Method of producing carbostyryl derivatives

专利摘要:
Novel carbostyril derivatives and their pharmaceutically acceptable salts. The carbostyril derivatives are represented by the general formula (1): <IMAGE> (1) wherein R1, A, B, l, and Z are as defined herein. These compounds possess antihistaminic and central nervous system controlling effects.
公开号:SU1367857A3
申请号:SU813257001
申请日:1981-03-04
公开日:1988-01-15
发明作者:Банно Казуо；Фудзиока Такафуми；Осаки Масааки；Накагава Казуюки
申请人:Оцука Фармасьютикал Ко,Лтд (Фирма)；
IPC主号:

专利说明:

where R is a hydrogen atom, a lower alkyl: group, a phenyl-lower alkyl group, a lower alkenyl group, a lower alkynyl group; A - group С 0, CH) - OH or R, R,
-CHI -C-CHj-CH- where Rj is a hydrogen atom, a lower alkynyl group;
- possible carbon-carbon bond,
B is a lower alkylene-a group;
1 to 1, if A is a group;: C O or CH-OH or or 1,
R is a phenyl or is substituted by a phenyl group containing as a substituent a halogen atom, a lower alkyl group, a lower alkoxy group, or Ry is a fesch-lower alkyl group, a lower alkyl group or a group of the formula
or rj. - hydrogen atom, ok sygroup, lower alkanoyl.
if R is a hydrogen atom, the carbon-carbon bond in the 3,4-piperidine ring position can be double, and if RJ is a hydrogen atom, the carbon-carbon bond in position 3,4 of the carostyryl skeleton is is simple
The connection is that
formulas
A- (8) j, -X
 ".
. Where R, A, B, 1, have the indicated
value; X is a halogen atom,
subjected to interaction with the compound of the General formula
HN
ABOUT
where Z has the indicated values, at a temperature ranging from room temperature to a subsequent generation of the desired products, ll ri or test.
03/06.80 A - group - C- or) CH-OH
/ I
ABOUT
RJ - all values except phenyl-lower alkyl group, 08/20/80. A.- group
one
This invention relates to a process for the preparation of new carbostille derivatives with general formulas.
(LL
A- (B) - N () Z
de R / is a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkenyl group, a lower alkynyl group; group С О,; CH-OH or R.
And I
RO
, -CH, 2-CH- where R is a hydrogen atom, a lower alkyl group;
carbon-carbon bond;
lower alkylene group; 1, if A is a group x C O or), or or 1 if A is a group or
R,
(R,
7
 N-R group, where RT, is fe0
five
0
five
nilna substituted or the phenyl group having as from 1 to 3 substituents of halogen atom, low boiling alkoksigrulpu, a lower alkoxycarbonyl group, a lower alkyl group, a carboxyl group, a lower alkanoyl group, a lower alkiltnogruppu, the hydroxyl, cyano or nitroamino or a lower alkylenedioxy, phenyl lower alkyl, 1,2,3,4-tetrahydronaphthyl group, or
Z is a group where
 five
R is a phenyl or substituted phenyl group containing, as a substituent, a halogen atom, a lower alkyl group, a lower alkoxy group, or an R 5 phenyl lower alkyl group, a lower alkyl group or a group of the formula
thirty
or Rj is a hydrogen atom, an oxigroup, a lower alkanoyl, in case R; - hydrogen atom, carbon-carbon. the bond at the 3,4-piperidine ring position can be double, and the carbon-carbon bond at the 3,4-position of the boiling-hair skeleton is simple,
possessing antihistamine properties and the ability to regulate the activity of the central nervous system.
The purpose of the invention is to obtain new carbostyril derivatives, which have pharmacological advantages over their known structural analogues.
Example 1. 120 ml of chlorooxabutyl chloride and 160 g of pulverized anhydrous aluminum chloride are suspended in 300 ml of carbon disulfide. The suspension is heated to reflux. Another suspension of 29.4 g of 3,4-dihydrocarbostyril in 100 ml of carbon disulfide is added dropwise to the first suspension in 1 hour, after which the reaction is carried out for 4 hours at reflux. After completion of the reaction, the reaction mixture is poured into ice water and the resulting precipitate is collected by filtration, washed with water and ether. The washed residue is recrystallized from acetone to yield 25.5 g of 6- (4-chloro-1-oxobutyl) -3,4-dihydrocarbostyril as yellow needle-like crystals. M.p. 158-160 S.
Example 2. Analogously to Example 1, 6-chloroacetyl-carbostyryl is obtained in the form of colorless needle-like crystals. Mp 233-234 ° C (from methanol / chloroform).
Example 3. Analogously to Example 1, 1-methyl-6- (3-chloropropionyl) -3,4-dihydrocarbostyryl is obtained in the form of colorless needle-like crystals 121-123 0 (from isopropano
ten
15
20
25
temperature methanol is distilled off under reduced pressure. The residue is extracted with chloroform, the chloroform layer is washed with water and dried. The chlorine of the forms is distilled off under a pony ;;, enan dal dii of the scientific research institute, the obtained residue is cross-tized from an ethanol-water mixture until obtaining 1.2 g of 6- (1-hydroxy-4-chlorobutyl) -3,4- dihydrocarbostyril in the form of colorless needle-like crystals. M.p. 120-121 ° C.
Example 5. 4.0 g of 6- (4-hlop) -l-oxybuty (3) -3,4-dhydrocarboxylate is placed in 200 ml of methanol, the resulting suspension is stirred at room temperature. 2.0 g of sodium borohydride are gradually added to the suspension and the reaction is carried out for another 1 hour. Then 3 ml of concentrated hydrochloric acid is added to the reaction mixture, the mixture is concentrated under reduced pressure at reflux to obtain the residue, which is extracted with chloroform, the chloroform layer is washed with water and then dried. Chloroform is distilled off under reduced pressure to give a residue, which is recrystallized from ethanol to obtain 2.4 g of 6- (4-chloro-1-butene) -3,4-dihydro-borate in the form of yellow needle-like crystals. M.p. 153-155 ° C.
Example 6. 14.4 hz, 4-dihydrocarbostyril and 10 g of butyrolactone are mixed with 120 g of polyphosphoric acid and stirred at 80–90 ° C for 10 hours. Then the reaction
The 40 mixture was poured into 300 ml of ice water and left overnight. The precipitate thus obtained is collected by filtration and washed with water, and recrystallized from ethanol-ethyl acetate.
45 to obtain 9.5 g of 6- (4-hydroxy-1-oxobutyl) -3,4-dihydrocarbostyril with m.p. 175-176 0 in the form of colorless prism-like crystals. 5 g of 6- (4- -oxo-1-oxobutyl) -3,4-dihydrocarbosteryl and 0.5 g of palladium black are mixed in 160 ml of ethanol, the mixture is subjected to catalytic reduction in gaseous water 3 kg / cm- at 60 ° WITH
thirty
35
50
fishing m.p. la)
Example .4. 2.0 g of 6- (1-oxo-4-chlorobutyl) -3,4-dihydrocarbostyril is mixed with 100 ml of methanol, the mixture is stirred at gg rooms for 6 hours. The reaction mixture is cooled to ambient temperature. Then gradually add to the cake and 1 ml of a concentrated mixture is added, 1.0 g of sodium borohydride is added. After stirring the reaction mixture for 2 hours at room temperature
kind of pressure
hydrochloric acid, then subjected to catalytic reduction under hydrogen gas pressure
0
five
0
five
temperature methanol is distilled off under reduced pressure. The residue is extracted with chloroform, the chloroform layer is washed with water and dried. The chlorine of the forms is distilled off under a pony ;;, enan dal dii of the scientific research institute, the obtained residue is cross-tized from an ethanol-water mixture until obtaining 1.2 g of 6- (1-hydroxy-4-chlorobutyl) -3,4- dihydrocarbostyril in the form of colorless needle-like crystals. M.p. 120-121 ° C.
Example 5. 4.0 g of 6- (4-hlop) -l-oxybuty (3) -3,4-dhydrocarboxylate is placed in 200 ml of methanol, the resulting suspension is stirred at room temperature. 2.0 g of sodium borohydride are gradually added to the suspension and the reaction is carried out for another 1 hour. Then 3 ml of concentrated hydrochloric acid is added to the reaction mixture, the mixture is concentrated under reduced pressure at reflux to obtain the residue, which is extracted with chloroform, the chloroform layer is washed with water and then dried. Chloroform is distilled off under reduced pressure to give a residue, which is recrystallized from ethanol to obtain 2.4 g of 6- (4-chloro-1-butene) -3,4-dihydro-borate in the form of yellow needle-like crystals. M.p. 153-155 ° C.
Example 6. 14.4 hz, 4-dihydrocarbostyril and 10 g of butyrolactone are mixed with 120 g of polyphosphoric acid and stirred at 80–90 ° C for 10 hours. Then the reaction
The mixture was poured into 300 ml of ice water and left overnight. The precipitate thus obtained is collected by filtration and washed with water, and recrystallized from ethanol-ethyl acetate.
5 to give 9.5 g of 6- (4-hydroxy-1-oxo-butyl) -3,4-dihydrocarbostyril with mp. 175-176 0 in the form of colorless prism-like crystals. 5 g of 6- (4- -oxo-1-oxobutyl) -3,4-dihydrocarbosteryl and 0.5 g of palladium black are mixed in 160 ml of ethanol, the mixture is subjected to catalytic reduction in gaseous water 3 kg / cm- at 60 ° WITH
0
five
0
g for 6 h. The reaction mixture is cooled and 1 ml of concentrated
kind of pressure
within 6 hours. The reaction mixture is cooled and 1 ml of concentrated
hydrochloric acid, then subjected to catalytic reduction under hydrogen gas pressure
of aluminum chloride, 6 g of sodium chloride and 6 g of potassium chloride are mixed, the mixture is melted, heating and stirring at 150-170 ° C for 1 h, then drank into ice water and. is left overnight until a crystalline precipitate is obtained. The precipitate is collected by filtration, washed with water and dried, resulting in 12 g of 6 ™ hydroxy-74 (3-chloropropionyl) -354 dihydrocarburil as white after recrystallization from methanol. crystals, So pl. 205-208 ° C.
