JPH03218379A - Novel morphine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is H, lower alkyl or lower alkanoyl; R2 is H, lower alkylthio, aryl, lower alkoxycarbonyl-alkyl or lower alkyl; R3 is lower cycloalkylmethyl). EXAMPLE:3-Acetyl-6beta-methylthio-N-cyclopropylmethylnormorphine. USE:A medicine having excellent analgesic activity and narcotic antagonistic action. PREPARATION:A cycloalkylmethylnormorphine of formula III derived from normorphine of formula II is converted to a ditosylate compound, reacted with a compound of formula R5SX (R5 is lower alkyl, etc.; X is alkali metal), hydrolyzed and, as necessary, acylated or alkylated at the 3-site.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is based on the general formula: alkylthio group,
NR3 represents an aryl group, a lower alkoxycarbonyl alkyl group or a lower alkyl group, and NR3 represents a lower alkylmethyl group.

) A novel 6β-thiomorphine derivative represented by:

The compound represented by the general formula (I) has strong analgesic effects, narcotic antagonistic effects, and extremely low drug dependence, making it a powerful analgesic that is expected to be non-narcotic. It is a powerful substance as a medicine.

[Prior Art Problems to be Solved by the Invention] Morphine is a compound known as the main component of opium alkaloids, and is frequently used as an anesthetic, analgesic, and other pharmaceuticals. However, it has the problem of easily causing morphine addiction.

Furthermore, naloxone represented by the formula (■), which is known to have an anesthetic antagonizing effect like the compound of the present invention, has a weak analgesic effect and is not very suitable as an analgesic.

Therefore, it has been desired to develop a drug that has a strong analgesic effect, has a narcotic antagonistic effect, and is less addictive.

In order to solve these problems, the present inventors have found that the compound represented by the general formula (I) exhibits superior analgesic activity to morphine and has narcotic antagonistic effects.
Furthermore, it was discovered that it exhibits excellent effects as a medicine even when administered orally, leading to the present invention.

[Means for solving problems]

That is, the present invention provides novel 6β represented by general formula (I)
- thiomorphine derivatives.

The 6β-thiomorphine derivative of the present invention can be obtained, for example, as shown in the formula below. That is, from normorphine represented by formula (III) Gates and Montzk
Method a CM. Gates, T. A. threshold ontzka
;J. Med. Chew. , 7, 127. 19
According to [i4], cycloalkylmethylnormorphine represented by the formula (-4-■) was obtained, and then this was converted into the ditosylate form (general formula (■)) by a conventional method.
)), and RsSX (R5 represents a lower alkyl group, a lower alkylthio group, an aryl group, a lower alkoxyl group, or a hydrogen atom, and X represents an alkali metal.

) by reacting the compound represented by the general formula (
It can be obtained by obtaining the compound represented by (2), further hydrolyzing it, and, if necessary, acylating or alkylating the 3-position by a conventional method.

The lower alkanoyl group in Rl of the compound of the present invention includes those having 2 to 7 carbon atoms, and preferred examples include an acetyl group and a propionyl group. Examples of the lower alkylthio group in R2 include those having 1 to 6 carbon atoms, preferably a methylthio group or an ethylthio group. The aryl group is preferably a phenyl group or a substituted phenyl group, and the lower alkoxy group is preferably exemplified by -5-, such as ethoxy group ponylethyl or methoxycarponylethyl. Examples of the lower alkyl group in R1 and R2 include those having 1 to 6 carbon atoms, and preferably,
Examples include methyl group, ethyl group, and n-probyl group. Preferable examples of the lower cycloalkylmethyl group in R3 include a cyclopropylmethyl group and a cyclobutylmethyl group.

(II1) (IV) (■) -6 (In the formula, R4 is a lower cycloalkyl group, NRB is a lower alkanoyl group or a lower alkyl group, TS is a tonnol group, and NR5 and X are the same as above.) Further, the compound represented by the general formula (I) can be converted into an acid addition salt, if necessary. The acids in acid addition salts are:
When used for medical purposes, there are no particular limitations as long as the acid is a medically acceptable acid addition acid. Specifically, citric acid,
Organic acids such as fumaric acid, maleic acid, tartaric acid, or hydrochloric acid,
Examples include mineral acids such as hydrobromic acid, nitric acid, and sulfuric acid.

The analgesic effect of the compound of the present invention was investigated in experiments using mice as shown in Experimental Examples below, and as a result it showed stronger analgesic activity compared to controls such as morphine and pentazocine. or,
The analgesic effect upon oral administration was also excellent, indicating that it is excellent as a medicinal agent such as an analgesic.

Particularly preferred embodiments of the compounds of the present invention include the following compounds.

These compounds are particularly excellent as medicines such as analgesics.

〔Example〕

Next, the present invention will be specifically explained with reference to Examples.

Example 1 Cyclopropylmethylnormorphine-3 obtained by tosylation of cyclopropylmethylnormorphine by a conventional method
．． 1 in a solution of 3.0 g of 6-ditosylate in 15 ml of DMF.
Add 4 ml of 5% methylmercabutan sodium salt aqueous solution and stir at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated brine.
After dehydration over anhydrous sodium sulfate, the solvent was distilled off and the mixture was purified by silica gel chromatography to obtain 2.0 g of 6β-methylthio N-cyclopropylmethylnormorphine-3-tosylate. 0.2 g of this tosylate
After hydrolysis with N potassium hydroxide-ethanol, 1.5 g of 6β-methylthio N-cyclopropylnormorphine hydrochloride is obtained as a hydrochloride.

