Bicycle vasporession agonists

A compound and selected technology, applied in the direction of blood diseases, active ingredients of heterocyclic compounds, extracellular fluid diseases, etc., can solve the problems of low oral bioavailability, poor water solubility, etc.

Inactive Publication Date: 2002-11-27
FERRING BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compounds disclosed in these documents are not ideal, in particular, they have low oral bioavailability, possibly due in part to their poor water solubility

Method used

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  • Bicycle vasporession agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A4

[0061] Example A 4-(tert-Butoxycarbonylaminomethyl)-3-chlorobenzoic acid A1. Methyl 4-bromomethyl-3-chlorobenzoate

[0062] To the solution of methyl 3-chloro-4-methylbenzoate (5.0g, 27.1mmol) in carbon tetrachloride (50ml) was added NBS (5.8g, 32.0mmol) and AIBN (0.442g, 2.70mmol) and stirred The mixture was refluxed for 18 hours. The mixture was allowed to cool to room temperature and then concentrated under vacuum. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate: petroleum ether=0:100-5:95), yield = 5.96 g (84%). A2. 4-(tert-Butoxycarbonylaminomethyl)-3-chlorobenzoic acid

[0063] To a saturated ethanol solution (170 ml) of ammonia was added methyl 4-bromomethyl-3-chlorobenzoate (5.5 g, 20.9 mmol) obtained in Example A1, and the mixture was stirred at room temperature for 1 hour, and then Concentrate under vacuum. Triturate the residue with ether, filter the white crystals obtained, and wash with more ether. Add (BOC) to the solid water (100m...

Embodiment B4

[0064] Example B 4-cyano-3-methylbenzoic acid

[0065] Under a nitrogen atmosphere at -78°C, to a solution of 4-bromo-2-methylbenzonitrile (2.0g, 10.2mmol) in THF (100ml) was added dropwise a 2.5M solution of n-butyllithium (4.48ml, 11.2mmol) mmol). The mixture was stirred at -78°C for 1 hour, then poured onto solid carbon dioxide (5 g) in THF (50 ml), and the mixture was warmed to room temperature. Water (200 ml) was added, and the mixture was extracted three times with ether. Concentrated hydrochloric acid was added to acidify the aqueous layer and extracted three times with chloroform. The combined chloroform extracts were washed with water, dried over magnesium sulfate, and concentrated under vacuum to obtain a white solid, yield = 1.2 g (73%).

Embodiment C

[0066] Example C4-cyano-2-methylbenzoic acid

[0067] The 4-bromo-3-methylbenzonitrile (2.0g, 10.2mmol) was reacted according to the method of Example B to obtain a yellow solid, which was triturated with hexane and filtered. Yield=0.96g (59%) .

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PUM

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Abstract

Compounds according to general formula (1), and pharmaceutically acceptable salts thereof, wherein V is a covalent bond or NH, X is selected from CH2, O and N-alkyl, Z is either S or -CH=CH-, R<1 >and R<2 >are independently selected from H, F, Cl, Br and alkyl, R<3 >is selected from OH, O-alkyl and NR<4>R<5>, R<4 >and R<5 >are each independently H or alkyl, or together are -(CH2)q-, p is 0, 1, 2, 3 or 4, and q is 4 or 5, are new. They are agonists at the asopressin V2 receptor and are useful as antidiuretics and pro-coagulants.

Description

Invention field [0001] The present invention relates to a new class of chemical substances (entities) as agonists of the peptide hormone vasopressin. They can reduce the amount of urine excreted from the kidneys, so they can be used to treat certain human diseases characterized by urination. They can also be used to control urinary incontinence and bleeding. Background of the invention [0002] Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It acts on the kidneys to increase water retention and reduce urine output. For this reason, vasopressin is also known as "urinary hormone". Vasopressin also acts on the vasculature, producing a boosting effect. The cell receptors that mediate these two effects have been characterized, showing that they are different. The urinary action is mediated by the type 2 vasopressin receptor, which is commonly referred to as V 2 Receptor. Able with V 2 Receptors interact and activate V in the same way as vasopressin 2 The r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/12A61K31/55A61K31/551A61K31/553A61P7/04A61P7/12A61P13/10C07D223/16C07D267/14C07D401/12C07D403/12C07D495/04
CPCC07D223/16C07D495/04A61P13/10A61P7/00A61P7/04A61P7/12C07D243/14C07D267/14
Inventor D·M·阿什沃思G·R·W·皮特P·哈德森C·M·叶R·J·富兰克林
Owner FERRING BV
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