前苏联专利SU1598874A3 Method of producing decahydroquinolines or their acid-additive salts

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专利摘要:
The invention relates to substituted decahydroquinolines, in particular the preparation of compounds of the general formula R 1 R 2 N @, where R 1 = R 2 is C 1 -C 5 alkyl or NR 1 R 2 is 5 or 6 membered heterocycle A - - (CH 2 ) 0-2 or -CH (CH 3 ) - Z is naphthyl or phenyl (it can be mono- or polysubstituted with halogen, CF 3 , NO 2 , alkoxygroup), alkyl or pyridinyl, indolyl, thienyl, benzothienyl, or their enantiomers, distereioisomers, or their additive salts with acids having affinity to opiate receptors K, analgesic, diuretic, antiarrhythmic, antiischemic and antihypertensive properties, which can be used in medicine. The goal is to create new ones with a broad spectrum of activity of substances of the specified class. The synthesis is carried out by the reaction of 8-chloro-5,6,7,8-tetrahydroquinoline with the corresponding amine, followed by reduction of the obtained compound and further condensation with a functional acid derivative of the formula ZAC (O) OH. The desired product is isolated as enantiomers, either distereisomers, or necessary salts. To obtain trans isomers, it is better to perform the reduction in the presence of metallic sodium in a vacuum of 250-300 mm Hg, and to obtain cis isomers, it is better to perform a catalytic reduction. New substances have low toxicity and have a better activity than their counterparts. 1 hp f-ly, 2 tab.
公开号:SU1598874A3
申请号:SU874028897
申请日:1987-01-12
公开日:1990-10-07
发明作者:Клеменс Франсуа；Фортэн Мишель；Де Мартрэ Одиль；Дельвалле Франсуаз
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for the preparation of new decahydroquinolines, which exhibit a strong affinity for opiate retgeptors, in particular K receptors, possess central analgesic properties, and diuretic properties, in addition to that.
some of them have anti-arrhythmic, anti-ischemic, and hypotensive properties.
The purpose of the invention is the synthesis of new decahydroquinolines, possessing a whole set of important pharmacological properties, and for a whole range of activities

