Method of producing the derivatives of piperidinedion-2,6 or salts thereof

专利摘要:
The invention relates to piperidine derivatives, in particular the preparation of piperidinedione-2,6 or their salts of the general formula: KM-iC (, 0) -NR / -C (O) -CHR, j, where K 2-piperidyl, M CH-CH2N ( L) 2; L CH (CH,). J; R, R, j and R, H or R H or C (-C-alkyl or (Rj + RA) - (CHj), which have an antiarrhythmic effect and can be used in medicine. The goal is to create new active substances of the specified class Their synthesis is carried out from 2-pyridylacetonitrile and 1-chloro-2-diisopropylaminoethane in the presence of benzyltriethylammonium chloride and 50% aqueous NaOH at 10-35 ° C, followed by treatment of the resulting product with nitrile RR, C, as indicated above, in the presence of benzyltrimethylammonium hydroxide at O-30 ° C. Next, the resulting dinitrile is heated to 100-150 ° C in the presence of and acids (HC1) followed by, if necessary, alkylation on nitrogen and the release of the target product in free form or in the form of salt New substances have an antiarrhythmic effect on ventricular tachycardia for 1.5-4 hours Table 1 FROM co co K 00 sy
公开号:SU1333237A3
申请号:SU833661804
申请日:1983-11-05
公开日:1987-08-23
发明作者:Бернар Клод；Готрельс Вернер；Готье Патрик
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

