Method for preparation derivatives of 1,2,5,6 tetrahydropyridine or their hydrochlorides or benzenes

专利摘要:
New compounds (I): <IMAGE> in which R denotes a hydrogen, a hydroxyl or an alkyl containing up to 8 C, optionally substituted by a carboxy or R denotes an aralkyl containing up to 10 C or -COOZ, Z being an alkyl containing up to 8 C or an aralkyl containing from 7 to 10 C, R1 denotes an alkyl containing up to 8 C, R2 denotes a hydrogen or an alkyl containing up to 8 C, -COalk1 or (CH2)2N(alk2)2, alk1 and alk2 denoting an alkyl containing up to 8 C, it being understood that if R denotes an alkyl, R2 does not denote a hydrogen, and their addition salts with acids.
公开号:SU1678203A3
申请号:SU884355793
申请日:1988-04-22
公开日:1991-09-15
发明作者:Галльяни Джулио；Барцаджи Фернандо；Бонетти Карла；Тоя Эмилио
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

used in the treatment of Alzheimer's disease or senile dementia, as well as in the treatment of memory disorders.
The purpose of the invention is to create, on the basis of known methods, a method of obtaining new 1,2,5,6-tetrahydropyridine derivatives with valuable pharmacological properties.
The goal is achieved by the fact that 3-acetylpyridine of the general formula
From
N
C-R,
and about
where the Ra values are as indicated above, they are reacted with a compound of the general formula
NH20R3-HCI,
where the values of Hz are as indicated above,
to obtain the oxime of the general formula
where the values of R2 and Yaz are as indicated above, which are reacted with a halide of the general formula
Ri x,
where Ri1 is methyl or benzyl;
X is bromine or iodine, to obtain the salt of General formula
R2
C NOR3
N -f X
k
where the values of Ri, R2 and Kz are as above, which are exposed to a hydrogenation agent, such as sodium borohydride or metallic sodium in ethanol, to give a compound of the general formula
ABOUT
N
Ri
one
(Q)
where the values of Ri, R2 and RS are as indicated above and, if desired, either a compound of general formula II. when Ra is hydrogen, is exposed to a compound of the general formula
RaHal,
where the value of P3, except for RS is hydrogen, is indicated above;
Hal is bromine or iodine, or when RI is benzyl, the compound is total
Formula II is exposed to a. chloroformate ethyl chloroformate followed by heating to give a compound of the general formula I, where Ri is hydrogen,
0 or when Ri is hydrogen or benzyl, the compound of general formula II is exposed to chloroformic acid ethyl or benzyl ester to obtain a compound of general formula I, where RI is ethoxy5 or benzyloxycarbonyl, to release the desired product in free form, in the form of hydrochloride or benzenesulfonate.
PRI me R 1, 3-acetyl-1,2,5,6-tetrahydropyridinoxime hydrochloride.
Stage A. Bromide 1-benzyl-3-acetylpyridinoxime.
7.4 g of 3-acetylpyridinoxime derived from 3-acetyl pyridine and hydroxylamine hydrochloride, so pl. 115-117 ° C, a solution of 5 in 80 cm of ethanol, 8 cm3 of bromobenzyl are added and refluxed for 6 hours. The solvent is removed and crystallized in ether-methanol. 14.21 g of sought product is obtained.
0 m.p. 200-201 ° C.
Calculated,%: C 54.74; H 4.92; N 9.12. Found,%: C 54.56; H 4.98; N 9.07. Stage B. 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridoxime.
5 13.76 g of the product obtained in stage A, dissolved in 100 cm3 of methanol, cooled to 0 ° C, 2.54 g of sodium borohydride was added, the temperature was allowed to rise to room temperature and stirred
45 min, concentrated under reduced pressure, add water and extract with chloroform. The organic layer is dried, the solvent is removed, the residue is chromatographed on silica (e-ethyl5-cetagtoluene 8: 2), and after crystallization of the residue in ethyl acetate, 7.8 g of the expected product are obtained. M.p. 103-105 ° C.
Calculated,%: C 73.01; H 7.88; N 12.16. Found,%: C 72.74; H 7.81; N 12.04.
0 Stage B. 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine trimethylsilyloxime.
3.6 g of the product obtained in stage B are dissolved in 60 cm3 of benzene, 1.86 g of 1,4-diazabicyclo {2.2.2) octane and added over 5 minutes in an inert atmosphere 2.07 cm3 of trimethylchlorosilane . The suspension is boiled under reflux for 3 hours, cooled, filtered and concentrated to dryness. The residue is taken up in ethyl ether, filtered off and the solvent is removed.
under reduced pressure, 4.5 g of the expected product are obtained. Bp 150 ° C under 0.05 mbar.
Calculated,%: C 67.50; H 8.66; N 9.26. . Found,%: C 67.33; H 8.59; N9.19.
Stage G. 3-acetyl-1,2,5,6-tetrahydropyridinoxime hydrochloride.
