Method of producing morphine derivatives

专利摘要:
Novel derivatives of morphine having the general formula: <IMAGE> wherein R1, R2, R3, R4, R5 and R6 are certain specified values, and their pharmaceutically acceptable salts. The compounds exhibit activity in the central nervous system and may be presented in the form of pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
公开号:SU921467A3
申请号:SU782595556
申请日:1978-03-21
公开日:1982-04-15
发明作者:Юрек Кобылески Рышард；Джоффри Гест Ян；Вильям Льюис Джон；Вильям Кирби Гордон
申请人:Рекитт Энд Колман Продактс Лимитед (Фирма)；
IPC主号:

专利说明:

(54) METHOD FOR OBTAINING ANALYTIC MORPHIN
one
The invention relates to a process for producing new morphine derivatives of the general formula
where R 1 is a hydrogen atom;
Rj is a hydrogen atom or cycloalkyl with 3-7 carbon atoms, alkyl with 1-4 carbon atoms; Jaz - hydrogen atom, alkyl with 1-12 carbon atoms, alkenyl with 3-8 carbon atoms, cycloalkyl with 3-7 hydrogen atoms - alkyl- with 1-4 carbon carbon atoms, aralkyl with 1-5 carbon atoms in the alkyl part or aralkenype with 3-5 carbon atoms in the alcoholic part, provided that the RE does not contain structural groups - CH CH -, associated with the nitrogen atom in position 14;
R4 is a hydrogen atom, alkyl with 1-3 carbon atoms or COR groups, where R7 is a hydrogen atom, alkyl with 1-11 carbon atoms, aryl, arylalkyl with 1-5 carbon atoms in the alkyl part, aralkenyl with 2-5 carbon atoms in the alkenyl moiety, cycloalkyl with 3-8 carbon atoms or cyclopropylmethyl, and in the indicated radicals, aryl is phenyl or phenyl substituted by chlorine, alkyl with 1-3 carbon atoms or hydroxyl;
10 RS is a hydrogen atom;
Re is hydroxyl or RS and Re is co-oxygen, the most perfect line means an optional bond.
The common formula I possess
15 narcotic effect and can be used in medicine.
Known methylmorphine (codeine) of the formula
Hjco
20
II
H-CH 3 -HgO 39 alkaloid contained in OTG, which has a narcotic effect 1. The aim of the invention is to obtain new compounds that expand the arsenal of means of action on a living organism. This goal is achieved by a process for the preparation of compounds of the general formula 1, which consists in the fact that the compound of the general formula I is: where RI is methyl; Rz. e RS and Hb have the above values, are reacted with boron tribromide at temperatures from -30 to -10 ° C; or for the preparation of compounds of general formula 1, where RS and Re are oxygen together, compounds of general formula I, where RI is methyl, RS and Re bba methoxy, react with tribromide boron at temperatures from -30 to -10 ° C. preferably in a chlorinated aliphatic hydrocarbon environment, such as methylene chloride. Compounds of general formula T have pharmacological effects exerted by attenuated receptors. They have an active action in the presence and / or absence of a standard agonist (etorfin) in transmurally stimulated seed wires of mice. The narcotic antagonistic effect of the compound I of formula I is determined by the characteristics of these compounds to counteract the weakened receptor — an indirect effect caused by Etorphin in this tissue. Compounds have been studied for chong agonistic action in rats, using tail compression as a painkiller, as well as on the antagonistic effect of morphine on the roof using the method of light jerking of the tail used on lips. The pain irritant in this test is hot water (55 ° C). Compounds exhibiting activity in said anti-tumor receptive selection act as agonists or partially as agonists at weakened receptors and may find a classic use as anesthetic agents. Example 1. 14- | b-Amino-N-cyclopropylmethylnormorphinone. a) A solution of 14- {L-amino-N-cyclopropylmethyl norcodefinyl dimethyl ketal (2.0 g) in dichloromethane (60 ml) is cooled to -60 ° C, treated with boron tribromide (3.0 ml), and the mixture is stirred at from -20 to -30 ° C for 1 hour. This reaction mixture is diluted with methyl alcohol (10 ml), alkalified by adding 2N dropwise. Sodium hydroxide solution until pH 13 is reached, held for 5 minutes, neutralized by passing of acid gas. The reaction mixture is extracted with chloroform / methyl alcohol (4: 1), the extracts are dried and extruded to give an oily brown solid. This material was passed through a short column of aluminum (ni) i by elution with chloroform, and then with chloroform / methanol (10%). The eluents of the pale yellow 1pc were scrubbed, on the floor, a yellow solid, which was recrystallized from diethyl ether / petroleum ether (b.p. 40-60 ° C) to give 14- (L-amio-E-cyclopropylmethylnormorphinone (0, 56 g, 33%) in the form of needle-shaped pale yellow crystals with mp 138-141 ° C. 6) A solution of 14-ft -nitro-M-cyclopropylmethylnorcodeinone (or the corresponding dimethylketal) in methylene chloride is cooled to -60 ° C, treated with boron tribromide and stirred at -20 to -30 ° C for 1 hour. The reaction mixture under Shirt methyl Yergali processing, is introduced into the sodium hydroxide solution, neutrals) gazuyut by passing carbon dioxide and extracted with methylene chloride. After extraction of the extracts and recrystallization of a field} 1Ac1 of a solid substance using diethyl ether / petroleum ether (b.p. 40-60 ° C), 14- (L-nitro-N-cyclopropylmethylnormorphinone) is obtained in the form of pale yellow needle-like crystals. Example 2 14-fi-methylamino-L-cyclopropylmethylnormorphinone. A solution of 14-i-methylLamino-N-cycloylpropylmethylnorcodeinone (1.0 g) in dichloromethane (60 ml) is cooled to; , 5 ml) and stirred at -20 to -30 ° C for 1 hour. The mixture is diluted with methyl alcohol (S ml), injected into a dilute sodium oxide solution, incubated for 5 minutes; is neutralized by passing carbon dioxide and the resulting mixture is extracted with chloroform / methanol (4: 1). The United extracts are dried, evaporated in vacuo and the resulting oil is passed through a column filled with aluminum oxide (111), eluted with chloroform- to remove the pablar impurities and then elute with chloroform / methanol (10%). The specimens are extruded to form a solid, which is recrystallized from diethyl ether / petroleum ether (b.p. 40-60 ° C) to give 14-methyl-m-cyclopropylmethyl; normorphinon (0.44 g, 46%) in a pale yellow crystalline product with a melting point of 225 ° C. (melting with decomposition).
Example 3. 14-fb-Amino-M-cyclobutylmethylnormorphinone.
This product is obtained in the usual manner of Example 2. After recrystallization from diethyl ether / petroleum ether (with m.p. 40-60 ° C), it is obtained as colorless needle-like crystals with m.p. 135138 ° С (before the vitreous melt).
Example 4, 14- (L-Hexanoyl-aminormorphinone.
A solution of 14-fb -hexanoyl-aminoronodeinone is subjected to dealkylation according to Example 2, and after recrystallization of the formed substance from ethanol, the product is obtained in the form of continuous pink crystals with a mp. 26
269 ° C
The table describes the preparation of compounds of general formula
in the above examples; The last column of the table indicates the solvent used during recrystallization.

