Method for separation of mixture

专利摘要:
The separated d and l enantiomers of medetomidine and their salts are selective and potent alpha 2-receptor agonists.
公开号:SU1648248A3
申请号:SU884356076
申请日:1988-06-28
公开日:1991-05-07
发明作者:Йоханнес Карьялайнен Арто；Эйнари Виртанен Раимо；Юхани Саволайнен Эйно
申请人:Фармос-Ихтюмя Ой (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new optical isomers of 4- - JJ - (2,3-dimethylphenyl) ethyl -1H-imidazole (medetomidine), which is known as a selective potent torus receptor stimulus.
The purpose of the invention is to obtain the d- and 1-enantiomers of medetomidine, which significantly increase the & 2-selectivity and potency of $ 2 ReCept ° Moat compared to the racemate of medetomidine.
Example. 14 g of medetomidine (base) is dissolved in 50 ml of methanol. 10.5 g of (+) - tartaric acid is dissolved in 50 ml of methanol. The solutions are mixed and the solvent is evaporated to a volume of 50 ml. The mixture was placed in an ice bath and 9 g of white precipitate were obtained. The precipitate is suspended in 25 ml of ethanol, the mixture is subjected to
14 minutes under ultrasound and filtered. The precipitate is dissolved in a mixture of 20 ml of absolute alcohol and 60 ml of methanol while heating on a steam bath. 5 g of sediment (degree of rotation + 55 °) is obtained after cooling. After recrystallization from 60 ml of methanol, 4.1 g of product are obtained with a degree of rotation of + 60 °. The recrystallization is repeated until the degree of rotation ceases to increase. The d-enantiomer tartrate is dissolved in water, the solution is alkalinized, and the d-enantiomer is dissolved in an organic solvent, for example dichloromethane or diethyl esier. The degree of rotation of the d-enantiomer in the base Lorma is +75. 1-zanantiomer can be isolated from the mother liquor, d- and 1-enantiomers of medetomi
Dyne are selective and potent stimulators of o receptors.
Adrenergic receptors are physiologically important binding sites specific for norepinephrine and adrenaline and are located on the surface of cell membranes. Adrenoceptors of the sympathetic nervous system are classified as two different subtypes - alpha (00 and beta (A) receptors), which can then be divided into subgroups, namely #, and o (gi f}, and}} 2 Among these receptors are ft ,, (( The legs are mainly localized postsynaptically on the surface of, for example, smooth muscle, and thus affect the contraction or relaxation of the smooth muscle at the same time O-receptors are mainly localized presynaptically at the end of noradrenergic nerves. receptors are stimulated by norepinephrine in physical logical conditions, the release of norepinephrine leads to a decrease in activity (2 ReDept ° P °, i.e., in this case, negative feedback is observed. This negative feedback phenomenon can also be caused by some synthetic stimuli t ° Rami like medomidomine, and some derivatives close to him.
In animal experiments, the proposed d- and 1-enantiomers, especially the d-enantiomer, showed themselves that, as substances that significantly increase -selectivity and potency -receptors compared to a racemate (ie, medetomidine), the d-enantiomer may as, for example, a drug with a sedative-analgesic effect, an antidepressant, an anti-depressant medication. In addition, it can be used as a pharmacological tool in studying the physiology and pharmacology of # 2 adrenoceptors.
The pharmacological activity of the proposed compounds is determined as follows.
Alpha-2 stimulation in vitro.
 -stimulation is determined on isolated, electrically stimulated preparations isolated from mouse vessels. In this model (-sti

the multiplier is able to block muscle contraction induced by electricity due to the activation of presynaptic β-adrenoceptors and, thus, reducing the effect of secretion on the motor nerve. As a sample, the known Yg-stimulators are used: detomidin, medetomidin, and clonidine. The results are shown in Table 1, in which the effect of stimulation of the receptor is represented by the expression pP2 (negative logarithm of the molar concentration of the compound causing a 50% inhibition maximum).

The results presented in Table 1 show that the d-enantiomer of medetomidine has an upper limit to the activity of stimulation (Xj receptors. Compared with other preparations, the d-enantiomer exhibits an increased activity in stimulation of α-receptors.
Table 1
Compound
(-stimulation in vicro (vessels from p1) 2)