O4
superior structural analogs possessing the same kind of activity. Example 1. Hydrochloride f 4aRS (4ao,, 8a)} () decahydro-1- (3,4-dichlorophenyl1 |; etyp) - 8- (1-pyrrolidinyl) quinoline.
Stage A. Wh-Pyrrolidinyl-5,6, 7,8-tetrahydroquinoline.
With heating and stirring for 7 minutes, 50 ml of pyrrolidine is added to a solution containing 20 g of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride in 50 ml of water. At the end of the addition, the temperature reaches 57 ° C, perennially (5 are stirred for 1 h 30 min at this temperature. The temperature is allowed to go down to 20 ° C, they are added by adding 17 g of sodium chloride, extracted with ether, the combined organic layers are dried, 20% are removed under reduced pressure. . Obtain 20.22 g of the desired product in the form of oil. Step B. 4aRS (4a (/,,) J
(1) Decahydro-8- (1-pyrrolidinyl) chinoline.
This product is obtained as a mixture with other diastereoisomers by reduction of the product obtained in stage A by catalytic hydro genification or with a mixture of sodium; ethanol. Stage B. Hydrochloride | 4aK5 (4ao /, 8aC, BaooO 1 (1) decahydro-1- (3,4-dichlorophenyl) adyl yl} -8- (1-pyrrolidinyl) quinoline.
The solution containing 873 mg of 3,4-dichlorophenyl acetic acid, 690 mg of carbonyldiimidazole in tetrahydrofuranone is stirred for 1 hour at 20-25 ° C, then 645 mg of the product, Q obtained in step B, is added in solution in 3 ml tetrahydrofuran.
The mixture is stirred at room temperature for 4 hours, the tetrahydrofuran is removed under reduced pressure at less than 45 ° C, the residue is taken up in 20 ml of ether, the solution is washed with a saturated sodium bicarbonate solution and then with water, dried with sodium chloride, the ether layer is dried and distilled are d6-, "dry under reduced pressure. 1.39 g of final product is obtained in the form of a base.
Preparation of hydrochloride. 1.298 g of the last product obtained is dissolved in 5 ml of ether, filtered, rinsed with ether, 2 ml of ethanol are added to the filtrate and 1.25 ml of ethanol solution of hydrochloric acid (5.75 N) are added in pH 1.2.
Crystallization is seeded, left for 2 hours at 20-22 ° C, sucked off, rinsed with ethanol: sufur (3: 1) and ether, dried under reduced pressure to obtain 852 mg of hydrochloride. 825 m of the latter are recrystallized in ethanol and 722 mg of the desired product are obtained, so pl. 233
Found,%: C 58.7; H 7.0; N 6.5; C1 24.6.
Calculated,%: C, 58.41; H 6.77; N 6.48; C1 24.63.
Preparation of 8-chloro-5,6,7,8-tetra hydroquinoline (hydrochloride).
At room temperature, under stirring and in an inert atmosphere, 3 ml of methanesulfonyl chloride is slowly added to 1.49 g of 5,6,7,8-tetrahydroquinoline. It is then heated for 4 hours at 80-82 ° C, and then cooled to 20 ° C. It is poured onto 20 ml of saturated sodium bicarbonate solution and then sodium bicarbonate is slowly added until the alkaline pH is obtained. It is extracted with methylene chloride, washed with water, the combined organic solutions are dried, distilled to dryness under reduced pressure, and 1.53 g of the expected product are obtained in the form of an oil. . Preparation of hydrochloride.
The resulting oil was dissolved in 2 ml of ethanol, and 2 ml of ethanolic hydrochloric acid solution (5.75 N) was added. The hydrochloride crystallizes. Slowly diluted at 20–25 s in 4 ml of ether, sucked off, rinsed with ethanol: ether (1: T), and then with ether, cyiuaT under reduced pressure at 20 ° C. After recrystallization in ethanol, 0.893 g of the expected product is obtained, mp. .
Example 2. C4aRS oxalate (4ao (, 8p., 8aot) (1) decahydro-1- (3,4-dichlorophenyl) acetyl J-8- (1-pyropolydinyl) quinoline). I -. -.
Similar to stage B of Example 1, but starting from 876 mg of 4aRS (4ao, 8, 8аоО 7 (t) decahydro-8- (1-pyrrolidinyl) quinoline, 1.660 g of product are obtained.
After chromatography on silica (the eluant is ethyl acetate containing 1% triethylamine), 316 mg of the expected product are obtained, m.p. 90.C, in the form of vanilla.
Preparation of oxalate.
280 mg of the product obtained are dissolved in 1.5 ml of 100% ethanol, filtered, rinsed with ethanol and 130 mg of oxalic acid are added to the filtrate. The resulting solution was slowly diluted with 6 mL of ether, crystallization seeded, left for 1 hour at room temperature, sucked off, sugaat under reduced pressure at and receive 319 mg of product. 286 mg are recrystallized in ethanol and 223 mg of the expected product are obtained, i.e. .
Found,%: C 54.5; H 5.9; N 5.4; C1 13.2.
Calculated,%: C 54.34; H 5.89; N 5.28; C1 13.37.
Froze - Hydrochloride 4aRS (4al, “(/, 8a) 3 (±) decahydro-1- (3,4-dichlorophenol) acetyl)} - 8- (1-pyrrolidinyl) quinoline.
For 1 h at 20-22 ° С moving 15988746
chlorophenol) acetyl)} - 8- (1-pyrrolidinsh quinoline.
Similar to stage B of Example 1, but starting from 707 mg of (, n, 8ap) J (t) decahydro-8- (1-pyrrolidinyl) quinoline, 1.384 g of product is obtained.
The resulting oil is then burned in 10 ml of n-hexane. Crystallization is seeded, sucked off, rinsed with n-hexane, ground under reduced pressure at and 746 ml of the desired product is obtained as a base, mp. 82-84 S.) 5 Preparation of fumarata.
At this stage, 817 mg of the obtained product is dissolved in 8 ml of ethanol, filtered, rinsed with boiling ethanol, 20 285 mg of fumaric acid are added to the filtrate, and the mixture is heated under reflux with stirring. The mixture is allowed to crystallize, cooled, sucked off, rinsed with ethanol and ether, with
1 stitch a solution containing 1.98 g 3.4–25 under reduced pressure and under dichlorophenyl acetic acid, 1.56 g yield 0.49 mg of product, mp. .
carbonyldiim 1dazole in 17 ml of tetrahydrofuran. Then, 1.679 g of 4aRS (4a, 80, 8a / j) J (l) of dehydrogen-8- (1-pn-propidinyl) quinoline in solution in 5 ml of tetrahydrofuran is added.
The solution is stirred for 4 hours at 20-22 ° C, the tetrahydrofuran is removed under reduced pressure at less than 45 ° C. The resulting residue is concentrated in 15 ml of ether and in 5 ml of saturated sodium bicarbonate solution, sucked off, rinsed with water and then ether, dried under reduced pressure and get 2,320 g of the desired product in the form of a base, so pl. 138 ° C. Preparation of hydrochloride. Under reflux, 2.309 g of the base are dissolved in 2 ml of ether, 2 ml of ethanolic hydrochloric acid solution (5.75 N) are added, filtered off in a hot form, the product crystallizes while cooling in the filtrate, the crystals are sucked off, rinsed with ethanol and ether, dried under reduced pressure at 65-70 € and get 1,816 g of the target product, so pl. 214 s.
Found,%: C 58.6; H 6.8; N 6.6; C1 24.6.
Calculated,%: C 58.41; H 6.77; N 6.48; C1 24.63.
Limer 4. Fumarate 4aRS (4ae, 8 / J, 8a / h) (1) decahydro-1- (3,4-diIdan,%: C 58.4; And 6.3; N 5, 4 ;, C1 13.7.
Calculated,%: C 58.71; H 6.31; 30 N 5.48; C1 13.86.
Preparation of diastereoisomers used in examples 1-4;
C4aRS (4ao, 80, 8aof J (±) decahydro 8- (1-pyrrolidinyl) quinoline (diastereo-JJ isomer cis-A);
i; 4aRS (4a (/, 8/3, Pao /) 3 (t) decahydro-8- (1-pyrrolidinyl) quinoline (diastereoisomer cis-B);
4aRS (, 8b, 8a / l) J (t) decahydro 40 8- (1-pyrrolidinyl) quinoline (diastereoisomer transg.-A);
C4aRS (4ao, 8 / j, 8a / S)} (+) decahydro-8- (1-pyrrolidinyl) quinoline (trans-B diastereoisomer).
45 These diastereoisomers are obtained by reduction of example 1 obtained in stage A of 8-pyrrhaline 1-5,6,7,3-tetrahydroquinoline.
Catalytic reduction. 50 6.24 g of 8-pyrrolidine particles: -5.6, 7.8-tetrahydroquinoline, 62 ml of methanol, 6.2 MP of hydrochloric acid and 690 mg of platinum oxide are introduced into the hydrogenation apparatus. Under the pressure of about 22-25 0 under pressure, about 1850 mbar for 17 h; Hydrogen uptake lasts about 4 hours and 30 minutes. The catalysts are filtered, the mash is rinsed and distilled.
5988746
chlorophenol) acetyl)} - 8- (1-pyrrolidine) quinoline.
Similar to stage B of Example 1, but starting from 707 mg of (, n, 8ap) J (t) decahydro-8- (1-pyrrolidinyl) quinoline, 1.384 g of product is obtained.
The resulting oil is then burned in 10 ml of n-hexane. Crystallization was seeded, sucked off, rinsed with n-hexane, ground under reduced pressure at and 746 ml of the desired product were obtained as a base, m.p. 82-84 S.) 5 Preparation of fumarata.
At this stage, 817 mg of the obtained product is dissolved in 8 ml of ethanol, filtered, rinsed with boiling ethanol, 20 285 mg of fumaric acid are added to the filtrate, and the mixture is heated under reflux with stirring. The mixture is allowed to crystallize, cooled, sucked off, rinsed with ethanol and ether, with
-25 under reduced pressure and obtain 0.49 mg of product, m.p. .
25 under reduced pressure and obtain 0.49 mg of product, m.p. .
Found,%: C 58.4; And 6.3; N 5.4; C1 13.7.
Calculated,%: C 58.71; H 6.31; 30 N 5.48; C1 13.86.
Preparation of diastereoisomers used in examples 1-4;
C4aRS (4ao, 80, 8aof J (±) decahydro 8- (1-pyrrolidinyl) quinoline (diastereo-JJ isomer cis-A);
i; 4aRS (4a (/, 8/3, Pao /) 3 (t) decahydro-8- (1-pyrrolidinyl) quinoline (diastereoisomer cis-B);
4aRS (, 8b, 8a / l) J (t) decahydro 40 8- (1-pyrrolidinyl) quinoline (diastereoisomer transg.-A);
C4aRS (4ao, 8 / j, 8a / S)} (+) decahydro-8- (1-pyrrolidinyl) quinoline (trans-B diastereoisomer).
5 These diastereoisomers are obtained by reduction of example 1 obtained in stage A of 8-pyrrhaline 1-5,6,7,3-tetrahydroquinoline.
Catalytic reduction. 0 6.24 g of 8-pyrrolidine particles: -5.6, 7.8-tetrahydroquinoline, 62 ml of methanol, 6.2 MP of hydrochloric acid and 690 mg of platinum oxide are introduced into the hydrogenation apparatus. Subjected to Hzrogenesis 5–25 at 22–25 0 under pressure of about 1,250 mbar for 17 h; Hydrogen uptake lasts about 4 hours and 30 minutes. The catalysts are filtered, the mash is rinsed and distilled.
dry under reduced pressure. 8.67 g of product are obtained.
Crystallization of diaste hydrochloride of the dis-A reoisomer.
The diluted resin was dissolved at 50-60 ° C in 16 ml of isopropanol and crystallized at 20 ° C. Then 12.5 mp of ether was diluted, sucked off, rinsed with isopropanol: ethyl ether (1: 1), and then with ether, dried under reduced pressure, the resulting product is crystallized in 42.5 ml of isopropanol, containing 27, water, sucked off, rinsed with isopropanol, and then ether. Obtain 2.156 g of the desired product in the form of the hydrochloride, so pl. 2in (J.
Return to basement. 1 g of the hydrochloride is dissolved in 10 ml of water, and 2 ml is added. 2 n. sodium hydroxide, extracted with ether, decanted, washed with water, saturating
sodium chloride. Dry the ether

solution and distilled to dryness under reduced pressure. 0.680 g of the desired product is obtained in the form of a base.
Preparatory chromatography of mother solutions of crystallization of chlorine hydrate diastereoisomer cis-A.
Combine the mother solutions of the crystallization of the isomer of cis-A hydrochloride and produce a return to the base in aqueous and ethyl ester of acetic acid using sodium hydroxide. The extraction is washed with water, using sodium chloride, dried and distilled to dryness under reduced pressure. Chromatography on silica was carried out at room pressure (eluant — ethyl acetate: methanol: triethylamine, 85: 10: 5). Collect successively diastereoisomers cis-B

tr an s-A and cis-A.
Diastereoisomer cis-B.
Reducing to dryness under reduced pressure homogeneous elution fractions and -.
2.059 g of the expected product are obtained.
Diastereoisomer trans-A.
The following fractions are brought to dryness under reduced pressure and 0.564 g of product is obtained. Hydrochloride is prepared and ethanol:: ether (1: 1) is crystallized in a mixture and then is returned to the base with 201 mg of hydrochloride in water, ether and 2N. hydroxides
five
0
5 with less than
on three . Obtain 139 mg of the desired product.
Diastereoisomer cis-A.
The corresponding eluants are brought to dryness under reduced pressure and 0.686 g of brown resin is obtained, which the hydrochloride gives, t.p. .
Chemical recovery.
With and under pressure of 2.5-3 cm Hg. The solution containing 10.14 g of 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline is heated to reflux in 400 ml of ethanol, and then 18 g of sodium are introduced under reflux in small fractions for 7 hours. Bring under nitrogen and leave overnight, then reheat with reverse cooling and inject 14 g sodium in small pieces over 5 hours. Under a nitrogen atmosphere and pour the reaction mixture into 400 mp ice-water with stirring, ethanol is removed by distillation under reduced pressure.
saturate os0
50
45
.

