Method for preparation of oxime derivatives of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde

专利摘要:
The invention relates to heterocyclic compounds, in particular to the preparation of the oxime derivatives 1,2,5,6-tetrahydropyridine-3-carboxadine dehyde hlc OR (0) C-C-fi-CH2-CH2-CH C (CH NORiH : H2, where Rl is CH2 or 2-propynyl; R is C- | -C4-alkyl, straight or branched, possibly substituted with a trimethylsilyl group, adamantyl, phenyl, possibly substituted with one or two groups selected from CI, isopropyl, methoxy : Phenylethyl or methylsulfonylethyl with cholinomimetic activity. The goal is to develop a method for producing more active compounds. they react by connecting ± Ts1 f-ly NH-CH2-CH2-CH-C (CH NOlRi) -CiH2, where RI is the indicated value with the compound of the f-file XC (0) OR, where X is a halogen atom or para-nitrophenoxy, R - indicated values. 3 tab.
公开号:SU1681723A3
申请号:SU4356622
申请日:1988-08-19
公开日:1991-09-30
发明作者:Галиани Джулио；Барцаги Фернандо；Бонетти Карла；Тоя Эмилио
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

The invention relates to the field of the production of new chemical biologically active compounds, namely oxime derivatives 1,2,5,6-tetrahydropyridine-3-carboxes, on ice, with cholinomimetic activity. This property suggests the possibility of using these compounds in medicine.
The purpose of the invention is to obtain new 1,2,5.6-tetrahydropyridine-3-β-carboxaldehyde oxime derivatives, showing improved cholinomimetic activity in this series of compounds.
Example 1. Methyl 1-methoxycarbonyl-1,2,5,6-tetrahydropyridin-3-carboxaldehyde methyl ester.
To a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0-methyl oxime in 40 cm3 of benzene was added 1.5 cm3 of triethylamine at 10 ° C and slowly 0.83 cm of methyl chloro ether acid. The mixture is stirred for 30 minutes at room temperature, washed with 15 cm3 of 5% hydrochloric acid and then with water. It is evaporated to dryness under reduced pressure, and then the residue is distilled at 140 ° C under 0.05 mbar. 1.91 g of the expected product are obtained. T. pl. 37 ° C
Calculated,%: C 54.53; H 7.12; N 14.13.
SdNtsNoz
Found,%: C 54.31; H 7.17; N 14.00.
Example 2. 1-ethoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl oxime ester.
Method A.
To a solution of 3.6 g of 1-benzyl-1,2,5,6-tetrahydropyridine-3-carbox, and here hydroxy-0-methyl oxime in 30 cm3 of dichloroethane is added
2 cm of ethyl ester of chlorogolic acid and incubated for 3 hours with reflux. The reaction mixture is cooled and the organic layer is washed with 20 cm 5% hydrochloric acid, and then with 2 times 25 cm of water. The solvent is distilled off and the residual oil is distilled at 15 ° C under 0.05 mbar. 1.5 g of the expected product are obtained.
Calculated,%: C 56.59; H 7.60; N 13.20.
Syun- | b.Oz
Found,%: C 56.82; H 7.66; N 13.04.
Method B.
To a solution of 3.75 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0-methyloxime in 60 cm3 of benzene is added at room temperature not exceeding 10 ° C, 3.75 cm of triethylamine and 2.7 see chlorotic acid ethyl ester. Stir for 1 h at room temperature, add 20 cm 3 of water, decant and extract with benzene. The mixture is evaporated to dryness under reduced pressure and the residue is chromatographed on silica (eluant: ethyl acetate - toluene 1-1). The residue is distilled at 160-165 ° C under 0.07 mbar. 5.32 g of the expected product are obtained.
Calculated,%: C 56.59; H 7.60; N 13.20.
PlotMaOZ
Found,%: With 56.41; H 7.54; N 13.31.
Example 3. 1-n-propyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl oxime ester.
1.5 cm3 of triethylamine are added to a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0-methyloxime in 60 cm of benzene and keeping the temperature between 5 and 10 ° C, slowly add 1 , 23 cm of chlorobolic acid propyl ester. After 30 minutes at room temperature, it is washed with 20 cm of 1N hydrochloric acid and then with water. The solvent is distilled off under reduced pressure and distilled at 170 ° C under 0.07 mbar. 2.3 g of the expected product are obtained.
Calculated,%: C 58.39; H 8.02; N 12.38.
СцНв№Оз
Found,%: C 58,12; H 8.06; N 12.12.
Example 4. Methyl ether oxime 1-allyloxycarbonyl-1,2,5,6-tetrashydropyridine-3-carboxaldehyde. “