one
This invention relates to a process for the preparation of new chemical compounds of the piperidine series, namely, the derivatives of piperidyl-dione-2.6 with the general formula
CH (
Heat with a reflux condenser in the heat of R,, Rj. and Rj is hydrogen or methyl;
R4 is hydrogen or C, -C4-alkyl, or 5 h 2 mixture of 22.7 g previously obtained RJ and R BMecTe - group - (CH,.) -, or their salts, which have aytirrhythmic effect and can find application in medicine.
The purpose of the invention is to develop, on the basis of a known method, a method of obtaining new chemical compounds of the piperidine series, which possess valuable pharmacological properties ..
Example 1. 5 (8) -methyl-3 (e) -. - (2-diisopropylaminoethyl) 3 (a) - (2-pyridyl) -2,6-piperidinedione dihydrochloride (1a).
a) 4-Diisopropylamine-2- (2-pyridyl) -bu tironitria |.
80 g of 2-hsyridylacetonitrile, 8.8 g of 1-chloro-2-diisopropylamino-ethane and 2.7 g of benzyltriethylammonium chloride are mixed. Maintaining the temperature below 35 ° C, 350 ml of an aqueous solution of 50% sodium hydroxide are gradually added.
The mixture is heated at 35 ° C for 5 hours. After cooling, water is added and extracted with ether. The organic phase is separated, dried over sulfate, sodium, then the solvent is evaporated to dryness.
Distillation of the residue yields a yellow color (94 g); m.p. 132 - 134 ° C / 0.6 mm.
b) 2- (2-Diisopropylaminoethyl) -4-methyl-2- (2-pyridyl) -pentanedinitrile.
To a solution of 17.3 g of nitrile, previously obtained in 70 ml of tetrahydrofuran, was added 3.2 ml of a 40% aqueous solution of benzyltrimethylammonium hydroxide in methanol. A solution of 5.2 g of methacrylonitrile in 35 ml of tetrahydrofuran is added dropwise and then left to stir for 1 hour.
The solvent is evaporated to dryness and water is again added to the residue.
136 ml of hydrochloric acid and 136 ml of acetic acid
foot dinitrile, lots (d 1,19) acids.
Evaporated to dryness in vacuo and
20 is added again to the residue with some water. A saturated solution of sodium bicarbonate is added and extracted three times with chloroform. Combine organic 3i contracts, dry over
25 sodium sulfate and evaporate the solvent to dryness.
16 g of pure product are obtained consisting of a mixture of two diastereoisomers. Chromatograph on the column
30 with alumina. After washing with a mixture of ethyl acetate-pentane (3: 7), first get one of the diisteIJeomerovs pure (5.35 g).
one .
35 A study of the NMR spectrum of the product shows that in this diastereomer, methyl in α-position 5 and the group (2-diisopropylaminoethyl) in position 3 are equatorial, while group 2 pi
40 Ridilaxial.
Dihydrochloride.
5.02 g of the indicated pure diastereomer are dissolved in 50 ml of absolutely 45 th ethanol and 3.07 g of hydrochloric acid (d 1.19), dissolved in 50 ml of absoluent ethanol, are added. The solvent is evaporated and acetone is added to the residue. The crystalline dihydrochloride 50 appears in the form of colorless crystals. Dried and washed with a small amount of acetone. Bes 6.26 g, m.p. 157-160 C. The dihydrochloride crystallizes with 1 molecule of water. 55 Example 2. 3 - (.- Diisopropyl-aminoethyl) -3- (2-pyridyl) -2,6-piperidinedione (16).
a) 2-Diisopropylamino-2- (2-pyridyl) -pentanedinitride.
3332372
ether. The ether phase is separated off and the aqueous phase is again extracted with ether. The ether extracts are combined, taken up in water and dried over sodium sulfate. Evaporate the solvent until dry.
A yellow-orange liquid (22.7 g), obtained as 10 for further operations, is obtained.
c) 5 (e) -methyl-3 (e) - (2-diisopropyl-aminoethyl) -3 (a) - (2-pyridyl) -2,6-pyperidinedione dihydrochloride.
Heated with a reflux condenser in flow
For 2 hours, a mixture of 22.7 g of previously obtained 136 ml of hydrochloric acid and 136 ml of acetic acid
foot dinitrile, lots (d 1,19) acids.
Evaporated to dryness in vacuo and
add some water to the residue again. A saturated solution of sodium bicarbonate is added and extracted three times with chloroform. Combine organic 3i contracts, dry over
sodium sulfate and evaporate the solvent to dryness.
16 g of pure product are obtained consisting of a mixture of two diastereoisomers. Chromatograph on the column
with alumina. After washing with a mixture of ethyl acetate-pentane (3: 7), first get one of the diisteIJeomerovs pure (5.35 g).
one .
The study of the NMR spectrum of the product shows that in this diastereomer methyl at position 5 and group (2-diisopropylaminoethyl) at position 3 are equatorial, whereas group 2 is pyridylacetal.
Dihydrochloride.
5.02 g of the indicated pure diastereomer is dissolved in 50 ml of absolute ethanol and 3.07 g of hydrochloric acid (d 1.19), dissolved in 50 ml of absolute ethanol, are added. The solvent is evaporated and acetone is added to the residue. The dihydrochloride crystallizes in the form of colorless crystals. Dry and wash with a small amount of acetone. Bes 6.26 g, m.p. 157-160 C. The dihydrochloride crystallizes with 1 molecule of water. Example 2. 3 - (. - Diisopropyl-aminoethyl) -3- (2-pyridyl) -2,6-piperidinedione (16).
a) 2-Diisopropylamino-2- (2-pyridyl) -pentanedinitride.