50
:five
polishing medium 28 g of sodium chloride, extracted with ether, washed the ether layers with water saturated with sodium chloride, dried, distilled to dryness under reduced pressure, to obtain 6.68 g of the desired crude product as a mixture. Then, prepared xrymatography is performed to separate the trans-isomers of trans-trans, trans-a and cis-a.
Chromatographic on silica (eluant - ethyl ester of acetic acid: methanol: triethylamine 85: 10: 5).
Diastereoisomer trans-B. The fractions containing the first isomer are brought to dryness under reduced pressure and 1.183 g of oil are obtained. 1.163 g of this oil is dissolved in 2 ml of ethanol, filtered, rinsed with ethanol, and then 830 mg of oxalic acid is added to the filtrate. The resulting solution is slowly diluted with 40 ml of ether, a precipitate is formed. The upper layer is decanted, the resin is washed with ether, dissolved in 7 ml of water, and 20 ml of ether and 2 ml of sodium hydroxide are added. The mixture is stirred in a flask, decanted, washed with saturated sodium chloride water, the ether solutions are dried, rinsed and distilled to dryness under reduced pressure. Obtain 1.010 g of the desired product.
Diastereoisomer trans-A. Homogeneous fractions of chromatography are adjusted to dryness under reduced pressure, respectively 715
trans-A isomers, and 2.332 g of oil is obtained. 2.322 g of this oil is dissolved in 2.5 ml of ethanol, the filtrate is diluted with 9.5 ml of ether and 5 ml of hydrochloric acid in ethanol (5.75 N) is added. The hydrochloride obtained is filtered off with suction, washed with ethanol: eLir (1: 1) and ether, dried under reduced pressure at 60 ° C, and 2.569 g of the diastereoisomer are obtained as the hydrochloride. Returning to the base is carried out by treating 2.46A g of hydrochloride with 10 ml of water and 2 ml of 32% sodium hydroxide. Stir, decant, re-extracted with ether. The ether layers are washed with water, saturated with sodium chloride, dried, distilled to dryness under reduced pressure, and 1.679 g of the expected product is obtained.
F
Diastereoisomer cis-A. The homogeneous fractions of chromatography corresponding to the cis-A diastereomer are reduced to dryness under reduced pressure to obtain 0. 579 g of the expected product. The solution is dissolved in 5 ml of isopropanol, 2 kp of a solution of dry acid in isopropanol (4.4 M) is added, filtered, diluted with 7 ml of ether, 0.15 ml of water is added, crystallization is seeded, sucked off, rinsed with a mixture of isopropanol: ether and cypiaT ether under reduced pressure at and receive 504 mg of the diastereoisomer of cis-A in the form of hydrochloride, so pl. 210 ° C. Return to the base is carried out on 64 mg of hydrochloride, as for the trans-A diastereoisomer hydrochloride. 42 mg of the desired product is obtained.
EXAMPLE 5 Chlorohydrate f4aRS (4a (/,) (t) 1- (4-chlorophenyl) acetyl) decahydro-8- (1-pyrrolidinyl) quinoline.
Similarly to stage B of example 1, 554 mg of 4-chlorophenylacetic acid, 527 mg of carbonyldiimidazole and 520 mg of the product obtained in stage A of example 1 were used, and, keeping the reaction medium under stirring for 5 hours, after crystallization of the chlorohydrate in isopropanol : ether (1: 1), 752 mg of the expected product are obtained, m.p. с1222 С (decomposition).
Found,%: C 63.6; .H 7.6; N 6.8; C1 17.8. .
CiilI gClN O, HC1 (397,391).
Calculated,%: C 63.47; H 7.61; N 7.05; C1 17.84.
n) 5
20
25
30 j 40
45
ten
EXAMPLE 6 Chlorohydrate f4aRS (4a «,, 8l (/) (±) 1-G (4-trifluoromethyl-phenyl) acetyl decahydro-8- (1-pyrrolidinyl) quinoline.
Analogously to example 5, starting from 663 mg of 4-trifluoromethylphenyl acetic acid and given with stirring for 16 hours, after crystallization of the hydrochloride in ethanol, 921 mg of the desired product are obtained, mp. / 2: 208 С (decomposition).
Found,%: C 61, D; H 7.1; N 6.4; C1 8.1; F 12.9.
., HC1 (430,944).
Calculated,%: C, 61.32; H 7.02; N 6.50; C1 8.23; F 13.22.
PRI me R 7. Khporohydrat G4-K8. (4AU, 8rt,) 7 (±) G (4-bromphensht) acetyl; decahydro-8- (1-pyrrolidinyl) quinoline.
Analogously to Example 5, using 699 mg of 4-bromophenylacetic acid and detergent by stirring for 20 hours, after crystallization of the hydrochloride in isopropanol, 685 mg of the desired product are obtained, mp. (decomposition).
Found,%: C 57.4; H 6.9; N 6.3; C1 7.8; Br 18.0.
C ,, H ,, gBrNjO, HC1 (441,847). . Calculated,%: C 57.09; H 6.84; N 6.34; C1 8.02; Rr 18.08.
Example. Hydrochloride 4aRS (, 8c /, 8a) 7 (±) (4-nitrophenyl)
acetyl Jdecahydro-8- (1-pyrrolidinyl) -quinoline.
Analogously to stage B of example 1, starting with 471 mg of p-nitrophenylacetic acid, 422 mg of carbonyldiimidazole and 417 mg of the product prepared in step B of Example 1, and, while stirring for 3 hours, 606 mg of the desired product is obtained after crystallization of the hydrochloride in ethanol m.p. (decomposition).
Found,%: C 61.8; H 7.5; N 10.1; C1 8.5.
it C1 (407,944). Calculated,%: C, 61.83; H 7.41; N 10.30; C1 8.67.
Example 9. Chporohydrate С4 -К8 (4ао /, 8о, naoOJ (±) 1 - (; (з, 4-dimethoxyphenyl) acetylJdequagydro-8- (1-pyropoly-5 Dinsht) quinoline.
Analogously to example 8, taking 510 mg of 3,4-dimethoxyphenylacetic acid and loops with stirring for 20 h, get 571 mg
0
eleven .
target hydrochloride, so pl. 250 ° C (decomposition).
Found,%: C 65.3; H 8.4; N 6.4; C1 8.4.
. HC1. (422,999). Calculated,%: C 65.31; And 8.34; N 6.62; C1 8.38.
Example 10. HporhydratG4aK5 (4av, V, 8ac /) 7 (1) 1-С (2,4-dichlrphenyl) acetyl7decahydro-G - (1-pyrrolidinyl) quinoline.
Analogously to Example 9, by using 533 mg of 2,4-dichlorophenyl acetic acid and disinfectant with stirring for 4 hours, the expected product is obtained, mp. 260 ° C.
Found,%: C 58.7; H 6.8; N 6.5; C1 24.6. , HC1 (431.836).
Calculated,%: C 58.41; H 6.77; N 6.48; C1 24.63.
Example 11. t4aRS hydrochloride (4ао, 8о,) 3 (±) (1-naphthalenyl) acetylDecca-8- (1-pyrrolidinsh1) quinoline.
Analogously to example 8, having consumed 484 mg of o-naphthyl acetic acid and holding under stirring for 20 hours, 769 mg of the desired product are obtained, mp. :: f.
Found,%: C 72.9; H 8.2; N 6.8; C1 8.7.
C,, HC1 (413,007).
Calculated,%: C, 72.70; H 8.05; N 6.78; C1 8.58.
Example 12. 4aRS hydrochloride (4ao (f, Py, 8 OOZ (±) 1-Г2- (3,4-dichlorophenyl) -1-oxopropyl 11 decahydro-8- (1-pyrrolidinyl) quinoline (isomer A).
Analogously to Example 8, using 482 mg of b -methyl-3,4-dichlorophenyl acetic acid, dl and bicarbonate with stirring for 24 hours, obtain 334 mg of the desired hydrochloride.
Found,%: C 59.2; H 7.0; N 6.3; - C1 23.6. C, IsoC1., HC1 (445,863).
Calculated,%; C, 59.26; H 7.01; N 6.28; C1 23.85.
Example 13. 4aK8 hydrochloride (4ao; ao, 8aoOT (t) (3,4-dichlorophenyl) -1-goxopropyl decahydrb-8- (1-pyrrolidinyl) quinoline (isomer B).
159887412
20 mg of 4-dimethylaminopyridine and 635 mg of dicyclohexylcarbodiimide. The dichloro-IJ hexylurea formed is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue is taken up in 50 cm of ether, washed with an aqueous solution, using sodium bicarbonate and then with water.
JO and sutlg. The solvents are removed under reduced pressure, the residue is taken up in ether and the crystalline product is sucked off. Uterine crystallization solutions are concentrated to dryness.
15 and get 905 mg of the final product, which is chromatographed on silica (eluant is ethyl acetate with 2% triethylamine). 378 mg of isomer A and 303 mg of isomer B as base are obtained. 287 mg of base (isomer B) are dissolved in 1 cm of ether, filtered, rinsed with ether and ethanol, 0.5 cm of ethanolic hydrochloric acid solution (5.75 N,) is added to the filtrate, concentrated under reduced pressure to a volume of 0 , 5 cm and add 10 cm of ether. The crystalline product is filtered off with suction, dried at 70 s under reduced pressure. Collect 146 mg of target; mp. s; 254 s (20