3 kg / cm is filtered off and the mother liquor is concentrated under reduced pressure. The residue is recrystallized from ligroin to yield 3.2 g of 6 (4-β-butyl) -3,4-dihydrocarboxyryl with Mp = 133-134 ° C, then 3.2 g of 6- (4- - oxybutyl) - 354-dihydrocarbostyril and 5 ml of thionyl chloride are admixed to 50 ml of chloroform, the mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated under reduced pressure, the residue is recrystallized from ligroin to obtain 1.8 g 6 (4- - chlorbutyl) -3,4-dihydrocarbostyril with T. mp, 119 121 C as colorless prism-like crystals.
Example 7, 2.5 g of b (4-chlor-1-butenyl) of 3,4-dihydrocarbostyril and 25.3 g of DCX (2h3 dichloro 5.6 dicyano-benzoquinone) are mixed in 160 ml of ocean and the mixture is heated under reflux heating up for 6h. 1.1 g of DDH are added to the reaction mixture and the mixture is heated to reflux for 3 hours. The reaction mixture is cooled, the precipitate formed is filtered, and the mother liquor is concentrated under reduced pressure to give a residue. The latter is dissolved in a mixture of 100 ml of chloroform with 5 ml of methanol and this solution is passed through a silica gel column to remove unreacted DCX. The residue is recrystallized from methanol to obtain 1.6 g of 6- (4- -chloro-1-™ butensh1) -carbostyril as yellow needle-like crystals. Mp 215-218 ° C.
Example 8. 20 g of b-C / 3-chloro-propionyloxy) -3,4-dihydrocarb istril, 60 g of pulverized anhydrous


ten
15
20
25
35
40
gQ,
N
zo
.
3678576
Calculated,%: C, 56.82; H 4.77; 5.52.
C ,, - H ,, OjNCl (253,69)
Found,%: C 56.98; H 4.51; N 5.44.
Example 9. 5.06 g (3 chloropropionyl) -3,4-dihydrocarbostyryl and 1.8 g anhydrous pyridine are mixed with 50 ml of dimethylformamide. The mixture was cooled with ice, 2.5 g of methylene sulfonyl chloride was added to it and stirred at room temperature for 3 hours. The reaction.-Mixture was then poured into 100 ml of saturated aqueous sodium chloride solution and extracted with chloroform. The chloroform layer is washed with water, dried and the chloroform is removed by distillation under reduced pressure to obtain a residue. After adding 80 ml of hexane to this residue, crude crystals are collected, which are collected by filtration and recrystallized from ethanol to obtain 4.5 g of 6-methylsulfonyloxy-7- (3-chloropropionyl) -3,4-dihydrocarbostyril as white crystals.
Calculated,%: C, 47.06; H 4.25, - 4 22.
C.jHi OjSNCl (331.78)
Found,%: C 47.33; H 4.02; . 4.19.
Example 10. 3.0 g of 6-methylsulfonyloxy-7- (3-chloropropopyonyl) -3,4-dihydrocarbostyril and 0.5 g of NajT-ladium black are suspended in 200 ml of ethanol and catalytic reduction of this suspension is carried out at room temperature and pressure of gaseous hydrogen and 3 atm. for 5 hours. The reaction mixture is then filtered and the mother liquor is concentrated under reduced pressure until a residue is obtained. The latter is recrystallized from ethanol to obtain 1.2 g of 7- (3-chloropropionyl) -3,4-dihydrocarbostyril as a colorless crystalline powder. M.p. 159-61 ° C.
Calculated,%: C 60.64; H 5.09; 5.89.
N
N
. (237.69)
Found,%; C, 60.59; H 5.24; N 5.91.
Example 11. Analogously to Example 8 using 6 acetyloxy-3,4-β-dihydrocarbostyryl as starting material, 6-hydroxy-
7-acetogene-3,4-dihydrocarbostyryl in the form of light yellow-green needle-shaped crystals, tggs. 253 ° C.
Example 12. Similarly to Example 9, using 6 hydroxy-7-acetyl-3,4-β-dihydrocarbostyryl as the starting material, 6-methylsulfonicloxy-7-acetyl-3,4-dihydrocarbostyryl was obtained as colorless pigments. - Loob-shaped crystals, so pl. 219 - 221 C.
Example 13. Analogously to Example 10, using b-methylsulfonyloxy-7-acetyl-3,4-dihydrocarbostyryl as a starting material, 7-acetyl-3,4-dihydrocarbostyryl is obtained in the form of colorless needle-like crystals, mp. 177-179 ° C.
Example 14 9.45 g of 7-acetyl-3,4-dihydrocarbostyril was dissolved in 30 ml of glacial acetic acid with stirring, then a mixture of 2.6 ml of bromine was added dropwise with 10 ml of glacial acetic acid at room temperature. temperature for 30 minutes with stirring. The reaction mixture is cooled with ice to precipitate crystals, and then recrystallize from a 50% aqueous solution of ethanol to obtain 7c / -bromo-acetyl-2,4-dihydrocarbostyril as colorless needle-like crystals. Yield 9.4 g, m.p. 202-203 S.
Calculated,%: C 49.28; H 3.76; N 5.22.
WITH
Found,%: C-49.24; H 3.79; N 5.18.
Example 15. 5.0 g of 6- (1-oxo-chlorobutyl) -3,4-dihydrocarbostyril and .3.5 g of sodium iodide are mixed in 100 ml of acetone and the resulting mixture is stirred at 40-50 for 5 hours. Then 80 ml of dimethylformamide are added to the mixture and the acetone is removed from the mixture by distillation under reduced pressure. 5.0 g of 4-phenylpiperazine and 5 g of triethylamine are added to this reaction mixture, after which it is stirred at 70-80 ° C for 6 hours.
The reaction mixture is concentrated under reduced pressure and, with stirring, 50 ml of 5% sodium bicarbonate solution is added to it in order to induce crystallization. The crude crystals thus obtained are collected by filtration, washed with water and dried. Dried up
.. (268.11)
the crude crystals are dispersed in 80 ml of chloroform and stirred at room temperature for 1 hour. A portion insoluble in chloroform is separated from the solution and the chloroform is removed by distillation to obtain a residue. 50 ml of methanol and 10 ml of concentrated hydrochloric acid are added to the resulting residue. the mixture is concentrated to dryness under reduced pressure. 50 ml of acetone is added to the obtained residue and stirred to obtain crude crystals. The latter are collected by filtration and crystallized with acetone, then recrystallized from ethanol-water and to obtain 5.7 g of 6-1-oxo-4- (4-phenyl -1 -1 piperazinyl) butyl 3,4-dihydro - carbostyryl monohydrochloride in the form of a yellowish crystalline powder. mp. 195-196 S.
Calculated,%: C, 66.74; H 6.82; N. 10.15.
, gO, NjCl
Found,%: C, 66.83; H 6.60; N 10.23.
Analogously to Example 1, using the appropriate starting materials, the following compounds are prepared.
Example 16. 6- {-Oxo-3- 4 - (3-chlorophenyl) -1-piperazinyl-propyl-3,4-dihydrocarbostyryl monohydrochloride. Colorless needle-shaped crystals (from a mixture of ethanol - water). M.p. 233-234 0 (with decomposition).
Example 17. 6- {1-Oxo-4- 4- - (2-chlorophenyl) -1-PNPA and ZINYL-U util-3,4-dihydrocarbostyryl monohydrochloride monohydrate. Colorless needle-like crystals (out of water). M.p. 266 - (with decomposition).
Example 18, 6-fl-OKCO-4- 4- - (2-ethoxyphenyl) - -piperazinyl} -butyl-3, 4-dihydrocarbostyryl-mono hydrochloride. Colorless needle-shaped crystals (from a mixture of ethanol - water), So pl. 240-241 ° C (with decomposition) about
Example 19. 6-1-Oxo-4 (4-methylphenyl) -1-piperazinyl-propyl 1-3,4-dihydrocarbostyryl monohydrochloride. Light yellowish needle-shaped crystals (from a mixture of ethanol and water). M.p. 224-226 ° C.
Example 20. 2.4 g of 6- (1-oxy-3-chloropropyl) -3,4-dihydrocarbyl reel and 1.6 g of sodium iodide are mixed with 60 ml of isopropanol, the mixture is stirred at 50-40 ° C in those-
9136785710
2 hours. Then to this reactive sodium bicarbonate solution,
mixtures were added 2.0 g of 4-phenylpiperazine and 3, O g of DBC (1.5 diazabicyclo 5.4 0 undecane 5) and heated to reflux for 6 hours. Then the reaction mixture was added and ml of a 5% aqueous solution of sodium bicarbonate and stirred at room temperature for 1 hour. The insoluble part is collected by filtration, washed with water and dried, then recrystallized from methanol-chloroform to obtain
nie)
Calculated, -%: C 67.35; H 7.07; N 9.82.
 С, 4НзоОа ЗС1
Found,%: C 67.36; H 6.95; N 9.80. .
