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    • 专利摘要:
    METHOD OF OBTAINING DERIVATIVES OF Pyridoxine or their salts with acids, The method of producing pyridoxine derivatives of the general formula OCH2-CHOH-CHjKHR sngone HjC ' sgONH f I where CH-CH-ORj L -CH5 (CHg) „CH2-O1 2 or (CKj n-CH2R2. Y where and O or: 1; X and X, | have different meanings and represent hydrogen or methyl; Y represents hydrogen or methyl; Rj means phenyl, unsubstituted or C3 substituted with one or two substituents, such as chlorine, methyl, ethyl, I-propyl, isopropyl or methoxy, or their salts with acids, about the fact that 3, O-
    公开号:SU1077566A3
    申请号:SU813289800
    申请日:1981-05-18
    公开日:1984-02-29
    发明作者:Декамп Марсель；Юрбэн Марсель
    申请人:С.А.Лабаз-Санофи Н.В. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of novel pyridoxine derivatives of the general formula OCH2-CHOH-CH | 1Ш1 НЗС „Jx- CHjOH sAcHiOH where R is CH-SI-OV | -CH- (CH2) -CH7 RJ - ft afttF aSTR where | 1 0 and 1; X and X have different meanings and represent hydrogen or methyl; Y is hydrogen or methyl; fig phenyl unsubstituted or substituted by one or two substituents, such as chlorine, methyl, ethyl, (-propyl, isopropyl or methoxygroup, possessing valuable pharmacological properties that can be used in medicine. Interaction of epoxy compounds with amines is known is carried out in an organic solvent by heating f, and the reaction of hydrolysis of ketals in a medium of mineral acids 2 is also known. Pyridine derivatives are known to have blocking activity with respect to ft-adrenergic receptor The purpose of the invention is to develop a method for producing new pyridoxine derivatives with anti-adrenergic and pressure-lowering properties on the basis of a known method. The goal is achieved by the fact that according to the method of producing pyridoxine derivatives, formula 1 or their salts with acids 3.0- (2, 3-zpoxypropyl) -c1, "c-isopropylidenepirkdoxol of the general formula / 0h O-CHj-Ott-CHj HcC / CH | -K iJ CKi-O is reacted with an amine of the general formula where R has the indicated values, in an organic solvent boiled reactionary aces, ny obtained ketal hydrolyzed in strong acid medium at 25-80 ° C and purposeful howling vschel product dissolved in free form or in the form of salts with an acid. Preferably, the compounds of the general formulas I and III are reacted in methanol and the ketal is hydrolyzed in hydrochloric acid. The target products can be isolated in the form of a salt with an inorganic acid, for example, with hydrochloric or with an organic acid, for example oxalic, fumaric, maleic or pamoins. Example. 4,5-Dioxymethyl-3-2-hydroxy-3- (2-methylphenoxyethyl-amine) -propoxy-2-methylpyridine and its salts. a) 3.0-Allyl-o (, c-isopropylidene pyrene). In a 1 L flask equipped with a condenser and stirrer, 400 ml of absolute ethanol is added to which is added in portions of 9.2 i (0.4 g atom) sodium. At the end of the reaction and after cooling the mixture, 49.15 g (0.2 mol) of o1, o-isopropylidenepyridoxol and then 15.31 g (0.2 mol) of allyl chloride are introduced into the mixture. over a period of 4 days at the boil. Most of the ethanol is evaporated under vacuum, after which the residue is dissolved in water. The extraction is carried out with ether, then the extract About once they are pressed in an aqueous solution of sodium hydroxide (approximately 2.5 HJ and then in water. After drying, the ether is evaporated and the resulting residue is used as received. Thus, 30 g of 3.0, allyl-C, et-isopropyl idenpyridoxol are obtained. Yield 60%, mp, after recrystallization of oxalate in ethyl acetate, 97-98 ° C. c) 3.0- (2,3-Epoxypropyl), ctisopropylidene pyridine, in a 1 liter flask equipped with a stirrer, injected 200 ml of simple ether, 49.8 g (0.2 mol) of 3.0-шли-lisopropylidenepyridoxol, 36.6 g (0.2 mol) of N-bromosuccinimide and 200 ml of water. The mixture is stirred for 5 days at. After neutralizing the sodium bicarbonate, the insoluble residue is filtered off and washed with water and ethyl ether. Thus, receive the first fraction of brsm-Idrin. The second part is obtained from an ether-containing solution, which is washed, dried and evaporated to dryness under vacuum. The residue is dissolved in diisopropyl ether or diethyl ether, treated, and filtered. After combining the two
    parts get a mixture of 52-55 g, melting at a temperature of about and representing two hot spots on thin layer chromatography. This mixture is transferred into a suspension in 160 ml of ethyl ether, after which it is stirred for 4 hours, in the presence of 160 ml of aqueous 1N. sodium hydroxide solution. After decanting, washing and drying, the ether-containing phase is evaporated to dryness under vacuum (yield 90-100%).
