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
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[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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