Example 26. Similarly to Example 25, .6-1-oco 4 - G4- (3.5-
then water twice and dried over anhydrous sodium sulfate, then the chloroform is removed by distillation to obtain a residue. To the resulting residue is added a mixture of ether and hexane, the insoluble part is collected by filtration and the concentrated hydrochloric acid-ethanol-water is recrystallized from 10 mixture to obtain 2.6 g 6 {oxo-1-3 - 4- (2,3-dimethyl - phenyl) -1-piperazinyl-propyl} -3,4- -dihydrocarbos thyrsht-monohydrochloride 1.92 g of 6-G1-oxo-3 (4-phenylpiperazi 15 in the form of colorless needle-like crystal.) propyl 3,4- dihydrocarbohydrate in tally. M.p. 273-274 ° С (with decomposition of the form of colorless flakes. So pl., 196-197 ° C. ...
Calculated,%: C, 72.70; H 6.93 N 11.56. .20
CliH ,, 0, N3.
Found,%: C 72.52; H 7.08; N11.81.
In analogy to Example 20, using the appropriate starting materials, 25 dichlorophenyl) -1-piperazinyl-butyl}, the compounds of Examples 21-24 are prepared. 3,4-dihydrocarbostyril. Colorless
Example 21. 6-p. -Oxo-3-4-needle-like crystals (from isoprop- - (2-fluorofensch1) -1 piperazinyl-propanol). M.p. 194-195 ° C. drank | -3,4-dihydrocarbostyril. Colorless ° -. Example 27. 3.0 g of 6- (1-oxo crystalline powder (from mixtures of 30 -2-bromoethyl) -3,4-dihydrocarbostyril and dimethylformamide - water). M.p. and 5.5 g of 4- (3-chlorophenyl) piperazine 200-201 C. Disperse in 50 ml of dioxane .. and semi
Example 22. 6-1-oxo 4-part dispersion is stirred at - (4-bromophenyl) -1-piperazi1 Chl -bu 50 ° C for 5 h. Then, the reaction, 4-dihydrocarbostyryl. The colorless mixture is cooled, insoluble needle-like crystals (from the mixture, some of the reaction mixture is removed, ethanol is water). T; pl, 184-185 ° C. and dioxane mother liquor is
Example 23, 6- 1-Oxo-4-center under reduced pressure -G4- (4-nitrophenyl) -1-piperazinyl - to dryness. Add to the dried α-butyl-3,4-dihydrocarbostyryl. Yellow solid 80 ml of ether for token needle-like crystals (from go to cause crystallization, mixtures of dimethylformamide - water). M.p. The crude crystals obtained were pere- 255-256 ° C (with decomposition). The dioxane was recrystallized from the mixture. Example 24. 6-1-Oxo-4-G4-water to obtain 3.1 g 6-1-oxo 2- - (ztoxycarbonylphenyl) -1-piperazinsh1 45 (3-g Slorphenyl) - -piperazinsh1 - -butyl-3,4-dihydrocarbostyryl. Bes-ethnyl-3,4-dihydrocarbostyril into needle-like crystals (from de light yellow needle-like crystal ethanol). M.p. 191-192 S. tallov. M.p. 214-215 C.
Example 25 2.4 g of 6- (1 oxo-Calculated,%: C 65.96; H, 5.61; -3-chloropropyl) -3,4-dihydrocarbyl; 50 N 10.81.
WITH.
Found,%; C 65.96; H 5.61; N 10.81.
Analogously to example 27, using
and 4.5 g of 4 (2,3-dmethylphenyl) -nipersin is mixed with 80 ml of xyloyl and the resulting mixture is refluxed for 24 hours.
Then the reaction mixture is concentrated with the appropriate starting materials, under reduced pressure, to dryness. The compounds of Examples 28-30 are prepared. The resulting solid is dissolved by Dr M and R 28. 6 {1-Oxo-2-G4
(2,3-Dimethylfvnil) -piperazinyl-α-ethyl} -carbostyryl. Colorless needle
in 100 ml of chloroform, the chloroform layer is washed twice with 5% water,
Calculated, -%: C 67.35; H 7.07; N 9.82.
 С, 4НзоОа ЗС1
Found,%: C 67.36; H 6.95; N 9.80. .
Example 26. Similarly to Example 25, .6-1-oco 4 - G4- (3.5-
then water twice and dried over anhydrous sodium sulfate, then the chloroform is removed by distillation to obtain a residue. To the obtained residue is added a mixture of ether and hexane, the insoluble part is collected by filtration and the concentrated hydrochloric acid-ethanol-water is recrystallized from the mixture to obtain 2.6 g of 6 {oxo-1-3 - 4- (2,3-dimethyl-) phenyl) -1-piperazinyl-propyl} -3,4- -dihydrocarbos thirsh-monohydrochloride in the form of colorless needle-like crystals. M.p. 273-274 ° С (with decomposition
dichlorophenyl) -1-piperazinyl-butyl} - -3,4-dihydrocarbostyryl. Colorless
shaped crystals (from a mixture of meta NOL - chloroform). M.p. 199,200 C.
Example 29. 6- {1-H) KCO-2-C4- (3-chlorophenyl) -1 piperazinyl-butyl} -carb osyl-m-but hydrochloride. Colorless needle-shaped crystals (from isopropanol). M.p. 209 210 C (with decomposition).
Example 30. (3- -chlorophenyl) -1-piperazinyl-butyl} -, 4 dihydrocarbostyryl monooxalate. Colorless needle-shaped crystals (from isopropanol). M.p. 135-136 ° C.
Example 31 5.0 g of 6- (1-oxo 4-chlorobutyl) -3,4-dihydrocarbostyryl and 7.5 g of sodium iodide are dispersed in 120 ml of anhydrous dimethylformamide and the resulting mixture is stirred at 2 hours. To this reaction The mixture was added 10 g of 4 (3-chlorophenyl) piperazine and 5 ml of triethylamine and stirred at 50-60 ° C for 6 hours, then stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to getting residue. To the obtained residue, 80 ml of 5% aqueous solution of bicarbonate-sodium was added and the organic layer was extracted with chloroform. The chloroform layer is washed with water, dried and the chloroform is removed by distillation. The resulting residue is crystallized from ether to obtain inert crystals, which are recrystallized from ethanol to obtain 6.5 g of 6-1-oxo-t4 (3-chlorophenyl) -piperzinyl bytyl 3,4-dihydrocarbenyl as uncolored needle-shaped crystals. M.p. 158-159 ° C.
Calculated,%: C 67.06; H 6.36j N 10.20.
-C H isOiNjCl
Found,%: C, 66.98; H 6.40; N 10.20.
In analogy to Example 31, using the appropriate starting materials, the compounds of Examples 32-
0..
Example 32. 6-1-Oxo-4 - - jl4 (4-methylphenyl) -α-piperazinyl-butyl-3,4-dihydrocarbostyr or. Light yellow needle-like crystals (from ethanol). M.p. .
Example 33. 6- {Oco 4-t4- - (3,4, 5 trimethoxyphensh1) -1 -piperazinyl} butyl 3,4 dihydrocarbostyryl-dihydrochloride. Colorless crystalline powder (from methanol-water mixture). M.p. 261-263 C (with decomposition).
Example 34. b-G1-Oxo --3 P4
- (4-cyanophenyl) -1 piperaznilo Iro--, 4 dihydrocarbosyl 1 l, Colorless cakes of the crystals (pz ethanol). M.p. 206-207 ° C.
Example 35 6- 1-Oke-4- - (4-acetylphenyl) -1-piperazinyl-butyl | -3,4-dihydrocarbostyryl. Yellow needle-like crystals (from a mixture of dimethylformamide - water). M.p. 218 - 219 C.
Example 36. 6- 1-Oxo-4- (4-methylthiophenyl) -1-piperazinyl-butyl-3,4-dihydrocarbostyryl. Light yellow needle-like crystals (from ethanol). M.p. 187-188 ° C.
EXAMPLE 37 6-l-Oco-3- 4- - (2-methoxyphenyl) -l-piperidinyl-prop, 4-dihydrocarbatil-monohydrochloride. Light yellow needle-like crystals (from a mixture of dioxane - water). M.p. 212-212.5 ° C.
Example 38. 6-1-Oxo-4, -. (4 Carboxyphenyl) -1-piperazinyl "butyl - 3,4-dihydrocarbostyryl monohydrochloride. Colorless crystalline powder (from ethanol). M.p. 264-265 S.
EXAMPLE 39. 6-P Oxo-4- (4-hydroxyphenyl) -1-piperazinyl-butyl-3,4-dihydrocarboc with tiryl. Precious crystalline powder (ethanol, mp. 192-194 ° C.
Example 40. (4-Nitrophenyl) -l-piperazinylJ, nb, 4-dihydrocarbyl. Yellowish crystalline powder (from ethanol). Mp. 239-242 ° C.
Analogously to Example 31, the following compounds are prepared.
5-1-oxo-3- (4-feshch) -1-piperazi nyl-propyl-3,4-dihydrocarbostyryl. Colorless needle-shaped crystals (from a mixture of ethanol - methanol). M.p. 180-1824.
5- 1-Oxo-3- 4- (2-ethoxyphenyl) -1-piperazinyl} -propyl-3,4-dihydrocarbostyryl. White crystals (from a mixture of methanol - water). M.p. 223-235 0 (with decomposition).
5- {1-Oxo-3- 4- (2-hydroxyphenyl) -1- piperazinyl-propyl-3.4 dihydrocarboyl styryl. M.p. 215-218 With (from a mixture of methanol - chloroform).
5 (; 4- (4-1Г butylphenyl) - - 1 -piperazinyl-propyl-3, A-dihydrocarbostyryl - monohydrochloride. Colorless needle-like crystals (from ethanol-water mixture), mp. 218 222 ° C.