20 g of the product obtained in stage B, dissolved in 20 cm3 of methylene chloride, cooled to 0 ° C in an inert atmosphere, 21.6 g of CE-chloro ethyl acetate of chloroformic acid are added, and the mixture is heated under reflux for 2.5 hours. , cooled, filtered, the solvent is removed, the residue is taken up in ethyl ether, triturated and filtered. The solvent is distilled off, the residue is treated with methanol, boiled under reflux for 30 minutes, concentrated to dryness, the residue is treated with methanol and ethyl ether, filtered, crystallized in ethanol, and 2.1 g of the desired product is collected. M.p. 237 ° C (decomposition).
Calculated,%: 047.59; H 7.42; N 15.86.
C7Hi2N20-HCI
Found,%: C 47.74; H 7.38; N 15.78.
PRI mme R 2. Chlorohydrate 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime.
Stage A. 3-Acetylpyridin-O-methyl oxime.
6.85 g of methoxylamine hydrochloride are added to 10 g of 3-acetylpyridine in 50 cm3 of methanol, refluxed for 3 hours, and the solvent is removed under reduced pressure. The residue is dissolved in water, made basic with potassium carbonate, extracted with ethyl acetate, evaporated and 11 g of the expected product are obtained. Bp 115-118 ° C / 18mmHg
Step B. Iodide 1-methyl-3-acetylpyridine-0-methyloxime.
20.5 methyl iodide is added to 11 g of the product obtained in stage A in 110 cm of ethyl acetate, boiled for 3 hours under reflux, cooled, filtered and the product is crystallized in ethanol. 19.3 g of the expected product are obtained. M.p. 155-157 ° C.
Stage B. 1-Methyl-3-acetyl-1,2,5 hydrochloride, b-tetrahydropyridine-0-methyl-c-sym.
1.7 g of sodium borohydride was added to a solution of 10 g of the product obtained in stage B in 100 cm3 of methanol, cooled to 5-10 ° C, stirred for 1 hour at room temperature, the solvent was removed under reduced pressure. The residue is treated with water, extracted with ethyl ether, evaporated to dryness, treated with ethyl ether, filtered on activated charcoal and converted into salt using hydrochloric acid gas. The salt is recrystallized in isopropanol-ethyl ether to obtain 2.8 g of the expected product. M.p. 169-171 ° C.
Calculated,%: C 52.80; H 8.37; N 13.68.
C9Hi6N20-HCI
Found,%: C 53.06; H 8.44; N 13.57.
PRI me R 3. 3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime hydrochloride.
Stage A. Bromide 1-benzyl-3-acetylpyridine-0-methyloxime.
27.8 cm of bromobenzyl was added to 23.4 g of the product obtained in Step A of Example 2, dissolved in 200 cm3 of ethyl acetate, refluxed for 8 hours, cooled, filtered and the solid crystallized in ethanol. 46 g of the expected product are obtained. M.p. 191-192 ° C.
Calculated,%; C 56.09; H 5.34; N 8.72.
Found,%: C 56.24; H 5.37; N 8.67.
Stage B. 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-methyloxime.
20 g of the product obtained in stage A and dissolved in 150 cm of methanol is cooled to 0 ° C. At this temperature, 3.6 g of sodium borohydride is added, stirred for 1 hour at room temperature, the methanol is removed under reduced pressure, the residue is treated with water, sodium carbonate is added to saturation, extracted with ethyl ether, the organic layer is dried and the solvent is distilled off. 10.66 g of the expected product are obtained. Bp 128-130 ° C at 0.4 mbar.
Calculated,%: C 73.74; H 8.25; N 11.47.
Found,%; C, 73.56; H 8.21; N 11.52.
Step B. - Chloroethoxycarbonyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-methyloxime.
7.2 g of the product obtained in stage B, dissolved in 100 cm of dichloroethane, are cooled to 0 ° C and 6.05 g of a-chloroethyl chloroformate dissolved in dichloroethane is added in 20 minutes and the mixture is heated under reflux 1, 5 h, cooled, filtered and the solvent is removed under reduced pressure. The residue is treated with ethyl ether and re-filtered. The solvent is evaporated and 8.44 g of product are obtained, which is used in this form in the next step. Bp 210 ° C at 0.06 mbar.
Calculated,%: C 50.68; H 6.57; N 10.75.
Found,%: C 50.86; H 6.46; N 10.59.
Stage G, 3-Acetyl-1,2,5,6-tetrahydropyridine-0-methyloxime hydrochloride.
The product obtained in stage B in 70 cm of methanol is heated for 2 hours with a reflux condenser, cooled, evaporated to dryness and the residue is crystallized in ethanol. 3.9 g of the expected product are obtained. The resulting product is converted to the hydrochloride according to Example 2. mp. 199-200 ° C.
Calculated,%: C 50.39; H 7.93; N 14.69.
Found,%: C 50.31; H 7.84; N 14.55.
EXAMPLE 4 Chlorohydrate 1-methyl-3-acetyl-1,2,5, b-tetrahydropyridine-0-ethyloxy.
Stage A. 3-Acetylpyridin-O-ethyloxy.
about
4.8 cm of 3-acetylpyridine is dissolved in 50 cm of methanol ribava 4.27 g of 0-ethylhydroxylamine hydrochloride, heated with reflux for 3 hours, cooled, evaporated to dryness under reduced pressure, treated with water, neutralized with sodium bicarbonate and extracted with ethyl acetate then dried and concentrated to dryness under reduced pressure. 6.9 g of the expected product are obtained, which is used in the next stage, which crystallizes out of a mixture of ether-isopropanol as hydrochloride. Mp. 160-162 ° C.