25
thirty
product, live).
T1amdeno,:
C, 59.3; H 7.0; N 6.3; C1 23.7. 35, HGl (445.8635.
Calculated,%: C 59.26; H 7.01; N 6.28; C1 23.85.
Example 14. Hydrochloride C4aRS (4ао (, 8о /, 8ао;) 3 (±) 1-С (benzo (b) thien-4-40 yl) acetic acid2decahydro-B- (1-pyrrolidinyl) quinoline.
Analogously to Example 8, by using 500 mg of 4-tianaphthalene acetic acid and keeping under stirring for 45 hours, 655 mg of the desired hydrochloride are obtained, m.p. .
Found,%: C 65.8; H 7.6; 6.6; S 7.3; C1 8.7.
N
50
C jHaoNjO, HC1 (419.032).
At room temperature, mix with quinoline.
Calculated,%: C 65.93; H 7.46; N6.68; S 7.65; C1 8.46.
Example 15. FumaratG4aYa8 (4a “i, Kd, 8ao) 3 (1) 1- (1H-indol-3-yl) acetyl Zdekahydro-8- (1-pyrrolidinsht)
40 h 570 mg o (α-meth-1-3,4-dichlorophenylacetic acid, 417 mg of the product obtained in stage B of example 1, 5 cm of methylene chloride in the presence of the product is prepared as a base, as in Example 8, using 455 mg of 3-indole acetic acid and incubated for 40 hours with Fu5 and get 905 mg of the product, which is chromatographed on silica (eluant is ethyl ester of acetic acid with 2% triethylamine.) 378 mg of isomer A and 303 mg of isomer B are obtained as 287 mg of base (isomer B) are dissolved in 1 cm of ether, filtered, rinsed with Fir and ethanol, 0.5 cm of an ethanolic hydrochloric acid solution (5.75 N,) was added to the filtrate, concentrated under reduced pressure to a volume of 0.5 cm and 10 cm of ether added. The crystalline product was sucked off, dried at 70 with reduced pressure: 146 mg of target is collected; mp; 254 seconds (of product, live).
T1amdeno,:
C, 59.3; H 7.0; N 6.3; C1 23.7. 5, HGl (445.8635.
Calculated,%: C 59.26; H 7.01; N 6.28; C1 23.85.
Example 14. Hydrochloride C4aRS (4ао (, 8о /, 8ао;) 3 (±) 1-С (benzo (b) thien-4-0 yl) acetst2decahydro-B- (1-pyrrolidinyl) quinoline.
Analogously to Example 8, by using 500 mg of 4-tianaphthalene acetic acid and keeping under stirring for 5 hours, get 655 mg of the desired hydrochloride, m.p. .
Found,%: C 65.8; H 7.6; 6.6; S 7.3; C1 8.7.
N
0
C jHaoNjO, HC1 (419.032).
with quinoline.
Calculated,%: C 65.93; H 7.46; N6.68; S 7.65; C1 8.46.
Example 15. FumaratG4aYa8 (4a “i, Kd, 8ao) 3 (1) 1- (1H-indol-3-yl) acetyl Zdekahydro-8- (1-pyrrolidinsht)
The product is prepared as a base as in Example 8, using 455 mg of 3-indole acetic acid and holding for 40 hours while stirring. Fu131598874
Marat receive, as in example 4, and after recrystallization in methanol receive 233 mg of the target product, so pl.
Found,%: C 70.8; H 8; N.
, N, 0, (423,560).
Calculated,%: C, 70.89; H 7.85; N 9.92.
Example 16. Fumarate G4aEZ (4ao |, ps (, 8aaOJ (±) 1- (Lenylacetyl) decahydro-8- (1-pyrrolidinyl) quinoline.
Analogously to example 14, consumed 422 mg of aenylacetic acid, 527 mg
ten
carbonyldiimidazole and 521 mg of products; 15 2; S 7.02.
Similarly, 512 mg of the thiophene product, the floor of Example 1, 816 diimide and Om after 42 hours of the first decay temperature, Marat according to method 4. Collected fumarate, ing).
Found%:
the one obtained in Example 1 in stage B, and superior for 16 hours while stirring, after crystallization in ethanol, 641 ml of Marat target fug are obtained, m.p. .
Found,%: C 67.8; H 7.8; N 6.3.
, (442,560).
Calculated,%: C 67.85; H 7.74; N 6.33.
Example 17. Fumarate; 4aKZ (4ao, 8o) (t) 1- (4-methylphenyl) acetyl7 decahydro-8- (2-pyrrolidinyl) quinoline.
Analogously to Example 8, but using 390 mg of paratolylacetic acid and stirring for 6 hours, the product is obtained in base form, which is converted to fumarate by the methods described in Example 4. After recrystallization in isopropanol, 458 mg of the desired product is obtained, mp. 198 C.
Found,%: C 65.1; H 7.5; N 5.3.
, 1 ,, (514,624).
Calculated,%: C 65.35; H 7.44: 5.4.
. Example 18. Fumarate1; 4aKZ (4as8o /, 8ao;) J, (t) 1 - (4-pyridinyl) acetyl E ekahydro-8- (1-pyrrolidinyl) quinoline.
Analogously to Example 8, having consumed 52 mg of 4-pyridylacetic acid and vyrzhiva with stirring for 3 hours, the product is obtained as a base, which is converted into fumarate according to the method described in example 4. 73 mg of the desired fumarate are obtained, mp. 232 ° C. Found,%: C 62.2; H 7.1; 8.4.
, 1.5 (501.585).
Calculated,%: C 62.26; H 7.03; 8.38.
EXAMPLE 19 FumaratG4-K5 (4a (/, e /, 8a «) J (t) 1- (2-thienstateyl) decagide-o-8- (1-pyrrolidine) quinoline.
It is calculated N 6,24; S 7.15
PRI me R 20 (4ао (,, 8a)) benzoyl) quinoline decagid.
At room 40 hours, 25 510 mg of sludge chloride with 417 mg of ol of stage B are supplied. An example of a crude product in the second translates to 30 indicated in the example of the target product.
Found %: N 6.3; C1 8.0.
C ,,., Calculated, N 6.38; C1. 8.0
Example (4ao, 3o (f, 8ao) decagid) o-8- (1 Similarly, 483 mg of chloride in 22 reaction reaction, I get bases, which are 45 by the method of re 4. Collect duct, so pl. 20
Found,%: N 5.5; Vg 15.6
Calculated,% N 5.52; Hr 15.7
PRI me R 8o, 8av) (±) 1- (55 kagidro-8- (1-pi
Similarly, p 461 mg chloride agitated at room temperature t
40
14
2; S 7.02.
Analogously to Example 13, having consumed 512 mg of thiopheneacetic acid, 512 mg of the product obtained in Step B of Example 1, 816 mg of dicyclohexylcarbodiimide and 0 mg of dimethylaminopyridine, after 42 hours of stirring at room temperature, the product is obtained as a base, which is converted into Marat according to the method indicated in Example 4. 648 mg of the target fumarate is collected, m.p. 252 C (decomposition).
Found,%: C 61.5; H 7.3;
15 2; S 7.02.
;
(448,585). Calculated,%: C, 61.58; H 7.19; N 6.24; S 7.15.
EXAMPLE 20. X11 hydrochloride C4-C8 20 (4ao (,, 8a)) (±) 1- (3,4,5-trimethoxy benzyl) decagidro-8- (1-pyrrolidinyl) quinoline.
At room temperature, for 5 hours, 5 510 mg of 3,4,5-trimethoxybenzoyl chloride is reacted with 417 mg of the product obtained in Step B of Example 1 in ether. The crude product is obtained in the form of a base, which is converted into hydrochloride, as indicated in Example 1. 319 mg of the expected product are obtained, m.p. from 260 ° C.
Found %: C 62.7; H 8.1; N 6.3; C1 8.0.
With ,,., PS1 (438,999). Calculated,%: C 62.93; H 8.04; N 6.38; C1. 8.07.
EXAMPLE 21 Fumarate C4aRS (4ao, 3o (f, 8aib) (±) 1- (4-bromobenzoyl) decagide) o-8- (1-pyrrolidinyl) quinoline. Similarly, npj4iepy 20, consuming 483 mg of bromobenzene chloride and dissolving the reaction for 22 hours at room temperature, give the crude product as a base, which is converted into fuma-5 rat according to the method indicated in Example 4. 457 mg of the desired product is collected. m.p. 206 s (decomposition).
Found,%: C 56.6; H 6.2; N 5.5; Br 15.6.
, S4P404 (507,434).
Calculated,%: c 56.80: H 6.16; N 5.52; Br 15.74.
EXAMPLE 22 Lumarate 4-K8 (4ao, 8o, 8a) (±) 1- (3,4-dichlorobenzoyl) de- 5 kahydro-8- (1-pyrrolidinyl) quinoline.
Analogously to example 20, consumed 461 mg of 3,4-dichlorobenzonl chloride and Condensing the reaction for 20 hours at room temperature
0
15
With the product as a base, which is converted into fumarate according to the method indicated in Example A. 547 mg of the expected product are collected, m.p. 202 C.
Found,%: C 57.7; H 6.2; N 5.6; C1 14.1.
.C ,, M, 0, (497.423).
Calculated,%: C 57.95; H 6.08; N 5.63; C1 14.25.
EXAMPLE 23 Chlorohydrate f4aRS (, I. /, GaOH (+) 1-C (3,4-dichlorophenyl) acetyl decahydro-8-dimethylamino-quinoline.
159887416
Return to base.
1.237 g of the product obtained is dissolved in 5 cm of water, saturated with sodium chloride, 2 cm 2 n are added. sodium hydroxide, extracted with ether, dried and the solvent removed under reduced pressure. 0.962 g of the expected product is obtained in the form of a base.
Preparation of cis-B isomer
Combine the mother solution of crystallization of the isomer of cis-A hydrochloride and concentrate them to dryness under reduced pressure.