5-f 1- ° 0kso-3 G 4 (2 chlorophenyl) -1- piperazinyl-propyl} 3 e D-dihydrocar bostyril Colorless powdery substance (out of water). M.p. 259 - 263 ° С.
5 1 0 x 3 4 -. (2,3 dimethyl) 1- piperazinyl - the compound 5-3.4 dihydrobrostyryl - monohydrochloride. White crystals (from a mixture of methanol - water). M.p. 231-234 ° C.
6 1-H) 1 (ensyl) - I-nmieparazinyl propyl 3,4 dihydrocarbyls rylo Colorless needle-shaped crystals (from a mixture of ethanol - water), So pl.
6 NOxo-3- (1-tetralinyl) - - - piperazinyl3-propyl-3,4 dihydrobrostyryl “Colorless prism-like crystals (from ethanol –– mixture). M.p. 187 88 S.,
5-11 Ok co-2 (A-phenyl-1 piperazyl nyl) ° ethyl-3,4-dihydrocarbstyryl. Colorless needle-like crystals (from methanol) .. So pl. 195 198 ° C (with decomposition).
Example 41, 2.6 g of 1-methylg 5- (1 oxo-3-chloropropsh) Ze4-dihydro carbostyryl, 1.2 g of pyridine and 2.0 g of A enylpiperazine are mixed in 30 ml of dimethylformamide and the mixture is stirred at 70–80 ° C for 7 hours. Pour the reaction mixture into 100 ml of sodium bicarbonate solution and extract with chloroform. The chloroform layer is washed with water, dried and the chloroform is removed by distillation. The resulting precipitate is dissolved in acetone, the pH of the solution is adjusted to 4 by adding a solution of oxalic acid in acetone to obtain a crystalline precipitate. This precipitate was collected by filtration and recrystallized from ethanol-water mixture to give 2.8 g of 1-methyl-6-11 oxo-3 -, (4 phenyl 1-piperazinyl) propyl 3,4 dihydrocarbostyryl monoxalate as colorless flakes, m.p. 164
,
Calculated, 8.99, CliHjTOiN (COOH) /:
%: C, 64.22; H 6.25;
0
five
0
five
35
Found: C 64.48; H 6.12; N 9.03 ..
In analogy to Example 41, using the appropriate starting materials, the compounds of Examples 42-44 are prepared,
Example 42. 1-Hexyl-6-G1-ok co-3- (4-phenyl-1-piperazinyl) -propyl, 4 digi, crocarbostyryl-monoox lat. Colorless flakes (from a mixture of ethanol - water). M.p. 142-144 C.
Example 43. 1-Benzyl-6- 1-oxo-3- (4-phenyl-1-piperazinyl) pil3-3, 4-dihydrocarb ostiril mono-oxalate. Colorless needle-like crystals (from ethanol – water mixture), m.p. 171-172 ° С.
Example 44, 1-Allyl-6-G1 H: Kso-3- (4-phenyl-1-piperazinyl) -pro, 4-- dihydrocarbostyryl monooxalate. Colorless flakes (from ethanol-water mixture). M.p. 169-170 C.
Example 45, 2.7 g of 6- (4 chlorbutyl) 3,4-dihydrocarbostyril and 1.5 g of sodium iodide are mixed in 30 ml of dimethyl sulfoxide and the mixture is transferred at 50 ° C for 2 hours. Then, 2 , 0 g of 4 (3,4-methylenedioxophenyl) piperazine and 3 g of DBC and the reaction mixture is stirred at 70 for 5 hours. After completion of the reaction, the reaction mixture is poured into 10 ml of 2%. sodium bicarbonate and the organic layer is extracted with chloroform. The chloroform layer was washed with water, dried, chloroform was removed by distillation. 50 ml of methanol and 5 ml of concentrated hydrochloric acid were added to the resulting residue, and then the mixture was concentrated under reduced pressure to dryness. The remainder is crystallized by adding ethanol-acetone mixture, the resulting crude crystals are recrystallized from ethanol-water mixture, to obtain 2.1 g of 6- - 1 oxo-4- 4 ™ (3,4-methylenedioxy NIL) -1-piperazish-butyl -3, 4-dihydrocarbostyryl-monohydrochloride as a colorless crystalline
40
45
50
powder, eat it).
Topl. 246-248 ° С (with decomposition
35
55
Calculated,%: C, 62.95; H 6.16; N 9.18,
  HC1
Found,%: C 63.12; H 6.01: N 9.25.
15
Example 46 2.8 g of 6 - “(I-OKC 4-chlorobutyl) -3,4-dihydrocarbonyl and 1.8 g of sodium iodide are mixed in 60 ml of dimethylformamide and the resulting mixture is stirred at room temperature for 7 Part of the reaction mixture was added 2 g of triethylamine and 2.5 g of 4-enyl piperazine and continued to stir at room temperature for 24 hours.
Then the reaction mixture was poured into 200 ml of an aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform is washed with water, dried and the chloroform is removed by distillation under reduced pressure. The residue obtained is recrystallized from nzopropanol and 2.5 g of 6-1 hydroxy-4 - (phenyl 1-piperazinyl butyl 3,4-dihydrocarbo-styryl are obtained. Colorless needle-like crystals, mp. 167-168 ° WITH.
Calculated,%: from 72.79; H 7.70; N 1.07.





 .Nj.
Found,%: C 73.01; H 7.59; N 11.21.
Similarly, Examples 46, using the appropriate starting materials, prepared the compounds of Examples 57.
Example 47. 6- 1-Oxy 3 (4- -phenyl-1-piperazinyl) -propyl-3, dihydrocarboxyryLv Colorless needle-like crystals (from isopropanol). M.p. UV-Ua C.
Example 48. (2 Chlorophenyl) 1 piperazinyl-butyl} 394 dihydrocarbostyryl .. Weighed needle-like crystals (from isopropane nol). M.p. 163-164 C.
Example 49. 6- 1-Oxy-3- 4- - (2-methoxyfennl) -1 piperazinyl1-pro, 4-dihydr6carbostyryl. Colorless needle-shaped crystals (from isopropanol), T. pl. 145 147 С,
Example 50. 6-.1 Oxy-3 4-- - (2,3 dimethylphenyl) -1-piperazinyl U), 4 -digid, rocarbostil. Bes colored needle-shaped crystals (made from ethanol). M.p. 173-175 ° C (with decomposition).
%
Example 51 6- 1-Oxy-3 14- (4-methylphenyl) -1 piperazinyl Pro-, 4-dihydrocarbostyryl, Colorless needle-like crystals (from isopropanol). Mp: 171 ™ 172 ° C,
52, 6 - Octr-4G
-butyl
l gp; with
Example
(3 Chlorophenyl) 1 pnperazin11l 3,4-dihydrocarbone:;,:. Fe, i needle-like crystals (.:; -:: ;; reforms - npocToii),:, li, 157 С,
Example 53 (3 ™ chlorfiens) 1-piperazinyl1-butyl ™, 4 dihydrocarbostyryl. Colorless flakes (from a mixture of ethanol and chloroform). M.p. 2 5- 216 C.
Example 54. 6- ((3-chlorophenyl) -1 -piperazinyl-butyl-β-carbostyryl. Colorless needle-like crystals (from a mixture of isopropanol, chloroform), mp 243-244 ° C (with decomposition).
Example 55. 6 (1 Oxy-2 4- (2,3-dimethylphenyl) -P1 Sher1azinyl 3Tmilj Kap6ocTHpi-ui. Colorless needle shaped crystals (from a mixture of isopropanol - chloroform). T. 245-246 C (with decomposition).
Example 56. 1- Met1Sh 6 - 1-ok- (4 phenyl-1 piperazinyl) -propyl-3,4-dihydrocarbostyryl ™ monooxal To Colorless flakes (from ethanol-water mixture), m.p. 155-156 ° С „
Example 57, - ° Benzyl 6 ™ I (4 phenyl-1-piperazinyl) ™ ™ 4 4 dihydrocarbostyryl monoox lat. Colorless needle-shaped crystals (from a mixture of ethanol and water), m.p. ,
5 1 -Oxy 3- (4 phenyl-1 piperazinyl) propyl, 4 dihydrocarbostyril c. Colorless needle-shaped crystals (from ethanol). M.p. 158-160 ° Co
1 Al. I -oxo ™ 3 (4 phenyl.1 piperazinyl) propyl-3,4 dihydrocarbostyryl monooxalate. Colorless Chloride (from ethanol / water mixture) So pl., 169-170 ° C.
Example 58 of 2.8 g 6-CH4-Chloro-1-butenyl) -3,4-dihydrocarbostyril and 2.1 g of sodium iodide are dissolved in 40 ml of dimethylformamide and stirred for 1 hour. To this solution is added 2 , 7 g of 4- (™ 6-methylphenyl) ha-sherazine and 1.5 g of triethylamine and the resulting mixture is stirred for 5 hours. At that, the reaction mixture is concentrated under reduced pressure to obtain a residue. 10 N. MaON and ether are added to the mixture and mixed: at a room temperature for 30 minutes prior to the heating of the crystals.
The crystals were separated by chromatography on silica gel and recrystallized from ethanol / acetone / chloroform to give (2-chlorop-6 methyl phenyl) -l-piperazinesch1 1-butenyl-3, 4-dihydrocarbatiryl as colorless prism-like crystals. Exit 2.7 g. T.pl 179.
Analogously to Example 58, the compounds of Examples 59-81 are prepared.
P p and not p 59. (4 Phenyl 1 piperazins) -1-prspenil, 4 -digid rocarbostiril. Colorless prism-like crystals (from ethanol). M.p. 186--187 ° C.
