Novel cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators

A technology of alkylamino and alkyl, which is applied in the direction of extracellular fluid diseases, drug combinations, diseases, etc., and can solve the problems of lack of oral activity

Inactive Publication Date: 2004-06-02
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Peptide oxytocin antagonists lack oral activity as they also display vasopressin antagonist activity and many of these peptides are non-selective antagonists

Method used

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  • Novel cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators
  • Novel cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators
  • Novel cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators

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preparation example Construction

[0118] The present invention also provides processes for the preparation of the compounds of the present invention.

[0119] Method of the invention

[0120] Compounds of the invention can be prepared according to one of the general methods outlined below.

[0121] A compound of general formula (1), wherein: , R 3 and R 4 As defined above, it can be prepared according to the method shown in Flowchart I very conveniently.

[0122] Flowchart I

[0123]

[0124] Thus, in the presence of an inorganic base such as potassium carbonate, or an organic base such as pyridine, 4-(dimethylamino)pyridine, or a tertiary amine such as triethylamine or N,N-diisopropylethylamine In the presence of an aprotic solvent, such as dichloromethane, N, N-dimethylformamide or tetrahydrofuran, at a temperature of -5 ° C to 50 ° C, with an appropriately substituted acylating agent, such as aromatic Acyl halides, preferably suitably substituted acid chlorides or bromides of...

Embodiment 1

[0206] 10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1 , 4] Benzodiazepines

[0207] Step A. Methyl 4-amino-5-chloro-2-methoxybenzoate

[0208] 4-Amino-5-chloro-2-methoxybenzoic acid (50.0 g, 248 mmol) was suspended in methanol (500 mL) and the slurry was cooled to 0°C. Thionyl chloride (54.3 mL, 744 mmol) was then added dropwise over 20 minutes. A clear solution initially formed, which later turned into a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. The solvent was evaporated and the resulting slurry was suspended in ether (1 L). The solid was filtered and rinsed well with ether to give the hydrochloride salt of the title compound (50.9 g). The salt was suspended in 1N sodium hydroxide and stirred vigorously for 30 minutes. Filtration, rinsing thoroughly with water gave the free base as a white solid, mp 136-137°C.

[0209] 1 H NMR (DMSO-d 6 , 400MHz): 87.57(s, 1H), 6.43(s, 1H), 6.14(s, 2...

Embodiment 2

[0242] Example 2: (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-(4-cyclohex-1-ene- 1-yl-3-methyl-phenyl)-methanone;

[0243] Step A. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-(4-bromo-3-methylphenyl )-methanone

[0244] To a stirred mixture of 4-bromo-3-methylbenzoic acid (21.5 g, 100 mmol) and N,N-dimethylformamide (0.251 mL, 3.00 mmol) in anhydrous dichloromethane (200 mL) Oxalyl chloride (9.16 mL, 105 mmol) was added dropwise. The mixture was heated to reflux for 1.5 hours, then cooled to room temperature and the solvent was evaporated. Fresh anhydrous dichloromethane (200 mL) was added, the resulting solution was concentrated, and the residue was dried in vacuo. The crude acid chloride thus obtained and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (17.5 g, 95.0 mmol) were dissolved in anhydrous dichloro Methane (200 mL) was mixed followed by N,N-diisopropylethylamine (19.2 mL, 110 mmol). After stirring at room temperature for 18 ho...

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Abstract

The present invention provides novel tricyclic diazepine compounds and methods and pharmaceutical compositions utilizing them for the treating or preventing disorders including diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding and coagulation disorders, congestive heart failure or for inducing temporary delay of urination, and in conditions with increased vascular resistance and coronary vasoconstriction; and for the treating or preventing disorders remedied or alleviated by oxytocin antagonist activity, including suppression of preterm labor, dysmenorrhea, endometritis, and for suppressing labor at term prior to caesarean delivery. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders.

Description

[0001] The present invention relates to a novel tricyclic diazepine having affinity for vasopressin and / or oxytocin receptors, which can be used as a modulator of vasopressin and / or oxytocin action in vivo, and its preparation method, Methods of treatment and pharmaceutical compositions using these compounds. [0002] The compounds of the present invention can be used as therapeutic agents to treat conditions in mammals, especially humans, where it is desired to reduce vasopressin concentrations, such as congestive heart failure, conditions with excessive renal water reabsorption and increased vascular resistance and coronary vasoconstriction situation. They are also useful as therapeutic agents in the treatment of diseases in mammals, especially humans, affecting the vasopressin system characterized by excretion of excessively large amounts of dilute urine, including central or nephrogenic diabetes insipidus, in the treatment of nocturnal enuresis, nocturia , urinary incontine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517A61P5/06A61P5/10A61P7/02A61P7/04A61P13/02A61P15/00A61P43/00C07D487/04
CPCC07D487/04A61P13/02A61P15/00A61P15/06A61P43/00A61P5/06A61P5/10A61P7/02A61P7/04
Inventor 阿米德·阿图罗·法伊利威廉·詹宁斯·桑德斯尤金·约翰·特雷布尔斯基
Owner WYETH LLC
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