Step B. Iodide 1-methyl-3-acetylpyridine-0-ethyloxime.
5.3 g of the product obtained in stage A and
1o
4.1 cm of methyl iodide in 80 cm of ethanol is stirred for 8 hours at reflux, distilled to dryness, 9.3 g of the expected product, crystallized from ether-isopropanol, are obtained. M.p. 95 ° C.
Stage B. 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-ethyloxy hydrochloride.
To a solution of 9.1 g of the product obtained in stage B in 90 cm of methanol, maintained at 5 ° C, 1.7 g of sodium borohydride was added. After 4 hours at room temperature, it is evaporated to dryness under reduced pressure. The residue is treated with water, extracted with ethyl acetate and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel (eluant chloroform: methanol 5: 1). 3.5 g of the resulting oil is dissolved in ether and salified with hydrochloric acid gas. Evaporated to dryness to obtain 3.7 g of the desired product, recrystallized from isopropanol-ether. M.p. 186-188 ° C.
Calculated,%: C 54.91; H 8.76; N 12.81.
Found,%: C 54.88; H 8.94; N 12.76.
PRI me R 5. Chlorohydrate of 3-acetyl 1,2,5,6-tetrahydropyridine-O-ethyloxime.
Stage A. Bromide 1-M-benzyl-3-acetylpyridin-0-ethyloxime.
6.9 g of the product obtained in Stage A of Example 4 are dissolved in 70 cm3 of ethanol, bbmblesha is added cm3, boiled under reflux for 6 hours, cooled, evaporated to dryness under reduced pressure and separated from ether 13.9 g target product.
Stage B, 1-M-benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-ethyloxime.
a. To a solution of 0.8 g of sodium in 50 cm3 of ethanol was added 3.8 g of the product obtained in Step B of Example 1 and 1.25 cm3 of bromethane. After 3 h at reflux, cool and concentrate to dryness. 2.84 g of the desired product is isolated after elution on a column (eluent ethyl acetate: toluene 3: 2). Bp 180-190 ° C at 0.05 mbar.
B. The product can also be obtained in 71% yield by reduction with sodium borohydride, acting as in stage B of example 1, starting from the product obtained in stage A of example 5.
Stage B. Z-acetyl-1,2,5,6-tetrahydropyridine-0-ethyloxime hydrochloride.
2.7 g of the product obtained in stage B are dissolved in 50 cm3 of dichloroethane, 1.8 g of a-chloro ethyl ester of chloroformic acid is added at 0 ° C, boiled under reflux for 1.5 hours, evaporated to dryness, treated with ether, the insoluble matter is filtered off and evaporated to dryness under reduced pressure. The residual oil is treated with 40 cm of methanol, boiled under reflux for 1.5 hours, evaporated to dryness, the residue is extracted with ether, filtered and 4.2 g of the desired product crystallized from ether-mesanol are separated.
The resulting product is converted to chlorohydrate according to example 2. So pl. 198 199 ° C (decomposition).
Calculated,%: C, 52.81; H 8.37; N 13.69.
Found,%: C 52.59; H 8.25; N 13.48.
PRI me R 6, 3-acetyl-1,2,5,6-tetrahydropyridine-0-2-propynyl-xyme hydrochloride.
Stage A. 1-Y-benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-2-propynyloxime.
To a solution of 1.1 g of sodium in 50 cm3 of ethanol was added 5 g of the product obtained in Step B of Example 1. At 0 ° C, 3.95 g of bromallylene was added, the mixture was heated at 40 ° C for 3 hours, the insoluble matter was filtered off, the solvent was evaporated and chromatographic on silica (eluent
ethyl acetate). 4.5 g of the expected product are obtained.
Stage B. Z-acetyl-1,2,5,6-tetrahydropyridine-O-2-propynyloxime hydrochloride.
7.5 g of the product obtained in stage A is dissolved in 100 cm of dichloroethane, boiled for 1 h under reflux, the solvent is evaporated, extracted with ether, the insoluble matter is filtered off and the mixture is evaporated to dryness. The residue is dissolved in methanol, boiled under reflux for 30 minutes, evaporated to dryness, the residue is treated with sodium bicarbonate solution, extracted with ethyl acetate and evaporated to dryness. The residue, purified with ether, is salified with hydrochloric acid gas. Obtain 1.25 g of the desired product, isolated from a mixture of ether-ethanol. M.p. 178 ° C.
Calculated,%: 055.94; H 7.04; N 13.05.
Found %: C 55.72; H 7.01, N 12.99.
PRI me R 7. 1-methyl-3-acetyl tetrahydropyridine-O-2-propynyloxy hydrochloride.
Stage A. 3-Acetylpyridin-O-2-prolynyloxime.