Example 60 (4 gphenyl-1-piperaznyl) 1 butenyl-3,4-dihydrocarbostyryl. Colorless prism-shaped crystals (from ethanol. Chloroform mixture). T, pl. 187-188 ° C.
Example 61. b- (3 Chlorophenyl) -1 -piperazinyl -1 -butenyl - -3,4 -dihydrocarbostyryl, Colorless prism-like crystals. M.p. 175 176 ° C
Example 62. (Phenyl) - 1 piperazinyl 1-propenyl - -354-dihydrocarbostyryl. Colorless prism-like crystals (from a mixture of ethanol - chloroform). T.P. 151.5 152.5 C.
PRI me R. 63. (3 Chloro phenyl) -1 piperazinyl -1 Propenyl - -3,4-dihydrocarbostyryl. Colorless prism-forming crystals (from a mixture of ethanol - chloroform). M.p. 163 - 164 C.
Example 64. (Phenyl) -1-piperazinyl 1-propenyl} - -3.4 - dihydrocarbostyryl, Colorless prism-shaped crystals (from ethanol-chloroform mixture), m.p. 224.5 - 225.5 ° C.
Example 65. (2-Fluoro-phenyl) -1 piperazinyl 1-propenyl 3,4-dihydrocarbostyryl. Colorless prism-like crystals (from a mixture of ethanol - chloroform). M.p. 188.5 190 ° C ..
P p and meper 66. (2-Etoc syphenyl) -1 piperazinyl - 1 propenyl J-3,4-dihydrocarboxyryl. Colorless needle-like crystals (from methanol – chloroform mixture). M.p. 204 ° C.
P-example 67. 4- (2-Etho-siphenyl) -1-piperazinyl -1-butenyl - -3,4-dihydrocarbostyryl. Colorless
needle-shaped crystals (from a mixture of ethanol and chloroform). Mp 205-206 ° C.
Example 68 (3-Methylphenyl) -1-piperazinyl -1-propenyl-3,4 dihydrocarbostyryl. Colorless .. prismlike crystals (from ethanol). Topl. 167-168 ° C
Example 69 6- {4- 4- (3-Methylphenyl) -1-piperazinyl -1-butenyl | - -3,4-dihydrocarbostyryl. Colorless prism-like crystals (from ethanol, mp. 171.5-172.5 C. 1 Example 70. (4-Methylphenyl) -1-piperazinyl -1-butenyl - -3,4-dihydrocarbostyryl. Colorless prism-like crystals ( from a mixture of ethanol - chloroform). Tpl. 202-203 ° C.
Example 71. (toxphenyl) -1-piperazinyl -1-pro-, 4-dihydrocarbostyryl. Colorless needle-shaped crystals (from a mixture of ethanol - acetone - chloroform). M.p. 174-175 sec.
Example 72. (2,3-. -Dimethylphenyl) -1-piperazinyl -1 -benzenyl} -3,4-dihydrocarbostyryl. Colorless prism-like crystals (from a mixture of ethanol - acetone - chloroform).
five
0
five
0
five
Example 73. (4-Ethoxycarbonylphenyl) - -piperazinyl -1-propenyl-3,4-dihydrocarboxyr1. Colorless needle-shaped crystals (from a mixture of ethanol - chloroform). M.p. 190-192 C.
Example 74 (4-Methyl-thiophenyl) -1-piperazinyl -1-butenyl - -3,4-dihydrocarbostyryl. Colorless needle-like crystals (from a mixture of this NOL chloroform). M.p. 175.5-177 ° C.
PRI me R 75. (4-Acetyl phenyl) -1 -piperazinyl - 1-butenyl 1-3,4-dihydrocarbostyryl. Colorless prize erythemic crystals (from a mixture of ethanol and chloroform). M.p. 213-215 C.
Example 76, (nophenyl) -1-piperazinyl -1-propenyl-3,4-dihydrocarbostyryl. Colorless prism-like crystals (from a mixture of ethanol - chloroform). M.p. 196-198 ° Co
Example 77 6- (3-C4- (2-hydroxyphenyl) -piperazinyl 1 propenyl-3,4-dihydrocarbostyryl. Colorless prism-like crystals (from ethanol-chloroform mixture). Mp. 192-194 ° C,
Example 78. 1-Methyl-6- 3- 4- - (3-methylphenyl) -1-piperazinyl -1-pro19
penyl-3, hydrocarbostyryl-t is oxalate. Light yellowish needle-like crystals (from ethanol). M.p. 78 -179CH.
Example 79. 1 Benzsh1 6 (3- 4 (3 methylphenyl) 1-piperazinyl -1-- propenyl-3 4 dihydrocarbostyril - monooxapate. Colorless needle-like crystals (from ethanol). Mp. 176 - 179 C.
Example 80. 1 Allyl-6- 3- - (3 T4-methylphenyl) -1g-piperazinyl 1-propenyl-3, 4 dihydrocarboxy-1-monooxalate. Colorless needle-like crystals (from ethanol) So pl. 167 -.
Example 81. 1 C2-Propionyl) 4- (3 meslphenyl) -l-piperazylneal 1-propenyl 3,4-dihydrocarbo styrene mono-oxalate. Colorless needle-shaped crystals (from ethanol). M.p. .
(4-Phenyl 1-shherazinyl) -1-propenyl 3-3,4-dihydrocarbostyryl. Colorless:; prism-like crystals; (from methanol). M.p. 177 180 ° C.
Example 82 2.5 g 6 (4-chloro-butyl-3.4 dihydrocarbostyril and 1.8 g of sodium iodide are mixed with
80 ml of acetone and stirred for 2 hours. To the reaction mixture are added 80 ml of dimethylformamide and acetone is removed by distillation, followed by adding 2.0 g of 4- (4 tolyl) -shg-perazine and 2.0 g triethylamine, and all stirred at 70-80 ° C for 5 hours.
 The reaction mixture is then concentrated under reduced pressure to give a residue. 50 ml of a 5% aqueous solution of sodium bicarbonate is added to this residue and mixed. The resulting precipitate is collected by filtration, washed with water and dried. After recrystallization from a mixture of isopropyl alcohol and diisopropyl ether, 3.1 g of 6- {4- (4-tolsh1) -1-piperazinyl-butyl - -3.4 dihydrocarbostyril in the form of colorless prism-like crystals, m.p. 160-161 ° C.
Analogously to Example 82, the compounds of Examples 83-99 are prepared.
Example 83. (4-Phenyl-l-piperina zinyl) -b, 4-dihydrocarboxyp. Colorless prism-like crystals (from a mixture of isopropyl
1367857. 20
alcohol and diisopropyl ether).
five
0
five
ABOUT
Q
M.p. 151-152 C.
Example 84. 6-4-C4- (3-Methylphenche1) -1-piperazin1i1 butyl} -3,4-β-dihydrocarbostyryl. Colorless chlorine (from a mixture of isopropyl alcohol - diisopropyl ether). M.p. 138.5-139.5 ° C.
Q Example 85. (2,3-Dimethylphenyl) -1-piperazikyl-butyl} - -3,4-dihydrocarbostyryl-monohydrochlo - REED. Colorless cakes (from methanol). M.p. 234-235 C.
Example 86. 6- 4-4-Phenyl--1-piperazinyl-butyl} -3,4-dihydrobrostyryl. Colorless prism-like crystals (from a mixture of isopropyl alcohol - diisopropyl ether). M.p. 150.5-151.54.
Example 87. (2-Chlorophenyl) -1 -piperazinyl-butyl J-3,4-di-. hydrocarbyl styryl. Colorless prism-like crystals (from a mixture of isopropyl alcohol and diisopropyl ether). M.p. 128.5-129.5 ° C.
Example 88. (3-Chorophenyl) -1-piperaenzyl-3-butyl-3,4-di-hydrocarbostiril. Colorless pellet-shaped crystals (from a mixture of isopropyl alcohol - diisopropyl ether) So pl. 149-150 C.
PRI me R 89. (3-Chloro-phenyl) -1-piperazinsh1-propyl-3,4-dihydrocarbostyryl. Colorless cake-like crystals (from a mixture of isopropyl alcohol. - diisopropyl ether). M.p. 141.5-142.5 ° C.
Example 90. (2-Etho-ciphenip) -l-piperidinyl-propyl 3,4-dihydrocarbyl. Colorless prism-like crystals (from diethyl
ether). M.p. 122-123 ° C.
Example 91. (2-Etho-5 syphenyl) -1-piperazinyl-butyl-3,4-β-dihydrocarbostyryl. Colorless prismlike crystals (from a mixture of isopropyl alcohol - diisopropyl ether). M.p. 131.5-132 ,.
Example 92 (tilphenyl) -1-piperazinyl-propyl} -3,4-dihydrocarbostyryl. Colorless needle-like crystals. M.p. 116 -
five
55
117 ° C.
Example 93 (2-ethoxyphenyl) -1-piperazinyl-propyl-3,4- -dihydrocarbostyryl. Colorless prism-like crystals (from a mixture of isopropanol diisogopropyl ether), m.p. 145-146 ° C.
Example 94, 1- (3-Phenylpropyl) -6- 3-4-4 (current siphenyl) -1 razinyl-propyl, 4 dihydrocarbyl reel monoxalate. Colorless pellet-shaped crystals (from acetone-water mixture). M.p. .