    If necessary, the residue is crystallized in diisopropyl ether. Thus, 3.0- (2,3epoxypropyl) -Y, b -isopropylidenepyridoxol is obtained. The yield of crystallized substance is about 90%, so pl. .
    (c) 4,5-Dioxymethyl-2-Oxy-32-methyl-phenoxy-ethylamine) pro-3-methylpyridine.
    A solution of 795 g (3 mol) of 3.0- (2.3 epoxy-propyl) -ob, 66-isopropyl idenpyrodoxol and 453 g (3 mol) of o-methylphenoxy-ethyl-Ea in 200 mp of methanol BEV is kept at boiling for 4 hours. After this stage, the reaction the mass is evaporated in vacuo.
    The residue is hydrolyzed under stirring, first at 20 ° C for 12 hours in the presence of a solution of 700 ml of hydrochloric acid in 2500 ml of water, and then for 30 minutes at 80 ° C. After cooling, the medium is made alkaline by adding 700 g of potassium carbonate, after. which lead extraction first with a mixture of 2000 ml / 400 ml of chloroform / pbutanop, and then 500 ml of chloroform. Collect the organic phases, wash them with triisides in water and cyiTiaT on sodium sulfate. After filtration, 2000 ml of methanol is introduced. In this way, 4,5-dioxymethyl-3-2-hydroxy-3- (2-methylphenoxy-ethylamine) -propoxy-2-methyl-pyridine is obtained as a free base. M.p. about 100 ° C. Yield 26.62%.
    i) Sesquioxalate 4,5-dioxymethyl-3- - -oxy-3- (2-methylphenoxyethylamine) -propoxyT -2-methylpyridine.
    To the free base obtained in the previous step, add 540 g of oxalic acid (anhydrous) in 1000 ml of methanol. The precipitated oxalate is filtered off and washed in methanol.
    After three-fold crystallization, 380 g of sesquiocsstate 4,5-dioxymethyl-3-f-2-oxy-3- (2-methylphenoxy-ethylamine) propoxy-1-2-methylpyridine are obtained from methanol. M.p. 150-1510С. Yield 24.78%.
    e) Monofurmate 4,5-dioxymethyl-3 2-hydroxy-3- (2-methylphenoxyethylamine) propoxy 1G | - 2-methylpyridine.
    37.6 g (0.1 mol) of the free base obtained in step c, dissolved in isopropanol, are introduced into the flask. After this operation, 23.2 g (0.2 mol) of fumaric acid in isopropanol are introduced into the flask. The mixture is kept at refpux and concentrated. After this operation, ethyl acetate is added and the mixture is again concentrated. Upon cooling, a mass of 0 is formed, which is dissolved in ethyl acetate. After filtering the mixture, it is crystallized in ethyl acetate / methanol.
