Inhibitor compounds of phosphodiesterase type 10A

Patent metadata

Field	Value
Publication number	US-9475808-B2
Application number	US-201514854835-A
Country	US
Kind code	B2
Filing date	Sep 15, 2015
Priority date	Mar 14, 2013
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention relates to compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof:

In formula I the variables Het, A, X, Y, Z, R1, R2, R3, R4, R5 and Q are as defined in the claims.
The compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof are inhibitors of phosphodiesterase type 10A. Thus, the invention also relates to the use of the compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof 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.

First claim

We claim:

1. A method for treating a medical disorder, selected from the group consisting of schizophrenia, cognitive dysfunction associated with schizophrenia, a bipolar disorder, depression, cognitive dysfunction associated with Alzheimer's disease, diet-induced obesity, Huntington's disease, and anxiety which can be treated by inhibition of phosphodiesterase type 10A, said method comprising administering an effective amount of at least one compound of formula (I) to a subject in need thereof:

wherein
X is CR x1 R x2 or C(O), where
R x1 and R x2 , independently of each other are selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl, or the radicals R x1 and R x2 , together with the carbon atom to which they are bound, form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms, which are independently selected from the group consisting of O, S and N, as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents independently selected from the group consisting of fluorine and methyl;

Y is CR y1 R y2 or C(O), where
R y1 and R y2 , independently of each other are selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl, or the radicals R y1 and R y2 , together with the carbon atom to which they are bound, form a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms, which are independently selected from the group consisting of O, S and N, as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents independently selected from the group consisting of fluorine and methyl;
provided that one or both of X and Y is/are C(O);

A is O, [C(R 6 ,R 7 )] k with k=1 or 2, OC(R 6 ,R 7 ), C(R 8 )═C(R 9 ) or C≡C;
Het is independently selected from the group consisting of
i. monocyclic 5- or 6-membered hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from the group consisting of O, S and N as ring members, which is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R a ,
ii. fused 8-, 9- or 10-membered bicyclic hetaryl having one heteroatom selected from the group consisting of O, S and N and optionally 1, 2 or 3 nitrogen atoms as ring members, where the fused bicyclic hetaryl is unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R a , and
iii. phenyl, which carries a monocyclic hetaryl radical having 1 or 2 nitrogen atoms and optionally a further heteroatom selected from the group consisting of O, S and N as ring members, which in addition to monocyclic hetaryl, may carry 1, 2 or 3 identical or different substituents R aa , and where hetaryl is unsubstituted or carries 1, 2 or 3 radicals R a ;
R a is independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 3 -C 6 -cycloalkyl, cyclopropyl substituted by 1, 2 or 3 methyl groups, fluorinated C 3 -C 6 -cycloalkyl, O—C 3 -C 6 -cycloalkyl, benzyloxy, C(O)O—(C 1 -C 4 -alkyl), O—(C 1 -C 4 -alkyl)-CO 2 H, C 1 -C 4 -alkyl-OR 11 , C 1 -C 4 -alkyl-SR 12 , C 1 -C 4 -alkyl-NR 13 R 14 , C 1 -C 6 -alkoxy, OC 1 -C 4 -alkyl-OR 11 , OC 1 -C 4 -alkyl-SR 12 , OC 1 -C 4 -alkyl-NR 13 R 14 , NR 13 R 14 , C(O)NR 13 R 14 , C 1 -C 4 -alkyl-NR 13 R 14 , —NR 15 —C(O)—NR 13 R 14 , NR 15 —C(O)O—(C 1 -C 4 -alkyl), —NR 15 —SO 2 —R 12 , CN, —SF 5 , —OSF 5 , —SO 2 R 12 , —SR 12 and trimethylsilyl, or
two radicals R a , which are bound to adjacent ring atoms may also form linear C 3 -C 5 -alkanediyl, wherein 1 or 2 CH 2 moieties can be replaced by C═O, O, S, S(═O), S(═O) 2 or NR′, and where alkanediyl is unsubstituted or may carry 1 or 2 radicals independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -fluoroalkoxy;

R aa has one of the meanings given for R a or one radical R aa may also be phenyl or a 5- or 6-membered hetaryl having 1 or 2 nitrogen atoms and optionally a further heteroatom independently selected from the group consisting of O, S and N as ring members, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 radicals independently selected from the group consisting of halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy;

Q is O or S;
Z is independently selected from the group consisting of a chemical bond, CH 2 , O, O—CH 2 , C(O)O, C(O), NR z , NR z —CH 2 , S(O) 2 —NR z , C(O)—NR z , S, S(O), S(O) 2 , C(O)—O—CH 2 , C(O)—NR z —CH 2 , 1,2-ethanediyl, 1,2-ethenediyl and 1,2-ethynediyl, where R z is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylsulfonyl, and C 1 -C 4 -fluoroalkylsulfonyl;
R 1 is independently selected from the group consisting of phenyl, naphthyl, C 3 -C 8 -cycloalkyl, 3- to 8-membered saturated or partially unsaturated heteromonocyclic radicals, saturated or partially unsaturated 7- to 10-membered heterobicyclic radicals, 5- or 6-membered monocyclic hetaryl, and 8- to 10-membered bicyclic hetaryl, where the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals have 1, 2, 3 or 4 heteroatoms or heteroatom containing groups as ring members, which are selected from the group consisting of O, S, SO, SO 2 and N, and where the 5- or 6-membered monocyclic hetaryl and the 8- to 10-membered bicyclic hetaryl have 1, 2, 3 or 4 heteroatoms as ring members, which are selected from the group consisting of O, S and N, where C 3 -C 8 -cycloalkyl, the saturated or partially unsaturated heteromonocyclic and heterobicyclic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R C1 or one radical Y′—R C2 and 0, 1, 2, 3 or 4 radicals R C1 ; where phenyl, naphthyl, the mono and bicyclic heteroaromatic radicals are unsubstituted or carry 1, 2, 3, 4 or 5 radicals R C3 or one radical Y′—R C2 and 0, 1, 2, 3 or 4 radicals R C3 ; where
R C1 is independently selected from the group consisting of halogen, OH, CN, NO 2 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulfanyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, cyano-C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, C 1 -C 4 -alkylsulfonyl, C(O)R h , Z′—C(O)OR b , Z′—C(O)NR c R d , NR g SO 2 R h , S(O) 2 NR c R d and Z′—NR e R f , where
R b , R g independently of each other are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 1 -C 4 -fluoroalkyl,
R c , R d independently of each other are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy,
R e , 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 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy,
R h is independently selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -fluoroalkyl,
Z′ is a covalent bond or C 1 -C 4 -alkanediyl,
or two radicals R C1 which are bound at adjacent carbon atoms may form a fused 5- or 6-membered carbocyclic radical or a fused 5- or 6-membered heterocyclic r

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Geneste Hervé
• Ochse Michael
• Drescher Karla
• Behl Berthold
• Laplanche Loic
• Dinges Jürgen
• Jakob Clarissa

Classifications

• A61P43/00

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

• A61P25/18

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title