5 g of 3-acetylpyridine are dissolved in 20 cm3 of water, 3.45 g of sodium bicarbonate and 4.45 g of hydrochloride 0-2-propynyl hydroxylamine are added in 30 cm of water, left for 16 hours and then heated for 3 hours at 40 ° C. It is concentrated, extracted with ethyl acetate, evaporated to dryness and purified on silica gel (eluent ethyl acetate). 5.7 g of the expected product are obtained after crystallization in isopropanol. M.p. 156-157 ° C.
Stage B. Iodide 1-M-Methyl-3-acetylpyridine-O-2-propynyloxime.
5.6 g of the product obtained in stage A is dissolved in 60 cm3 of methanol and 8.6 g of methyl iodide is added, refluxed for 3 hours, evaporated to dryness, treated with a mixture of acetone and ether and filtered. 9.7 g of product are obtained after crystallization in isopropanol, m.p. 150-151 ° C.
Stage B. 1-Methyl-3-acetyltetrahydropyridine-O-2-propynyloxy hydrochloride.
9.7g of the product obtained in stage B is dissolved in 100 cm of methanol, 2.35 g of sodium borohydride is added at 0 ° C. After 1 hour at 0 ° C, it is evaporated, the residue is taken up in water, extracted with ethyl acetate, dried and evaporated to dryness. The residue is converted into a salt in ether with hydrochloric acid gas and 2.7 g of the expected product are obtained after recrystallization in isopropanol / ether. M.p. 195-196 ° C.
Calculated,%: C 57.76; H 7.49; N 12.25. ScN1b№0-НС1
Found,%: C 57.59: H 7.38; N 12.11.
Example 3-Propionyl-1,2,5,6-tetrahydropyridine oxime hydrochloride.
Stage A. Bromide 1-Y-benzyl-3-propionylpyridinoxime.
A mixture of 17.8 g of 3-propionylpyridinoxime and 18 cm3 of bromobenzyl in 250 cm3 of ethyl acetate is heated under reflux for 7.5 h, cooled, filtered off with suction and 36.5 g of the desired product are obtained.
after crystallization in a mixture of ethanol-ether. M.p. 178-180 ° C.
Stage B. 1-Y-Benzyl-3-propionyl-1,2,5,6-tetrahydropyridoxime.
36.2 g of the product obtained in stage A
dissolved in 250 cm of methanol and at 10 ° C, 6.4 g of sodium borohydride are added in portions, stirred for 3 hours, evaporated under reduced pressure, treated with water, extracted with ethyl acetate, dried, the solvent is evaporated, purified by chromatography on a column (eluant ethyl acetate) and 21 g of the expected product are obtained after crystallization in ethyl acetate. M.p. 111-112 ° C.
Stage B. 1-M-Benzyl-3-propionyl-1,2,5,6-tetrahydropyridine-O-trimethylsiloxy.
6 g of the product obtained in stage B, 70 cm of benzene and 2.95 g of 1,4-diazabicyclo (2.2.2) octane are mixed, and 3.25 cm3 of trimethylsilyl chloride are added. boil under reflux for 3 hours, cool, insoluble matter is filtered off, the solvent is evaporated, treated
the residue is taken up in ether, the insoluble matter is filtered off and evaporated to dryness. 7.5 g of the expected product are obtained. Bp 250 ° C at 0.06 mbar.
Stage G. 3-Propionyl1, hydrochloride, 2,5,6-tetrahydropyridinoxime.
16 g of the product obtained in Step B are dissolved in 150 cm of dichloroethane, cooled to 0 ° C, and 16.2 g of a-chloro ethyl ester of chloroformic acid are added.
The mixture is boiled under reflux for 3 hours and then the solvent is evaporated, treated with ether, filtered and concentrated to dryness. The residue is dissolved in 100 cm3 of methanol and refluxed. 6
h. Methanol is distilled off and then purified by chromatography on alumina (eluent chloroform-methanol 7: 3 and then methanol), evaporated to dryness, dissolved in ethanol, filtered on charcoal and precipitated
hexane and filtered. After purification in ethanol-hexane mixture, 1.3 g of the expected product are obtained. The resulting product is converted to the hydrochloride according to Example 2. mp. 205-206 ° C.
Calculated,%: C 50.39; H 7.93; N 14.69.
C8Hi4N20-HCI
Found,%: C 50.08; H 7.87; N 14.48.
PRI me R 9. Chlorohydrate 3-propionyl-1,2,5,6-tetrahydropyridine-O-methyloxime.
Stage A. 1-M-Benzyl-3-propionyl-1,2,5,6-tetrahydropyridine-O-methylox.
To a solution of 1.2 g of sodium in 80 cm of ethanol was added 6.11 g of the product obtained in Step B of Example 8, then added 1.58 cm3 of methyl iodide, refluxed for 6 hours, cooled, concentrated to dryness under reduced pressure and treated with water, extracted with ethyl acetate, dried, evaporated to dryness, the residue is chromatographed (eluent ethyl acetate: toluene 6: 4). 2.5 g of the expected product are obtained. Bp 170 ° C at 0.05 mbar.
Stage B. 3-Propionyl-1,2,5,6-tetrahydropyridine-O-methyloxime hydrochloride.
3.5 g of the product of stage A is dissolved in 50 cm3 of dichloroethane, 2.04 ra-chloroethyl chloroformic acid is added at 0 ° C, boiled for 3 hours under reflux, the solvent is evaporated. The residue is taken up in ether, filtered and evaporated to dryness, dissolved in 30 cm3 of methanol and refluxed for 30 minutes, then evaporated to dryness, the mixture is crystallized in ethanol-ether and 1.17 g of the expected product are obtained. The product is converted to the hydrochloride mixture according to Example 2. mp. 210-212 ° C. Calculated,%: C 52.53; H 8.26; N 13.56.
