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Phosphodiesterase-5 inhibitor

A compound, hydroxyl technology, applied in the field of medicine, can solve the problems of short half-life and inability to treat diseases

Active Publication Date: 2013-10-30
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its short half-life, the half-life in the human body is about 1.2 hours, so it can only be used for the monotherapy of erectile dysfunction, but not for the treatment of diseases such as BPH / OAB

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0150] Example 14-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazol[5,1-f][1,2,4]triazine- 2- Base)-N-(((1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)methyl)benzenesulfonamide (compound 1)

[0151]

[0152] (1) Preparation of (1R,5S)-9-(4-methoxybenzyl)-9-azabicyclo[3.3.1]nonan-3-one (intermediate 1-2)

[0153] Add 3-oxoglutaric acid (raw material 1-1) (5.0g, 0.034mol) and p-methoxybenzylamine (20mL) into a 250mL eggplant-shaped bottle, under nitrogen protection, heat up to 80°C, and stir for 10h . Dichloromethane was added, stirred and filtered with suction, and the filtrate was distilled and purified by column chromatography to obtain 5.0 g of light red oily substance of Intermediate 1-2, with a yield of 56%.

[0154] (2) Preparation of (1R,5S)-9-(4-methoxybenzyl)-9-azabicyclo[3.3.1]nonane-3-carbonitrile (intermediate 1-3)

[0155] Add intermediate 1-2 (5.1g, 19.69mmol), TOSmic (p-toluenesulfonyl isonitrile, 6.91g, 35.44mmol) and ethylene glycol dimethyl ether ...

Embodiment 24

[0168] Example 24-ethoxy-N-(2-((1S,8R)-3-methyl-3-azabicyclo[3.2.1]octane-8-yl)ethyl)-3-(5 -Methyl-4- Preparation of oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (compound 2)

[0169]

[0170] (1) Preparation of 2-((1R,5S)-3-azabicyclo[3.2.1]octane-8-yl)acetic acid (intermediate 2-2)

[0171] 2-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-yl)acetic acid (raw material 2-1) (0.5g, 1.86mmol) Dissolve in 10mL CH 2 Cl 2 , adding 5mL of TFA, stirring at room temperature for 3 hours, the reaction solution was rotary evaporated to dryness under reduced pressure to obtain intermediate 2-2 (0.28g), the yield was 89%.

[0172] (2) Preparation of 2-((1R,5S)-3-methyl-3-azabicyclo[3.2.1]octane-8-yl)acetic acid (intermediate 2-3)

[0173] Intermediate 2-2 (0.25 g, 1.48 mmol) was dissolved in 10 mL of methanol at room temperature, and aqueous formaldehyde (37%) was added dropwise, and the reaction was stirred overnight under 1 atm of ...

Embodiment 34

[0188] Example 34-ethoxy-N-(((1R,5S)-3-methyl-3-azabicyclo[3.2.1]octane-8-yl)methyl)-3-(5-methyl yl-4-oxo Preparation of substituted-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (Compound 3)

[0189]

[0190] (1) Preparation of (1R,5S,8s)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (intermediate 3-2)

[0191] Dissolve (1R,5S,8s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (raw material 3-1) (0.5g, 2.0mmol) in 10mL CH 2 Cl 2 5 mL of TFA was added, and after stirring at room temperature for 3 hours, the reaction solution was spin-dried to obtain intermediate 3-2 (0.26 g), with a yield of 84%.

[0192] (2) Preparation of (1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid (intermediate 3-3)

[0193] At room temperature, the intermediate 3-2 (0.26g, 1.7mmol) was dissolved in 10mL of methanol, 0.2mL of formaldehyde aqueous solution (37%) was added dropwise, and stirred overnight under 1 atm of hydrogen gas. ...

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Abstract

The invention belongs to the technical field of medicines and specifically relates to a phosphodiesterase-5 inhibitor as shown in a general formula (I) and a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R3, R4, R5, L and W are as defined in the description. The invention further relates to preparation methods of compounds, pharmaceutical compositions containing the compounds, and applications of the compounds and the pharmaceutical compositions in preparation of medicaments for treating and / or preventing diseases related to sexual dysfunction and lower urinary tract symptoms.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a phosphodiesterase-5 inhibitor, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a preparation method of these compounds, a pharmaceutical preparation and a pharmaceutical composition, and the preparation of these compounds Use for the treatment and / or prevention of sexual dysfunction and lower urinary tract symptoms caused by cGMP signal transduction dysfunction. 2. Background technology [0002] cGMP (guanosine-3',5'-cyclic phosphate, cyclic guanosine monophosphate) is a cyclic nucleotide found in animal and plant cells and is an intracellular second messenger involved in a wide range of cellular responses , it can be hydrolyzed by PDE-5 (phosphodiesterase-5). When PDE-5 is inhibited, the level of cGMP will increase, thereby producing a variety of physiological effects, such as vascular smooth muscle relaxation. Therefore, PDE-5 inhibitors ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/53A61P15/10A61P13/00
Inventor 吴永谦
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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