Stage A. M, M-Dimethyl-5,6,7,8-tetra-pressure. The rest is taken
Rahydro-8-quinolinamine.
4.08 g of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride prepared as was stirred for 75 minutes. in example 1, in 20 cm of a 40% aqueous solution of dimethylamine. It is heated for 1 hour at, allowed to cool to room temperature, the reaction medium is mixed with sodium chloride and 0.3 cm 2 n is added. sodium hydroxide. Extracted with ether, washed with water, dried and the solvent was removed under reduced pressure. 3.35 g of the expected product are obtained, which is consumed in this form in the next stage.
Stage B. t4aRS (, By /, .8avO (±) (N, 1-Limethyl decacidro-8-quinolinamine (cis-A isomer) and C4aRS (4arf, 8j9, 8aW) (1) N, N-dimethyl decacidro-8- quinolin-min (cis-B isomer).
Catalytic reduction.
3.35 g of the product obtained in Step L, 33 cm of methanol, 3.3 cm of hydrochloric acid in the presence of 0.37 g of 80% platinum oxide are introduced into the pyrogenation apparatus. Hydrogenated for 7 h at 22-24 s at a pressure of 1840 mbar. Catalysis is filtered 25
10 cm of water, filled with sodium chloride, refined with 2 sodium hydroxide, extracted with efrom, dried and the solvent 20 is removed with reduced pressure. After chromium on silica (eluant ethyl acetate: methanol: triethylamine 85: 10: 5), 384 g of the expected product are collected.
Stage and. Chlorohydrate 4AH5 (4ao,, Val) Kt) 1-C (3,4-dichlorophenyl) ac THTiJ decahydro-8-dimethylaminoquinols 1.160 g of dicyclohexylcarbodium are added to a solution containing 855 g of cis-A isomer as base and 1.160 g 4-dichlorophenylacetic acid in 15 cm of methyl chloride are mixed for 18 hours, the formed urea is removed from the filter, the filtrate is concentrated to dryness under reduced pressure, and the precipitate is taken up in 50 s of ether, washed with sodium bicarbonate, drained with ether, dried and 2.5 g of product is removed. in the form of osn and dissolved in 15 cm of ethane was added 2 cm 5.75 n. eganilose hydrochloric acid solution, given off
thirty
35
40
rinse, concentrate to-45 | Talise for 1 hour, filter and dry the crystals, rinse them with ethanol and then ether, and dry at 50 ° C under reduced pressure. Obtain 1.064 g of the target product, so pl. 5; 256 C.
dry under reduced pressure and obtain 4.85 g of the expected product.
Crystallization of cis-A isomer hydrochloride.
The dry extract is taken in 15 cm of isopropanol, crystallization is seeded, left for 1 hour at room temperature, filtered, the crystals are rinsed with isopropanol and ether, dried under reduced pressure while and after recrystallization in ethanol, 1.27 g of the desired product is obtained in the form of hydrochloride, m.p. .
pressure. The rest is taken
10 cm of water, filled with sodium chloride, refined with 2N. from sodium hydroxide, extracted with ether, dried and the solvent removed under reduced pressure. After chromatography on silica (eluant: ethyl acetate: methanol: triethylamine 85: 10: 5), 384 g of the expected product are collected.
Stage and. Chlorohydrate 4aYa5 (4ао,, Val) Kt) 1-С (3,4-dichlorophenyl) ace-THTiJ decahydro-8-dimethylaminoquinoline. 1.160 g of dicyclohexylcarbodiimide was added to a solution containing 855 g of cis-A isomer as a base and 1.160 g of 3,4-dichlorophenylacetic acid in 15 cm of methylene chloride. The mixture is stirred for 18 hours, the urea formed is removed by filtration, the filtrate is concentrated to dryness under reduced pressure and the precipitate is taken up in 50 cm of ether, washed with aqueous sodium bicarbonate solution, extracted with ether, dried and the solvent is removed under reduced pressure. 2.5 g of the product is collected in the form of a base and dissolved in 15 cm of ethanol, 2 cm of 5.75 N are added. hydrochloric acid solution
| Talizovatsya within 1 h, filtered
crystals are rinsed and dried, rinsed with ethanol, and then with ether, and dried at 50 ° C under reduced pressure. Obtain 1.064 g of the desired product, so pl. 5; 256 C.
Found,%: C 56.1; H 6, .7; N 6.8; SG 25.8.
C „H, jCljN, 0, NS (405,798).
Calculated,%: C 56.24; H 6.70; N 6.90, C1 26.21.
PRI me R. .four. Oxalate 4-K8 (4av, 8 / i, Ya.cho /) 3 (t) 1- (3,4.-dichlorophenyl) acetyl dehydro-8-dimethylaminoxinoline.
ten
15
Similarly to stage B of example 23, starting from 844 mg of the cis-B isomer obtained in stage B of example 23, 2.065 g of product is obtained as the base. 1.22 g of this base and 0.7 g of oxalic acid dihydrate are dissolved in 5 cm of ethanol, filtered, rinsed with ethanol, 30 cm of ether are added to the filtrate, the crystals are sucked off, rinsed with ethanol: ether (1: 3), and then ether and. cyiuaT them under reduced pressure at 70 s. Obtain 1.132 g of the desired oxalate, so pl. 159 C.
Found,%: C 54.8; H 6.0; N 6.9: C1 15.2,
C, (459.373).
Calculated,%: C 54.90; H 6.16; N 6.10; C1 15.44.
EXAMPLE 5 Chlorine hydrate f4aRS (4ао /, 8V, 8al) (1) 1-C (3,4-dichlorophene I) acetyl} decahydro-8- (1-piperidinyl) quinoline.
Stage A. 8- (1-Piperidinyl) -5,6,7, 25 8-tetrahydroquinoline.
3.9 cm of piperidine are introduced into a solution consisting of 2 g of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride in 5 cm of water, stirred for 15 minutes, heated for 2.5 hours at 57t2 G, cooled to room temperature. temperature, saturate the medium with sodium chloride and extracted with ether. The solvent is removed under reduced pressure and 2.07 g of the expected product are obtained.
Stage B.C4aK5 (4ae /,,) 3 (f) Lecahydro-8- (1-piperidinyl) quinoline (and cis-A omer); C4aRS (, 8 / i, 8ао /)
20
thirty
35
ester of acetic acid: methanol: triethyl amine 85: 10: 5). 551 mg of cis-A isomer, 733 mg of cis-B isomer, and 353 mg of trans-A isomer are obtained.
Stage B. 4aYAZ hydrochloride ((, 8c (, 8аоО J (t) 1- С (3,4-dgoslorphenyl) acetyl} decahydro-8- (1-piperidyl) quinoline,
Within 6 hours, 479 mg of 3,4-dichlorophenyl acetic acid is reacted with 467 mg of the cis-A isomer obtained in stage B in 7.2 cm of methylene chloride in the presence of 482 mg of dicyclohexylcarbodiimide. The dicyclohexyl-urea formed is filtered off, the filtrate is concentrated to dryness under reduced pressure, and the residue is taken up in 30 cm of ethyl acetate. The organic layer is washed with an aqueous solution, saturated sodium bicarbonate, and then water, dried, and the solvent is removed under reduced pressure. 1. 117 g of final product is obtained as a base, which is converted into the hydrochloride according to the method indicated in Example 1. 600 mg of the desired product is collected, m.p.
Found,%: C 59.4 | H 7.2; , 2; C1 24.0. CiaHioCliN O, HC1 (445.863).
Calculated,%: C 59.26; H 7.01; N 6.28; C1 23.85.
PRI me R 26. Fumarate 4-K8 (4av ,., 8fwl} J (t) 1- (3,4-dichlorophenyl) acetyl decahydro-8- (1-piperidinyl) quinoline.
Act as in stage B of example 25, use 550 mg of 3,4-dichlorophenylacetic acid and 537 mg of isome (±) decahydro-8- (1-piperidinyl) quinoline dd cis-B, obtained in stage B at- ( isomer cis-B) and (4ao, 8cC, 8afi) j (i) decahydro-8- (1-piperidinyl) quinoline (trans-A isomer).
For 6 hours at a pressure of 1850 mbar and room temperature, hydro- | J5 rat, as in Example 4. 202 mg are collected.
measure 25, and allow to react for 20 h at room temperature. 1.296 g of crude product is obtained in the vi, cent base, which is converted to fumarogenic 1.974 g obtained in stage A,
product, semi- 30 cm of ethanol
target product, so pl. 277 C.
Found,%: C 59.3; H 6.8; N 5.1; C1 13.5.
in the presence of 3 cm hydrochloric acid and 0.2 g of platinum oxide; the catalyst is filtered off, rinsed and. concentrate the filtrate to dryness under reduced pressure. The residue is taken up in 10 cm of water, 12 cm of caustic soda is added, extracted with ethyl acetate, dried and the solvent is removed under reduced pressure. This gives 2.04 g of product, which is chromatographed on silica (eluant is ethyl