The compound was prepared as in Example 1b, starting from the nitrile of Example 1a, but replacing methacrylonitrile with acrylonitrile,
b) 3- (2-Diisopropylaminoethyl) -3- - (2-pyridyl) -2,6-piperidinedione.
Heated at 115 ° C for 1 hour 30 minutes 11, .6 g of the previously obtained compound and 110 g of polyphosphoric acid. After cooling, the reaction medium is dissolved in water and leached with potassium carbonate. Extracted with ethyl acetate, dried over sodium sulfate, then evaporated to dryness.
Chromatograph the residue on a column of 15 nitrile.
h
Ke with alumina, rinsing with a mixture of ethyl acetate / pentane, first in a ratio of 1: 1, then 3: 1. Thus, an oil is obtained which slowly crystallizes}. Recrystallized in isopropyl ether and get colorless crystals (5.25 g), so pl. 96-97 ° C.
Example 3. 5 (e) -Isopropyl- -3 (e) - (2-dinzopropylaminoethyl) -3 (a) - - (2-pyridyl) -2,6-piperidinedione (1c).
a) 2- (2-Diisopropylaminoethyl) -4-isopropyl-2- (2-pyridyl) -pentanedinitrile.
The compound was prepared as in example 16, starting from the nitrile of example 16, but replacing methacrylonitrile with an equivalent amount of 2-isopropylacrylonitrile.
b) 2- (2-Diisopropylaminoethyl) -4- -isopropyl-2- (2-pyridyl) -2,6-piperidinedione.
17 g of the previously obtained dinitrile are dissolved in 100 ml of concentrated sulfuric acid (d 1.83), then heated at 100-110 ° C for 1 hour. Pour the reaction mixture over ice and extrude the solution with 40% sodium hydroxide solution. Extracted with ethyl acetate and dried the organic solution over sodium sulfate.
The solvent is evaporated to dryness and the residue is chromatographed on a column of alumina. Washing with a mixture of ethyl acetate-pentane in a ratio of 1: 4, get first 5.3 g of pure dia
stereomer, then 3.3 g of a mixture of two diastereomers.
The pure diastereomer is recrystallized in isopropyl ether, so pl. 123-125 C.
Analogously to Example 3, but by varying the acrylonitrile used in step a), from 2-11з6 butyl acrylonitrile 5 (e) -isobutyl-3 (e) - (2-di-isopropylaminoethyl) -3 (a) - (2-pyridyl) - 2,6-piperidinedione (1g), so pl. 112- 114 ° C (hexane), with 2-ethyl acrylonitrile 5 (e) -ethyl-3 (e) - (2-diisopropyl-aminoethyl) -3 (a) - (2-pyridyl) -2,6- piperidinedione (1d), so pl. YuT-YUE S (hexane).
Example 4. 5-tert-Butyl-3- - (2-diisopropylaminoethyl) -3- (2-pyridyl) -2,6-piperidinedione (1e).
a) 2- (2-Diisopropylaminoethyl) -A- -t-butyl-2- (2-pyridyl) -pentane 5
0
The compound was prepared as described in example 16, replacing methacrylonitrile with 2-tert-β-butyl acrylonitrile in equivalent. quantity.
b) Cyclization.
Act as in the example of ST, based on the resulting product.
The pure reaction product was chromatographed on a column of alumina (25 g of alumina per 1 g of product), washing with a 3:17 mixture of ethyl acetate and pentane.
First, the first diastereomer 5 (e) -tert-butyl-3 (e) - (2-diiso-0-propylaminoethyl) -3 (a) - (2-pyridyl-2) - -2,6-piperidinedione is obtained, the weight 8.7 g, m.p. 101-102 ° C (hexane).
Then both isomers (2.7) are mixed, the second diastereomer is separated in pure 5 form: 5 (e) -t-butyl-3 (e) - (2-diisopropylaminoethyl) -3 (a) -2-pyridyl- -2,6-piperidinedione, weight 5.1 g, mp, 102-103 s (hexane).
40
Example 5. 4,4-Dimethyl-3- (2- -diisopropylaminoethyl) -3 (2-pyridyl) -2 -2-piperidinedione (1g).
a) 2- (2-diisopropylaminoethyl) -3,3-dime dime-2- (2-pyridyl) -lentandinityl 45 is prepared as in Example 16.
b) 4,4-dimethyl-3- (2-diisopropyl-aminoethyl) -3- (2-pyridyl) -6-piperidinedione.
The cyclization is carried out with sulfuric acid in Example 36. The desired product is obtained in. the form of colorless crystals, so pl. 105-Yub C (cyclohexane-hexane).
Example 6. 4- (2-Diisopropyl minoethyl) -4- (2-pyridyl) -decahydroisoquinolindione-1,3 (Is).
 a) 2- (2-cyanocyclohexyl) -4-dnzopropylamino-2- (2-pyridyl) -butyronitrile.
50
In a solution of 36.75 g of 4-diisopropyl-amino-2 (2-pyridyl) -butyronitrile (Example 1a) in 300 ml of tetrahydrofuran-, 71.7 g of benzyltrimethyl ammonium hydroxide was added at room temperature, then 15, 9 g of 1-cyclohexene. 4.75 g of base is dissolved in 50 ml of absolute alcohol and 2.7 g of hydrochloric acid (d 1.18) is added. You soar to dryness, add ether, Recrystalline precipitate from isopropanol.
carbonitrile dissolved in 100 ml
tetrahydrofuran. Leave overnight
stir at room temperature - - | g Colorless crystals (5 g) are obtained,
re (approximately 20 s), then discharged, pl. 167-169 C. Dichlorohydrate crystallize the solvent to dryness. Water was added to the residue and extracted three times with ether. The solvent is evaporated and the residue is chromatographed on a column of alumina. The mixture is washed with a mixture of pentane-ethyl acetate 4: 1, to obtain 1 d 20 g of the expected product used in this form for cyclisadium. b) 4- (2-Diisopropylaminoethyl) -4- (2-peridyl) -decahydroisoquinolin-dione-1,3.
A mixture of 20 g of the product obtained and 200 ml of concentrated sulfuric acid (d. 1583) is heated at 100 ° C for 1 h. After cooling, the mixture is poured on ice, then alkylated with a 40% alkali solution, cooled so that the temperature of the mixture does not exceed 30 ° C. Extracted three times with ethyl acetate and dried the organic extracts over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed on a column of alumina. Washing with a mixture of pentane-ethyl acetate 9: 1, the expected product (4.3 g), ToPL, 159- (isopropyl ether) is obtained.
