For use in the treatment of neurological disorders or metabolic combinations used in obstacles

A technology of PDE10 and inhibitors, applied in the field of phosphodiesterase 2 inhibitors

Active Publication Date: 2018-03-06
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Thus, PDE10 inhibitors may have a pharmacological profile similar to current antipsychotic drugs that primarily treat the positive symptoms of schizophrenia, but PDE10 inhibitors also have the potential to improve the negative and cognitive symptoms of schizophrenia, Concomitant lack of non-target related side effects such as EPS or prolactin release commonly observed with currently effective antipsychotics

Method used

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  • For use in the treatment of neurological disorders or metabolic combinations used in obstacles
  • For use in the treatment of neurological disorders or metabolic combinations used in obstacles
  • For use in the treatment of neurological disorders or metabolic combinations used in obstacles

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0471] Examples 1a and 1b

[0472] 1-(5-Butoxypyridin-3-yl)-4-methyl-8-(morpholin-4-ylmethyl)[1,2,4]triazol[4,3-a]quinoxa Phenoline hydrochloride (B-1a) and oxalate (B-1b)

[0473]

[0474] .2HCl(B-1a) or .x C 2 h 2 o 4 (B-1b)

[0475] Formation of B-1a

[0476] To intermediate compound I-5 (7.5g, 18.19mmol) in THF / H 2 Add Pd(AcO) to a solution in O (10:1, 180 mL) 2 (0.12g, 0.54mmol), XantPhos (0.52g, 1.09mmol), Cs 2 CO 3 (23.88 g, 72.76 mmol) and intermediate compound 1-20 (4.51 g, 21.82 mmol). The reaction mixture was closed in a sealed tube and stirred at room temperature for 10 min and then at 114 °C for 45 min. Then, the crude mixture was washed with EtOAc and H 2 Diluted with O, the organic layer was separated and dried (MgSO 4 ), filtered and the solvent was concentrated in vacuo. The crude mixture was purified by chromatography (silica, MeOH in DCM, 0 / 100 to 2 / 98), the desired fractions were collected and the solvent was concentrated in vacuo to give ...

example 2

[0481] 1-(5-Butoxy-2-chlorophenyl)-4-methyl-8-(morpholin-4-ylmethyl)[1,2,4]triazole-[4,3-a] Quinoxaline hydrochloride (B-2)

[0482]

[0483] B-2 was synthesized as previously described for the synthesis of final compound B-1a. Starting from I-11a (0.2 g, 0.45 mmol) and intermediate I-20, the final compound B-2 (0.03 g, 14%) was obtained. 1 HNMR (300MHz, DMSO-d 6 )δppm 0.93(t, J=7.4Hz, 3H), 1.44(sxt, J=7.3Hz, 2H), 1.73(quin, J=6.9Hz, 2H), 2.93(br.s., 1H), 2.97( s,3H),3.19(br.s.,1H),3.77(br.s.,2H),3.92(br.s.,2H),3.98-4.14(m,2H),4.31(br.s. ,2H),5.76(s,2H),7.25(br.s,1H),7.33-7.50(m,2H),7.73(d,J=8.8Hz,1H),7.96(br.s.,1H) , 8.16 (d, J=8.1 Hz, 1H), 11.31 (br.s., 1H).

example 3

[0485] 1-(2-Chlorophenyl)-4-methyl-8-(morpholin-4-ylmethyl)[1,2,4]triazol[4,3-a]-quinoxaline (B- 3)

[0486]

[0487] To a stirred solution of Intermediate 1-8 (2.3 g, 7.12 mmol) dissolved in DCE (50 mL) was added morpholine (1.37 mL, 15.67 mmol) and the mixture was heated at 80 °C for 15 min under microwave irradiation (with The reaction was divided into three batches). Sodium triacetoxyborohydride (1.81 g, 8.55 mmol) was then added in portions and the mixture was heated again under the same conditions as previously described for 20 min. The mixture was then treated with H 2 O quenched and extracted with DCM. The organic layer was separated and dried (Na 2 SO 4 ), filtered and evaporated the solvent in vacuo. The crude compound was purified by chromatography (silica, MeOH in EtOAC, 2 / 98 to 10 / 90), the desired fractions were collected and the solvent was evaporated to give the final compound as a light yellow solid B-3 (1.6 g, 57%), this compound was further washed w...

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PUM

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Abstract

The present invention relates to combinations of inhibitors of phosphodiesterase 2 (PDE2) and inhibitors of phosphodiesterase 10 (PDE10). In particular, the present invention relates to 1-aryl-4-methyl-[1,2,4]triazol[4,3-a]-quinoxaline derivatives and inhibitors of phosphodiesterase 10 (PDE10) Combination of this derivative has been found to inhibit phosphodiesterase 2 (PDE2). Particular PDE10 inhibitors are selected from the group consisting of MP-10, PQ-10, TP-10, papaverine, and compounds disclosed in WO 2011 / 051342 and WO 2011 / 110545. The invention also relates to pharmaceutical compositions comprising these combinations, to processes for the preparation of these compositions, to PDE2 inhibitors, in particular 1-aryl-4-methyl-[1,2,4]triazole[ 4,3-a]-quinoxaline derivatives for the enhanced use of said PDE10 inhibitors and to said PDE10 inhibitors for said PDE2 inhibitors, in particular 1-aryl-4-methyl Use of ‑[1,2,4]triazol[4,3‑a]‑quinoxaline derivatives for enhancing the effect and to the use of these combinations and compositions for the prevention and treatment of disorders involving PDE2 and PDE10 , such disorders as neurological and psychiatric disorders, and endocrine or metabolic diseases.

Description

field of invention [0001] The present invention relates to combinations of inhibitors of phosphodiesterase 2 (PDE2) and inhibitors of phosphodiesterase 10 (PDE10). In particular, the present invention relates to 1-aryl-4-methyl-[1,2,4]triazol[4,3-a]-quinoxaline derivatives and inhibitors of phosphodiesterase 10 (PDE10) Combination of this derivative has been found to inhibit phosphodiesterase 2 (PDE2). Particular PDE10 inhibitors are selected from the group consisting of MP-10, PQ-10, TP-10, papaverine, and compounds disclosed in WO 2011 / 051324 and WO 2011 / 110545. The invention also relates to pharmaceutical compositions comprising these combinations, to processes for the preparation of these compositions, to PDE2 inhibitors, in particular 1-aryl-4-methyl-[1,2,4]triazoles [ Use of 4,3-a]-quinoxaline derivatives for the enhancement of said PDE10 inhibitors and to said PDE10 inhibitors for said PDE2 inhibitors, in particular 1-aryl-4-methyl - the use of [1,2,4]triazol[4,3-a]-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4709A61K31/517A61K31/5377A61P21/00A61K45/06A61K31/4725A61K31/472
CPCA61K45/06A61K31/4709A61K31/472A61K31/4725A61K31/517A61K31/5377A61P21/00A61P25/00A61P25/04A61P25/18A61P25/22A61P25/28A61P25/36A61P3/00A61P43/00A61P5/00A61K2300/00A61K49/06
Inventor A.A.H.P.梅根斯X.J.M.兰格洛伊斯G.C.P.范霍夫J.I.安德雷斯-吉尔M.德安格里斯P.J.J.A.布伊恩斯特斯A.A.特拉班科-苏亚雷兹F.J.R.罗姆博特斯
Owner JANSSEN PHARMA NV
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