Benzazepines compounds serving as vasopressin receptor antagonism

Abstract

The invention relates to a benzazepines compounds serving as vasopressin receptor antagonism, in particular to a benzazepines compound shown in formula (I) or pharmaceutically acceptable salt thereof and a preparation method thereof, and a medicinal composition containing a compound containing curative dose of the compound or the pharmaceutically acceptable salt thereof, and application in preparing medicament for treating diseases related to the vasopressin thereof.

Description

technical field

[0001] The present invention relates to a benzoazepine compound or a pharmaceutically acceptable salt thereof and a preparation method thereof, as well as a pharmaceutical composition containing a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, and its preparation for treatment and Use in medicine for vasopressin-related diseases. Background technique

[0002] Vasopressin is a nonapeptide hormone mainly secreted by the posterior pituitary gland. The hormone acts through vascular V1 receptors and renal V2 receptor subtypes. The V2 receptors in the kidney can stimulate adenylate cyclase to achieve Urinary effect. Vasopressin receptor antagonists are widely used and can be used to treat the following diseases: hypertension, congestive heart failure, liver cirrhosis, renal failure, cerebral edema, etc.

[0003] Benzoazepines are a class of small molecule vasopressin V2 receptor antagonists, and tolvaptan is the fi...

Examples

Embodiment 1

[0027] N-[4-[5-(2-aminoacetoxy)-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-benzene represented by formula (V) The preparation of base]-2-methylbenzamide hydrochloride

[0028]

[0029] Include the following steps:

[0030] 1) Preparation of N-[4-[5-hydroxyl-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-phenyl]-2-methylbenzamide

[0031] N-[4-[5-oxo-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-phenyl]-2-methylbenzamide 2 g In 10ml of methanol and 10ml of THF mixture, add 0.8g of sodium borohydride twice at room temperature, stir for 1 hour after the addition, concentrate to remove the solvent, add 30ml of water to the residue, stir for 1 hour, filter, and dry to obtain a light yellow powder, MS- ESI: 401.5 [M+H].

[0032] 2) Preparation of N-[4-[5-(2-(N-tert-butoxycarbonyl)aminoacetoxy)-2,3,4,5-tetrahydro-1-benzazepine-1-methyl Acyl]-phenyl]-2-methylbenzamide hydrochloride

[0033] Add 494 mg of the product in 1), 475 mg of BOC-glycine to 20 ml of dichloromethane, add 500 mg...

Embodiment 2

[0037] N-[4-[5-(2-amino-3-methylbutyryloxy)-2,3,4,5-tetrahydro-1-benzazepine-1 represented by formula (VI) Preparation of -formyl]-phenyl]-2-methylbenzamide hydrochloride

[0038]

[0039] Following the same method as in Example 1, except that glycine was replaced by valine, an off-white solid was obtained, melting point: 183-185° C., MS-ESI: 501.5 [M+H].

technical field

[0001] The present invention relates to a benzoazepine compound or a pharmaceutically acceptable salt thereof and a preparation method thereof, as well as a pharmaceutical composition containing a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, and its preparation for treatment and Use in medicine for vasopressin-related diseases. Background technique

[0002] Vasopressin is a nonapeptide hormone mainly secreted by the posterior pituitary gland. The hormone acts through vascular V1 receptors and renal V2 receptor subtypes. The V2 receptors in the kidney can stimulate adenylate cyclase to achieve Urinary effect. Vasopressin receptor antagonists are widely used and can be used to treat the following diseases: hypertension, congestive heart failure, liver cirrhosis, renal failure, cerebral edema, etc.

[0003] Benzoazepines are a class of small molecule vasopressin V2 receptor antagonists, and tolvaptan is the fi...

Examples

Embodiment 1

[0027] N-[4-[5-(2-aminoacetoxy)-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-benzene represented by formula (V) The preparation of base]-2-methylbenzamide hydrochloride

[0028]

[0029] Include the following steps:

[0030] 1) Preparation of N-[4-[5-hydroxyl-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-phenyl]-2-methylbenzamide

[0031] N-[4-[5-oxo-2,3,4,5-tetrahydro-1-benzazepine-1-formyl]-phenyl]-2-methylbenzamide 2 g In 10ml of methanol and 10ml of THF mixture, add 0.8g of sodium borohydride twice at room temperature, stir for 1 hour after the addition, concentrate to remove the solvent, add 30ml of water to the residue, stir for 1 hour, filter, and dry to obtain a light yellow powder, MS- ESI: 401.5 [M+H].

[0032] 2) Preparation of N-[4-[5-(2-(N-tert-butoxycarbonyl)aminoacetoxy)-2,3,4,5-tetrahydro-1-benzazepine-1-methyl Acyl]-phenyl]-2-methylbenzamide hydrochloride

[0033] Add 494 mg of the product in 1), 475 mg of BOC-glycine to 20 ml of dichloromethane, add 500 mg...

Embodiment 2

[0037] N-[4-[5-(2-amino-3-methylbutyryloxy)-2,3,4,5-tetrahydro-1-benzazepine-1 represented by formula (VI) Preparation of -formyl]-phenyl]-2-methylbenzamide hydrochloride

[0038]

[0039] Following the same method as in Example 1, except that glycine was replaced by valine, an off-white solid was obtained, melting point: 183-185° C., MS-ESI: 501.5 [M+H].

Images