Method of producing n-substituted derivatives of aziridine-2-carboxylic acid or sodium salt thereof

专利摘要:
The invention relates to N-substituted aziridine-2-carboxylic acid derivatives, in particular the preparation of compounds of the general formula I: N 5 C — CH — CH 1 —N — CH — C CH — CH CR 2 -N CR, where R is lower alkoxy ; R, 2-C (0) OH, C (0) 0-alksh1, OHCHj, formyl, C (0) NH2, or Na-salts of the acid, which have an immunostimulating effect, which can be used in medicine. The goal is to create new, more active substances of the specified class. Synthesis of lead from compounds f-ly II and III: CH CBr-CN (II) and HaN-CH7-C CH-CH CRY-c R H (III), where R, - has the specified value; (0) OH or C (0) 0-alkyl. The desired product is isolated either in free form or in the form of an acid Na salt. In the case when (0) is 0-alkyl, this group is reduced with sodium borohydride and lithium chloride in organic solvent to obtain the group R; 2 CHjOH in the target product. The latter is converted into a compound, where R is formyl, by oxidation with activated pyrolusite. In the case when R, j-C (0) OH, is treated with triethylamine and isobutyl ether, chlor-ant of another acid in tetrahydrofuran medium to obtain (0) NHj in the target product. The new compounds, compared to cyamexone, have a 10-fold better immunosuppressive effect (GVH - and NUS reactions) at a dose of 0.01-10 mg / kg. 2 tons abl. I CO 4i CO O Oh
公开号:SU1431676A3
申请号:SU853991691
申请日:1985-12-20
公开日:1988-10-15
发明作者:Бозис Эльмар；Энделе Рихард；Пальке Вульф
申请人:Берингер Маннхайм Гмбх (Фирма)；
IPC主号:

专利说明:


cm
. The invention relates to the field of obtaining new: derivatives of schenous aziridium-2 - carboxylic acid of the general formula
N CH, Q-.R,
R
one
1 where R is lower alkoxyg t1pa;
I R - carboxyl, alkoxycarbonyl,
: oxymethyl, formyl or car: boksiamid,
: or sodium salt of acid with immunostimulating action.
The aim of the invention is to develop, on the basis of the known methods, the method of producing compounds: the aziridine series, which possess high-rise immunostimulating activity with low toxicity. I Example 1, 5-C (2-Cyan-1-aziridinyl) -methyl-6 methoxypyridine 2-carboxylic acid (sodium salt),
2.33 g (44 mol) of acrylonitrile was diluted with 1 ml of diethyl ether, after which, with stirring and irradiation, 7.05 g (44 mol) of bromine was added dropwise to the mixture. By means of periodic cooling, the position is reached so that the temperature inside the reaction vessel does not exceed 40 ° C. The reaction mixture is further stirred for 5 minutes, diluted with 60 ml of methyl alcohol, then a solution of 6.55 (44 mol) of triethanolamine is added dropwise 60 ml of methyl alcohol. After the expiration of the next number, a solution of 6.55 (44 mol) of triethanolamine in 60 ml of methyl alcohol and a solution of 8 g (44 mol) of 5-aminomethyl-6-methoxypyridine-2 carboxylic acid (t, pl. 269-270 ° C, with decomp.) In 1 liter of methyl alcohol and 200 ml of water. Hold the reaction solution for 24 hours, evaporate on a rotary evaporator, get an aqueous solution by adding 2N hydrochloric acid to pH 4.5, after which for 2 days, continuous extraction with methylene chloride is carried out. The methylene chloride phase is dried and evaporated. This gives 4.8 g of an oily substance, which is dissolved in 50 ml of ethyl acetate.
five
0
five
0
five
0
five
five
alcohol. In case of cooling, the solution is mixed with a solution of 440 mg of sodium in I5 ml of ethyl alcohol.
The sodium salt of 5- (2-cyano-1-aziridinyl) -methyl-6 methoxypyridin-2 carboxylic acid is precipitated; after adding 100 ml of isopropyl alcohol, the product is filtered off, dried and washed with diethyl ether, as a result of 3.7 g (33% of the theoretically calculated value) of the desired compound with m.p., 230-232 ° C are obtained.
From methyl chloride extract pos-. distilling off the methylene chloride and dissolving the oily residue in a small amount of isopropyl alcohol followed by the addition of the diethyl ether gave 5- (2-cyano-α-azididinyl) -methyl-6-methoxypyridine-2-carboxylic acid with T-m-t-2-carboxylic acid and T-2-carboxypyridine-2-carboxylic acid with T-m
Applied as a source
5-aminomethyl-6-methoxypyridine-2-carboxylic acid material is prepared as follows:
3-Cyano-2-methoxy-6-methylpyridine is oxidized in an aqueous solution with potassium permanganate, resulting in 5-cyano-6-m-toxypyridine-2-caroic acid, m.p., 235-237 ° C. Immediately after this, the product is hydrogenated in the presence of palladium on carbon in a mixture of isopropyl alcohol, water and hydrochloric acid, and the result is the desired compound.
In a similar way, by reaction of 2-bromo-acrylonitrile obtained by bromination of acrylonitrile and subsequent cleavage of hydrogen bromide with 5-aminomethyl-6-methoxypyridine-2-carboxylic acid methyl ester (m.p. 224-226 ° C), 5- (2-cIan-1 -aziridine-methyl-6-methoxypyridine-2-carboxylic acid methyl ester, t, mp, is obtained (from isopropyl alcohol) 156-158 ° C, yield 57%.
Methyl 5-aminomethyl-6-methoxypyridium-2-carboxylic acid methyl ester used as starting material is obtained by the following procedure.
5-Cyan-6-methoxypyridin-2-carboxylic acid is converted in methyl alcohol under the action of trimethylchlorosilane to methyl 5-cyano-6-methoxypyridine-2-carboxylic acid (mp. 1 24-1). As a result of the subsequent hydrogenation in methyl alcohol in the presence of hydrochloric acid and using palladium on charcoal as a catalyst, the desired aminomethyl compound is obtained (mp 224-22 C). The solution obtained after hydrogenation with a few drops of triethanolamine is neutralized to pH 7 and used to carry out the next reaction.
11 example2. 1- (6-Oxymethyl-2-methox 1-3-pyridinyl) -methyl} -2-aziridinecarbonitrile,
247 mg (1 mol) of 5- f (2-cyano-1-aziridinyl) methyl J-6-methoxypyridine-2-carboxylic acid methyl ester (see Example I) is dissolved in 10 ml of absolute tetrahydrofuran, after which 74 mg (2 mmol) of sodium borohydride and 84 mg (2 mol) of lithium chloride were added to the prepared solution. The reaction mixture is then stirred for 12 hours at room temperature, the indicated amounts of sodium borohydride and lithium chloride are added to it once more, the mass of the mixture is removed from within 12 hours, and then 5 ml of water is added to it. Immediately after this, the reaction mass was evaporated, the resulting residue was dissolved in ethyl alcohol, the solution was filtered, the filtrate was evaporated, the residue was dissolved in acetone, the solution was filtered and again evaporated. The residue obtained is purified on a column filled with silica gel (eluent: mixture of acetone and toluene in a volume ratio of 1/3; the value of Cl is approximately 0.3). The result is 120 mg (55% of the theoretically calculated value) of the desired compound with the like. 68-70 ° C.
Example 3.5- (2-Cyan-1-aziridinyl) -methyl-6-ethoxypyridine-2-carboxylic acid.
By analogy with example 1, by reaction of 2-bromoacrylonitrile obtained by bromination of acrylonitride and subsequent cleavage of hydrogen bromide with 5-aminomethyl-6-ethoxypyridine-2-carboxylic acid (m.p. 266-228 with ) 5% (5-cyano-1-aziridinyl) -methyl-6-ethoxypyridin-2-carboxylic acid, new acid (mp. 108-1 11 C) is obtained in 35% yield.
0
five
0
five
0
five
0
five
0
five
The 5-aminomethyl-6-ethoxypyridine-2-carboxylic acid used as the starting material is obtained by the above method.
The 2-chloro-6-methylpyridin-2-carbonitrile is converted into 2-ethoxy-6-methyl-yridin-3-carbonitrile (mp 90-92 ° C), as a result of the interaction with sodium ethylate in ethyl alcohol, this compound is oxidized with potassium permanganate to 5-cyano-6-ethoxypyridine-2-carboxylic acid (t.p. 185-190 ° C). As a result of the catalytic hydrogenation of the obtained compound in the presence of palladium on carbon, 5-aminomethyl-6-ethoxypyridine-2-carboxylic acid is obtained.
Example 4. 5- (2-Cyano-l-aziridinyl) -methyl-6-metoccIffliridine-2-carboyl aldehyde.
2.4 g of 1- (6-hydroxymethyl-2-methoxy-3-pyridinyl) - methyl} -2-aziridinecarbonitrile described in example 2 is dissolved in 80 ml of methylene chloride, after which 6 g of activated precursor is added to the prepared solution. . The reaction mass is stirred for 24 hours at room temperature, the specified amount of activated pyrolusite is added to it again, and then again stirred for 324 hours at room temperature. Directly after this, filtration is performed, the filtrate is evaporated, and then the resulting residue is subjected to purification on a silica gel-filled column (eluting medium: a mixture of dioxane and ligroin in a volume ratio of 1: 3). The fraction containing the desired compound is evaporated. after which the residue is recrystallized from toluene. Yield 1.4 g (59 from the theoretically calculated value). M.p.104-105 S.
Example 5.5- (2-Cyan-1-aziridinyl) -methyl-6-labels si-pyridine-2-carbamide.
To 3 g (13 mmol) of 5- (2-cyano-1-aziridinyl) methyl-6-methoxy-pyridine-2-carboxylic acid in 30 ml of abs. Tetrahydrofuran at 0 ° C, 1.3 g are added dropwise at the same time. triethylenamine in 20 ml of abs. tetrahydrofuran and 1, in g of isobutyl ether chloroformic acid in 20 ml of abs. tetrahydrofurag on with stirring. After 30 minutes, suction is performed, the filtrate is cooled with ammonia gas while cooling. After
overnight exposures to the fridge cabinet produce a suction of sediment, B result is 1 ,, 6 g 53% of the theoretical amount of the compound with t, mp, l70-i72 C.
Below is the test data on the pharmacological effect of the compound in comparison with the current cyamexon.
Tsnemekson's effect on local Graft-A; -ersus Host (GVH) and Host versus-Graft (HVG) in mice
As shown in experiments on animals (see, tabl}) J in which the effect of cyamexon is compared with that of the known compound cyclosporin} cyamexon is an immunodepressant pharmaceutical substance,
Loka-GVl-1-reakii is induced by introducing 5 i 1 O ° parenteral (Ba1b / e) spleen cells into the hind paw (057BT / 6 - Ba1b / s) P mice. The same NUMBER of F spleen cells was administered 3 control opposite paw. HVG - reacts are called by introducing 5 1 O cells (BaTv / s x C57BI / 6) F, mpl into the parenteral NfbiLuei; (Ba1b / s). Such a number of Ba1b / s spleen cells is injected into the opposite (control) paw, GVH Measure or Hc reaction is determined using popliteal lymph nodes. On the five: th (GVH) their third (HVG) dengo after the introduction of the cells, the popliteal lymphatic node; remove and weigh. For the measure of GVH / HVG, the reactions take an increase in the weight of the weights of the nodes on the experimental foot as compared with the nodes in the control. Cyamexone or cyclosporine was orally administered to animals. Daily dose of O l- iOO mg / kg. The drugs are administered starting on the day of injection (day 0; time 0) and before the fourth (B case of GVH) or the second (in the case of HVG) day after injection.
From the data of comparative tests, it follows that udiamexon, like cyclosporine, clearly suppresses the same-called; the way GVH- and HVG - reactions. Under comparable conditions, the I-munodepressive effect of 2-cy an-1 (2-methoxy-6-carboxypyridin-3-yl) -methyl 1 aziridine (example 1) and 2-cyano- (2-methoxy-5- hydroxy 1et 1lpyridine-3-yl) -methyl aziridine. (example 2) and compared with the similar effect of ciam exon. Daily dosage: in the range of 0.01-10 MG / .H.G,
Comparison of the data in Table 2 (local Graft-versus - Host reaction shows that 2-cyan-1 (2-methoxy-6-carboxypyridin-3-yl) -methyl-aziridine and 2-cyano-1 C (2- methoxy-6-hydroxymethylpyridin-3-yl) -methyl-aziridine has 10 times higher activity than cyamexon.