Example 95. 1 “Isopentyl b - (2 ™ ethoxyphenyl) -1-piperazyl nyl propyl-3,4 dihydrocarbostyryl monooxalate. Colorless cake-like crystals (from a mixture of acetone - water). M.p. 150-151 C,
Example 96. (2-Hydro-phenyl) -1-piperazinyl butyl J-3, 4-di hydrocarboxyryl. Colorless needle-shaped crystals (from ethanol). M.p. 67--169 ° C. ,
Example 97. 6-p-C4 enyl -1 piperazinyl pro11yl, 4 dihydrocarbostil. Colorless cake-like crystals (from a mixture of isopropyl alcohol - diisopropyl ether) .. Т.11Л. 136.5-137.5 ° C.
Example 98 6g- {3- 4- (4-Nitrophenyl) -1-piperazinylZ-PROPIL-3,4-dihydrocarbostyryl. Yellowish needle-like crystals (from isopropanol) „So pl. 189-192 ° C. EXAMPLE 99 6 ™ 4-4-Phenyl 1-piperazinyl 3-butyl carbostyr MO but hydrochloride. Colorless needles b - different crystals (from methanol). M.p. 23-3-235 ° C.
5- (4 ™ Phenyl 1 -piperazinyl) saws -3,4-dihydrocarbostyryl monohyd-rochloride. Colorless needle-shaped crystals (from a mixture of ethanol - water). M.p. 230-233 C.
Example 100 2.45 g of 6- (4 ghloro-l butenyl) -3,4-dihydrocarbosteryl and 1.6 g of sodium iodide are dispersed in 60 ml of acetone and refluxed for 2 hours. 80 ml of dimethylformamide are added to the reaction mixture and acetone is removed under reduced pressure, then 2.2 g of 4- (2 ethoxyphenyl) Razin and 2 ml of triethylamine are added and stirred at 70-80 ° C for 6 hours The reaction mixture is concentrated under reduced pressure, 80 ml of 5% aqueous sodium bicarbonate solution is added to the residue, stirred, and the organic layer is extracted with chloroform. The m and the chloroform layer is washed with water, dried and the chloroform is removed by distillation. The residue thus obtained is recrystallized from methanol to give 3.1 g of 6-14-4- (2-ethoxyphenyl) -1-piperazinyl-1-butenyl} carbostyrip as colorless needle-like crystals. M.p. 225-228 0.
Analogously to example 100, the compound of example 101 is obtained.
Example 101 (4-Pem l-l-piperazinyl) -1-butenyl-carbostyryl monohydrochloride. Colorless needle-like crystals (from methanol). M.p. 233-235 S.,
Example 102: 2.4 g of 6- (1-oxy-3-chloropropyl) -3,4-dihydrocarbostyril and 1.6 g of sodium iodide are mixed in 60 MP of isopropanol and stirred at 40-50 ° C for 2 hours. Then, 2.2 g of 4-benzylpiperidine and 3.0 g of DEC are added to the reaction mixture and refluxed for 6 hours. Then the reaction mixture is poured into 100 ml of 5% aqueous sodium bicarbonate solution and stirring at room temperature for 1 hour. The resulting insoluble material is collected by filtration, washed with water and dried, then recrystallized from ethanol to a half. Student 1.8 g 6- 1-oxo-3-4 (benzyl-1-piperid Ш1) -pr, 4-di hydrocarboyl or in the form of light yellow cakes. M.p. 170-171 ° C.
 EXAMPLE 103: 2.4 g of 6- (1-oxy-3-chloropropyl) -3,4-dihydrocarbostyryl and 3.6 g of 4-phenyl-4-hydroxypiperidium are mixed in 80 ml of xylene and refluxed for 24 hours. The reaction mixture is then concentrated under reduced pressure to dryness, and the resulting residue is dissolved in 100 ml of chloroform. The chloroform layer is washed with an aqueous solution of sodium bicarbonate, twice with water. It is then dried over anhydrous sodium sulfate and the chloroform is removed by distillation. Ether-hexane was added to the resulting residue, and the insoluble part was collected by filtration, then recrystallized from ethanol-chloroform to obtain 1.7 g of 7-G1-OXO-4- (4-phenyl-4-hydroxy-1- piperidyl) butyl-3,4-di-hydrocarbostyril as colorless flakes. M.p. 196-197 0.
23
Example 104. 2.6 g 6 (1 - oxo - 4 chlorobutyl) -3,4-dihydrocarbostyl, 1.2 g pyridine and 2.7 g 4-enyl-4-acetyl piperidine are mixed in 30 ml dimethylformamide and stirred at 70-80 ° C for 7 hours. The reaction mixture is poured into 100 ml of 5% aqueous sodium bicarbonate and the organic layer is extracted with chloroform, then the chloroform layer is washed with water, dried and the chloroform is removed by distillation. The resulting ocTafoK is recrystallized from ethanol to give 6-1-oxo-4- (4-phenyl-4-acetyl-1-piperidyl) butyl-3,4-dihydrocarbostyril as light yellow cakes. Output 2.1 g. T.Sh1. 166-167 With
13
Example 105. 5.0 g of 6- (1-oxo-4 chlorophenyl) -3,4-dihydrocarbosteryl and 7.5 g of sodium iodide are dispersed in 100 ml of anhydrous dimethylformamide and the mixture is stirred at 50-60 ° C in for 2 hours Then, 8.1 g of 4-phenyl-1,2,5,6-tetrapahydropyridine and 5 ml of triethylamine are added to the reaction mixture and stirred at 50-60 ° C for 6 hours. Then the reaction mixture is stirred at room temperature in 24 hours, then concentrated under reduced pressure to a residue. 80 ml of a 5% aqueous solution of sodium bicarbonate is added to the residue and extracted with chloroform, the chloroform is washed with water and dried, then the chloroform is removed by distillation. As a result of recrystallization from ethanol, 6.0 g of -oxo-3- (4-phenyl-l, 2,5,6-tetrahydro-1-pyr, idyl) propyl, 1-3,4-dihydrocarboetyl are obtained in the form of light - yellow cake shaped crystals. M.p. 167-168 ° C. Example 106: 5.0 g of 6- (1-oxo-4-chlorobutyl) -354-dihydrocarbostyril and 3.5 g of sodium iodide are mixed in 100 ml of acetone and the resulting mixture is stirred at 40-50 ° C for 5 h 80 ml of dimethylformamide is added to the reaction mixture and acetone is removed by distillation under reduced pressure, then 5.0 g of 4-phenylpiperidine and 5 g of triethylamine are added and the resulting mixture is stirred at 70-80 ° C for 6 hours The reaction mixture is concentrated under reduced pressure, 60 ml of an aqueous solution of bicarbonate are added to the residue.
- -,
. -
36785724
 sodium to obtain raw crystals. The latter are collected by filtration, washed with water and dried, then
g is dispersed in 80 chloroform and
stirred at icoi. iiiimteptereprate for 1.0 h, le, j - :: CTBOnH - iyso in chloroform, part is removed, l chloroform is removed by distillation. Obtained by
10 This residue is recrystallized from
ethanol to obtain 5.6 g of 6- 1-oxo- (4-phenyl-1-piperidyl) -butyl-3,4-dihydrocarbostyryl in light yellow cakes.
15 m.p. 167-168 ° C.
Analogously to example 106, using the appropriate starting materials, the compounds of examples 107-129 are prepared,
20 Example 107, 6- 1 0ксо-3- (4-phenyl-1-piperidyl) -propyl-3,4-diphenvodrocarbostyryl. Colorless needle-shaped crystals (from ethanol). M.p. 183-184 S.
25 Example 108 6- 1-Oxo-4- - (4-benzyl-l-piperid) - byt-3,4 - -dihydrocarbostyryl. Light yellow cakes (ethanol). M.p. 120-121 C.
30 PRI me R. 109. 6 - 1-Oxo-3- - (4-b Enzyl-1-piperidnl) -pro saw-3,4-dihydrocarbostyryl. Light yellow pellet-shaped crystals (nz ethanol). M.p. nO-ni C.
Example 110 6-1-Oxo-4- (4-phenyl-4 oxy ™ l-piperidyl) -butyl - 3, 4-dihydrocarbostyryl. Colorless flakes (from ethanol ™ chloroform mixture), m.p. 196-197 with „
40 Example 111. 6- 1-Oxo-3- - (4-phenyl-4-OXY-1-piperidyl) -propyl-3,4-dihydrocarbostyryl. Colorless needle-shaped crystals (from a mixture of ethanol - ethyl - acetate). T, pl, 20545 206 ° C.
Example 112. 6- 1-Oxo-4- (4-chlorophenyl) -4-hydroxy-1-piperidyl-butyl-3,4-dihydrocarbostyryl. Shine-
35
50
55
lo flociform crystals (from ethanol – chloroform mixture). M.p. 210-211 C.
Example 113, 6 1-Oxo-4- ™ 4-phenyl ™ 4 ™ acetyl-1 piperidyl-butyl | -354-dihydrocarbostyl. Light yellow cakes (ethanol).
Example 114 6 G1-Oxo-4- 4- (2-benzimidazolino-7L) 1 piperidyl-butyl) 3.4 dihydrocarbyl.
25
Colorless crystalline powder (from methanol). M.p. 247-248 ° C.
Example 115 6-0-3 3 g (2-6 enimidazolino 1 g-1-T1L) 1 nir peridyl-propyl-3,4-dihydrocarbo styryl monohydrochloride. Colorless cake-like crystals (from methanol-chloroform). M.p. 242 - (with decomposition).
Example 116. 6-G1-Oxo 4 - (4 Phenyl 52,5,6 tetrahydro-1 pyrydyl) butyl-3,4-dihydrocarbostyryl ° monohydrochloride. Light yellow cakes (ethanol). Topl. I 70-1 71 C,
Example 117, 6-NOxo-3 (4-phenyl-52,5,6-tetrahydro-pyridyl) -propyl-3,4-dihydrocarbostyryl “Light yellow cake-like crystals. (From ethanol).