9.3
6.0 (partial
stimulator
9.0
8.5
8.5
# r WJ-selectivity. The selectivity of the d-enantiomer as stimulation of the th / g receptors is studied in receptor binding experiments using rat brain membranes. The ability of the d-isomer and basic compounds to compete with H-clonidine (for L-receptors) and with% (tff-β-prazosin (for 0 (t-receptors)) is studied according to a known method. The results of this testing are presented in Table. .2, in which the ability of the studied drugs to compete with 3H-clonidine and H-prazosin for binding is expressed as 1C 50 (the molar concentration of the competing ligand is necessary to replace 50% of the radioactive ligand).
Table
half spontaneous suspension in mice.
Table 4
1.2
46 3.3
3.7
6.4
55019 45849
189975 16700
232 6200
4129 5060
65 969
The results in Table 2 indicate the extreme selectivity of the enantiomer as a stimulator (X receptors in comparison with metatomidine and other basic compounds.
Sedative analgesic effects
Sedative and analgesic properties. The proposed drugs are studied by testing spontaneous motility and muscle cramps in mice. The spontaneous mobility of mice and rats is measured using a device that determines the Ahimex activity. Test compounds are administered 30 minutes before the 2-minute measurement periods are administered intraperitoneally.
When studying the effect of the compounds on muscle convulsions, the compounds and salt were injected into rats under the scapula and after 45 minutes, 1 ml of 1% acetic acid was administered intraperitoneally. The number of convulsions was recorded every 25 minutes (Kascer et al., Tred. Proc. 1j3 , 412, 1959). The results are shown in table 3 and 4.
for the studied compounds the concentration at which it falls
Note. KP-- corresponds for the studied compounds to the concentration at which a drop in convulsive contractions caused in mice with acetic acid is twofold.
The results given in Tables 3 and 4 indicate that the d-enantiomer has, in comparison with the racemate (medetomidin) and other related drugs, increased sedative-analgesic properties. The sedative-analgesic effect of medetomidine is due to the d-enantiomer.
Anxiolytic effect
The anxiolytic effect of the proposed compounds is studied according to a known method: the method of exploiting free and bound paws in a rat in a suspended labyrinth is being studied. increase the relative exposure of free paws. The rat is placed in the center of the c-maze and the number of open and closed (free and connected) exits is recorded for 5 minutes 40. The results are shown in table.5.
Spreadsheets
45
The results in table 5 indicate that d-enanti
7164
An omer in a test with a suspended t-maze reveals an anxiolytic effect.
Anxiety (a state of fear) associated with withdrawal symptoms is caused by noradrenergic over-activity. As a result, such symptoms can be easily eliminated (cured) with the help of drugs that reduce the level of norepinephrine, for example, clonidine. Experiments conducted on rats show that the d-enantiomer is capable of reducing the release of norepinephrine and, thus, strengthening the sympathetic nerve of both the peripheral and central nervous systems. This is demonstrated by measuring the CSF concentrations of MHPG-SO / j (the main metabolite of central norepinephrine) in rats after administration of C1 enaitomer. The results are shown in Table 6.
Table

CSF MHPO-SOf,% of control (4 hours after d-enantiomer a)
100 -10 -20 -30 -65
Antihypertensive effect.
The ability of the proposed compounds to reduce the pressure is studied as follows.
Normal weight Sprague-Dauleg rats are first anesthetized with urethane. After that, the femoral artery is connected to a blood pressure transducer with a polyethylene tube. After this, the test compound is injected into the femoral vein and the blood pressure and pulse rate are recorded using a recording device. The antihypertensive effect of the d-enantiomer on anesthetized rats is shown in Table 7.
i
The results presented in
Table 7 shows that the d-enantiomer has a pronounced antihyper. Table 7
-
five
five
0
0
five
0
45
0
five
tensile and bradycardic effects.
d- and 1-enantiomers and their non-toxic, pharmaceutically acceptable acid addition salts or mixtures based on them can be administered parenterally, intravenously or orally. An effective amount of the compound is combined with a suitable pharmaceutically acceptable carrier. An effective amount is that amount that leads to the desired effect without causing adverse effects. The exact amount used in particular situations depends on numerous factors: the method of administration, the type of mammal, the conditions in which the derivative is used and others, as well as the structure of the derivative.
Pharmaceutically acceptable carriers that are used with the compounds of the invention may be liquid, solid, and are usually selected depending on the intended route of administration of the drug. For example, solid carriers include lactose, sucrose, gelatin, and agar, and liquid carriers include water, syrup, olive, and peanut oils. Other suitable carriers are well known to those working in the field of drug preparation. The combination of the derivative and the corresponding carrier can lead to the creation of a large number of various pharmaceutically acceptable forms: tablets, capsules, solutions, pollen, emulsions and powders.

权利要求:
Claims (2)
[1]
1. A method for separating a mixture of d- and 1-enantiomers of 4- 1- (2,3-dimethylphenyl) ethyl T-1H-imidazole9, characterized in that racemic 4-JJ- (2,3-dimethylphenyl) -1-ethyl -imidazole is treated optically active
[2]
2. Method of claim 1, about tl and h of aa acid, followed by dividing and with the fact that as a mixture of diastereomeric salts of optically active acid using fractional crystallisation. 5 SOCC (+) - tartaric acid.

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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

---

GB8716803A|GB2206880B|1987-07-16|1987-07-16|Optical isomers of an imidazole derivative|LV930435A| LV5241A3|1987-07-16|1993-05-28|enantiomeric mixture distribution method 4-N-ethyl? -1h-imidazole d- and l-|

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LTRP761A| LT2214B|1987-07-16|1993-07-07|4-ETHYL) -H-IMADAZOLO D-AND 1-ENANTIOMER MUSIC SEPARATION|