0
five
five
0
0
five
ester of acetic acid: methanol: triethyl-amine 85: 10: 5). 551 mg of cis-A isomer, 733 mg of cis-B isomer, and 353 mg of trans-A isomer are obtained.
Stage B. 4aYAZ hydrochloride ((, 8c (, 8аоО J (t) 1- С (3,4-dgoslorphenyl) acetyl} decahydro-8- (1-piperidyl) quinoline,
Within 6 hours, 479 mg of 3,4-dichlorophenyl acetic acid is reacted with 467 mg of the cis-A isomer obtained in stage B in 7.2 cm of methylene chloride in the presence of 482 mg of dicyclohexylcarbodiimide. The dicyclohexyl-urea formed is filtered off, the filtrate is concentrated to dryness under reduced pressure, and the residue is taken up in 30 cm of ethyl acetate. The organic layer is washed with an aqueous solution, saturated sodium bicarbonate, and then water, dried, and the solvent is removed under reduced pressure. 1. 117 g of final product is obtained as a base, which is converted into the hydrochloride according to the method indicated in Example 1. 600 mg of the desired product is collected, m.p.
Found,%: C 59.4 | H 7.2; , 2; C1 24.0. CiaHioCliN O, HC1 (445.863).
Calculated,%: C 59.26; H 7.01; N 6.28; C1 23.85.
PRI me R 26. Fumarate 4-K8 (4av ,., 8fwl} J (t) 1- (3,4-dichlorophenyl) acetyl decahydro-8- (1-piperidinyl) quinoline.
They act as in stage B of example 25, using 550 mg of 3,4-dichlorophenylacetic acid and 537 mg of the cis-B isomer obtained in stage B
Mate, as in example 4. Collect 202 mg
measure 25, and allow to react for 20 h at room temperature. 1.296 g of crude product is obtained in VI, cent base, which is converted to fumarate as in Example 4. 202 mg are collected.
target product, so pl. 277 C.
Found,%: C 59.3; H 6.8; N 5.1; C1 13.5.
CjjHjoCljN O,. (525,177).
Calculated,%: C 59.43; H 6.52; N 5.33; C1 13.49.
PRI me R 27. Bromide C4aRS (4ae, 8oi, 8ac /.). (T) 1 t Cl- (3,4-dichlorophenyl) acetyl} decahydro-8-quinolenyl (1-methyl) pyrrolidini.
A solution containing 401 mg of the product of example 1 as a base in 6 cm of tetrahydrofuran is added to 6 g of methyl bromide. Move 24 hours
nineteen
to
15
at room temperature, sucked off, rinsed with crystallized product using tetrahydrofuran, and then with ether and dried under reduced pressure at 70-80 ° C. Obtain 455 mg of the desired product, so pl. 170 s.
Found,%: C 53.8; H 6.5; N 5.5; C1 13.7; Br 14.9.
,, BrCl-jN O (490.319)
Calculated,%: C 53.89; H 6.37; N 5.71; C1, 14.46; Вг 16,3.
P r i m e p-28. Tablets of the following composition are prepared: the product of example 1 is 200 mg; Excess solvent in sufficient quantity up to 800 mg (lactose, talc, starch, magnesium stearate were used as excipients).
EXAMPLE 29 A dissolved substance is prepared for injection (intramuscularly) of the following composition: product of example 1 50 mg; sterilized solvent c. enough to 5 ml.
Pharmacological study, Contact with opiate receptors K in vitro.
They use membrane precipitates from centrifugation, stored at -30 {; for about 30 days, which are derived from guinea pig cerebellums.
These sediments are introduced into the suspension in Tris buffer solution RP 7.7. Distribute 2 ml fractions into hemolysis tubes and add 1 nM ethyl ketocyclazocine and izueni product. The product was first tested at 5x10-M (3 times). When the test product shifts more than 50% of the radioactivity specifically associated with the receptor, it is re-tested over a range of 7 doses to determine the dose that inhibits the radioactivity specifically associated with the receptor by 50%. In this way, a 50% inhibitory concentration is determined.
25
thirty
.JJ
40
45
The nestingifice bond determines with the addition of the product V - 50488 N at (3 times). Incubated at 25 ° C for 40 min., Set on V
50 solution of acetic acid in water. The dose that drives the syndrome is 0.01 cm / g under these conditions, i.e. 100 mg / kg acetic
at a time of 5 minutes, filtered off. The test product is injected into mice in a vacuum, rinsed through the mouth half an hour before the injection of uksunoic acid on an empty stomach from the eve of the experiment. Sweatings are monitored and counted for - each time for 15 minutes.
Tris buffer solution pH 7.7 and radioactivity counted in the presence of Tritione scintillator.
to
15
m -
20
20
Results are expressed at an inhibitory concentration of 50% (C), i.e. at the concentration of the studied product necessary to translocate 50% of specific radioactivity fixed on the receptor under study:
Approximately 1.5-0, nM
1 g;, 7.
66
79.5
817
1012
11. 6
125.4, 1 227.4
Analgesic activity. A sample of the mountains whose tiles. G-B-females, weighing 22 to 24 g, are placed one by one on a copper plate, maintained at 5b sec: the pain reaction manifests itself in licking. The front paws of animals, the time of this reaction is noted and left only react less than 8s.
Animals are distributed in homogeneous groups and treated with the product being studied (injected subcutaneously), 30 with one group not receiving it. The response time to pain is measured again 30-60 minutes after the administration of the product. The active dose (M) is
a dose that increases the reaction time .J by 100%, 30 minutes after treatment, taking into account changes in the reaction time of control animals. For the product of Example 1, the PA is 20 mg / kg. .
40 Sample sweat givani.
The test used is based on the fact that intraperitoneal injection of acetic acid stimulates repetition of sweating and trrcium in your mouth,
45 can last for more than 6 hours. Painkillers prevent or reduce this syndrome, which can be seen as a manifestation of diffuse abdominal pain. Consume 1%
50 solution of acetic acid in water. The dose that drives the syndrome is 0.01 cm / g under these conditions, i.e. 100 mg / kg acetic
ten
15
Starting immediately after acetic acid injection.
Results are expressed by DA ,. i.e. the dose that allows you to get a 50% reduction in the number of sweats 5 in relation to the control animals:
Example MjT), mg / kg 118
621
820
Antiarrhythmic effect in rats.
Anaesthetized with 1.20 g / kg urethane intraperitoneally, rats sam-15-1 weighing 300-350 g undergo a tracheotomy and artificial respiration (40-50 infusions of 3 ml / min). A needle is inserted under the skin so as to record - an electrocardiogram of rats on the response of signal 20 of signal D11.
The test products are administered by the intravenous route. Five minutes after the product was injected, the rat's vein of the rats was perfused with 10 µg / ml 25 x 0.2 MP aconitrin solution and the time of appearance of the heart rhythm disorder was noted.
The results are expressed as a percentage of the lengthening time for the seizure of the cardiac rhythm system in relation to the control and depending on the dose of the studied product. The data are given in table. one.
Test of asphyxial anoxia.
The study is conducted on male rats (Charles River CD) weighing 250–300 g, anesthetized with ether, tracheotomized, paralyzed with d-tubocurarine chlorhydrate (0.5 mg / kg IV) and subjected to artificial respiration with a mixture of 70% nitrous oxide nitrogen and 30% oxygen. The body temperature is maintained at 37 ° C with an automatic temperature control device. Two silver and silver chloride electrodes are implanted on the skull box and fortified with dental cement into the areas of the visual cortex and cerebellum for recording the electroencephalogram (EEG). A catheter is guided through one common carotid artery to record blood pressure and heart rate. The values of pap, pASO and pH are measured to noxia, and the frequency of the respiratory pump is adjusted to obtain normal values. Anoxia is carried out using a breathing pump according to the technique written by I. Rosner, J. Legros and C. Beau
45
50
55
ten
15
five
20
25
-jn