To a solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0-methyl oxime in 40 cm of benzene was added, at 5 ° C, 1.5 cm of triethylamine and 1.17 cm3 of chlorophenol acid 2-propenyl ester. Stir for 30 minutes at room temperature, and then treat with 20 cm 5% hydrochloric acid, and then 2 times with 20 cm of water. The solvent is distilled off, and then
the residue is poured at 200 ° C below 0.08 mbar. 2.25 g of the expected product is obtained.
Calculated,%: 058.91; H 7.19; N 12.49. ScN1b NOz Found;%: C 58.96; H 7.25; N 12.41.
Example 5. Methyl ether oxime 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridin-3-carboxylic acid.
Method A.
0 To a solution of 8 g of 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyl-oxime in 100 cm of benzene was added 23 cm 3 of benzyl ester of chlorogolic acid (50% solution in toluene ). Heat for 4 hours with boiling, cool, rinse with 2N hydrochloric acid, and then with water. The solvent is distilled off under reduced pressure, and then distilled at 0 ° C under 0.05 mbar. Obtain 4.1 g of the 0 target product, Method B.
To a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime in 20 cm of benzene and 1.08 g of triethylamine, 5 is slowly added at 10 ° C to 3.4 cm 50% a-benzyl chloroic acid ester in toluene. The mixture is stirred at room temperature for 1 h, washed with 5% hydrochloric acid in water, the solvent is distilled off and the residue is distilled at 230 ° C under 0.06 mbar. Get 2.1 of the desired product.
Calculated,%: C 65.54; H 6.72; N 10.14. S14ZhbNOZ 5 Found,%: C 65.68; H 6.61; N 10.21.
Example 6. 1-Phenyloxycarbonyl-1,2,5,6-tetrahydryl-iridine-3-carboxaldehyde methyl ester methyl ester.
Method A.
0 To a solution of 3.3 g of 1-methyl 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methoxime in 30 cm3 of dichloroethane was added 4.5 g of chloroic acid phenyl ester and heated for 3 hours. reflux. The insoluble material is filtered off (the starting product hydrochloride) and then evaporated to dryness under reduced pressure, the residue is chromatographed on silica (eluant: benzene-ethyl ester 0 acetic acid 8-2). 4 g of the expected product are obtained after distillation at 220 ° C under 0.06 mbar. Method B.
To a solution of 3 g of 1-ethyl 1,2,5,6-tetrahydro-5 pyridine-3-carboxaldehyde-0-methyloxime in 30 cm3 of dichloroethane was added 4.7 cm3 of chlorobolic acid phenyl ester. Heat with reflux for 3 hours and then treat with 20 cm 5% hydrochloric acid, and then 2 times with 20 cm 3
water. The solvent is distilled off, and then taken up in diethyl ether, the insoluble matter is filtered off and the filtrate is evaporated to dryness. The residual oil is distilled at 210 ° C under 0.03 mbar. 2.18 g of the expected product is obtained.
Calculated,%: C 64.6; H 6.20; N 10.76.
ScN1b№Oz
Found,%: C 64.72; H 6.35; N 10.65.
Example 7. 1- {2-methylsulfonyl) ethoxycarbonyl-1,2, 5,6-tetrahydropyridine-3-carboxaldehyde methyl ester oxime.
To a solution of 1.5 g of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde-O-methyloxime in 40 cm3 of anhydrous benzene and 1.5 cm3 of triethylamine, which is cooled to 5 ° C, is added 3, 1 g of carbonate (2-methylsulphonyl) -ethyl-4-nitrophenyl. The reaction is continued for an hour at room temperature, the organic layer is washed with water, and then evaporated to dryness under reduced pressure. The residue is chromatographed on silica (eluant: ethyl acetate) to obtain 1.6 g of the desired product crystallized in benzene. T. pl. 93-94 ° C.
Calculated,%: C: 45.50; H 6.25; N 9.65.
CnHi8N205S
Found,%: With 45.63; H 6.29; N 9.61.
Example 8. 1-Adamantyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl oxime ester.
To a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxeldehyde-O-methyloxime in 40 cm3 of benzene and 1.5 cm of triethylamine at 5 ° C was added 2.13 g of adamantyl ester of fluorocarbonate. After 15 minutes at room temperature, they are washed with 2N hydrochloric acid and then with water. Evaporated to dryness under reduced pressure and crystallized in hexane. 2.6 g of the expected product are obtained. T. pl. 105-106 ° C.
Calculated,%: C 67.90; H 8.23; N 8.80.
С1вН2б№Оз
Found,%; C 68.02; H 8.28; N 8.76.
Example 9. Methyl ether oxime 1-isopropyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde.