    Thus, monofur5 mat 4,5-dioxymethyl-3-2-hydroxy-3 (2-methylphenoxy-ethylamine) -propoxy 2-methylpyridine is obtained. M.p. 119-120 ° C (decomposition). Yield 23.72%.
    1) 4,5-Dioxymethyl 3-12-hydroxy-3- (2-methylphenoxy) -propoxy -2-methylpyridine dichlorohydrate.
    37.6 g (0.1 mol) of the free base obtained in step c, dissolved in 5 methanol / ethyl ether, are introduced into the flask. After that, sparging with dry hydrochloric acid is carried out, and then ethyl ether is introduced. Recrystallized twice in ethyl acetate / methanol with the formation of a precipitate.
    Thus, 4,5-dioxymethyl-3-t2-oKCH3- (2-methylphenoxyethyl amine) -propoxy | dichlorohydrate is obtained. 2-methylpyridine. M.p. 151-152 ° C (decomposition). Yield 24.66%.
    ) Dimeate 4,5-dioxymethyl-3 2-hydroxy-3- (2-methylphene syethylamine) propoxy -2-methylpyridine.
    37.6 g of the free base obtained in stage c, 0 dissolved in methanol are introduced into the flask and kept at reflux in the presence of 23.2 g (0.2 mol) of maleic acid. The mixture is evaporated under vacuum to dryness) and then washed twice with 5 in dry ethyl ether. After this operation, the contents are crystallized in acetone / ethyl acetate, and then crystallized again in isopropanol / methanol.
    Thus, dimaleate 4, 5-dioxymethyl-3-2-hydroxy-3- (2 methylphenoxyistilamine) -propoxy 3-methylpyridine is obtained. M.p. IZ-Ib with. Yield 22.18%.
    5h) Pamoate 4,5-dioxymethyl-3-2-oxy-3- (2-methylphenoxy-ethylamine) propox - 2-methylpyridine.
    37.6 g (0.1 mol) of the free base obtained in step c, dissolved in methanol, are introduced into the flask and kept at reflux in the presence of 38.8 g (0.1 mol) of pamoic acid. The mixture is evaporated to dryness in vacuo, then the residue is washed with dry ethyl ether.
    After this operation, the content is crystallized in isopropanol, and then methanol and isopropanol is crystallized again in a mixture.
    Thus, pamoate of 4, 5-dioxymethyl-3-2-hydroxy-3- (2-methylphenoxy-ethylamine) propoxy -2-methylpyridine is obtained. M.p. 177-179 C. Yield 23.51%.
    Similarly, the following compounds are obtained:
    So pl., C Dioxalate 4,5-dioxymethyl-3-2-hydroxy-3- (2-fench1-1-98-99-methylethylamine / -propoxy - (iopropanol) 2-methylpyridine. Yield 15.01% Dioxalate 4,5-dioxymethyl-3- (2-hydroxy-3-phenoxy-110-115 ethylamine propoxy) -2-methyl- (pyridine methanol. Yield 16.22% Dioxalate 4,5-dioxymethyl-152-154 3- | 2-hydroxy-3- (3-phenyl- (isopropyl-methyl-1-propyl) amine - pan / propoxyJ-2-methylpyridine. Methanol Yield 10.8% Cesquioxalate 4,5-dioxymethyl-3-2-hydroxy- H- (3-168-169 methylphenoxyethylamine) - (methano propoxy si -2-methylpyridine. Yield 23.45% Cescrioxalate 4,5-dioxymethyl-W-3- (2-ethylphenoxy-149-151 ethylamine) -2-oxypropoxy - (I ano 2-metsh1PIridina. Yield 12.93% Cesquioxalate 4, 5-dioxime-tyl-3- 3- (2,6-dimethylphenol-133-f 35 noxyethylamine) -2-oxypro- (methanol poxy -2-methylpyridine. Output 12.93% Sesquioxalate 4,5-dioxymethyl-3-2-ox-3- (3, 5178-179 dimethylphenoxy-ethylamine) - methanol propoxy-2-methylpyridine Yield 19.02% Oxalate 4,5-dioxymethyl-3- (2 -oxy-3-phenethylamine 160-161 propoxy) 3-methylpyridi- (methadr. Yield 17.56% Dioxalate 4,5-dioxymethyl 3-3- (3,4-dimethoxyphenethylamine -2-hydroxypropoxy - 116-118 2-methylpyridine, Yield (methanol 17.04% Cesquioxalate 4,5-dioxymethyl-3 - 2- hydroxy-3-f2-metho132-133 xyphenoxyethylamine) -pro (methanol coxy -2-methylpyridine, n Yield 21.32%
