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Novel benzoazepine compound, composition and applications of novel benzoazepine compound and composition

A compound and heterocyclic group technology, applied in the field of new benzazepine compounds, can solve the problems of insufficient activity, side effects and physicochemical properties

Pending Publication Date: 2021-05-28
XUZHOU MEDICAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] As therapeutic drugs for the above diseases, benzazepines There are still some deficiencies in the activity, side effects and physicochemical properties of these compounds.

Method used

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  • Novel benzoazepine compound, composition and applications of novel benzoazepine compound and composition
  • Novel benzoazepine compound, composition and applications of novel benzoazepine compound and composition
  • Novel benzoazepine compound, composition and applications of novel benzoazepine compound and composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] N-(4-(7-chloro-5-((3-morpholinopropyl)amino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine Preparation of -1-carbonyl)-3-methylphenyl)-2-methylbenzamide (compound 1)

[0138] Step 1: N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine - Preparation of -1-carbonyl)-3-methylphenyl)-2-methylbenzamide (intermediate IV):

[0139]

[0140] Dissolve tolvaptan (1.0 g, 2.23 mmol) in dichloromethane (30 mL), add active manganese dioxide (1.0 g), and stir under reflux overnight. The solvent was evaporated to dryness under reduced pressure, and the solid residue was purified by silica gel column chromatography (eluent: 100% EA) to obtain light yellow oily intermediate IV (0.90 g, yield: 90.4%)

[0141] HRMS (ESI) calculated for C 26 h 24 Cl N 2 o 3 + [M+H] + 447.1470; Found: 447.1473

[0142] Step 2: N-(4-(7-chloro-5-((3-morpholinopropyl)amino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-carbonyl)-3-methylphenyl)-2-methylbenzamide (compound 1) preparation:

[0143] ...

Embodiment 2

[0147] N-(4-(7-chloro-5-((4-morpholinobutyl)amino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine Preparation of -1-carbonyl)-3-methylphenyl)-2-methylbenzamide (compound 2)

[0148] Step 1: Preparation of 4-morpholinobutyronitrile (intermediate V):

[0149]

[0150] 4-Chlorobutyronitrile (0.90 g, 8.69 mmol) was dissolved in morpholine (4.0 mL), and stirred overnight at room temperature. Silica gel column chromatography (eluent: MeOH / DCM = 1:20) separated intermediate V (0.85 g, yield: 63%) as a pale yellow transparent liquid. 1 H NMR (800MHz, CDCl 3 )δ3.75–3.65(m,4H),2.54–2.33(m,8H),1.87–1.78(m,2H).HRMS(ESI)calculated for C 8 h 15 N 2 o + [M+H] + 155.1179; Found: 155.1178.

[0151] Step 2: Preparation of 4-morpholino-1-butylamine (intermediate VI):

[0152]

[0153] Intermediate V (0.31 g, 2 mmol) was dissolved in methanol (10 mL), palladium / carbon catalyst (10% Pd, 300 mg) and concentrated hydrochloric acid (0.5 mL) were added. Stir at 45°C for 2 hours under hydrogen ...

Embodiment 3

[0158] N-(4-(7-chloro-5-((5-morpholinopentyl)amino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -1-carbonyl)-3-methylphenyl)-2-methylbenzamide (compound 3) preparation:

[0159]

[0160] The 4-chlorobutyronitrile in Step 1 of Example 2 was replaced by 5-bromovaleronitrile, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 2 to obtain white foamy compound (I-3). 1 H NMR (800MHz, CDCl 3 )δ7.70–6.45(m,10H),4.57–4.01(m,1H),3.87–3.64(m,5H),3.21–3.05(m,1H),2.71–2.39(m,14H),2.11– 1.97(m,2H),1.81–1.32(m,8H).HRMS(ESI)calculated for C 35 h 44 ClN 4 o 3 + [M+H] + 603.3096; Found: 603.3098.

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Abstract

The invention relates to a novel benzoazepine compound, which comprises a pharmaceutically acceptable salt thereof. The invention also provides a pharmaceutical composition containing the compound and the pharmaceutically acceptable salt thereof. The present invention also relates to the use of the compounds and said compositions in the prevention or treatment of diseases associated with the arginine vasopressin V1a receptor, the arginine vasopressin V1b receptor, the arginine vasopressin V2 receptor, the sympathetic nervous system or the renin-angiotensin-aldosterone system.

Description

technical field [0001] The present invention relates to novel benzazepine Compounds, compositions and uses thereof. Background technique [0002] Arginine vasopressin (AVP) is a naturally occurring neurohormone that is released in the brain and blood. AVP plays an important role in regulating water, blood pressure and the secretion of pituitary adrenocorticotropic hormone (ACTH), and exerts its physiological effects by binding to specific G protein-coupled receptors in the central nervous system and some peripheral parts or tissues. and behavioral effects. In the brain, AVP regulates circadian rhythms, promotes learning and memory in the hippocampus, and plays an important role in regulating social behavior in neurobehavioral disorders through actions in the limbic circuit. [0003] Three distinct AVP receptor subtypes have been identified on a pharmacological and functional basis: V 1a , V 1b and V 2 . These receptors are located in the liver, blood vessels (coronar...

Claims

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Application Information

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IPC IPC(8): C07D223/16C07D401/12A61K31/55A61P9/12A61P15/00A61P15/06A61P13/12A61P5/38A61P25/24A61P9/04A61P1/16
CPCC07D223/16C07D401/12A61P9/12A61P15/00A61P15/06A61P13/12A61P5/38A61P25/24A61P9/04A61P1/16
Inventor 郭栋曹旭东闫文仲程建军孙莹苏丽敏任莹王若琦张浩然袁昊星
Owner XUZHOU MEDICAL UNIV
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