40
45
50
five
her. After 3 minutes, the breathing pump starts up again and the ventilation is removed for another 30 minutes.
Before anoxia, at the end of anoxia, and after 2.10 and 30 minutes after the start of ventilation, an EEG is recorded on an encephalograph, and the EEG power spectra are analyzed on a POP 11/34 digital computer. During EEG recording, measures are taken to avoid visual and auditory stimulation. Five periods of 10 s each minute are selected by visual control to avoid artifact, the analysis is carried out by Fourier transform. The power spectrum is measured between 0 and 25 Hz with a resolution of 0.2 Hz,
The test product is dissolved in Metocel (0.5%) and administered intravenously at 1 and 5 mg / kg 3 minutes before the pump stops. The values of the pAO, PASO and RP were re-measured 30 minutes after anoxia. Mean arterial pressure (s.a.d.) and cardiac frequency (c.p.) are recorded. The experiments were carried out in groups of 10 animals.
The results of the spectral analysis of the electroencephalogram of rats anesthetized for 3 min after suffocating anoxia are given in table. 2. The total power and energies of different frequency bands are expressed as a percentage of those recorded during the control before anoxia. Standard deviations are given to indicate data dispersion. The Mann Whitney II test is used to calculate the degree of difference between No. 1 between the control (physiological sodium chloride solution) and the treated group (, 05; PO, 05j P: 0.01).
The introduction of the proposed product intravenously at a dose of 5 mg / kg provides a good premature recovery of electrocortical activity in all frequency bands. 30 minutes after anoxia, the different polo values from the frequency of the treated group (5 mg / kg) are almost equal to the base values, while in the control group a significant slow component (the delta band) continues, which indicates still suffering of the brain. Even with a dose of 1 mg / kg, premature recovery of electrocortical activity is observed, while the effect on the normalization of the path is more obvious. Indeed, every 30 minutes after the end of anoxia is sign
ten
15
20
The delta band is approximately double the base.
Test.sheated plate. Females with a weight of 22-24 g are placed one by one on a copper plate maintained at 56 ° C: the reaction to pain occurs in the front paws licking to animals, the time of this reaction is noted and only -,
mishy, peggypyyyu9 e less than 8 s.
Animals are divided into homogeneous groups and treated with the test product administered orally, one group receives only excipient. The pain response time is measured again 30–60 minutes after treatment. An effective dose or ED ... is a dose that increases the reaction time by 100% after 30 minutes
after treatment, taking into account the deviations from the reaction time of the control animals.
1 foo of the product of example 1, composition - 5 ls 50 mg / kg, E: paracetamol 300 mg / kg.
Test for analgesia on inflamed tissues (a variant of the method of Randall and Selitta. Method for measurement of anal, eti.c on inflammed tissue. - Arch. Int. Pharmacodyn, 1957, III, 409).
The method consists in finding an anapic effect in the rat, the threshold of sensitivity to pain is reduced by inflammation, occurring in a la. injection of carragenin (0.25 mg) under the plantar aponeurosis of the hind paw. Pain is caused by mechanical pressure applied to the dorsal surface of the paw and regularly increased with an analgesimeter. The pain threshold is defined. divided by the pressure required to initiate the paw withdrawal reaction or the animal's beep response. The products are administered orally 4 hours after the injection of the stimulus, measurements of the pain sensitivity threshold are made immediately before the injection of the irritant, then 1 hour after the treatment.
Determine the dose that will increase
24
analog agonists, preferably attached to the most chemically close receptor-K.
The latest is the Upjohn product known under the code U-50488, which has excellent affinity for the k receptor and weak fixation on the p receptor.
The receptor / is an opiate receptor that does not cause addiction, as opposed to receptor f, which is better affected by morphine analgesic derivatives, which lead to addiction and respiratory depression.
Using the proposed compounds, one can find analgesic selective, K agonists, devoid of the usual side effects of opiate products.
The results show that the product of example 14 has an affinity comparable to that for the receptors, with an affinity for the Upjohn analog product, but less attached to the receptor 14 than the analog product.
K agonists have other properties, in particular anti-ischemic.
In addition, comparative results show that the product of Example 1 is more active than the analogue product in the cerebral ischemia test caused by clogged arteries.
The product Upjohn and-50488 has the following 2 structural formula:
CH3, N-CO-CH 30
45
50
U h
in
t
Link to the opiate receptor and vitro.
Use membrane residues stored for about 30 days and obtained from the brain of rats.
These residues are suspended in a pH 7.7 buffer solution. Fractions of 2 MP are distributed in hemolysis tubes and 0.7 nM 1, 3N-dihydromorphine and the product to be studied are added. Products are first tested at 5x10-11 (three times). When tested, the threshold is 50% after 60 minutes. ED ,, GGr ";, ;;.
On the whole, EO /, radioactive
nnnnvTCTa grp rrnutvfontr 1 gt t -papot p / pial i ivice
the product of example 1 is 20 mg / kg, ED.d. of paracetamol 200 mg / k1 Comparative results; of the compounds and products specifically bound to the receptor, they are again tested in the range of 7 doses in order to determine the dose that absorbs 50% of the radioactivity.
a24
ten
15
0
- five
Q
analog agonists, preferably attached to the most chemically close receptor-K.
The last is the product Upjohn, known under the code U-50488, which has excellent affinity for the receptor k and weak fixation on the receptor p.
The receptor / is an opiate receptor that does not cause addiction, as opposed to the f receptor, on which morphine analgesic derivatives are better, leading to addiction and respiratory depression.
Using the proposed compounds, one can find analgesic selective, K agonists, devoid of the usual side effects of opiate products.
The results show that the product of example 14 has an affinity comparable to that for the receptors, with an affinity for the Upjohn analog product, but less attached to the receptor 14 than the analog product.
K agonists have other properties, in particular anti-ischemic.
In addition, comparative results show that the product of Example 1 is more active than the analogue product in the cerebral ischemia test caused by clogged arteries.
The product Upjohn and-50488 has the following structural formula:
CH3, N-CO-CH 0
five
0
U h
in
t
Link to the opiate receptor and vitro.
Use membrane residues stored for about 30 days and obtained from the brain of rats.
These residues are suspended in a pH 7.7 buffer solution. Fractions of 2 MP are distributed in hemolysis tubes and 0.7 nM 1, 3N-dihydromorphine and the product to be studied are added. Products are first tested at 5x10-11 (three times). When tested products GGy ";, ;;.
ioremeg ayut oOL eO /, radioactive
i ivnis
These receptor-specific receptors are again tested in the range of 7 doses to determine the dose that will absorb 50% of the radioactivity.
25
to
20
25
specifically bound to the receptor. In this way, an inhibitory concentration of 50% is determined.
A non-specific bond is determined by adding morphine at (three times). Incubate at 25 seconds for 40 minutes, place for 5 minutes in a bath at 0 ° C, filter under vacuum, rinse with Tris buffer solution, pH 7.7, and calculate radioactivity in the presence of Trition blinks.
The results are expressed in inhibitory concentration of 50% (,), i.e. at the concentration of the investigated product, J5 is required to transport 50% of the specific radioactivity attached to the receptor studied. CI.,. . nM :.
Product and-50488 1541
The product according to example 142100
Link to the opiate receptor C in vitro.
Membrane residues, stored at -30 ° C for about 30 days and obtained from the cerebellum of guinea pigs, are used.
These residues are suspended in Tris pH 7.7 buffer solution. Distribute 2 ml fractions in hemolysis tubes and add 1 nM 9 N ethyl ketocyclazocine and the test product. Products are first tested at 5 x 10 M (three times). When the products tested move more than 50% of the radioactivity specifically bound to the receptor, they are tested again in a range of 7 doses to determine a dose that inhibits 50% of the radioactivity specifically bound to the receptor. In this way, an inhibitory concentration of 50% is determined.
The non-specific bond is determined by adding the product U-50488 at (three times). Incubated at 25 ° C for 40 minutes, placed in a bath for 5 minutes, filtered under vacuum, washed with Tris buffer solution 7.7, and radioactivity is counted in the presence of Trition blinks.
Results are expressed at an inhibitory concentration of 50% (CIso) i.e. in the concentration of .studied product needed to move 50% of the speEO
35
45
50
55
digital radioactivity fixed at the studied receptor. CIj, nM:
Product and-504884.4

