Method of producing racemic or optically active derivatives of 9-or 11-aminoeburnancarboxylic acid o

专利摘要:

公开号:SU1428200A3
申请号:SU853923279
申请日:1985-07-11
公开日:1988-09-30
发明作者:Вердеш Андраш；Сантаи Чаба；Молдваи Иштван；Штефко Бела；Гроо Дора；Карпати Эгон；Кишш Бела；Лапиш Эржебет；Ласловски Иштван；Палоши Ева；Рис Миклош；Сомбатели Жолт；Спорни Ласло
申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
IPC主号:

专利说明:

(21) 3923279 / 23-04
(22) 07/11/85
(31) 2251/2703/84
(32) 07/11/84
(33) neither
(46) 09/30/88. Bul Number 36
(71) Richter Gedeon Veseseti D'R RT
(neither)
(72) Andras Verdesch, Chaba Santai, Istvan Moldvai, Bela Štefko, Dora Groo, Egon Carpati, Bela Kiss, Erzhebet Lapis, Istvan Laslovski, Eva Paloši, Miklos Ris, Zsolt Sombeli and Laslo Sporny (HU)
(53) 547.945.1.07 (088.8)
(56) Patent of France No. 244846, cl. C 07 D 471/22, 1980.
Patent of France No. 2342980, cl. C 07 D.519 / 04, 1977.
(54) METHOD FOR OBTAINING RACECOMIC OR OPTICALLY ACTIVE DERIVATIVES OF 9 OR OR AMINOEOBURNANKARBONIC ACID OR THEIR ACID-ADDITIVE SALTS
(57) Ieo.bretenie. Refers to hetero-. cyclic compounds, in particular
to obtain racemic or optically active derivatives of 9- or 11-amino-eeburnancarboxylic acid
formulas ,,
where R is an amino group or NHCORi group, where R (iH, C-Cd-ups1, cyclohexyl, phenyl, possibly substituted by halogen, thiophenyl, nitrophenyl, or R is a group, where R is C -C4-alkyl, R is H, Cj-C-alkyl, provided that R is an amino group, then R cannot be a Ci-alkyl group, or their acid addition salts, which possess valuable pharmacological properties. The purpose of the invention is to develop a process for the preparation of novel more active compounds Synthesis is carried out from an optically active or racemic derivative of a compound of the formula I, where in the position: NII 6- B, and in the position 7 -A and R -. Methyl or H, R -, A and B together form a bond or A - hydroxy group, B - H, and, if A and B together form a bond, then Ri - H, acyl- This is carried out with the subsequent possible re-esterification of the product obtained, after which it is dehydrated, if necessary, with p-toluenesulfonic acid. The desired products are isolated in the free form or as acid-addition salts. 5 tab.
about
cl
 tc os to