    Sesquioxalate 4,5-dioxymethyl-3-2-hydroxy-3- (2-phenoxy-2-methylethylamine) propoxy-2-methylpyridine Yield 13.68%
    Oak lettuce 4,5-dioxymethyl 3 - 2-hydroxy-3 - (1-methyl-2-18Y-181 phenoxyethylamine) -propoks - (TH & op 62-methyl propidith a .panol / Yield 8.57% methanol) Dioxalate 4, 5-dioxymethyl-3-2-hydroxy-3- (2-from-164-165 propyl-5-methylphenoxyethyl- (methanol) amine) -propoxy -2-methylpyridine. Yield 14.03% Cesquioxalate 4,5-dioxymethyl-3-2-hydroxy-3- (4-me-131-135 toxethylamine) propoxy - (methanol) 2-methylpyridine. Yield 12.51% Dioxalate 4,5-dioxymethyl-3-2-hydroxy-3- (2-propylphenoxyethylamine) propoxy -2-methylpyridine .143-145 Yield 6.84% (methanol) Dioxide t 4,5- Dioce Syme-i t Il-3- 2-ox-3- (2-iso165-166 propylphenoxyethylamine) (methanol) propoxy -2-methylpyridine. Yield of 7.10% Cesquioxalate 4,5-dioxymethyl-3-2-hydroxy-3- (3, 4-dimethylphenoxy ethyl 184-185 amine) -propoxy si -2-methyl (methanol) pyridine. Yield 16.74% 4,5-Diksimetil-Z-2102-103 hydroxy-3- (2-isopropylphenok (diisoproethylamine) -propox 2-ester / methylpyridine “Output 13.29% methanol) Sesquioxalate 4,5-dioxy 147-150 methyl 3-2-hydroxy-3- (3,4 (diisoprodimethylphenoxypropylamine) - sawn propoxy 3 -2-metsh1 Pyridine. ether / me / O exit 8,46% tanol) 107-lio 4,5-dioxymethyl-3-2-oxy sy -3- (2-me (ethyl acetate / labels siphenoxyethylamine) tanol) pronoxy -2-methylpyridine Yield 16.44% Sesquioxalate 4,5-dioxime methyl-3-2-hydroxy-3- (4 - chloro-112-11 5 phenoxyethylamine) -propoxy 2-methylpyridine. Yield (Methanol) 12.56% The proposed pyridox derivatives of Formula I or their salts have a more DJHPOKHM spectrum of action than the known analogs of. structure, and have pronounced anti-adrenergic properties of the type of / and the majority of these derivatives have, in addition, the interest of HbDvm with anti-adrenergic properties with respect to the receptors ft ,. Moreover, some of the proposed compounds have a pure hypotension effect, manifested on anesthetized animals, and normal blood pressure, which is expressed in the antihypotension effect on animals with hypertension. It is likely that this effect is a result of anti-iadrenergic activity, which P1d1eval reduces peripheral resistances and, in part, also reserpine-type activities. Stimulation of adrenergic recipes with endogenous catechol amines leads to an increase in cardiac activity and an increase in even more significant cardiac energy consumption. Ch1O medication with antiadrenergic effects has been found to have an anti-anginic character, protecting the heart from the catecholamine hypermetabolic activity. The proposed compounds decrease myocardial activity because they cause a decrease in blood pressure and, thus, a decrease in heart ejection resistance. Moreover, interest is known in compounds possessing antiadrenergic activity as hemisynthetic derivatives of the uterine horns, namely nicergoline, for the treatment of a number of cerebral disorders associated with disorders in the vascular system, in particular the insufficiency of the cerebral circulation and migraine. This effect is associated with a slight effect