Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists

A technology of azepine and benzo, which is applied in blood diseases, extracellular fluid diseases, drug combinations, etc., and can solve problems such as defects in vasopressin synthesis

A technology of azepine and benzo, which is applied in blood diseases, extracellular fluid diseases, drug combinations, etc., and can solve problems such as defects in vasopressin synthesis

CN1339035AInactive Publication Date: 2002-03-06AMERICAN HOME PRODUCTS CORPORATION
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  • Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 (5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-10-yl)-(1-methyl-

[0056] 1H-Indol-5-yl)methylketone Step A. 1-Methyl-indole-5-carboxylic acid methyl ester

[0057] A solution of methyl indole-5-carboxylate (2.5 g, 14.3 mmol) in dry tetrahydrofuran (20 ml) was added dropwise to potassium hydride (1.63 g, 14.3 mmol, oil, washed with hexane) under a nitrogen atmosphere with stirring. 35%) of the slurry. When hydrogen evolution ceased, iodomethane (1.3 mL, 21.5 mmol) was added to the stirred solution. After a further 30 minutes at room temperature, the precipitate was filtered off, washed with ether, the filtrate was concentrated in vacuo and the residue was triturated with hexane to give the title compound as a yellow solid (2.6g).

[0058] NMR (CDCl 3 , 400MHz): δ3.82(s, 3H), 3.93(s, 3H), 6.58(dd, 1H), 7.10(d, 1H),

[0059] 7.32(d, 1H), 7.92(dd, 1H), 8.39(s, 1H)

[0060] MS (EI, m / z): 189 [M] + , 158, 130 Step B. 1-Methy...

Embodiment 2

[0065] Example 2 Benzo[1,3]dioxol-5-yl-(5,11-dihydropyrido[2,3-b][1,5]

[0066] Benzodiazepin-10-yl) methyl ketone

[0067] Essentially in the same manner as in Example 1, from 3,4-methylenedioxybenzoic acid (0.332 g, 2 mmol) and 6,11-dihydro-5H-pyrido[2,3-b][1 , 5] Prepared from benzodiazepine (0.398, 2 mmol). After recrystallization from diethyl ether, the title compound was obtained as a white solid (0.400 g), mp 205-207°C.

[0068] NMR (DMSO-d 6 , 400MHz): δ4.06 (broad doublet, 1H), 5.54 (broad d, 1H), 5.97 (s, 2H),

[0069] 6.57-6.75 (m, 6H), 7.07 (t, 1H), 7.30 (d, 1H), 7.51 (broad singlet, 1H), 8.09 (m, 1H), 9.56

[0070] (s, 1H)

[0071] MS (EI, m / z): 345[M] + , 196, 181, 149C 20 h 15 N 3 o 2 Analysis for: Calculated: C 69.56; H 4.38; N 12.17

[0072] Found: C 69.10; H 4.58; N 12.04

Embodiment 3

[0073] Example 3 (2,3-dihydrobenzofuran-5-yl)-(5,11-dihydropyrido[2,3-b][1,5]benzodi

[0074] Azepin-10-yl) methyl ketone

[0075] Basically in the same manner as in Example 1, from 2,3-dihydrobenzofuran-5-carboxylic acid (0.328g, 2mmol) and 6,11-dihydro-5H-pyrido[2,3-b] [1,5]Benzodiazepine (0.398, 2 mmol) was prepared. After recrystallization from diethyl ether, the title compound was obtained as an off-white solid, mp 188°C.

[0076] NMR (DMSO-d 6 , 400MHz): δ3.05 (m, 2H), 4.06 (broad doublet, 1H), 4.47 (t, 2H), 5.60

[0077] (broad doublet, 1H), 6.51(d, 1H), 6.60(m, 2H), 6.75(m, 2H), 7.07(m, 2H), 7.31(d, 1H),

[0078] 7.50 (broad multiplet, 1H), 8.09 (m, 1H), 9.54 (s, 1H)

[0079] MS (EI, m / z): 343 [M] + , 196, 181, 147C 21 h 17 N 3 o 2 Analysis for: Calculated: C 73.45; H 4.99; N 12.24

[0080] Found: C 73.15; H 5.18; N 11.91

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Abstract

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

Description

[0001] The present invention relates to vasopressin V 2 Benzoheterocyclic amides of agonists, especially pyridobenzodiazepines and pyridobenzoxazepine amides, and methods of treatment and pharmaceutical compositions utilizing these compounds. Background of the invention [0002] Vasopressin (ADH), a non-peptide hormone and neurotransmitter, is synthesized in the supraoptic nucleus of the hypothalamus of the brain, transmitted to the posterior pituitary via the supraoptic pituitary tract and stored here. When brain osmoreceptors sense an increase in plasma osmolality or a decrease in blood volume or blood pressure (detected by baroreceptors and volume receptors), vasopressin is released into the circulation, causing vasopressin V on blood vessels to 1a Receptor activation, causing vasoconstriction and blood pressure increase; vasopressin V in nephrons of the kidney 2 Receptor activation, causing reabsorption of mainly water and a small amount of electrolyt...

Claims

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Application Information

Patent Timeline
06 Mar 2002
Publication
CN1339035A
IPC
A61K31/395; A61K31/5513; A61K31/553; A61P5/10; A61P7/04; A61P7/12; A61P13/00; A61P43/00; C07D471/04; C07D498/04
CPC
C07D471/04; A61P5/10; A61P7/04; A61P7/12; A61P13/00; A61P43/00
Inventors
R·J·斯蒂芬; A·A·费利