权利要求:
Claims (3)
[1]
13 claims
The method of obtaining the production of morphine 1X general formula I
RI
hydrogen atom;
Where
R2 is a hydrogen atom or cycloalkyl with
3-7 carbon atoms, alkyl with
1-4 carbon atoms; - hydrogen atom, alkyl with N2 carbon atoms, alkenyl with 3-8 carbon atoms, cycloalkyl with 3-7 carbon atoms - alkyl with 1-4 carbon atoms, aralkyl with 1-5 carbon atoms in the alkyl part or aralkyl with 3- 5 carbon in the alkenyl moiety, provided that Rj does not contain the —CH — CH— structural groups bound to the nitrogen atom at position 14;
R4 is a hydrogen atom, and a kil with 1-3 carbon atoms or a COR group, where K is a hydrogen atom, alkyl with 1-11 carbon atoms, alkesh with 2-7 carbon atoms, aryl, arylalkyl with 1-5 carbon atoms the alkyl part, aralkyl with 2-5 carbon atoms in the alkenyl part, cycloalkyl with 3-8 atoms) of terode or cyclopropylmethyl, and in the above radicals aryl is
921467
14
is phenyl or phenyl substituted by chlorine, alkyl with 1 to 3 carbon atoms or pyuoxyl;
RS is a hydrogen atom;
Re is hydroxyl or P $ and Rj is (well, oxygen.
optional link,
different in that; that the connection of the General formula G, where RI is methyl;
R2V Rsi R4f RS and Rg are as indicated.
or in the case of the preparation of compounds of general formula I, where RS and Rft together are oxygen;
RI. RZ, RS and R4 are as defined above,
The compound of General formula T,
where RI is methyl;
RS and Re are both methoxy; .
Ra, RS and R4 are higher. These values are reacted with boron tribromide at a temperature of from -30 to -10 ° C.
[2]
2. A method according to claim 1, characterized in that the process is conducted in a chlorinated aliphatic hydrocarbon environment.
[3]
3. Method pop. 2, characterized in that methylene chloride is used as the chlorinated aliphatic hydrocarbon.
Sources of information taken into account during the examination 1. Mashkovsky M. D. Medicinal products., M., Medicine, 1978, t. 1, p. 160. “

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB12325/77A|GB1593191A|1977-03-23|1977-03-23|Derivatives of morphine|

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