СЭН1б№0-НС1
Found,%: C 52.80; H 8.37; N 13.68,
Example 0. 1-M-Carboxyethyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-methyl oxime.
1.8 g of the product obtained in Example 3 is dissolved in 30 cm3 of benzene at 5 ° C, then 1.63 cm3 of triethylamine and 1.12 cm of ethyl chloroformic acid are added, stirred for 30 minutes at room temperature, washed with water, and evaporated to dryness and rectified. 2.56 g of the expected product are obtained. Bp 155 ° C at 0.07 mbar.
Calculated,%: C 58.39; H 8.02; N 12.38.
Found,%: C 58.41; H 7.88; N 12.29.
PRI me R 11. 1-M-benzyl-3-acetyl-1,2,5,6-tetrahydropyrmdine-O-methyloxime.
2.5 g of the product obtained in Step E of Example 3 are dissolved in 40 cm of anhydrous
benzene, 2.7 cm3 of benzyl ester of chloroformic acid are added, refluxed for 1 hour, cooled, washed with 10 cm35% hydrochloric acid, dried, and then the solvent is evaporated.
The chlorobenzyl formed is removed and 2.3 g of the desired product crystallized from cyclohexane are obtained. M.p. 90 ° C. Calculated,%: - C 65.68; H 6.61; N 10.21. Found,%: C 65.81; H 6.58; N 10.17.
PRI me R 12. lN-Hydroxyl-3-acetyl-1,2,5.6-tetrahydropyridine-O-methyloxime,
3.5 g of 3-acetylpyridin-O-methyloxime-M-oxide are dissolved in 50 cm of methanol, cooled to -10 ° C, then 2.4 g are added
sodium borohydride, stirred for 2 hours at room temperature, evaporated to dryness, dissolved in water, extracted with ethyl acetate, dried, evaporated to dryness, purified by chromatography on silica gel (eluent
ethyl acetate). 2.85 g of the expected product are obtained after crystallization in hexane. M.p. 94-96 ° C.
Calculated%: With 56,45; H 8.29; N 16.46. Found,%: C 56.28; H 8.32; N 16.31.
Example13. Benzosulfonat 1-methyl-3-cyclopropylcarbonyl-1,2,5,6-tetrahydr-opyridine-0-methyloxime.
Step A 3-Pyridylcyclopropylketon-O-methyloxime.
To a solution of 3.5 g of 3-pyridylcyclopropyl ketone in 50 cm of methanol was added 2.03 g of methoxylamine hydrochloride, refluxed for 4 hours, the solvent was distilled off and treated with aqueous
sodium bicarbonate solution, then extracted with methyl chloride, dried and evaporated. 4.1 g of the expected product are obtained. Stage B. Iodide 1-methyl-3 - csmkloprsilcarbonylpyridin-0-methyloxime.
To a solution of 5.3 g of methyl iodide in 50 cm3 of methanol was added 4 g of the product obtained in stage A, boiled for 3 hours under reflux, evaporated to dryness, concentrated in ethanol-ether and filtered to obtain
6.6 g of the target product crystallized from isopropanol. M.p. 133 ° C (decomposition).
Calculated,%: C 41.52; H 4.75; N 8.80.
CnHi5IN20
Found,%: C 41.17; H 4.66; N 8.76.
Stage B. 1-Methyl-3-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine-0-methyloxime benzenesulfonate.
To a solution of 6.4 g of the product obtained in stage B in 70 cm of methanol, 1.52 g of sodium borohydride is added at 0 ° C, left for 1.5 hours at room temperature, evaporated, dissolved in water, extracted with ethyl acetate, dried and evaporated to dryness, then purified by chromatography on aluminum hydroxide (eluent toluene: ethyl acetate 6: 4) and distilled at 1 ° C at 0.2 mm. 2.45 g of the obtained base is dissolved in 100 cm3 of benzene with 1.994 g of benzenesulfonic acid, evaporated to dryness, concentrated in a small amount of ethyl acetate, filtered, and 1.7 g of the desired product is obtained. M.p. 76 ° C (decomposition).
Calculated,%: C 57.93; H 6.86; N 7.95.
CiiHi8N20-C6H5S03H
Found,%: C 58.04; H 6.94; N 7.87. The following are examples of pharmaceutical formulations.
A. Prepared tablets that meet the following formula:
The product of example 3200 mg
A sufficient amount of excipient for one complete table. (Detail of excipient: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc) 300 mg
B. Prepared by the following formulas:
Product Example 1100mg
Sufficient amount of excipient
for one finished gut.
(detail excipient: talc,
magnesium stearate, aerosil) 300 mg
Century Prepared tablets that meet the following formula:
Product sample mg
Sufficient amount of excipient
for one complete tablet
(detail excipient; lactose,
processed wheat starch
starch, rice starch, stearate
magnesium, talc) 300 mg
The products obtained by the proposed method, as well as their pharmaceutically acceptable salts, can be used as drugs, in particular, in the treatment of Alzheimer's disease or senile dementia, as well as in the treatment of memory disorders.
It is known that memory disorders in elderly people are mainly associated with a lack of a central cholinergic system, in particular in senile dementia and Alzheimer's disease.