Example 118. 6- 1-Oxo 4 (4 ™ chlorophenyl) -1,2,5,6-tetrahydro -1-pyridyl-butyl-3 5 4-dihydrocarbosmiril monohydrochloride. Colorless cakes (ethanol). M.p. 188-189 p.
Example 119. 2-Isopentyl-6- 1 ™ ok co-3- (4-phenyl-1-piperidyl) -proyl-354-dihydrocarboxyethyl monohydrochloride. Colorless mica-like crystals (from a mixture of ethanol. Water) and Tpl, 205-206 with decomposition).
. Example 120, 1-Allyl b-l- -OK co-3- (4-phenyl-1-pin eidyl) propyl-3,4 dihydrocarbostyryl TU1Ono hydrochloride. Colorless cake-like crystals (from ethanol-water mixture) “T, pl. 98-199 S. (with decomposition)
Example 121, 1- (2-Propnnsh1- -6- -oxo-3- (phenyl-piperid.h) l-propyl-3,4-dihydrocarbostyryl-mono hydrochloride. Colorless cakeshaped crystals Hisz ethanol-water mixture). M.p. 203-204 ° С (with decomposition)
Example 122 „1- (3-Fesh lpropyl) -6-l-oco-3- (4g phenyl-piperidyl) -propyl-3,4-dihydrocarbostyryl monohydrochloride. Colorless crystalline powder (from isopropyl alcohol), m.p. 164-165 C.
Example 123, 1-Methyl-6- i- -OK with-3- (4-phenyl-1-piperidyl) -propyl-3., 4-dihydrocarbostyryl monohydrochloride. Light yellow cake-like crystals (from ethanol-water mixture), m.p. 213-214 C (with decomposition)
one
ten
15
6785726
Example 124. 6- 1-Oxo-3-C4- - (4-chlorophenyl) -1,2,5,6-tetrahydro-1-pyridyl-propyl} -3.4 dihydrocarbo-g styryl-1 / 4- hydrate. Light brown
flake / (from ethanol). M.p. , Example 125. 6 1-Oxo-4-4-C4-chlorophenyl-4-hydroxy-1-piperidyl-butyl-3,4-dihydrocarbostyryl, Light yellow flakes (from ethanol-roform form), T, pl. 210-211 ° C.
Example 126, 6-iI-Oco-4- 4- (3, 5-dimethylphensh1) 1 -piperidyl-butyl-3,4-dihydrocarbostyryl. Light yellow crista. 11 face powder,
(from ethanol). M.p. .
6 -, {1-oco-3-4 - (. 4-methylphenyl) - -1J 2.5 5 6-tetrahydro-1 pyridylJ-propyl 2,4-dihydrocarbostyryl. Light yellow mica-like crystals (from methanol-water mixture). M.p. 189-.
6 1 Oxo-3- 4- (4-fluorophenyl) -1,2,5,6-tetrahydro-1-pyridyl J-pro-, 4-dihydrocarbosteryl. Light yellow cakes (from ethanol-water mixture). T, pl. 181-182 C,
6- I-OKCO-3 G4- (3-methylphenyl) - 15 2,5,6-tetrahydro-1-pyridsh1-propyl-3, 4-dihydr ok arb o styryl. Light yellow pellet-shaped crystals (from ethanol – water mixture. So pl., 52 - 153 ° С.
20
25
thirty
6- 1-Oxo-3- 4- (3,5-dimethoxyphenyl. -Nyl) -1,2,5,6-tetrahydro-1-pyridyl - -propyl-3,4-dihydrocarbyl 1. Light yellow needle-like crystals (from ethanol - water mixture). M.p. 173 175 C.
6- -Oxo-3- 4- (j-3-methoxyphenyl) -1,2,5,6-tetrahydro-1-pyridyl} prop., 4-dihydrocarbostyryl. &amp; yellow needle-like crystals (from a mixture of ethanol - water). M.p. 155 - 156 С,
7- 1-Oxo-3- (4-phenyl-1-piperidyl) propyl-3,4-dihydrocarbostyril, colorless needle-like crystals
(from methanol) .- T. pl. 171 -173 ° C.
7-l-Oxo-3-p- (4-metSH1phenyl) 1-piperidyl-propyl-3,4-dihydrocarbostyryl. White crystals (nz mixture of ethanol - water), So pl. 212-216 C (with decomposition).
7-l-Oxo-3- (4-fluorophenyl) 1-piperidyl-propyl} -3 5 4-dihydrocarbidity ° ryl-monochloride. M.p. 231-235 С (from
27
methanol / water mixtures). Colorless needle-like crystals.
 7-f 1-Oxo-3- 4- (2-, 4 dimethylphenyl 1 ° piperidyl-propyl-354-dihydrocarbostyryl-monohydrochloride. White crystals (from methanol-water mixture). Mp. 22b-229 WITH.
Example 127. (4-Phenyl 1-piperidyl) -butyl - carbosty ryl-monohydrochloride. Colorless cakes (from methanol). M.p. leg-igo c.
Example 128.) Cs-2- (4 benzsch-1-piperidyl) butylcarbo-styryl monohydrochloride. Colorless crystalline powder (from a mixture of ethanol and water). M.p. 178-79 p.
PRI me R. 129. 6- |; 1 0ксо 2 (4 fenshg-1 C 2,5,6 tetrahydrog1 pyridyl) butyl carbostyryl-monochlo RID. Light yellow pellet-shaped crystals (from ethanol-water mixture). M.p. 190-191 ° C. Example 130. 2.6 g of 6- (ox-3-chloropropyl) -3,4-dihydrocarbyl reel and 1.8 g of sodium iodide are mixed in 60 ml of dimethylformamide and the resulting mixture is stirred at room temperature for 7 hours Then, 2.0 g of triethylamine and 2.5 g of 4-phenylpiperidine are added to the mixture and stirred at room temperature for 24 hours. The reaction mixture is poured into 200 ml of 1% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer is washed with water and dried, and the chloroform is removed by distillation. The residue thus obtained is recrystallized from ethanol to obtain 2.5 g. 6- (1 hydroxy-3- (4-phenyl-1-piperidyl)) -propyl 3,4-dihydrocarboxylate in the form of colorless cake-like crystals. 155.5-156.5 ° C.
Analogously to example 130, using the corresponding compounds as starting materials, the compounds of examples 131-134 are obtained.
Example 131, 6-1-Oxy-3 - (4-benzyl-1 piperidyl) -propyl-3, 4-; -dihydrocarbostyryl, Colorless sweet-like crystals (from methanol T "W1. 168-169 ° C.
Example 132. 6-and-Oxy-2 - (4-Phenium 4-oxy-piperidyl) -propyl 3,4-dihydrocarbostyryl. Colorless needle-shaped crystals (from ethanol). M.p. 102-103 S.

7857, 28
Example .133. b-P-Oxy-3 - - (4-phenyl-, 2,536-tetrahydro-1-pi-
Ridil) r1rOsh - 3, 4-DIG1 :: trg Kc rbS1STir1Sh.
Colorless leppea ioa. : -, - :: rj. crgstalls (from ethanol). Mpl 143 s,
Example 134, -m1-Ox1g-3
(4 Chlorophenyl-1, 2,5,6-tetrag1-schro-1 pyridyl) -propyl ™ 3,4-di hydrocarcaro0 styryl. Colorless cakes (ethanol), m.p. 169-170 ° C.
5- 1-Oxy 3- 4- (4 chlorfensh1- -1,2,5, b-tetra hydro-1-pyridsh-pro15, 4-dihydrocarbostyryl. Colorless cake-like crystals (of ethanol)., Mp. 169- -170 C.
6- 1-Oxy-3 G4- (3- {ethyl-phenyl) -1,2,5,6-tetrahydro-1-pyridyl pro
, 4-dihydrocarbostyril. Colorless cakes (ethanol). M.p. 142-143 C.
b 1 H) (4-methylphenyl) - 5 2з5,6 tetrahydro 1 pyridyl-pro, 4 dihydrocarbostyri Ls Colorless crystals similar to the subtype (from
ethanol). M.p. 59-160 C.
7 (, 4-phenyl l-piperidyl) -propyl 3,4 dihydrocarboster. Bes Tsvet 5-1 prism-like crystals (from the floor of the anola), So pl. 146 149 C.
five
0
five
ABOUT
five
Example 135, 5.0 g of 6- (1-ca.-00-4-chlorobutyl) 3,4-dihydrocarbostyril and 3.5 g of sodium iodide are mixed in 100 ml of acetone, the mixture is stirred at 40-50 ° C for 5 h. Then 80 NLT of dimethylformamide are added and the acetone is removed from the mixture by distillation under reduced pressure. 5 g of phenylpiperazine and 5 g of sodium hydrogen carbonate are added to this reaction mixture, stirred at 70 for 6 hours. The reaction mixture is concentrated under reduced pressure and 50 ml of 5% sodium hydrogen carbonate solution is mixed in to effect crystallization. The resulting crude crystals are collected by filtration, washed with water and tiato. Then, the unsoldered uncleaned crystals are dispersed in 80 ml of chloroform and stirred at room temperature for 1 hour. The insoluble in chloroform solution is removed from the solution and the chloroform is distilled off It is distilled to obtain a residue. To the latter, 50 ml of methanol and 10 ml of conc.
centered hydrochloric acid, the mixture is concentrated under reduced pressure to dry matter. 50 ml of acetone is added to the obtained solid and stirred to obtain crude crystals, which are collected by filtration, washed with acetone, and recrystallized from ethanol-water to obtain 3, 9 g of monohydrochloride 6 - 1 -oxo 4 (4 Fensch1 °° 1 piperazinyl) butyl ° 3,4- ™ - идhydrocarbostyril in the form of yellow powder crystals. M.p. 195196 ° С ,,
Example 136. 2.4 g 5 (co-chloro propyl) -Ze4-dihydrocarbyl ring and 1.6 g of sodium iodide are mixed with 60 ml of hexamethylphosphoryl triamide and the mixture is stirred at 40 ° C for 2 hours. In this reaction mixture are added 2 , 0 g of 4-phenylpiperazine, and 3.0 g of potassium carbonate and mixed ° are heated at 70-80 ° C for 6 hours. Over ° - the reaction mixture is poured into. , 100 ml of 5% sodium hydrogen carbonate solution and stirred at natal temperature for 1 h. The insoluble substance is collected by filtration, washed with water and dried, then recrystallized from a mixture of ethanol / chloroform to obtain 1.5 g of 6 oxo-3 (4 ° phenyl-1 piperazirshl) ° pr.opil 3 5 4 -dihydrocarbostyril in the form of colorless flakes. M.p. 196-
P
197 s.