cm
The invention relates to a process for the preparation of new synthetic derivatives of vincamine alkaloids containing in the 9- or 11-position a substituted amino group of eburnancarboxylic acid derivatives, their optically active isomers, or their salts of the general formula;
where R is an amino group or NHCORij
 j group
Rj is a hydrogen atom, C-C-alkyl, cyclohexyl, phenyl, possibly. Substituted by a halo atom, thiophenyl, nitrophenyl, or is the group NHSOj R, where Rj is Ci-Cd-alkyl; K is a hydrogen atom, C —C alkyl, provided that if RI is an amino group, then Rfl cannot be a Ci-alkyl group, or their acid addition salts, which possess valuable pharmacological properties.
The purpose of the invention is the creation of new derivatives of eburnancarboxylic acid, possessing a wide spectrum of pharmacological activity, surpassing that of known structural analogs and standard substances.
Example 1. 11-Benzoylamino-apovincynimic acid.
3.37 g (0.01 mol) of (+) - 11-amino-apovincaminic acid are dissolved in 100 ml of caustic soda and 1.7 ml (0.015 mol) of benzoyl chloride are added to the solution at room temperature. The mixture is stirred for 2 hours, then again mixed with the same amount of benzoyl chloride and stirred for another 2 hours. The mixture is neutralized with 10% hydrochloric acid, the precipitate is filtered and washed first with 50 ml of water at 50-60 ° C, then 50 ml of cold water and dried. 3.30 g (75%) of the title product is obtained, which has a melting point at 244-248 ° C.
Calculated,%: C 73.45; H 6.16, N 9.52 ..
0
five
0
five
0
five
0
five
0
five
 (, 52)
Acted,%: C 73.62; H 6.82; N 9.48.
Example 2. 11- (2-Thiophencarbonylamino) -povincaminic acid.
3.37 g (0.01 mol) of () -11-aminovic vamic acid is dissolved in 100 ml of sodium hydroxide solution and 3 ml (0.03 mol) of ti6phen-2-carbonyl chloride are added to the solution with stirring at room temperature of TeMnepatype acid. The mixture is stirred for half an hour and then neutralized by the addition of 10% hydrochloric acid. The precipitated crystals are filtered and washed three times, each time with 40 ml of water. After drying, 3.26 g (73%) of the title compound, which has a melting point at 246, is obtained.
Calculated,%: C 67.10, H 5.63; N 9.39.
 (,five)
Found,%: C 67.35, H 6.00; N 9.40.
Example 3. 11-amino-apovincaminic acid ethyl ester.
3.95 g (0.01 mol) of 11-nitro-apovincaminic acid ethyl ester is kept under stirring for 1 hour with a mixture of 50 ml of ethanol and 10 ml of concentrated hydrochloric acid with 6 g of tin dust. The mixture is filtered while hot and the resulting solution is vacuum-dried. The residue is taken up in 100 ml of water and using alkaline liquor, the alkaline medium is adjusted to pH 10. The precipitated precipitate is filtered, washed three times, each time with 40 ml of 1% sodium hydroxide, and three times with each time 40 ml of water. After drying, 2.80 g (77%) of the title compound is obtained, which has a melting point at 86-88 °.
A mixture of 3.83 g (0.01 mol) of ethyl 11-aminobenzoic acid ester, 7.0 g of p-toluene sulfonic acid and 150 ml of benzene was refluxed for 8 hours under reflux using a water separator. Then the mixture is cooled to room temperature, mixed with 100 ml of water and using alkaline aqueous ammonia to establish an alkaline medium to a pH of 8. The aqueous phase is separated, the organic
ten
15
25
the phase is washed three times, each time with 100 ml of water, dried over calcined sodium sulphate and, after filtration, evaporated to dryness in vacuo. The residue is triturated with ether, the resulting crystals are filtered, washed with ether and then dried. 3.0 g (82%) of the title compound are obtained.
Example 4. Ethyl ester of 11- (methylsulfonylamino) -apovin- {sdminovoy acid HC1.
1.62 g (0.0044 mol) of 11-amino-apovinic acid ethyl ester is dissolved in 10 ml of benign pyridine and 0.6 ml (0.008 mol) of methylsulfonyl chloride in 10 ml of chloroform is added to the solution while cooling. The mixture is stirred for 20 hours at 3 hours and then evaporated to dryness in vacuo. To the residue, add 50 ml of ethyl acetate, 25 ml of saturated aqueous sodium bicarbonate solution, and 50 ml of water. The phases are separated, from each other, the organic phase is washed twice, each time with 30 ml of water, then dried and evaporated in vacuo to; is dry. The residue (1.87) represents the title compound in the form of a base. It is dissolved in 15 ml of acetone and the solution is acidified to pH 3 by means of hydrochloric acid ethanol. After the addition of 45 ml of diisopropyl ether, the crystals precipitate, which are filtered, washed with pure ether and then dried. 1.56 grams (74%) of the title compound are obtained, which has a melting point at 230-234 ° C.
calculated,%: C 57.53; H 6.29; N 8.75; S 6.67; C1 7, .38.
With “NgaNz043. HC1 (, 11) Found,%: C 57.42 {H 6.87; N 8.56; S 6.43G C1 7.40.
Example 5. The 11-aminovinokinamic acid ethyl ester.