Thus, products that have a central cholinergic effect can be used in the treatment of these diseases.
Proved that zrekolin injected
by the intravenous route, it has a positive effect on patients who show memory deficit.
Arecoline use restriction
This is due to the fact that this product has very weak activity when applied through the mouth and has a short duration of action.
The products obtained according to the proposed method, after oral administration, show a higher central cholinomimetic activity compared to that obtained after the administration of arecoline and with a longer
0 action.
Normal nosologies vary depending on the disease, the patient himself and the route of administration, and can be between 50 and 300 mg / day, for example between 15 and 15 mg / day.
5 to 150 mg / day in one or more administrations for the product of Example 3, by mouth.
Products obtained by the proposed method, as well as their pharmaceutically
0 acceptable salts can thus be used to prepare pharmaceutical formulations that contain these products as an active principle.
5These pharmaceutical formulations may
to be solid or liquid and to be in pharmaceutical forms commonly used in medicine, for example tablets, dragees, gels, granules, reconciliations, preparations
0 for injection. These formulations are prepared in conventional manner.
The active principle or the active principles may be incorporated into excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, animal or vegetable fats, paraffin derivatives, glycols, various
0 wetting agents, dispersants, emulsifiers and preservatives.
d. Prepared tablets corresponding to the following formula:
Product example 1250mg
5Excipient in sufficient quantity
for one tablet (excipient part: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc) 300 mg
Biological activity
Products are tested as chlorohydrates.
Acute toxicity
The experiment is conducted on male mice (CDi Charles Rivers) weighing 22-24 g, on an empty stomach for 16 hours. Products are administered orally in doses of 1000, 500, 250, 125, 62 and 31 mg / kg. Mortality noted within 7 days, which follow after treatment (see tab. 1).
Table 1
Test on selected ileum guinea pig
They take part of the ileum of the guinea pig, mortified decapitations. the isolated ileum is placed in 10 cm3 of Tyroid's solution at 37 ° C and ventilated with a mixture of oxygen (95%) and carbon dioxide (5%). Contractions after the introduction of the products are recorded using a sensor connected to a polygraph. The test products are added at concentrations between
one
.
Products that exhibit a contraction effect are examined with respect to atropine and hexametonium in order to establish the activity of a muscarinic or nicotine type.
Agomistic activity is expressed in pD2 / negative logarithm of the dose, which produces 50% of the maximum effect (see Table 2).
table 2
0
five
0
Then the animals are placed separately in the cells, the bottom of which is covered with blotting paper, and monitored for 30, 60, 120 and 180 minutes.
Sheets of blotting paper are changed after each observation.
The consistency of feces is assessed following the scale of the following values:
0- hard consistency;
1 - slightly weak bowel movements with or without a wet ring;
2 - slightly weak bowel movements with the presence of a moist well defined ring;
3 - weak bowel movements with the presence of a large wet ring;
4- bowel movements without consistency with the presence of a very large wet ring.
For each product, a dose is noted that causes diarrhea in 50% of the animals (see Table 3).
Table 3
Hypothermic activity The experiment was carried out on male mice (Charles Charles Rivers), weighing 25-30 g, on an empty stomach for 6 hours.
The body temperature is edematted using a thermocouple inserted into the rectum to a depth of about 1.5 cm and connected to an electric recording device. Products are introduced into the mouth or by subcutaneous route and the temperature is noted at time 0, 30 minutes, 1, 2 and 2.5 hours after administration. The degree of hypothermia is defined as the difference between test subjects and control animals, and the dose required to lower body temperature (1) is determined (see Table 4).
Table 4
Diarrheal activity
The test is carried out on male mice (CDi Charles Rivers) weighing 25-30 g on an empty stomach for 6 hours. The product, dissolved by 5% in metocele, is administered through the mouth using an esophageal probe.
Control animals receive only excipient.
The duration of action of the products is estimated using a dose that lowers the body temperature by 1-1.5 ° C (see Table 5).
Thus, the obtained new tetrahydropyridine derivatives of the general formula I possess valuable pharmacological properties.