权利要求:
Claims (1)
[1]
Invention Formula
Method for preparing N-substituted aziridine-2-carboxylic acid derivatives of general formula I
CN
W
N
20
CH
RI
where rf R.
lower alkoxy group;
carboxyl, alkoxycarbonyl,
hydroxymethyl, formyl or carboxamide,
or sodium salt of the acid, characterized in that the compound of the general formula II
 I
Hal
where Hal is a bromine atom,
reacted with amine
General formula III
 /
where R ,, has the specified value; R is carboxyl or alkoxycarbonyl,
followed by the selection of the desired product in free form or as the sodium salt of the acid, or a compound of the general formula 1, where R is alkoxycarbonyl, in an organic solvent medium is treated with a mixture of sodium borohydride and lithium chloride, and the resulting compound of the general formula I, where R, 2 - hydroxymethyl is isolated or converted to a compound of the general formula I, where R, is formyl, using activated pyrolusite, or a compound of the general formula I, where R is carboxyl, is converted to a compound of the general formula I, where R / 2 - carboxamide, acting simultaneously triethylamine and isobutyl chloroformate in tetrahydrofuran medium.
Table I
Cyclr P 0, 05 (Students t-test).
Kontrolnyy9, 90,342,61,932,7L, 8
Tsiamekson 0,0110,90,838,93,528,03,3
0,19,09,726,42,317,4 2,1
1,09,90,423,61,013,, 2
10.09.9. 0,314,10,64,, 6
table 2
1431676
p 0.05 (Student s t-test)
10 Continuation of table 2

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引用文献:

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DE2833986C2|1978-08-03|1988-04-07|Boehringer Mannheim Gmbh, 6800 Mannheim, De|

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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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DE19843446713|DE3446713A1|1984-12-21|1984-12-21|N-SUBSTITUTED AZIRIDINE-2-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE SUBSTANCES|

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