7.4 g (0.02 mol) of 11-amine amines are boiled under reflux for 2 hours in 500 ml of ethanol in the presence of 0.5 g of potassium t-butylate. The mixture is evaporated to dryness in vacuo and the residue is triturated with a mixture of 200 ml of water and 40 ml of ethanol. The precipitated crystals are filtered and washed with three parts of a mixture of 100 ml of water and 20 ml of ethanol. 5.43 g (71%) of the title compound are obtained, which has a melting point at 184-186 s.
thirty
35
40
45
50
55
ten
15
25
20 ; 28200 4.
Example 6. Ethyl ester of 9-aminopovincaminate acid - hydrochloride.
Starting from 3.83 g (0.01 mol) of 9-aminovinamic acid ethyl ester is prepared by the method described in Example 3 in 2.84 (78%) of the base of the title compound. The base is dissolved in 20 ml of acetone, the solution is acidified with ethanol with hydrochloric acid to a pH of 3, and after the addition of 20 ml of isopropyl ether, the crystals are filtered, washed with ether and then dried. 2.7 g (69%) of the title compound are obtained.
thirty
35
40
45
50
55
which has a melting point at 218-222 C.
Calculated,%: C 65.68; H 6.71; N 10.44; C1 8.83.
 (, 96)
Found,%: C .65, -86; H 6.90, N 10.28, Cl 8.78.
3.37 g (0.01 mol) of (-) - 9-amino-apovincaminic acid in 100 ml of anhydrous ethanol in the presence of 1 g of a molecular sieve with a diameter of “ibp 3 A (Aldrich 20.859-2) is treated with dry gaseous saline acid. The mixture is first saturated with hydrochloric acid gas, then with continuous. The mixture was heated to reflux for 3 hours while passing gaseous hydrochloric acid. The solution is evaporated to dryness and the residue is mixed with 20 ml of ethyl acetate. The precipitated crystals are filtered, washed with ethyl acetate and dried. 3.13 g (86%) of the title compound are obtained which have a melting point at 218-222 ° C.
Example 7. Ethyl ester of 9- (methylsulfonamyl-amino) -quinokonamic acid HC1.
To a solution of 1.20 g (0.0027 mol): 9-amino-apovincaminic acid ethyl ester HCl in 15 ml of anhydrous pyridine is added with ice-cooling at 0.37 ml (0.005 mol) of methylsulfonyl chloride. The mixture is stirred at 2 hours and then evaporated to dryness in vacuo. The residue is dissolved in 50 ml of chloroform and the solution is washed first with 25 ml of saturated sodium carbonate aqueous solution, then washed three times with water, each time with 30 ml of water, dried over sodium sulfate and evaporated after filtration. 1.09 g (91%) of an oily substance is obtained, which is in the form
ten
51428200
bases of the title compound. The base is dissolved in 40 ml of acetone.
and the solution is acidified with hydrochloric acid ethanol to pH 4. The crystals are precipitated by addition of ether, which are filtered, washed with ether and then dried .. Yield 1.13 g (86%), melting point 189-192 ° C. Calculated: C 57.53, H 6.29, N 8.75; S 6.67, - C1 7.38.
CjsHa NjO / jS HC1 (, 11). Found,%: C 57.70; H 6.80; N 8.72; S 6.40, - C1 7.51.
Example 8. 9-aminovinokinamic acid ethyl ester.
Start from 7.4 g (0.02 mol) of 9-α-aminovinkamine and work as described in Example 5. Output.
5.82 g (75%), melting point 232234 ° C.
Pr and Ie p 9. Methyl ester of 11- (4-natrobenzoidamino) -povincaminic acid.
1.3 g (0.0037 mol) of 11-α-amino-apovinkamine in 10 ml of anhydrous pyridine is added to a solution of 1.3 g (0.007 mol) of p-nitrobenzoyl chloride at room temperature. The mixture is stirred at room temperature for 3 hours and then mixed with 100 ml of ice water and 150 ml of ethyl acetate. The pH is adjusted to 8 by means of sodium hydroxide. The organic phase is separated, washed four times with 25 ml of water each time, dried over calcined sodium sulphate and, after filtration, evaporated to dryness in vacuo. The residue is triturated with 100 ml of ether. The crystals that form are filtered, washed with ether and then dried. 1.68 g (91%) of the title compound is obtained, which has a melting point at 206 cm di and the battery withdraws cannibally by 15 cubic centimeters of 25%
CH Ar ka
mi
-a ba gi va re v o no ch
thirty
35
40
,
IHNMR (CDCl ,,),: Et 1.02t (3), 3.98 S (1), NH.8.58 S (1), Ar-H 7.32-8.08 m (7), protons frame 1,4- 3,26.
Example 10. P- (2-Fluorobenzo-ylamino) -winkamine. In a solution of 2.1 g (0.015 mol) of o-fluorobenzoic acid in 100 ml of anhydrous dimethylformamide is added with stirring
To a solution of 19.9. G (0.054 mol) 1 -aminovinkamine in 100 ml of pyridine d
4.0 g (0.02 mol) of dicyclohexylcarboxy-α-aminovincamine in 1 ml of pyridine diimide. The mixture was stirred for 10 minutes and added, while stirring, while mixing with 3.7 g (0.01 mol) 7.2 ml (0.067 mol) of 11-aminovinquamine chloride. Then stirred at another 1 h. The reaction
thiophene-2-carboxylic acid in 20 m benzene. The mixture is stirred at
6
0