of the central depressor, which should be accompanied by a decrease in cerebral metabolism. The most interesting compounds proposed in the invention in the treatment of cerebral insufficiency may be those compounds that have an anti-adrenergic effect, more pronounced than their hypotensor effect. Compounds I of the general formula 1 were also found to have a low toxicity, regardless of whether they were administered intravenously or orally, i.e. have a favorable toxico-pharmacological indicator, which is significantly higher than the similar indicator of known compounds used in therapy for the same indications. Among the proposed compounds with the most interesting spectrum of pharmacological activity can be called 4,5-dioxymethyl-3-2-hydroxy- H- (2-methylphenoxy-ethylamine) -propoxy-2-methylpyridine and 4,5-dioxymethyl-3-2-hydroxy-3- (2-methoxyphenoxy-ethylamine) -propoxy-2-methylpyridine; these compounds are in the form of a free base or a non-toxic salt attached to and for example oxalate, fumarate or dihydrochloride. Pha1 1acological tests, ocynie with 4,5-dioxymethyl-3-2-oxy-3- (2-methylphenoxy-ethylamine) -propoxy -2-methylpyridine, taken as its one-and-a-half oxalate (compound A), show that this compound detects after administering it intravenously to a dog is anti- (- adrenergic properties at a dose of 2 mg / kg and the ability to reduce elevated blood pressure at a dose of 0.1 - 0.2 mg / kg. Intravenously administered to the dog 4,5 dioxymethyl-3-2-hydroxy-3 - (2-methoxyphenoxyethylamine) -propoxy -2-methylpyridine in the form of dichlorate (compound I) shows an elongated anti- {6-ad nerve activity at a dose of 0.5 mg / kg Acute toxicity. Acute toxicity tests are performed on rats and mice using the proposed compounds.The following results are recorded when using these compounds:, CH3 Introduced as a sesquiota sate, LD JQ mg / kg: Mouse Rat intragastrically 700 2200 intraperitoneally intravenously 118 In the form of fumarate intragastric intravenous - (CH2) 20-O 9 In the form of dihydrochloride for mice inside the gastrointestinal LDjo 5000 mg / kg, 107756610 for the rat intravenously LD5o 245 mg / kg.
    权利要求:
    Claims (2)
    [1]
    METHOD FOR PRODUCING PYRIDOXINE DERIVATIVES OR THEIR ACID SALTS.
    The method of obtaining pyridoxine derivatives of the General formula
    H 3 C, -choh-ch 2 nhr sn 2 he sn 2 sn where I
    CH-CH-ORj
    X
    -CH 7 (CH ) „CH 2 -Oi 2 or en- (sn 2 ) p -sn 2 to 2
    Y where th = 0 or: 1;
    subjected to interaction with an amine of the general formula HjN-R (III) where R has the indicated meanings in an organic solvent at the boiling point of the reaction mixture, the obtained ketal is hydrolyzed in a strong acid medium at 25 - 80 ° C and the target product is isolated in free form or in the form salts with acid.
    [2]
    2. The method of pop. 1, characterized in that the interaction of the compounds of general formulas II and III is carried out in methanol, and the ketal is hydrolyzed in hydrochloric acid.
    SU „„ 1077566
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    同族专利:
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    法律状态:
    优先权:
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    GB8016516|1980-05-19|
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