To a mixture of 1.4 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime and 1.01 g of anhydrous triethylamine in 30 cm of benzene at 10 ° C was added 1.22 g of isopropyl ether chlorogolic acid in benzene solution. The mixture is stirred for 30 minutes at room temperature, decanted, the organic layer is washed, evaporated to dryness and the residue is chromatographed on silica (eluent: acetic acid toluene ethyl ester 8-2). Remainder
distilled at 180 ° C below 0.08 mbar 1.35 g of the expected product are obtained. T. pl. 40 to 41 ° C
Calculated,%: C 58.39; H 8.02; N 12.38.
CnHi8N203
Found,%: C 58.19; H 8.13; N 12.54.
Example 10. Oxymam-1-butyloxycarbonyl-1,2,5,6-tetrahydr-opyridine-3-carboxaldehyde methyl ester.
To a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime in 20 cm of benzene and 1.2 g of triethylamine at 10 ° C was added 1.46 g of chlorogolic acid butyl ester. The mixture is stirred at room temperature for 2 hours, washed with 2N hydrochloric acid, and then evaporated to dryness and the residue is distilled at 220 ° C under 0.07 mbar. 1.85 g of the expected product is obtained.
Calculated,%; C, 59.98; H 8.39; N 11.66.
C12H20№03
Found,%: 059.72; H 8.49; N 11.77.
Example 11. 1- (2- (Phenyl) -ethyloxy-carbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl ester methyl ester.
To a mixture of 1.4 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime and 1.01 g of triethylamine in 40 cm3 of benzene was added at 10 ° C 1.85 g (2-phenyl) - chlorotic acid ethyl ester. After 30 minutes at room temperature, washed with dilute hydrochloric acid and evaporated to dryness. Purified by chromatography on aluminum hydroxide (eluant: cyclohexane-ethyl acetate 9-1), and then distilling the residue under 0.07 mbar at 250 ° C. 2.2 g of the expected product are obtained.
Calculated,%: C 66.65; H 6.99; N 9.72,
С1бН2о№Оз
Found,%: C 66.51; H 7.10; N 9.79.
Example 12. Oxyma-1-parachlorophenyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl ester.
To a mixture of 1.4 g of 1,2,5,6-tetrahydropyridine-4-carboxaldehyde-O-methyloxime and 1.01 g of triethylamine in 40 cm3 of benzene was added at 10 ° C with 1.91 g of p-chlorophenyl chloro ether acids in 30 cm of benzene. After 3 hours at room temperature, washed with dilute hydrochloric acid and evaporated to dryness. Purified by chromatography on aluminum hydroxide (eluentschik - lexanethyl ester of acetic acid 7-3). 1.9 g of the expected product crystallized in cyclohexane are obtained. T. pl. 96-98 ° C.
Calculated,%; C 57.05; H 5.13; N9.51.
С14Н15№03
Found,%: C 56.78; H 4.97. N 9.37.
Example 13. Methyl ester of 1-p-eoprphenylphenyloxycarbonyl-1,2,5,6-tetrzhydropyridin-3-carboxaldehyde oxime.
K1.4 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0-methyloxime in 40 cm of benzene and 1.01 g of triethylamine at 10 ° C add 1.99 g of p-isopropylphenyl chlorogolic acid ester in a solution of 20 cm benzene. After one night at room temperature, it is washed with dilute hydrochloric acid and then evaporated to dryness. Purified by chromatography on aluminum hydroxide (eluent: cyclohexane - ethyl ester of acetic acid 9-1). After crystallization in cyclohexane, 2 g of the expected product are obtained. T. pl. 100-102 ° C.
Calculated,%: C 67.53; H 7.33; N 9.27.
C1 H22№03
Found,%: C 67.70; H 7.44; N 9.14.
Example 14. 1- {3,4-Dimethoxyphenyloxy) -carbonyl-1,2, 5,6-tetrahydropyridine-3-carboxaldehyde methyl ester oxime.
To a solution of 1.2 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime in 20 cm of benzene and 1.2 cm of triethylamine was added 1.86 g of 3,4-dimethoxyphenyl chlorofer ether acid. Stir for 45 minutes and wash with 10% hydrochloric acid and evaporate to dryness. The residue is chromatographed on aluminum hydroxide (eluent: cyclohexane - ethyl acetate 7-3). 1.85 g of the expected product crystallized in cyclohexane is obtained. Mp, 143-145 ° C.
Calculated,%: C 59.99; H 6.29; N 8.75.
С1бН2о№ About
Found,%: C 60.24; H 6.21; N 8.61.
Example 15. 2-Propynyl ester of 1-ethyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde oxime.
To a solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0- (2-propyniloxime) in 50 cm3 of benzene was added at 5 ° C with 1.42 cm3 of triethylamine and 1.02 cm3 of ethyl chloroformate in 95% . Stir for 30 minutes, then rinse with water and evaporate to dryness under reduced pressure. The residue is purified by chromatography on aluminum hydroxide (eluent: benzene-diethyl ether 1-1), evaporated to dryness and taken up in benzene, treated with sodium sulfate and activated carbon, filtered and brought to dryness under reduced pressure. 1.95 g of the expected product are obtained. T. pl. 55 ° C.