权利要求:
Claims (1)
[1]
Invention Formula
Method for preparing 1,2,5,6-tetrahydropyridine derivatives of general formula I
2
one
where RI is hydrogen, methyl, ethoxy or benzyloxycarbonyl;
R2 is methyl, ethyl or cyclopropyl;
R3 is hydrogen, methyl, ethyl or 2-propynyl,
provided that when Ri is methyl, Ra is not hydrogen, or their hydrochlorides, or benzene sulfonates, characterized in that 3-acetylpyridine of the general formula
ABOUT
-C-R.
N o
where the values of R2 are as described above, they are reacted with the general formula
NH20R3-HCI,
where the values of RG are given above, I eat oxime of the general formula
B
where the values of R2 and Hz are as indicated above, which is reacted with a halide of the general formula
Rix
where RI is methyl or benzyl;
X is bromine or iodine, to obtain the salt of General formula
C MOK3
Ni x
R;
where the values of Ki, R2 and Ra are as indicated above, which are exposed to a hydrogenation agent, such as sodium borohydride or metallic sodium in ethanol, to give a compound of the general formula II
2
L) ъ
N
Ri
wherein the values of Ri, Ra and R3 are as indicated above, and, if desired, either a compound of the general formula II, when RS is hydrogen, is exposed to a compound of the general formula
RaHal.
thirty
Where is the meaning of Jaz. except Ra, hydrogen, as indicated above;
Hal is bromine or iodine, or when RI is benzyl, the compound is total
Formula II is exposed to chloroformate a-chloroethyl ester followed by heating to give a compound of general formula I, where RI is hydrogen,
or, when RI is hydrogen or benzyl, the compound of general formula II is exposed to chloruronic acid ethyl or benzyl ester to form a compound of general formula I, where RI is ethoxy benzyloxycarbonyl, to liberate the desired product, in the form of hydrochloride or benzenesulfonate.
Note, p. - through the mouth; PC. - under the skin.
Table 5