to
20
25

J5
-.

EO
35
45
50
26
The product according to example 144.1. Anti-inflammatory activity. Cerebral ischemia is induced in rats of the Fischer family weighing 130-160 g by irreversible blockage of the left carotid artery and blockage of the right carotid artery for 4 hours. Under these conditions, the prevailing 18% (3/17). (Pretreatment (60 min) with the product I-50488 at a dose of 30 mg / kg IP brings this percentage to 72% (13/18). When used under the same conditions of the product as in example 1, all animals survive (18/18) .
The difference between the two treatments is very close to exponential (x2 3.71):
, 05, if 84.
Measurement of diuretic activity.
Males of rats of the Sprague Dawley family weighing 180-300 g do not give food for 17 hours before the experiment, but give Water ad libitum.
In the experimental group of 8 animals. The rats receive the test product or its carrier by the oral route.
Urine volume is measured every hour for 2 hours after product administration. At the end of this period, urine is collected, and the activity of the product is expressed as the percentage change in urinary volume5 corresponding to the period t -t. With the introduction of the product of example 1 at a dose of 1 mg / kg, an increase in urinary volume is 74%.
Acute toxicity study.
The lethal doses of the DL of the various compounds tested are evaluated after the oral administration of the medication. Under the Sh. Understand the maximum dose, not vyzhsayayu- mortality in 8 days. For the proposed DL products, mg / kg, then:
Example
1210
3200
4100 8 100
Invention Formula
1. A method for producing decahydroquinoline derivatives of the general formula
R, and R A xi N N I
/
I
Z (I)
are the same and are Cf-C alkyl or R, and Rj form together with the nitrogen atbm to which they are bound, a 5- or 6-membered heterocycle; chain (CH) p, where n-0-З,
SI
3
Z is a phenyl radical which may be substituted by one or more substituents such as halogen, trifluoromethyl, nitro, alkoxy or alkyl, naphthyl, pyridinyl, indolyl, thienyl or benzothienyl, J
their enantiomers, -; diastereoisome- or their additive salts with a sour, O, differently, 8-chloro-5,6,7,8-tetrahydroquinoline formula
g
TO
C1
(Ii)
subjected to interaction with the amine of the formula
/.
(Iii)
where RI and R-I are as defined, to give a compound of the formula
ten
five
2.5
one
2.5

权利要求:
Claims (2)
[1]
one
(
N
N,
(Iv)
which is reduced to give 10 compounds of the formula
N I -N N /
Ri RI
h /
(V)
where R / and R have the indicated meanings, and which is condensed with a compound of the formula (VI) or with a functional derivative of this compound:
soon
2
where A and Z have the indicated meanings, with isolation of the desired product as enantiomerone, diastereoisomers or salts with inorganic or organic acids.
[2]
2. The method according to claim 1, which is also distinguished by the fact that, to obtain trans isomers, the reduction of compounds of formula (IV) is carried out chemically under a pressure of 250-300 mm Hg. in the presence of metallic sodium, and catalytic reduction is impaired to produce cis isomers.
Table 1
+113.5 +56.5 + 31.5 + 17.5
+ 182 +93, 05. , 001 (Whitney's test and)

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同族专利:

公开号 | 公开日

DE3777852D1|1992-05-07|

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PT84091B|1989-07-31|

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AU597326B2|1990-05-31|

FR2592879B1|1988-04-29|

DK12087A|1987-07-14|

GR3004250T3|1993-03-31|

FR2592879A1|1987-07-17|

JPS62167767A|1987-07-24|

ES2037098T3|1993-06-16|

EP0233793A3|1989-04-19|

DK12087D0|1987-01-12|

JPH07116156B2|1995-12-13|

EP0233793A2|1987-08-26|

EP0233793B1|1992-04-01|

US4816465A|1989-03-28|

AU6747687A|1987-07-16|

ZA8742B|1988-03-30|

IE59794B1|1994-04-06|

HUT43570A|1987-11-30|

PT84091A|1987-02-01|

HU196593B|1988-12-28|

DK168068B1|1994-01-31|

CA1282784C|1991-04-09|

AT74352T|1992-04-15|

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DE3633977A1|1986-10-06|1988-04-07|Cassella Ag|TETRAHYDROQUINOL DERIVATIVES, A METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

FR8600354A|FR2592879B1|1986-01-13|1986-01-13|NOVEL DECAHYDROQUINOLEIN DERIVATIVES, PROCESS FOR THEIR PREPARATION, PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS AND COMPOSITIONS CONTAINING THEM|

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