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Remedies or preventives for urinary frequency or urinary incontinence and morphinan derivatives having nitrogen-containing heterocyclic group

A technology of substituents and urinary incontinence, applied in organic chemistry, drug combination, urinary system diseases, etc., can solve problems such as inability to use therapeutic or preventive agents, no disclosure, drug dependence and side effects

Inactive Publication Date: 2005-11-30
TORAY IND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] As morphinane derivatives having nitrogen-containing ring substituents, compounds described in JP-A-41-18824 and JP-A-41-18826, which are used as analgesics and antitussives at the same time, have been disclosed. The compounds described in Tetrahedron.50,9757(1994), Synth.Commun.22,913(1992), J.Med.Chem.27,1325(1984) etc. which are not described in use are used in these patents and documents for the treatment of or use to prevent urinary frequency or incontinence
In addition, from the point of view that it does not contain a nitrogen-containing heterocyclic substituent and has a morphinane structure, morphine, which is similar to the compound of the present application, has the effect of inhibiting the urination reflex (J.Pharm.Exp.Ther.254 (1984) etc. ), drug dependence, constipation and other side effects, can not be used as a treatment or preventive agent for urinary frequency or urinary incontinence

Method used

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  • Remedies or preventives for urinary frequency or urinary incontinence and morphinan derivatives having nitrogen-containing heterocyclic group
  • Remedies or preventives for urinary frequency or urinary incontinence and morphinan derivatives having nitrogen-containing heterocyclic group
  • Remedies or preventives for urinary frequency or urinary incontinence and morphinan derivatives having nitrogen-containing heterocyclic group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0167] The present invention will be described in more detail below by way of examples.

[0168] Reference example 1-1

[0169] Synthesis of 6β-dibenzylamino-17-cyclopropylmethyl-4,5α-epoxy-morphinan-3,14-diol

[0170]

[0171] 249.8 g (0.731 mol) of naltrexone (Naltrexone) was dissolved in a mixed solvent of 1,700 ml of THF and 1,700 ml of toluene, and 432.7 g (2.193 mol, 3.0 equivalents) of dibenzylamine was added. The pressure in the reaction vessel was reduced while stirring, and replacement with argon was performed. Then, 357.7 g (2.929 mol, 4.0 equivalents) of benzoic acid was weighed and put into a beaker, slowly added to the solution, and a white solid was precipitated. Heating of the reaction apparatus was started with an oil bath, and as the internal temperature rose, the precipitated crystals were dissolved to form a homogeneous solution. Reflux began at an internal temperature of 81.5°C, and the reaction began. The reaction is carried out at an internal temp...

reference example 1-2

[0176] Synthesis of 6β-naltrexamine (naltrexamine)

[0177]

[0178] Weigh 325.0 g (0.622 mol) of 6β-dibenzylamino-17-cyclopropylmethyl-4,5α-epoxy-morphinane-3,14-diol obtained in Reference Example 1-1, 10% 65.0 g (20% wt) of Pd / C (50% humidity) was put into a 5L reaction vessel and installed on the reaction device. Then, methanol 2561.3g (3.25L, 10mL / g raw material) was added and stirring was started, and argon replacement was performed 3 times. Weigh 91.0 g (1.740 mol, 2.8 equivalents) of formic acid (88% solution) into a beaker, and add dropwise at an internal temperature of 22.1 to 25.8° C. over 5 minutes using a dropping funnel. At this time, it was confirmed that the internal temperature rose and gas was generated. Heating was started after completion|finish of dripping, and reaction started when internal temperature reached 51.1 degreeC, and it analyzed by HPLC 2 hours after reaction start. The reaction was terminated in 2 hours. To proceed the reaction, stirring ...

Embodiment 1-1

[0181] 4,5α-epoxy-6β-tetrahydroquinolino-3-methoxy-17-methyl-morphinane (compound 201 )Synthesis

[0182]

[0183] 201

[0184] Dissolve 304g (1.02mmol) of dihydrocodone and 0.12ml (1.65mmol) of methanesulfonic acid in a mixed solvent of 20ml xylene and 10ml dimethylformamide, add 1,2,3,4-tetrahydro After 0.2ml (1.59mmol) of quinoline was removed with a 175°C oil bath, the water was azeotropically removed and heated to reflux for 12 hours. After the reaction solution was left to cool to room temperature, 50 ml of saturated aqueous sodium bicarbonate solution and 3 ml of ammonia water were added to the reaction solution, and extracted with chloroform (50 ml×3). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 309 mg of a crude product. The obtained crude product was dissolved in 20 ml of methanol, 1.014 g (16.1 mmol) of sodium cyanoborohydride was added, and then 0.17 ml (2.62 mmol) of metha...

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Abstract

It is intended to provide a morphinan derivative represented by the following general formula (I): (I) wherein R<1> represents methyl, cyclopropylmethyl, etc.; R<2> and R<3> represent each hydroxy, methoxy, acetoxy, etc.; Y and Z represent each a valence bond, -(C=O)-, etc.; X represents a C2-5 carbon chain constituting a part of the cyclic structure (wherein one of the carbon atoms may be substituted by oxygen, sulfur or nitrogen); (R<4>)k represents an optionally substituted fused benzene ring, carbonyl, etc.; R<9> represents hydrogen, etc.; R<10> and R<11> may be bonded together to form -O-; and R<6> represents hydrogen, etc.The above-described compound is useful as a novel remedy or preventive for urinary frequency or urinary incontinence showing an isolated side effect. Moreover, it is useful in a method for treating or preventing the above diseases and utilization for these diseases.

Description

technical field [0001] The present invention relates to a novel therapeutic or preventive agent for urinary frequency or urinary incontinence and a morphinane derivative having a nitrogen-containing ring substituent or a pharmacologically acceptable acid addition salt thereof. Background technique [0002] In recent years, with the advent of an aging society, the number of patients suffering from frequent urination or urinary incontinence tends to increase. Currently, anticholinergics such as propiverine hydrochloride, oxybutynin hydrochloride, and flavoxate hydrochloride are mainly used as therapeutic drugs for urinary frequency or urinary incontinence. However, in these existing medicines, in addition to thirst, digestive organ symptoms such as constipation, circulatory organ symptoms such as orthostatic hypotension, anuria, and residual urine have been reported as side effects. In addition, in the treatment of frequent urination or urinary incontinence accompanied by cer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P13/00A61P13/02C07D489/08
CPCC07D489/08A61P13/00A61P13/02A61P13/10A61K31/485C07D489/00
Inventor 泉本直树河合孝治川村邦昭藤村森广驹形俊和
Owner TORAY IND INC
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