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Diazacycloalkanes as oxytocin agonists

A technology of general formula and compound, applied in the field of non-peptide oxytocin agonists

Inactive Publication Date: 2004-11-03
FERRING BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far there have been no reports of non-peptide OT agonists

Method used

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  • Diazacycloalkanes as oxytocin agonists
  • Diazacycloalkanes as oxytocin agonists
  • Diazacycloalkanes as oxytocin agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] 1-Benzyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine

[0154]

[0155] 1A: Ethyl 5-amino-1-benzylpyrazole-4-carboxylate

[0156] Benzylhydrazine dihydrochloride (4.29g, 22mmol) was added to ethyl (ethoxymethylene)cyanoacetate (3.38g, 20mmol) and triethylamine (6.15ml, 44mmol, 2eq) in ethanol ( 40 ml) solution, the mixture was heated at reflux for 18 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (eluent 60% pet. ether / 40% ethyl acetate) to give a light yellow solid identified as 5-amino-1-benzylpyrazole-4-carboxy Acetate ethyl ester (4.3 g, 88%).

[0157] 1B: 1-Benzyl-5-(2′-nitrophenylamino)pyrazole-4-carboxylic acid ethyl ester

[0158] Sodium hydride (60% dispersion in oil, 520 mg, 13 mmol) was added portionwise to ethyl 5-amino-1-benzylpyrazole-4-carboxylate (2.2 g, 9 mmol) in anhydrous THF at 0 °C (30ml) solution. The mixture was warmed to room temperature and stirred for 2 hours, then 1-fluoro-2-n...

Embodiment 2

[0170] 1-Methyl-4,10-dihydropyrazolo[4,5-c]pyrido[2,3-b][1,4]diazepine

[0171]

[0172] 2A: Ethyl 1-methyl-2-(3′-nitro-2′-pyridylamino)pyrazole-4-carboxylate

[0173] Sodium hydride (60% dispersion in oil, 600 mg, 15 mmol) was added portionwise to ethyl 5-amino-1-methylpyrazole-4-carboxylate (1.69 g, 10 mmol) in anhydrous THF at 0 °C (15ml) suspension. The mixture was stirred at room temperature for 2 hours, then 2-chloro-3-nitropyridine (1.58 g, 10 mmol) was added and the resulting dark red suspension was stirred at room temperature for 18 hours. Join 1M KHSO 4 The reaction was quenched and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 0.3M KHSO 4 , saturated NaHCO 3 and washed with brine, in Na 2 SO 4Dry and concentrate in vacuo. The residue was purified by silica gel column chromatography (eluent 30% pet. ether / 70% ethyl acetate) to give 1-methyl-2-(3'-nitro-2'-pyridylamino)pyrazole- 4-Carboxylic a...

Embodiment 3

[0183] 4-Aminomethyl-3-chlorobenzoic acid tert-butyl ester

[0184]

[0185] 3A: tert-butyl 3-chloro-4-methylbenzoate

[0186] Thionyl chloride (11ml, 150mmol) was added to a suspension of 3-chloro-4-methylbenzoic acid (5.12g, 30mmol) in toluene (25ml), and the mixture was heated under reflux for 2 hours. The solvent was removed in vacuo and the residue was azeotroped three times with toluene, then dissolved in anhydrous THF (40ml) and cooled to 0°C. Lithium tert-butoxide (2.4 g, 30 mmol) was added, and the mixture was stirred at room temperature for 3 days. Water (5ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. solution with 0.3M KHSO 4 , saturated NaHCO 3 and washed with brine, in Na 2 SO 4 Drying on ethylene oxide and concentration in vacuo afforded a pale yellow gum identified as tert-butyl 3-chloro-4-methylbenzoate (5.4 g, 79%).

[0187] 3B: tert-butyl 4-bromomethyl-3-chlorobenzoate

[0188] N-bromosuccinimide (...

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PUM

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Abstract

Compounds according to general formula (1), wherein G1 is NR5R6 or a fused polycyclic group are novel. They are selective and potent oxytocin agonists. Pharmaceutical compositions of such compounds are useful in the treatment of, inter alia, erectile dysfunction.

Description

field of invention [0001] The present invention relates to non-peptide oxytocin agonists and pharmaceutical compositions comprising such compounds. Such compositions are useful in the treatment of certain physiological disorders such as erectile dysfunction. technical background [0002] nerve growth hormone [0003] The nerve growth hormones oxytocin (OT) and vasopressin (VP) are cyclic nonapeptides secreted by the posterior pituitary gland. The structure of oxytocin is as follows. [0004] [0005] oxytocin-ring 1，6 -Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH 2 [0006] Vasopressin differs from oxytocin in that phenylalanine at position 3 replaces isoleucine and arginine at position 8 replaces leucine. Both hormones can be synthesized in vivo as larger precursor-pohorin catalins, which are post-translationally processed and released as mature peptides. OT and VP act through a family of heptahelical receptors. [0007] The first ta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/55A61K31/551A61K31/5517A61K31/553A61P15/04A61P15/10A61P43/00C07D471/14C07D487/04C07D495/04C07D498/04
CPCC07D495/04C07D471/14C07D487/04A61P15/04A61P15/10A61P43/00
Inventor P·J·胡德森G·R·W·皮特D·P·洛克A·R·巴特C·M·S·海尼M·B·罗
Owner FERRING BV
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