Calculated,%: C61.00; H6.83; N 11.86.
Ci2HieN203
Found,%: C 61.23; H 6.66: N 11.71.
Example 16 Methyl 1-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl ester.
1.5 cm3 of triethylamine are added to a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-0-methyloxime in 40 cm of benzene. The mixture is cooled to 5 ° C and 2.33 g of tetrabutyl carbonate are added. After 10 minutes at room temperature, they are washed with 2N hydrochloric acid and then with water. It is evaporated under reduced pressure, and then the product is isolated by distillation at 150 ° C under 0.07 mbar. 2.2 g of the expected product are obtained.
Calculated.%: C 59.83; H 8.5; N 11.49.
С 2Н2С№03
Found,%: C 60.00; H 8.39; N 11.66.
Example 17. 1- (2-Trimethylsilyl-ethoxycarbonyl) 1,2,5,6-tetrahydropyridine-3-carboxaldehyde methyl ester methyl ester.
To a solution of 1.5 g of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime in 40 cm3 of benzene and 1.5 cm3 of triethylamine, 3.03 g (2-trimethylsi- lil) ethyl para-nitrophenylcarbonate. Stir for 3 hours at room temperature, wash with water, and then evaporate in vacuo. Purify by chromatography on silica (eluant: benzene-diethyl ether 1-1) and isolate the desired product by distillation at 220 ° C under 0.08 mbar.
1.3 g of the expected product are obtained.
Calculated,%: C 54.89; H 8.50; N 9.85.
C13H24N203SI
Found,%: C 54.85; H 8.59; N 9.76.
Pharmacological study.
Acute toxicity.
. The experiment is conducted in male mice (CDi Charles Rivera) weighing 22-24 g on an empty stomach 16h. Products are administered orally at doses of 1000, 500, 250, 125 and 62 mg / kg. Mortality is noted within 7 days following treatment:
Experience on a dedicated ileum guinea pig.
Bring you pieces of ileum guinea pig, mortified by decapitation. The isolated ileum is placed in a 10 cm3 solution.
Tyrode at 37 ° C and ventilated with a mixture of oxygen (95%) and carbon dioxide (5%). Contractions caused by the products are recorded using a sensor connected to the polygraph. The test products are added at concentrations between 1, 1.108 m / l.
Products contracting are examined with respect to atropine and hexametonium in order to establish muscarinic or nicotinic activity.
The possible antagonistic activity of the products studied is studied with respect to acetylcholine.
Antagonistic activity is expressed in pD2 (negative logarithm of the dose, which exhibits 50% of the maximum effect).
Antagonistic activity is expressed in DEso (a dose that reduces by 50% the maximum response administered by acetylcholine).
The data presented in Table. one.
Table 1
4 - defecation without consistency with the presence of a very large wet ring.
For each product, a dose is noted that causes diarrhea in 50% of animals, according to the method of Miller and Timer:
Hypothermic activity.
The experiment is conducted on male mice (CDi Charles Rivers) weighing 25-30 g on an empty stomach for 6 hours.
Body temperature is noted with a thermocouple inserted into the rectum 1.5 cm and connected to an electrical temperature sensor.
Products are administered orally or subcutaneously and temperatures are noted at 0 and 30 minutes, 1 hour, 2 hours and 2.5 hours after the products have been injected.
The degree of hypothermia is defined as the difference between treated and control animals. The dose needed to lower the body temperature by 1 ° C is determined. The data presented in Table. 2. The change in body temperature.
Diarrhea activity.
The experiment is carried out on male mice (CDi Charles Rivers) weighing 25-30 g on an empty stomach.
After entering the products, the animals are intramuscularly introduced into the cells, the bottom of which is covered with blotting paper and under observation for 30, 60, 120 and 180 minutes. Absorbent paper sheets change after each observation.
Stool consistency is assessed by the Randall and Baruth method according to the following scale:
0- hard consistency;
1 - slightly weak bowel movements with or without a wet crown;
2 - slightly weak bowel movements with the presence of a well-defined wet ring;
3- weak bowel movements with the presence of a large, wet ring;
table 2
The duration of the effect of the products was determined by using doses that can lower the temperature from 1 to 1.5 ° C. The data presented in Table. 3

