Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Azinone and diazinone V3 inhibitors for depression and stress disorders

A compound, selected technology, applied in medical preparations containing active ingredients, extracellular fluid diseases, drug combinations, etc.

Active Publication Date: 2008-07-02
PHARMACOPEIA INC
View PDF5 Cites 9 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although there are a number of non-peptide low-molecular-weight antagonists known to be selective for V1a or V2 receptors (for a recent review see Freidinger and Pettibone, Medicinal Research Reviews, 1997, 17, 1-16), only a few known non-peptide The ligand is selective for the V3 receptor (see eg WO 01 / 55130 and WO 04 / 009585)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Azinone and diazinone V3 inhibitors for depression and stress disorders
  • Azinone and diazinone V3 inhibitors for depression and stress disorders
  • Azinone and diazinone V3 inhibitors for depression and stress disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1. Synthesis of Intermediates 1-4

[0144]

[0145]

[0146] step 1 :

[0147] 3-Methoxyacetophenone (18.0g, 120.0mmol) and dimethylformamide dimethyl acetal (37.5g, 315mmol) were directly mixed in a microwave reactor and irradiated with microwave energy to 200°C for 10min. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (SiO 2 ; eluting with 7:3 hexanes / EtOAc followed by 1:4.5:4.5 MeOH / EtOAc / hexanes), 26.0 g (100%) of enaminone 1-1 were collected as a dark orange-red oil.

[0148] 1-1 data: 1 H NMR (300MHz, CDCl3): δ7.75(d, 1H), 7.41(m, 2H), 7.23(d, 1H), 6.95(ddd, 1H), 5.64(d, 1H), 3.80(s, 3H ), 3.08 (br s, 3H), 2.87 (br s, 3H); MS (ESI), m / z (relative intensity, assigned) 206.1 (100, [M+H] + ).

[0149] step 2 :

[0150] To a solution of 1-1 (26.8 g, 130.5 mmol) in dimethylformamide (250 mL) were added sodium hydride (60%, 6.27 g, 261 mmol) and cyanoacetamide (11.0 g, 130.5 mmol). The mixture was the...

Embodiment 2

[0158] Example 2. Preparation 2-4

[0159]

[0160] step 1 :

[0161] To a solution of 1-4 (1 g; 3.75 mmol) in 80% EtOH(aq) (10 mL) was added KOH (843 mg; 15.02 mmol). The reaction mixture was then heated to reflux for 16h. The mixture was cooled to room temperature under H 2 Partition between O (100 mL) and EtOAc (50 mL). The aqueous phase was acidified to pH 3 using 2N HCl (aq) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried (MgSO 4 ), filtered and concentrated in vacuo to afford 990 mg (93%) of 2-1.

[0162] 2-1 data: 1 H NMR (300MHz, CDCl3): δ14.3(br s, 1H), 8.55(d, 1H), 7.41(dd, 1H), 7.08(dd, 1H), 6.92(d, 1H), 6.87(d, 1H), 6.50(d, 1H), 5.89(ddt, 1H), 5.23(d, 1H), 4.92(d, 1H), 4.62(d, 2H), 3.82(s, 3H); MS(ESI), m / z (relative intensity, assigned) 286.1 (79, [M+H] + ).

[0163] step 2 :

[0164] To a solution of 2-1 (223 mg; 0.78 mmol) in THF (5 mL) was added CDI (253 mg; 1.56 mmol). The reaction mixture was heated to 50 °C whi...

Embodiment 3

[0174] Example 3. Preparation 3-3

[0175]

[0176] step 1 :

[0177] To a solution of acid 2-1 (442 mg; 1.55 mmol) in THF (10 mL) was added CDI (0.51 g; 3.10 mmol). The reaction mixture was heated to 50 °C and stirred for 1.5 h. After the mixture was cooled, it was concentrated in vacuo and the crude residue was dissolved in EtOAc (100 mL) and H 2 O (50mL). The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo.

[0178] NaH (60%; 65 mg; 1.63 mmol) was added to N'-hydroxy-3-(piperidin-1-yl)propionamidine (319 mg; 1.86 mmol) and 4 Å molecular sieves (1 scoop) in DMF (10 mL) The mixture was stirred at 23 °C for 30 min. To this was added the above imidazolide as a solution in DMF (3 mL w / 2 mL flush) via cannula. The reaction mixture was heated to 80 °C for 3 h. After the mixture was cooled, the H 2 Partition between O (100 mL) and 3:1 DCM / i-PrOH (3 x 40 mL). The combined organic phases were washed with brine (1×50 mL), dried (K 2 CO 3 ), f...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Substituted pyridines, pyrimidines, pyrazines, pyridinones, pyrimidinones, pyrazinones and phenylacetamides useful in treating depression, stress and other disorders are disclosed. The compounds are of the following formulae.

Description

field of invention [0001] The present invention relates to a class of chemically substituted pyridines, pyrimidines, pyrazines, pyridones, pyrimidones, pyrazinones and phenylacetamides that are useful in the treatment of depression, stress and other disorders. Background of the invention [0002] The hypothalamic-pituitary-adrenal (HPA) axis is the major axis of stress in humans and other mammals. Various stressors (and many other types of stimuli) can cause the release of the hormone ACTH (adrenocorticotropic hormone) from the pituitary gland. After ACTH enters the systemic circulation, it acts on the adrenal cortex to promote the synthesis and release of glucocorticoids (the main endogenous glucocorticoid in humans is hydrocortisone, and the main endogenous glucocorticoid in rodents is adrenal ketone). Glucocorticoids exert a broad spectrum of action and their main purpose is to mobilize various sources of energy for a successful response to, and eventual adaptation to, a...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4412A61K31/50A61K31/505C07D213/82C07D413/04C07D239/36C07D403/04C07D295/088C07D239/30C07D403/12A61P25/24
CPCC07D213/82C07D239/26C07D239/36C07D241/24C07D295/088C07D403/04C07D403/12C07D413/04A61P1/00A61P25/00A61P25/20A61P25/22A61P25/24A61P35/00A61P43/00A61P5/46A61P7/10
Inventor J·J·莱图尔诺何国勤M·J·奥尔迈耶P·乔基尔C·M·里维埃罗
Owner PHARMACOPEIA INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com