Example 7. 5 (e) -1-Dimethyl- -3 (e) - (2-diisopropylaminostil) -3 (a) - - (2-pyridyl) -2,6-piperidinedione dihydrochloride (1i) ,.
0.7 g of sodium hydride in 20 ml of dimethylformamide is added to the suspension under nitrogen atmosphere, then a solution of 7.2 g of the compound of example 1 in 2 ml of dimethylformamide is added dropwise.
After stirring for 1 hour at room temperature, a solution of 3.0 g of methyl iodide in 100 ml of dimethylformamide is added dropwise. The mixture is stirred for 1 hour at room temperature, then the solvent is evaporated to dryness, ether is added to the residue. The organic solution is washed with water and dried over sodium sulfate and evaporated to dryness with BaioT.
Chromatograph the residue in: olonke with alumina, washing with
Sue ethyl acetate pentane 3:17. An oil is obtained (4.9 g).
Dihydrochloride.
4.75 g of base is dissolved in 50 ml of absolute alcohol and 2.7 g of hydrochloric acid (d 1.18) is added. Evaporate to dryness, add ether, Recrystallize precipitate from isopropanol.
five
0
Talisates with 0.75 water molecules.
Antiarrhythmic action of the proposed compounds was evaluated in an animal model with ventricular arrhythmia.
A brod whose dog under anesthesia is inserted, by retrograde catheterization, a metal coil of the spiral into the coronary: layer. At the same time, a micro emitter - a frequency modulator is attached on the back of the animal and connected to two: pericardial electrodes.
In an animal, progressive thrombosis of the anterior interventricular artery of the heart is detected in its box. Thus, a localized transural myocardial infarction arises, generating abnormal, but 0 repeating electrical activity: ventricular tachycardia.
In this state, 16-24 hours after the introduction of the coil, the test compounds are introduced peros and the telemetry system makes it possible to observe in reality the change in dsarhythmia of the experimental dogs.
The calculation of systolic sinusoidal and pathological complexes is constantly provided by electronic processes. Thus, it is possible to determine the quality and for the duration of the effect of the preparation and observe the behavior of the animal.
The drug is considered active if it destroys at least 60% of the abnormal complexes and restores the sinusoidal rhythm.
The results obtained with the various proposed compounds after prescribing at a dose of 50 mg / kg peros are presented in the table,
In each case, the number of experiments and the duration of the effect of the compound are indicated. These results show that the proposed compounds have a strong effect on arrhythmia with a long duration of action in some of.
five
0
five
0
In addition, the proposed compounds are of low toxicity; no signs of toxicity were specifically identified in doses; in which they are active with dysarrhythmia.
0
five
0
where R ,, R and EZ - hydrogen or methyl; R is hydrogen or C-C4-alksh1, or R, j and R4 together - the group - (CH), or their salts, which differs with the fact that 2-pyridylacetonitrile is reacted with 1-chloro-2-di-isopropylaminoethane in in the presence of benzyltriethylammonium chloride and a 50% aqueous solution of sodium hydroxide at 10-35 ° C, the resulting 4-di-isopropylamino-2- (2-pyridyl) butyryl nitrile is reacted with a saturated nitrile of general formula
R / Lek
where Rj, Kz and R4 have the indicated
. meanings
in the presence of benzyltrimethylammonium hydroxide with dinitrile formed of the general formula
Thus, the proposed compounds have high antiarrhythmic activity,

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of pipyridine-2,6-General formula
SNGNGTA
.СН (СНэ) 2 СНССН-ЬН
, CH (CH3) 1 CHSSNZ) 2
thirty
five
Where
and R,
4 have indicated
1,
is heated to 100-150 0 in the presence of acid, followed by alkylation with nitrogen, if necessary, and the desired product is isolated in free form or in the form of a salt.
Editor H, dumb
Compiled by I. Bocharova Tehred L, SerdukoVa
Order 3853/58 Circulation 371 Subscription
VVIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, ul, Proektna, 4
Proofreader I. Muska

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US2664424A|1953-12-29|Dioxo-piperidines |

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GB1455687A|1972-12-28|1976-11-17|Aspro Nicholas Ltd|Pharmacologically active 3-phenyl-3-aminoalkyl-2,6-dioxo-hydro genated pyridines|

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US5238947A|1990-04-12|1993-08-24|University Of Georgia Research Foundation, Inc.|Synthetic piperidinediones with cytostatic activity|

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US9580427B2|2011-05-17|2017-02-28|The Regents Of The University Of California|Kinase inhibitors|

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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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FR8218706A|FR2535721B1|1982-11-08|1982-11-08|

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