权利要求:
Claims (1)
[1]
The invention The method of obtaining derivatives of oxides 1,2,5,6-tetrahydropyridine-3-carboxaldehyde of the general formula I
. x s- Cll-NOR
  AND
I
„0-C-GR, where Ri is methyl or 2-propynyl;
one
R is C1-4 alkyl, straight or branched, possibly substituted by a trimethylsilyl group, adamantyl, phenyl, possibly substituted by one or two groups selected from CI, isopropyl, methoxyphenylethyl or methylsulfonyl ethyl, characterized in that the compound of the general formula CH -NOR
to n
 Different values of controls that are indicative (p iO, 05). , 01.
where RI has the specified value, is subjected to interaction with the compound of the General formula
ss
about
five
where X is a halogen atom or paranitrofenk- 10 s; R has the indicated meanings.
Table 3

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IT1240603B|1990-03-14|1993-12-17|Roussel Maestretti Spa|DERIVATIVES OF 1,2,5,6-TETRAIDROPIRIDINA 3- OXY CARBOXALDEHYDE, THEIR PREPARATION PROCEDURE AND THEIR USE AS A MEDICINAL SUBSTANCE|

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IT1241138B|1990-05-15|1993-12-29|Roussel Pharma|OXIN DERIVATIVES OF 1,2,5,6- TETRAIDROPIRIDIN-3-CARBOXALDEHYDE, THEIR PREPARATION PROCEDURE AND THEIR USE AS MEDICINAL SUBSTANCES|

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

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

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

法律状态:
2005-05-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20030820 |

优先权:

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申请号 | 申请日 | 专利标题

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IT8721687A|IT1222526B|1987-08-21|1987-08-21|OXYME DERIVATIVES OF 1,2,5,6-TETRAIDROPIRIDIN-3-CARBOXALDEHYDE, THEIR PREPARATION PROCEDURE AND THEIR USE AS MEDICINAL SUBSTANCES|

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