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

FR1258847A|1960-02-12|1961-04-21|Ciba Geigy|Process for the preparation of novel pyridine derivatives, including 1-methyl-3 or 4-acetyl-1, 2, 5, 6-tetrahydropyridine oxime|

---

IL81610A|1986-02-27|1990-12-23|Roussel Uclaf|Derivatives of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime,their preparation and pharmaceutical compositions containing them|

---

JPH0641332B2|1986-09-17|1994-06-01|株式会社共同精機工作所|Sheet feeding device for cutting machine|

---

US4786648A|1986-12-08|1988-11-22|Warner-Lambert Company|O-substituted tetrahydropyridine oxime cholinergic agents|

---

US4710508A|1986-12-08|1987-12-01|Warner-Lambert Company|O-substituted tetrahydropyridine oxime cholinergic agents|

---

US4798841A|1987-03-31|1989-01-17|Warner-Lambert Company|Tetrahydropyridine oxime cholinergic agents and method of treatment|IL81610A|1986-02-27|1990-12-23|Roussel Uclaf|Derivatives of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime,their preparation and pharmaceutical compositions containing them|

---

US4786648A|1986-12-08|1988-11-22|Warner-Lambert Company|O-substituted tetrahydropyridine oxime cholinergic agents|

---

IT1222526B|1987-08-21|1990-09-05|Roussel Maestretti Spa|OXYME DERIVATIVES OF 1,2,5,6-TETRAIDROPIRIDIN-3-CARBOXALDEHYDE, THEIR PREPARATION PROCEDURE AND THEIR USE AS MEDICINAL SUBSTANCES|

---

AU3301689A|1988-04-15|1989-10-26|Beecham Group Plc|1-azabicyclo-alkyl derivatives|

---

SG48315A1|1989-04-13|1998-04-17|Beecham Group Plc|Novel compounds|

---

US5278170A|1989-04-13|1994-01-11|Beecham Group P.L.C.|Azabicylo oxime compounds|

---

PT98742A|1990-08-24|1992-07-31|Beecham Group Plc|PROCESS FOR THE PREPARATION OF AZABICYLIC COMPOUNDS|

---

GB9019095D0|1990-09-01|1990-10-17|Beecham Group Plc|Novel compounds|

---

CA2093823A1|1990-10-12|1992-04-13|Steven M. Bromidge|1,2,5,6-tetrahydropyridine oxime derivatives|

---

CA2080536A1|1991-10-17|1993-04-18|John S. Ward|Nicotinic activity of a series of arecolones and isoarecolones|

---

AU3142793A|1991-12-18|1993-07-19|Warner-Lambert Company|Transdermal delivery of -1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxaldehyde-O- methyloxine HCL and related compounds in the treatment of cognitive disorders and for analgesia|

---

US5362860A|1993-02-01|1994-11-08|Warner-Lambert Company|Neutral stabilization complex for CI-979 HCl, a cognition activator|

---

US5424301A|1993-02-01|1995-06-13|Warner-Lambert Company|Starch stabilized o-substituted tetrahydropyridine oxime cholinergic agents|

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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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IT20260/87A|IT1203971B|1987-04-24|1987-04-24|1,2,5,6-TETRAHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION PROCEDURE AND THEIR APPLICATION AS MEDICATIONS|

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