Tricyclic vasopressin agonists

A kind of technology of heterocyclic group and trifluoromethyl group is applied in the field of pyridotricyclic compounds or their medicinal salts to achieve the effect of good oral bioavailability

Inactive Publication Date: 2004-08-18
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Peptide vasopressin antagonists have the disadvantage of lacking oral activity, and many such peptides are not antagonists of choice because they also show partial agonist activity

Method used

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  • Tricyclic vasopressin agonists
  • Tricyclic vasopressin agonists
  • Tricyclic vasopressin agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0257] [2-Chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5,11-dihydro -pyrido[2,3-b][1,5]benzodiazepine-6-yl)-methanone

[0258] Step A. 6, 11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-5-one and hydrochloric acid 1:1 salt

[0259] A mixture of 1,2-phenylenediamine (52 g, 480 mmol) and chloronicotinic acid (76 g, 482 mmol) in cyclohexanol (480 mL) was refluxed under nitrogen for 2.5 hours. Precipitation appeared shortly after heating was started. With vigorous stirring, the hot reaction mixture was carefully poured into ice-cooled dichloromethane (1000 mL). The semisolid material was collected, washed well with dichloromethane and dried in vacuo to yield 98.9 g (83%) of the title compound, which was used in the next reaction without purification.

[0260]Step B. 6,11-Dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine

[0261] The diborane dimethyl sulfide complex (35 mL) was added via syringe to the 6,11-dihydro-5H-pyrido[2,3-b][1,5 ] Benzodiazepine-5-one and hydrochloric acid 1:...

Embodiment 2

[0273] [2-Chloro-4-(5-methyl-pyrazol-1-yl)-phenyl]-(5,11-di Hydrogen-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone

[0274] The fraction (0.543 g) containing the mixture of 3-methyl and 5-methylpyrazole regioisomers obtained in step E of Example 1 was passed through a flash chromatography column (silica gel Merck-60, eluent: toluene-acetic acid ethyl ester 90:10, followed by toluene-ethyl acetate-acetonitrile 90:10:5), to obtain 0.327 g of the 3-methyl isomer in Example 1 already described and 0.105 g of the title compound in diethyl ether- Sonicated in hexane, amorphous solid.

[0275] NMR (DMSO-d 6 , 400MHz): δ2.27(s, 3H), 4.16 and 5.45(dd, 2H, CONCH 2 ), 6.25(m, 1H), 6.54(m, 1H, pyrazole CH), 6.79(m, 2H), 7.01(m, 1H), 7.26(m, 1H), 7.40-7.54(mm, 3H), 7.61 (m, 1H), 8.11 (m, 1H, pyrazole CH), 9.56 (s, 1H, NH)

[0276] MS [EI, m / z]: 415 / 417 [M] + , 219 / 221, 196

Embodiment 3

[0278] [2-Bromo-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5,11-di Hydrogen-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone

[0279] Step A. 2-Bromo-4-fluorobenzoyl chloride

[0280] 2-Bromo-4-fluorobenzoic acid (6.87 g, 31.37 mmol) in dichloromethane containing a few drops of dimethylformamide was treated dropwise with a 2M solution of oxalyl chloride in dichloromethane (1.16 eq) under nitrogen. Methane (70 mL) suspension. After gas evolution had ceased, the reaction mixture was refluxed for an additional 25 minutes, then the solution was evaporated to dryness under vacuum. The crude acid chloride was used directly in the next step.

[0281] Step B. (2-Bromo-4-fluorophenyl)-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanol ketone

[0282] Add 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (5.15 g, 26.1 mmol) from Example 1, Step B under nitrogen to Potassium carbonate (7.95 g, 57.51 mmol) was added to a solution of methylformamide (70 mL). The mixture was coole...

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Abstract

The present invention provides compounds of general formula (I): wherein W is O or NH, optionally substituted, as well as methods and pharmaceutical compositions utilising these compounds for the treatment of disorder which may be remedied or alleviated by vasopressin agonist activity, including diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding and coagulation disorders, or temporary delay of urination.

Description

technical field [0001] The present invention relates to pyridotricyclic compounds or pharmaceutically acceptable salts thereof useful as vasopressin agonists, as well as therapeutic methods and pharmaceutical compositions using the compounds. Background of the invention [0002] Vasopressin (antidiuretic hormone, ADH), a non-peptide hormone and neurotransmitter, is synthesized in the supraoptic nucleus of the hypothalamus of the brain and is transmitted via the pituitary tract of the supraoptic nucleus to the in the posterior pituitary gland. Vasopressin is released into the circulation and activates vasopressin V on blood vessels when an increase in plasma osmolality is sensed by the brain osmoreceptors or a decrease in blood volume or blood pressure is detected by baroreceptors and volume receptors 1a receptor, causes vasoconstriction to increase blood pressure, and activates vasopressin V in nephrons 2 receptors, which retain mostly water and to a lesser extent electrol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/55A61K31/553A61P13/00A61P43/00C07D471/04C07D498/04
CPCC07D471/04A61P13/00A61P43/00
Inventor A·A·费利J·S·舒姆斯基R·J·斯特范
Owner WYETH LLC
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