the mixture is left overnight, the precipitated dicyclohexylcarbamide is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 400 ml of ethyl acetate and the solution is placed in a refrigerator overnight. The crystallized dicyclohexyl carbamide residues are filtered off again. The filtrate is washed four times with hydrochloric acid, each time with 50 ml, twice with water, each time with 50 ml, then three times with a saturated solution of sodium bicarbonate and 50 ml and again twice with 50 ml 15 with water. The organic phase is dried over calcined sodium sulfate and, after filtration, evaporated to dryness. The residue is dissolved in a mixture of 50 ml of ethyl acetate and 250 ml of petroleum ether in a hot condition. The crystals precipitated on cooling are filtered, rinsed with petroleum ether and then. dried Obtain 3.8 g (78%) of the title compound, which has a melting point of 5 at 202-205 s. .
1- NMR (CDClI) ;:: Et 0.90 t (3), CHjO 3.90 S (3), OH 4.76 S (1), Ar-H 7.05-8.70 m (7) , protons of the framework 1.00-3.4 m (12).
Example 11. 9-Adetaminovinka-min.
To a solution of 6.6 g (0.018 mol) of 9-α-aminovinkamine in 600 ml of methanol is added with 66 ml of acetic acid - hydride. The reaction mixture is stirred for half an hour and then mixed with mixing with 800 g of ice water and 120 g of potassium carbonate . The methanol is distilled off in vacuo, the remaining aqueous phase is extracted five times with dichloromethane, each time 100 ml. The combined organic phases are washed three times with 100 ml each time with water, dried over calcined sodium sulphate and evaporated to dryness after filtration. The residue is mixed with 50 ml of ether. The crystals are washed with 50 ml of ether and then dried. 5.92 g (80%) of the title compound are obtained, which has a melting point at 144-147 s.
Example 12. 11- (2-Thiofencarbonylamino) -vinkamine.
To a solution of 19.9. G (0.054 mol) of 11-α-aminovinkamine in 100 ml of pyridine do30
35
0
45
0
c-aminovinkamine in luu ml of pyridine bavl with stirring at 7.2 ml (0.067 mol) of acid chloride
aminovinkamine in luu ml of pyridine is added with stirring at 7.2 ml (0.067 mol) of acid chloride
thiophene-2-carboxylic acid in 20 ml of benzene. The mixture is stirred at a predetermined temperature for 2 hours and then mixed with 50 ml of saturated aqueous sodium bicarbonate solution, 50 ml of water and 200 ml of ethyl acetate. The phases are then separated from each other, the organic phase is washed twice with 30 ml of water, dried over calcined sodium sulphate and, after filtration, evaporated to dryness in vacuo. The residue is mixed with 200 ml of ether, the precipitated crystals are filtered off, and rinsed four times with 50 ml of ether. 18.4 g (71%) of the title compound are obtained, which has a melting point at 229-231 C.
Example 13 .. 11- (2-Thiophenylacetylamino) -vinkamine.
To a solution of 0.3 g (0.0022 mol) of thiophene-2-acetic acid in 10 ml of anhydrous dimethylformamide was added 0.43 g of dicyclohexylcarbodiimide. The solution is stirred at room temperature for 15 minutes and then mixed with 0.74 g (0.002 mol) of P-aminovinkamine. The mixture is stirred at room temperature for 24 hours and then placed in a refrigerator overnight. The crystallized dicyclohexyl-carbamide is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 30 ml of ethyl acetate and the solution is washed first with 10 ml of saturated aqueous sodium bicarbonate solution, then three times with 10 ml of water. The organic phase is dried over calcined sodium sulphate and, after filtration, evaporated to dryness in vacuo. The residue is mixed with 20 ml of ether, the precipitated crystals are filtered, washed simply with ether and then dried. This gives 0.51 (52%) of the title compound, which has a melting point at 153-155 seconds.
Ifj. NMR (CDCl1): Et 0.90 t (3), 1.7 q (2), CHjO 3.88 S (3), 3.94 S (2), H-3 4.00 S (1), OH 4.70 (1) Ar-H 6.80-7.65 m (6), CONH 7.48 (1).
Example 14 .. 9-Acetylamido-apovinkamine.
A solution of 5.6 g (0.014 mol) of 9-acetamidovinkamine s 300 ml of benzene is boiled in the presence of 6.8 g of p-toluene sulphonic acid using a water separator for 4 hours under reflux. The mixture is cooled, mixed with 200 ml of water, the pH of the aqueous phase is adjusted to 8
0
through concentrated ammonia and then extracted. The organic phase is washed four times with 100 ml water each time, dried over calcined sodium sulphate and then evaporated in vacuo. The residue is dissolved in hot form in 50 ml of ethyl acetate, the solution is cooled, precipitated
The Q crystals are filtered off and the mixture is washed with ethyl acetate. 5.0 g (91%) of the title compound are obtained, which has a melting point at 138-140 ° C.
 (CDC1,) J; Et 0.99 t (3),
5 CH, CO 2,16 S (3), CH 2 SO 2,16 S (3), CH 2 SO 3,80 S (3), H-3 4.05 & (1), H-15 6.18 S (1), Ar-H 7.0-7.65m (3).
Example 15. 11t (3,4,5-Tri-methoxybenzoylamino) apovinkamin.
1.3 g of 0.0023 mol) 11- (3,4,5-trimethoxybenzoylamino) -vincamine and 1.0 g of p-toluenesulfonic acid are boiled in 50 ml of benzene using a water separator for 2 hours under reflux. After
5, the mixture is mixed with 20 ml of water and the mixture is adjusted to pH 8 with concentrated ammonia, the phases are separated from each other, the organic phase is washed
