluorinated C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, fluorinated C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-N(R b )(R c ) and a moiety Z 1 —Ar 1 ;
R 2 is a radical of the formula CR 21 R 22 R 23 , where
R 21 and R 22 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a saturated 5- to 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group consisting of O, N, S, SO and SO 2 as ring members, where the carbocyclic ring or the heterocyclic ring are unsubstituted or substituted by 1, 2 or 3 identical or different substituents R g , and where the carbocyclic ring or the heterocyclic ring carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents R h ,
R 23 is selected from the group consisting of hydrogen, fluorine, C 1 -C 8 -alkyl and C 1 -C 4 -fluoroalkyl;
R 3 is selected from the group consisting of hydrogen, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-N(R b )(R c ), and trimethylsilyl;

R 4 is selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl and Z 4 —Ar 4 ;
R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkoxy, —Z 5 —Ar 5 , —O—Z 5 —Ar 5 , C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkoxy and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkoxy, where the cyclic radical in the last four mentioned groups may be unsubstituted, partially or completely fluorinated or carries 1, 2, 3 or 4 methyl groups;
Ar 1 is selected from the group consisting of phenyl, monocyclic 5- or 6-membered hetaryl and bicyclic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R h ;
Ar 4 and Ar 5 are independently of each other selected from the group consisting of phenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R k ;
Z 1 , Z 4 , and Z 5 are independently of each other C 1 -C 4 -alkylene;
R b , and R c , independently of each other are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and benzyl; or R b and R c form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C 1 -C 4 -alkyl;
R d is selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and benzyl;
R e , and R f , independently of each other are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and benzyl; or R e and R form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group consisting of O, N, S, SO and SO 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 C 1 -C 4 -alkyl substituents;
R g is selected from the group consisting of halogen, CN, OH, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, fluorinated C 3 -C 6 -cycloalkyl-C i-C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-N(R b )(R c ), C 1 -C 4 -alkoxy, and fluorinated C 1 -C 4 -alkoxy, where one R g together with a carbon atom to which R g is attached may also form a carbonyl group, where one R g may also be phenyl or benzyl, where the phenyl ring in the last 2 mentioned radicals is unsubstituted or carries 1, 2 or 3 radicals R h ;
R h is selected from the group consisting of halogen, CN, OH, C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, fluorinated C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkoxy, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkoxy, phenoxy, N(R b )(R c ), C 1 -C 4 -alkyl-N(R b )(R c ), C(O)O—R d , C(O)N(R e )(R f ), N(R ee )S(O) 2 (R ff ), S(O) 2 N(R e )(R f ), 3- to 7-membered heterocyclyloxy, 3- to 7-membered heterocyclyl-C 1 -C 4 -alkoxy, where heterocyclyl in the two last mentioned radicals has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, and 5- to 6-membered hetaryl-C 1 -C 4 -alkoxy, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N;
R k is selected from the group consisting of halogen, CN, OH, C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluorinated C 1 -C 4 -alkoxy, N(R b )(R c ), C(O)O—R d , C(O)N(R e )(R f ), N(R ee )S(O) 2 (R ff ) and S(O) 2 N(R e )(R f ); or two radicals R k that are bound to adjacent carbon atoms together with said carbon atoms may form a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring members selected from the group consisting of O, N and S, where the fused benzene ring and the fused heteroaromatic ring are unsubstituted or may carry 1, 2 or 3 radicals R h ;
R ee is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and benzyl;
R ff is selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl and phenyl, which is unsubstituted or carries 1, 2 or 3 radicals R h ; and
m is 0, 1, 2, 3 or 4;

or an N-oxide, hydrate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , where R h is selected from the group consisting of halogen, CN, OH, C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluorinated C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, N(R b )(R c ), C 1 -C 4 -alkyl-N(R b )(R c ), C(O)O—R d , C(O)N(R e )(R f ), N(R ee )S(O) 2 (R ff ) and S(O) 2 N(R e )(R f ).

3. The compound of claim 1 , where Y is O.

4. The compound of claim 1 , where R 1 is C 2 -C 8 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkylmethyl.

5. The compound of claim 4 , where R 1 is a radical of the formula CHR 1a R 1b , where R 1a is selected from the group consisting of hydrogen and C 1 -C 3 -alkyl and where R 1b is C 1 -C 4 -alkyl.

6. The compound of claim 1 , where R 1 is a moiety Z

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Geneste Hervé
• Ochse Michael
• Drescher Karla
• Dinges Jürgen
• Jakob Clarissa

Classifications

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/18

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title