Inhibitor compounds of phosphodiesterase type 10A

Patent metadata

Field	Value
Publication number	US-9938269-B2
Application number	US-201213534127-A
Country	US
Kind code	B2
Filing date	Jun 27, 2012
Priority date	Jun 30, 2011
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

The present invention relates to novel carboxamide compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating or controlling 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 compound of formula (I)

wherein
X 1 is N;
X 2 is N or C—R 2 ;
X 3 is N or C—R 3 ;
X 4 is N or C—R 4 ;
provided that 1 or 2 of the moieties X 1 , X 2 , X 3 or X 4 is N;
A is selected from the group consisting of O, S, S(═O), S(═O) 2 , NR 5a and CR 5 R 6 ;
Het is
i. monocyclic 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 x ,
ii. fused bicyclic 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, benzothienyl or benzofuryl, where bicyclic hetaryl, benzothienyl and benzofuryl are, independently of each other, unsubstituted or may carry 1, 2, 3 or 4 identical or different substituents R x , or
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 x ,
where
R x is selected from the group consisting of H, 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, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, OH, hydroxy-C 1 -C 4 -alkyl, O—C 3 -C 6 -cycloalkyl, benzyloxy, C(O)O—(C 1 -C 4 -alkyl), O—(C 1 -C 4 -alkyl)-CO 2 H, N(R x1 )(R x2 ), C(O)N(R x1 )(R x2 ), C 1 -C 4 -alkyl-N(R x1 )(R x2 ), —NR x3 —C(O)—N(R x1 )(R x2 ), NR x3 —C(O)O—(C 1 -C 4 -alkyl), —N(R x3 )—SO 2 —R x4 , phenyl, CN, —SF 5 , —OSF 5 , —SO 2 R x4 , —SR x4 and trimethylsilyl, where R x1 , R x2 , R x3 and R x4 , independently of each other are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl and C 3 -C 6 -cycloalkyl or R x1 and R x2 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 4 is Y-Cyc;
R 2 , R 3 independently of each other, are selected from the group consisting of hydrogen, halogen, OH, C 1 -C 4 -alkyl, trimethylsilyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy, C 2 -C 4 -alkenyloxy, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN, NR x1 R x2 and the moiety Y-Cyc;
provided that one or two or the radicals R 2 , R 3 , R 4 are Y-Cyc;
R 5 , R 6 independently of each other, are selected from the group consisting of hydrogen, OH, 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 5 , R 6 together with the carbon atom to which they are bound form a carbonyl group or a saturated 3- to 6-membered carbocycle or a saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine and methyl;
R 5a is selected from the group consisting of from 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, optionally substituted by 1, 2 or 3 methyl groups, fluorinated C 3 -C 6 -cycloalkyl, phenyl, benzyl, 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, and 5- or 6-membered hetarylmethyl having 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, where the rings in the last four mentioned radicals are unsubstituted or carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -fluoroalkoxy;
R 7 , R 8 , R 9 , R 10 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, and C 3 -C 6 -cycloalkyl, or the radicals together with the carbon atoms 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 as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine and methyl or either the radicals R 7 , R 8 or the radicals R 9 , R 10 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 as ring members, where the carbocycle and the heterocycle are unsubstituted or may carry 1, 2, 3 or 4 substituents selected from the group consisting of fluorine and methyl;
Y is a chemical bond, CH 2 , O, O—CH 2 , NR y , NR y —CH 2 , NR y —S(O) 2 , S, S(O), S(O) 2 , 1,2-ethandiyl, 1,2-ethendiyl or 1,2-ethyndiyl, where R y is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -fluoroalkylsulfonyl;
Cyc is a radical selected from the group consisting of phenyl, naphthyl, 4- to 8-membered saturated or partially unsaturated monocarbocyclic radicals, 7- to 10-membered saturated or partially unsaturated bicarbocyclic radicals, 4- 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 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 phenyl, naphthyl, the saturated or partially unsaturated mono- and bicarbocyclic radicals, the heteromonocyclic and heterobicyclic radicals and the mono and bicyclic heteroaromatic 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
R C1 is selected from the group consisting of hydrogen, 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 a , Z—C(O)OR b , Z—C(O)NR c R d , S(O) 2 NR c R d and Z—NR e R f , where
R a is selected from the group consisting of C 1 -C 4 -alkyl and C 1 -C 4 -fluoroalkyl,
R b is 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 is 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 is 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,
Z is a covalent bond or C 1 -C 4 -alkandi

Assignees

• Geneste Herve
• Ochse Michael
• Drescher Karla
• Behl Berthold
• Laplanche Loic
• Dinges Juergen
• Jakob Clarissa
• Jantos Katja
• Abbvie Inc
• Abbvie Deutschland

Inventors

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

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/18

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