0 three times 20 ml each time of water, dried over calcined sodium sulphate and, after filtration, evaporated to dryness in vacuo. The residue is dissolved in 3 ml of acetone in hot form, the solution is mixed with 15 ml of petrolinear ether and then cooled. The precipitated crystals are filtered, washed with ether and then dried. Obtain 1.03 g (83%) of the title compound, which has a melting point at 150-152 C.
Example 16. 11-Pivaloylamino-apovinkamine.
0.68 g (0.0015 mol) of 11-pavaloyl-aminovincamin is boiled in 20 ml of benzene in the presence of 0.70 g of anhydrous p-toluenesulfonic acid using a water separator for 3 hours under reflux. The mixture is cooled, mixed with 20 ml of water and then the alkaline medium is adjusted to pH 8 by means of concentrated ammonia. The organic phase is separated, washed four times with 10 ml of water each time, dried over calcined sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is dissolved in 25 ml of hot hexane with the addition of a few drops of acetone. The solution is cooled, precipitating
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9
the crystals are filtered, washed with hexane and then dried. This gives 0.44 g (68%) of the title compound, which has mp. at 110-114 C.
PRI me R 14. 11-Acetamido vincamine.
18.1 g (0.044 mol) of 11-acetamido vincamine in 900 ml of benzene is boiled - In the presence of 22 g of p-toluenesulfonic acid using a water separator for 5 hours under reflux. The mixture is cooled, mixed with concentrated ammonia to obtain an alkaline medium with a pH of 8. The benzene phase is washed three times with 300 ml of water, dried over calcined sodium sulphate and after filtration evaporated to dryness in vacuo. The residue is washed with 50 ml of diisopropyl ether and then dried. 14.35 g (83%) of the title compound, which has a melting point, are obtained at 136-140 °.
Example 18. 11- (2-Fluorobenzo-imino) -apovinkamine.
A mixture of 9.5 g (0.019 mol) of 11- - (2 - fluoroOenzoylamino) -vincamine, 20 g of p-toluenesulfonic acid and 500 ml of benzol and a boiling water using a water separator for 2 hours under reflux. The mixture is cooled, mixed with 200 ml of water and the alkaline medium is adjusted to a pH of 8 by means of concentrated ammonia. The organic phase is washed four times with 100 ml water each time, dried over calcined sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is crystallized from 300 ml of diisopropyl ether. 7.14 (86%) of the title compound are obtained, which has a melting point at 102-105 °.
: / ZS -2, (, dichloromethane). 1 d NMR (CDCl 3): Et 1.02 t (3), 1.95 q (2), CH 2 O 4.01 S (1), H-3 4.30 S (1), H-15 6.18 S (1), Ar-H 6.95-8.00 m (6), H-12 7.92 d (1), 7.14 dd and 8.22 dd (1), NH 8.45 and 8 , 62 S (1), protons of the framework 1.00 - 3.4 m (10).
Example 19. 11- (2-Thiophene-carbonylamino) -apovinkamine.
A mixture of 15.1 g (0.031 mol) of 11- (2-thiophene-carbonnlamino) -vincamine, 400 ml of benzene and 17 g of d-toluenesulfonic acid is boiled using a water separator for 2 hours under reflux. After cooling, the mixture is mixed with 100 ml of water and establish an alkaline medium.
2820010
to pH 8 by means of concentrated ammonia. The organic phase is separated, washed five times with 50 ml of water, dried over calcined sodium sulphate and evaporated to dryness in vacuo after filtration. The residue is crystallized from 100 ml of diisopropyl ether. Get 14.0 g
10 (96%) of the title compound, which has a melting point at 138-.
6.7 g (0.015 mol) of 11- (2-thiophene -carbonylamino) -apovinkamine cyano15 lots are dissolved in a mixture of 20 ml of acetone and 15 ml of sodium hydroxide solution and 1.5 ml of diol are added to the solution at room temperature with stirring - methyl sulfate. The mixture is stirred
20 90 min, then mixed with 0.5 ml of concentrated ammonia and concentrated in vacuo to half of its volume. The precipitated substance is filtered off and washed twice with 10 ml of water and
25 then dried. 6.5 g (95%) is the yield of the title compound, the physical data of which coincides with the physical data of the product made above. .
3Q Example 20. 11- (Benzosh1amino) -apovinkamine.
A solution of 4.4 g (0.01 mol) of 11-benzoylaminoapovinkamine in 100 ml of anhydrous methanol in the presence of 1 g of a modular sieve with a pore diameter of 3 A (Aldrich 20,850-2) is 1 g; With continuous transmission of hydrochloric acid gas, the mixture is boiled for 5 h.
. „With phlegm. Then the solution is evaporated to dryness. The residue is dissolved in a mixture of 100 ml of ethyl acetate and 50 ml of water and the alkaline medium is adjusted to pH 8 by means of concentrated ammonia. The organic phase is separated, washed twice with 30 ml of water each time and dried over calcined sodium sulphate. The solution is allowed to dry under vacuum and the residue is recrystallized from a 1: 1 mixture of diisopropyl ether and hexane (40 ml total) prepared. 3.9 g (86%) of the title compound are obtained, which has a melting point