Melting point = 184-6°C Specific rotation [α) D = -240.0° (C = 0.190.MeOH) Example 2 -9- 6β Methylthio N-cyclopropylmethylnormorphine 1 obtained in Example 1 3-acetyl-6β-methylthio N-cyclopropylmethylnormorphine hydrochloride can be quantitatively obtained by acetylating .5 g in acetic anhydride, adding ether to the reaction solution, and blowing hydrogen chloride gas into the reaction solution.

Melting point: 210~5℃ Elemental analysis value (C23H27NO3 S @HC l●H
20 molecular weight 451.998) CHN theoretical value (%): G1.12 B. 89 3.
10 Actual value (%) l0.82 B. 72 3.
08 Example 3 2ml of DMF with 200cm of sodium hydride excluding oil
Add 0.4 of propyl mercabutane to the solution at 0°C under a nitrogen stream.
After stirring at room temperature for 30 minutes, a solution of 1.5 g of N-cyclopropylmethylnormorphine-10-3,6-ditonlate in 5 ml of DMF was added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated brine, then dehydrated over anhydrous sodium sulfate, and the solvent is distilled off.

The residue is purified by silica gel chromatography (2.5% methanol-chloroform) to obtain 720 mg of 6β-propylthio N-cyclopropylmethylnormorphine-3-tosylate. Thereafter, the same treatment as in Examples 1 and 2 was carried out to obtain 3-acetyl-6βpropylthione N-chloropropylnormorphine hydrochloride.

Melting point = 225~8°C Elemental analysis value (C25H31NO3 S-HC 1 molecular weight 4E32.052) CHN Theoretical value (%): B4. ! 39 B. 98
3.03 Actual value (%): Ei4.75 11i
．． 99 2.98 Example 4 -Cyclopropylmethyl- -Dideha 17-cyclopropylmethyl-7,8-didehyde-4,5α-Example 1 using epoxy-3-methoxymorphinan-6α-ol as a starting material It can be obtained by processing in the same way.

Specific optical rotation [α) D=-263.44° (C=0.186, MeOH) Example 5 1.0 g of 3-acetyl-6β-acetylthio N-cyclopropylmethylnormorphine was added to an ethanol solution of methyl mercabutane 5i+1 The methyl disulfide compound is obtained by adding it to 40+1 of a 0.2N potassium hydroxide-ethanol solution containing 40+1 and treating at room temperature for 30 minutes.

Thereafter, the same treatment as in Example 2 is carried out to obtain 3-acetyl-6β-methyldithio N-cyclopropylmethylnormorphine hydrochloride.

Melting point: 215-7°C Example 6 Hydrochloride of 3-acetyl-6β-phenylthio N-cyclopropylmethylnormorphine is obtained in the same manner as in Example 3, using thiophenol instead of propylmercabutane.

Melting point: 240-5°C Example 7 The hydrochloride of 3-acetyl-6β-isobutylthio N-cyclopropylmethylnormorphine was prepared in the same manner as in Example 3 using isobutylmercabutane instead of propylmercabutane. get.

Melting point = 214-5°C Specific optical rotation [α:lD = -251.92°-13- (C = 0.156, MeOH) Example 8 In the same manner as in Example 3, from β-mercaptopropionic acid ethyl ester When the obtained product is esterified, 3
-acetyl-6β-monoethoxylponylethylthio N
- Obtaining the hydrochloride of cyclopropylmethylnormorphine.

Melting point: 192-4°C Experimental Example 1 The compound of the present invention, morphine hydrochloride, and pentazocine were each subcutaneously administered to Lysin mice (Slc: ddy, male), 5 weeks old (male), 30 minutes later. 0.6% acetic acid was intraperitoneally administered at a dose of 0.11 per 10 g of mouse, and 10 minutes later, the number of writhing was measured for 10 minutes. The EDsO values are shown in Table 1. [The acetic acid writhing method is described by R. Koste
r. -141M. Anderson, E. I. Debeer; Fed. Proc. ]8,4+2l959] Experimental Example 2 - Using 5-week-old mice (Slc: ddY, male), 7 mice per group, the compound of the present invention and morphine hydrochloride were each orally administered for 60 minutes. Afterwards, 0.75% acetic acid was intraperitoneally administered at a dose of 0.11 per 10 g of mouse, and 10 minutes later, the number of writhing was measured for 10 minutes. The EDSO values are shown in Table 2.

Table 2

Claims (1)

[Claims] 1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ alkoxycarbonylalkyl group or lower alkyl group, R_3 represents lower cycloalkylmethyl group) and pharmaceutically acceptable acid addition salts thereof. 2) The compound according to claim 1, represented by the formula ▲A mathematical formula, a chemical formula, a table, etc.▼, and a pharmaceutically acceptable acid addition salt thereof. 3) The compound according to claim 1 represented by the formula ▲A mathematical formula, a chemical formula, a table, etc.▼ and a pharmaceutically acceptable acid addition salt thereof.