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Methods of treating depression using orexin-2 receptor antagonists

A depression, subject technology, used in pill delivery, pharmaceutical formulations, liquid delivery, etc., to solve problems such as unmet medical needs

Active Publication Date: 2018-11-23
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There remains a high, unmet medical need to provide effective treatments for depression

Method used

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  • Methods of treating depression using orexin-2 receptor antagonists
  • Methods of treating depression using orexin-2 receptor antagonists
  • Methods of treating depression using orexin-2 receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] This example was performed to determine that [5(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2[ 1,2,3] Triazol-2-yl-phenyl)-methanone (compound A) plasma pharmacokinetics (PK) and biological utilization rate. The effect of semi-fasting conditions on the bioavailability of solid dosage formulations and the degree of tolerability of solid and oral suspension formulations is also discussed.

[0151] (i) Reagents and test parameters

[0152] [5(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3 ]triazol-2-yl-phenyl)-methanone (Compound A) was prepared as described in Method B in Example 107 of U.S. Pat. crystallization.

[0153] The internal standard is isotopically labeled [5(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2- [1,2,3]Triazol-2-yl-phenyl)-methanone, which has the following structure.

[0154]

[0155] The internal standard was prepared as described in Meth...

Embodiment 2

[0239] This example was conducted as a multicentre double-blind diphenhydramine and placebo controlled study. Men and women diagnosed with MDD between the ages of 18 and 64 (inclusive) were enrolled. At screening, subjects are on IDS-C 30 A total score of ≥30 corresponds to moderate to severe depression.

[0240] Blood and saliva are collected for evaluation of biomarkers, among other things. Venous blood samples (3 mL each) were collected under fasting conditions between 8:00 and 10:00 am for the determination of [5(4,6-dimethyl-pyrimidin-2-yl)-hexa Hydrogen-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone plasma concentration and correlation with immune Systemic activity-related biomarkers measuring hypothalamic-pituitary-adrenal (HPA) axis activation, neurotrophic factors, and metabolic factors. Pharmacokinetic (PK) blood samples were also collected. Plasma samples were analyzed to determine the concentration of Compound A using LC-MS / MS. S...

Embodiment 3

[0271] This example was performed to show that Compound A can be used in adjuvant therapy. Specifically, Compound A was administered to subjects diagnosed with MDD (i) as monotherapy and (ii) in combination with known antidepressants, and the subjects were assessed for depression using the HDRS17 and HAM-D6 scales symptom.

[0272] In Group 1, thirty-seven subjects were randomized (in a 2:1:1 ratio) to 20 mg Compound A, 25 mg diphenhydramine, or placebo q.d. in the evening after 10 days. In Group 2, ten subjects were randomized (in a 2:1:1 ratio) to 20 mg of Compound A, 25 mg of diphenhydramine, or placebo q.d. in the evening after 10 days. Each subject in Group 2 also took an amount of an antidepressant selected from duloxetine, citalopram, paroxetine, or sertraline, and as prescribed by their attending physician. Specified. To assess depressive symptoms in both groups, at screening and on day 11, i.e., the day after the 17 and HAM-D 6 Evaluations were performed independ...

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Abstract

The present disclosure is directed to, inter alia, methods of treating a subject suffering from or diagnosed with depression, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 to R4 are described herein and wherein the compound is administered prior to sleep.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 62 / 306,487, filed March 10, 2016, which is incorporated herein by reference. technical field [0003] The present disclosure relates to methods for treating depression, among other things. Background technique [0004] Orexin (also known as hypocretin) is a neuropeptide expressed by neurons in the peripheral area, the dorsomedial hypothalamus, and the lateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al., 1998, Cell 92, 573-585). Orexin neurons project to many regions of the brain, including other hypothalamic nuclei, midline paraventricular thalamus, brainstem nuclei, ventral tegmental area, and nucleus accumbens shell. (Peyron et al., 1998, J.Neurosci.18, 9996-10016) The orexin neuropeptide (classified as orexin-A or orexin-B) binds to seven transmembrane G protein-coupled receptors orexin- 1 (O...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/498A61K31/5377
CPCA61K31/506A61K45/06A61P25/24A61K2300/00A61K9/0095A61K9/10A61K47/38A61K9/2018A61K9/2027A61P43/00A61K31/50A61K31/53A61K9/0053
Inventor J.M.肯特W.C.德瑞维茨P.德波尔
Owner JANSSEN PHARMA NV
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