at 129-132 p. 55
45
50
1d NMR (CDCl1): Et 1.00 t (3), CHjO 4.00 S (3), H-3 4.10 S (1), H-15 6.12 S (1), Ar-H + NH 7.08-8.15 m (9).
eleven
Example 21 (2-hydroxyethyl) -sulfur 11- (benzoylamino) -appotinamic acid ester.
A mixture of 0.45 g (0.001 mol) of 11- - (benzoylamino) -apovinkamine, 10 ml of ethylene glycol and 0.01 g of potassium t-butylate is kept for 2 hours and then evaporated to dryness in vacuo. The residue is dissolved in 26 ml of water and the solution is extracted twice with 30 ml of ethyl acetate. The organic phase is washed twice with 10 ml of water, dried over calcined sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is crystallized from 8 ml of diisopropyl ether. 0.38 g (78%) of the title compound is obtained which has a melting point at 136-138 ° C.
Example 22. (2-Methylpropyl) - 11- (benzoylamino) -apovincamic acid ester chlorine hydrate ester,
A mixture of 0.8 g (0.0018 mol) of 11- - (benzoylamino) -apovinkamine, 20 ml of anhydrous isobutanol, and 0.01 g of tert-butyl potassium is boiled for 2 hours under reflux and then evaporated to dryness in vacuo. The residue is dissolved in 40 ml of dichloroethane and the solution is extracted four times with 5 ml of water. The organic phase is dried over calcined sodium sulfate and, after filtration, evaporated to dryness. 0.83 g (93%) of the title compound is obtained. The base is dissolved in 15 ml of ether, the solution is acidified to pH 3, the salt is filtered off, m.p. hydrochloride 185-186 C.
Example 23. 11- (Cyclohex Ch-amino) -vincamin.
To a solution of 1.85 g (0.005 mol) of 11-aminovinkamine.) In 80 ml of anhydrous pyridine, a solution of 1.46 g (0.01 mol) of cyclohexanecarboxylic acid chloride in a mixture of 20 ml of anhydrous benzene. The mixture was stirred at room temperature for 2 hours and then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 50 ml of ethyl acetate and 50 ml of water, the solution is adjusted to pH with concentrated ammonia and the phases are separated from each other. The organic phase is rinsed three times with 25 ml each time with water, dried and evaporated to 1/3 of its volume and placed overnight in a refrigerator. Crystals filtered
50
5 o
5 0 g
five
0
ZUU 1 2
rinsed, washed with cold water, m ethyl acetate and then dried. 1.67 g (70%) of the title compound are obtained, which has a melting point at 170-174 ° C.
Example 24. 11- (3-Bromopropionylamino) -apovinkamine.
To 2.0 g (5.5 mol) of 11-aminopovincamine in 50 ml of anhydrous pyridine, a solution of 1.71 g (0.01 mol) of 3-bromo-α-propionyl chloride is added with stirring and ice for 1 h. in 30 ml of anhydrous benzene. The mixture is stirred at room temperature for 2 hours and then evaporated in vacuo. The residue is dissolved in a mixture of 50 ml of ethyl acetate and 50 in water, the pH is adjusted to 8 with concentrated ammonia and the organic phase is separated. The solution is dried and then evaporated. The residue is dissolved in 10 t-in methanol and precipitated with ether. The precipitate is filtered off, washed with ether and then dried. 1.5 g (62%) are obtained: the most basic compound, which is%: em melting point at 175-180 ° C.
Example 25. 11-Cyclohexyl-aminopovinkamine.
A mixture of 4.79 g (0.01 mol) of II-β-cyclohexylaminovinkamine (Example 23), 220 ml of benzene and 5.5 g of p-toluene-sulfonic acid is boiled using a water separator under reflux .6 h. The mixture is cooled, mixed with 200 ml of water and set its pH to 8 using concentrated ammonia. The organic phase is washed four times with 100 ml water each time, dried over calcined sodium sulfate and, after filtration, evaporated in vacuo. The residue is triturated with ether, the resulting crystals are filtered, washed with ether and then dried. Obtain 4.0 g (87%) of the title compound, which has a melting point at 130-135 C.
The proposed compounds of general formula (I) and their acid addition salts have vasodilator, antispasmodic, antihypoxic and anti-convulsive effects.
The vasodilatory effect was studied in dogs, which were euthanized with a mixture of chloralose-pentoperonal. Blood circulation in the extremities was measured on the femoral artery, o blood circulation. In the brain, data were obtained by measuring irrigation for most of
13
 .
brain and soft dura mater of the sleep armpit. For the measurement, we used the electromagnetic rheometers, the test substances were administered at a dose of 1 mg / kg body weight to six dogs, and the changes that were made in the measured parameters were recalculated in percent. 6 As a reference substance, ethyl ester (+) - apovinka- | 1nova acid, used in medicine as a vasodilator. ; The results are shown in Table. 1. The antispasmodic activity of the compounds was determined on the pre-cooked guinea pig intestine using the classic method of Mahhus, R. Pflugees JArch 102, 123 (1904). Papaverine was used as a reference substance,



| then apovink-2o ethyl ester (luinyard, EA, et al .: I. Pharmacol. Ninic acid. The results are given in Exp. Ther 106, (1959). Animal shock
in tab. 2
The antihypoxic effect was determined in mice anesthetized by anesthesia with normobaric hypoxia. Five young men were placed in a 3 l glass cylinder, and a gas mixture of 96% nitrogen and 4% oxygen was injected into the cylinder. Time measured
These weights of 22–24 g were caused by a bent electrode (20 mA, 0.2 s, HSE shock type 207). Protected 25 were considered to be those animals that had no tonic extension of the hind limbs as a result of treatment.
Metrazol-induced seizures
between placing the animals in the cylinder and .JQ mice (Everett, S.M. and Richards j j by their death - Those animals that are ped, Pharmacol Exp. Thermally untreated controls / 1944). Animals received after pre-animals more than twice in time can be considered successfully cured. The test substances were administered to each of the 10 animals at a dose of 50 mg / kg, and they were intracutaneously administered with 125 mg / kg of pentylenetetrazole subcutaneously. The absence of persistent klobryushinno 30 minutes before the start of the experiment (Table 3) was recorded.
The antihypoxic effect was then also measured on asphyxial anoxia (Caillard S. et al .: Life / iSee 1, 1607 (1975)) and on hypoxic hypoxia (Waigaee I. et al .:: Pray. Soc. Biol. New York 132, 649 (1969)). At the same time, animals were starved for 16 hours, then treated by oral route and after 1 hour were placed in a well-closed glass vessel with a volume of 100 ml. The time was recorded from the time the vessel was closed: until the last Dakani.
Successfully treated can be considered as those animals that showed a survival time 30% longer than the average of the control group.
Activity on hypobaric hypoxia was studied for 16 hours on hungry animals.
45
nical convulsions and tonic convulsions of the extensor muscle.
Caused by strychnine convulsions (Kerley, T.L. et al .: I. Pharmacol. Exp, The W, 360 (1961)). Intraperitoneal injection of 2.5 mg / kg of strychnine nitrite caused extensor tonic convulsions. Those surviving animals were considered protected as having no convulsions due to treatment.
Neurotoxic side deist-- VIA was investigated as follows.
Measurement of muscle coordination (Rotarod) (H, Kwibara et al .: Japan J. Pharmacol 27,117 (1977) After the previous workout, animals were selected that remain in a 120 s state on the top of a horizontal 55 stick (diameter 20 mm, speed 12 min It was evaluated as uncoordinated muscle if animals fell over the time limit.
Uu
one.
sheet music, which for 1 h before the start of the experiment P.O. compounds were given.
The animals were placed in a vacuum desiccator and the pressure was reduced to 170 Torr for 20 s.
From this point onwards to the last breath, the duration of survival was measured. Those animals whose survival time is 100% longer than the average survival time of the control animals were considered successfully treated. From the percentage of protected animals, using the analysis according to Probit, the ED50 values were calculated (Table 4).
Anti-inflammatory action was investigated by the following methods.
Maximum electric shock in mice
(luinyard, EA, et al .: I. Pharmacol. Exp. Ther 106, (1959). Animal shock
These weights of 22–24 g were caused by a bent electrode (20 mA, 0.2 s, HSE shock type 207). Those animals that had no tonic extension of the hind limbs as a result of treatment were considered protected.
Metrazol-induced seizures
mice (Everett, S.M. and Richard j D j, Pharmacol Exp. Ther / 1944). Animals received after
Treatment of subcutaneously 125 mg / kg of pentylenetetrazol. A lack of persistent closures was reported.
nical convulsions and tonic convulsions of the extensor muscle.
Caused by strychnine convulsions (Kerley, T.L. et al .: I. Pharmacol. Exp, The W, 360 (1961)). Intraperitoneal injection of 2.5 mg / kg of strychnine nitrite caused extensor tonic convulsions. Those surviving animals were considered protected as having no convulsions due to treatment.
Neurotoxic side deist-- VIA was investigated as follows.
Measurement of muscle coordination (Rotarod) (H, Kwibara et al .: Japan J. Pharmacol 27,117 (1977) After the previous workout, animals were selected that remain in a 120 s condition at the top on a horizontal stick (diameter 20 mm, speed 12 min). Evaluated as uncoordinated muscles if animals fell over the time limit.
151428200
Muscle-relaxing action (pull force). Male mice weighing 18-22 g were hung with their front paws to a horizontal wire 5 mm in diameter. A reduced muscle tone was considered to be present in those animals that did not stretch their hind legs for 5 seconds up with the front legs (Table 5). 10 From these experiments it can be seen that the substitution in ring A has a very beneficial effect on the biological effect. It . found primarily in selective vasodilator action. The part of the compounds specifically accelerates the blood circulation of the brain, and the blood circulation in the extremities does not accelerate at all or accelerates only to a small extent. The vasodilating effect, especially in the case of the compounds substituted in the 11-position, is stronger than the vasodilating effect of the reference compound of a similar structure, while the substitution in the 9-position unexpectedly increases the peripheral vasodilatory effect. Of particular importance are the benzoylamino group; derivative to 11-benzoylamino group, derivative 11-benzoylamino shows significant vasodilatory
20
25
thirty
right now
F
op il you
gd
silt
silly
: the action in the brain, a derivative of 9-benzyl-amylamino, on the contrary, shows mainly peripheral vasodilator action.
In addition to the effects on the blood circulation, the compounds also have an antispasmodic effect on smooth muscle, which reaches or exceeds the effect applied as a standard substance papaverine.
Experiments have shown that fatal compounds with cerebral hypoxia prolong survival time. This may be beneficial in therapy in the treatment of disorders in the supply of blood and oxygen to the brain.
The compounds show an exceptionally good anticonvulsant effect, they are more effective in this direction than the standard substance mefenitinoin and do not show even in a tenfold amount of an anticonvulsant dose of neurotoxic workers.
action, while a reference substance in a 3–6-fold amount of an anti-convulsive dose already has a neurotoxic effect. Thus, the therapeutic range is
sixteen
the reference substance is significantly smaller than the therapeutic range of the proposed compounds.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining racemic or optically active derivatives of 9- or 11-aminoethnuronic acid of the general formula
h
RX where RI is an amino group or NHCORij group, where R is hydrogen, alkyl, cyclohexyl, phenyl, optionally substituted by halogen, thiophenyl, nitrophe;
or R is the group NHSGjRj, where Rg is C-f -C-alkyl;
hydrogen, Q -C-alkyl, with the proviso that if R is an amino group, then R cannot be a Cf-alkyl group, or their acid addition salts, characterized in that the optically active or racemic derivative of 9- or 11-amino-eaburnan- carboxylic acid of general formula
40
H, N
H
where Rjj- is methyl or hydrogen} A and B together form a bond or A is a hydroxy group, B is hydrogen, and if A and B together form a bond, then Cd- is hydrogen,
The product is acylated or etherified, followed by the possible transesterification of the product obtained, after which it is dehydrated, if necessary, with p-toluenesulfonic acid and the target products are given in free form or in the form of acid addition salts.
Table 1
The effect of a dose of 1 mg / kg of an insignificant intravenously active substance on the blood circulation of anesthetized dogs (percentage change)
Substance
Ethyl ester of apovincaminic acid (substance standard)
Ethyl ester of 11-thiophenecarbonylamine-apovincamine
acid.
Ethyl ester of 11-benzosch1-amino-apovincaminic acid
11-acetyl-amino-apovincaminic acid ethyl ester
Isobutyl ester 11 acetyl aminopovincamine
acids
Ethyl ester of 9-methanesulfonylamino-apovincamine,
acids
9-acetyl-amino-apovincaminic acid ethyl ester
Ethyl ester of 9-benzoylakinoapovinokinamovoy acid
 T a b. l and c
Sedation of barium chloride-induced contraction in the ileum dissected guinea pig
Tv
Sonna bej ;; peHHa) i artery artery
1428200
Table 3
Antihypoxic effect of compounds on normobargypoxic state of non-anesthetized mice
Substance Survival Time, (%)
min I%
II:
Control 6.0 ± 1.04
Ethyl
complicated
9-amino-apovinkamine ester
acids 7.3 + 2.31 22 10
 Life expectancy + scatter (min).
Table 4 substance 50 (mg / kg, oral)
asphyxia hypobarna anoxy hyoxy
Mephenytoin (substance standard)
Ethyl ester of apovincamic acid (substance-standard)
Methyl ester 11- (4-nitrobenzoylamino) -apovin-
kamic acid
Methyl ester 11-
-benzoylamino-apovinkamine
acids
20
780.0
750.0
42.1
50.0
21
1428200
Anticonvulsant action
Maximum electric shock
Convulsions caused by metrazol
Convulsions caused by strychnine
Neurotoxic Effect of Rotarod
Tee force
yy
Table 5
16,0
16.7
15.9
9.7
180 mg / kg No effect 180 mg / kg No action

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

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HU191938B|1984-07-11|1987-04-28|Andras Vedres|Process for production of new derivatives of 9 and 11 nitro-apovincamin acid|HU191693B|1984-07-11|1987-03-30|Richter Gedeon Vegyeszet|Process for production of derivatives of 9-or-11 substituated apovincamin acid|

---

HU191938B|1984-07-11|1987-04-28|Andras Vedres|Process for production of new derivatives of 9 and 11 nitro-apovincamin acid|

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FR2623501B1|1987-11-19|1990-03-16|Roussel Uclaf|NOVEL SUBSTITUTED DERIVATIVES OF 20.21-DINOREBURNAMENINE, THEIR PREPARATION PROCESS AND THE NOVEL INTERMEDIATES THUS OBTAINED, THEIR APPLICATION AS DRUGS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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EP0864571A4|1994-07-07|1998-12-02|Hiroyoshi Hidaka|Apovincaminic acid derivative and medicine containing the same|

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BR112017016819A2|2015-02-04|2018-04-03|Harbin Pharmaceutical Group Co., Ltd. General Pharmaceutical Factory|Diaza-benzo fluoranthene compound|

法律状态:

优先权:

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HU842703A|HU191694B|1984-07-11|1984-07-11|Process for production of new derivatives of amineburnan carbonic acid|

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