Example. 137. 5.0 g 6 (4 g chlorobutyl) - 3.4 dihydr, okarbosti- ° rila, 3.5 g sodium iodide, 10.0 g 4 phenylpiperazine and 10 g triethyla are mixed and the mixture is stirred for 10 h The reaction mixture is concentrated under reduced pressure and 100 ml of sodium hydrogen carbonate solution are mixed in to effect crystallization. The harvested crude crystals are collected by filtration and washed with water, then dried. The dried crude crystals are dispersed in 80 ml of chloroform and stirred at room temperature for an hour. The insoluble in the chloroform solution is removed from the solution and the chloroform is distilled off to obtain a residue. 50 ml of methanol and 10 ml of concentrated hydrochloric acid are added to the latter and the mixture is concentrated under reduced pressure.
pressure to dry residue. 50 ml of acetone is added to the obtained residue and stirred to obtain crude crystals, which are collected by filtration, washed with acetone and recrystallized from ethanol-water to obtain 2.1 g of monohydrochloride 6 G1-oxo-4- (4-phenyl-1 - piperazinyl) butyl-3 5 4 dihydrocarbo steryl as a yellowish crystalline powder. M.p., 195-I96 C, i
Example 138. Mix 2.8 6- (1 hydroxy 4 chlorbutyl) -3,4-dihydrobrostyryl and 1, 8 g of sodium iodide in 60 ml of dimethylformamide and stir at room temperature for 7 hours, K re 2 g of triztilamine and 2.7 g of 4- (4-aminophenyl-piperazine) are added to the mixture and stirred at 200 ° C. for 5 hours. The reaction mixture is poured into 200 ml of 1% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer is washed water, dried, and distilled chloroform under reduced pressure. The resulting residue is recrystallized from methanol to give 0.5 g of 6-1-hydroxy- (4-aminophene or -l-pipersazinyl - -butyl 1-3,4-dihydrocarbostyril, melting point 243-245 ° C, Brownish crystalline powder.
Example 139; 2.63 g of 6- (3-chloro-1-propenyl) -3,4-dihydrocarbostyril and 2.1 g of sodium iodide are dissolved in 40 ml of dimethylformamide and stirred at 50 ° C for 1 h, 2.07 g of 4-phenyl-1,2,5,6-tetrahydropyridine and 1.5 g of troethylamine were added to this solution, and the mixture was stirred at 50 ° C. Even for 5 hours. The reaction mixture was concentrated under reduced pressure to dryness, to give the residue to which 10 n is added, sodium hydroxide and ether are stirred at room temperature for 30 minutes. The precipitated crystals are separated by chromatography on silica gel and recrystallized from ethanol to give 6- 3- (4-phenyl) -1, 2,5,6-tetrahydro 1-pyridyl 1-propenyl-3,4-dihydrocarbonyl Bostyril in the form of light yellow lamellar crystals. Output 2.5 g. TPLo 182 183 ° C (with decomposition).
Analogously to Example 139, the compounds of Examples 140-146 are prepared.
Example 140. (4-Phenyl- -1 piperidyl) -1-propenyl-3,4-dihyd-
15
31 1367857
okarbostyril. Colorless plate crystals (from methanol). M.p. 163-164 ° C
Example 141. b-GB-SA-Ben zil) 1 piperidyl - 1-propenyl - 3,4-dihydrocarbostyryl. Colorless similar crystals (from ethanol). .ll 160-161 C.
Example 142. (4-Phenyl-4 acetyl l-piperidyl) l butenyl-J-3,4-dihydrocarbosteryl. Colorless lamellar crystals (from ethanol). .pl. 169-170 C.
Example 143. (4 — Me sh1phenyl) 1,2,5, b tetrahydro-1 pyrisch12-1-propenyl-3,4-dihydrocarboxylate. Light yellow plate crystals (of ethanol). M.p. 214-215 ° C.
Example 144. (4-Fensch--1,2,5,6-tetrahydro-l ™ pyridsh I) -l- -prc penyl-3,4 dihydrocar b about styryl. Light yellow lamellar crystals (from ethanol). M.p. l82: i83 ° C (with decomposition).
PRI me R 145. (4-Phenyl-1-piperidyl) -, 1-propenyl-3,4 dihydrocarbostiril. B. colored needle-like crystals (from methanol). Mp: 165-168 ° C.
Approx. 146. (2-Me topiphenyl) 1,2,5,6-tetrahydropyrivyl-propenyl-3,4 dihydrocarbity ° - pyl monooxalate. Colorless flakes, m.p. 201-205 ° C.
Example 147. 2.35 g of 6-p chloropropyl) -3.4-dihydro-carbostyryl and 1.8 g of sodium iodide in 80 ml of acetone are mixed and stirred at
20
1 bo 5 us by
bo 10 - cr
ti pa
- ri ly 11
then yes yes
op 6-1 Be T.
op 35 6 bu tv T.
40 ly my alo
25
thirty
50 ° C for 2 hours. 80 ml of dimethyl form amide are added to the reaction mixture and the acetone is distilled off, then 1.84 g of 4 Fensch piperazine and 2.0 g of triethylamine are added and the mixture is stirred for 5 h at 70--80 ° WITH. The reaction mixture is concentrated under reduced pressure to give a residue.
The residue is converted to a hydrochloride salt by addition of concentrated hydrochloric acid in ethanol. Upon recrystallization from methanol, 2.9 g of (piperidinyl) propyl-3,4 dihydrocarboyl 1 - mono hydrochloride are obtained in the form of colorless lamellar crucibles. M.p. 232 "233 ° С (with decomposition).
In analogy to Example 147., the compounds of the examples are obtained.
32
Example 148. (4-Yenyl-1-piperidyl) Propyl-354-dihydrocarbostyryl-myohydrochloride, Colorless lamellar crystalline (1z methanol). M.p. 232-233
Example 149 „6 h (- ljsHsm-- pnperidyl) propyl -3.4 digstercro booster. Colorless lamellar -crystals (from ethanol), Tp. 99 -.
Example -150. 6- 3-C4- (tilphenyl) -1-piperidyl-propyl} -3,4-ид -hydrocarbostyryl. Colorless lamellar crystals (from isopropanol-ntexan mixture). M.p. 125-126 C.
P.P. and Mer 151. 7-13 (4 - Fenshg- - -piperidyl) -propyl-3,4-carbostyryl. Colorless needle-like crystals (from a mixture of ethanol - water). M.p. 114-118 ° C.
Example 152. 6- 3-C4 -. (- 2-Metoxyphenyl) -1-piperidyl-propyl-3,4-dihydrocarbostyryl monooxalate. Bes color flake (from a mixture of ethanol - water). M.p. 178-181 ° C.
Example 153. According to the method described in example 41, (4-phenyl-1-pipera 3 ynyl) -2-methyl--1 (E) butensh 1 -3,4-dicarbostyryl is obtained. Colorless lamellar crystals. M.p. 187.0-187 ,.
Example 154. According to the method described in Example 58, (4-phenyl -1-piperazinyl) -2 methylbutyl-3,4-dihydrocarbostyryl is obtained. Colorless lamellar crystals. M.p. 167.5-167.5 C.
Calsdoe of the compounds of the general formula I has low toxicity and can be used as an active ingredient in pharmaceutical compositions.
The pharmacological activities of the compounds of general formula I have been determined. Lena by test methods. Below are the compounds used in the tests.
1.6-- 1-Oxo-3 - (4 11 eshsh 1-piperazinil) propyl-3 5 4 -dihydrocarbosti-- dr.
2.6-0xo-4 (4 phenyl 1-pinperazinyl) butyl 3, 4-dihydrocarbostyl-tironohydrochloride ”
3.6 1-Oxo 4 - 4- (2 Chlorfesh-w) 1-piperazinyl-butyl V-3,4-dihydroburostyryl monohydrochloride 5 monohydrate
4.6- 1 -OK 4- ° (3 chlorophenyl) -1
-piporasin butyl | Carbostyryl.
5.6 ((3 chlorophenyl) l-piperidinyl butyl - 3.4 dihydro carbostyryl,
6.6 l-Oxy-3 G4 (2,3 dimethylphenyl) -1-piperazinyl prop-3,4-dihydrocarbstyryl.
7.6- {1- Oxo 3 - 4 (3 - chlorophenyl) - - Npiperazinyl propyl 3,4 dihydrocarbostyryl monohydrochloride.
8.6- 3-C4-chlorofenshg-1 ° piperazinyl} -1-propenyl 1 -354 dihydrocarbostyryl.
9.b-p-G4- (2 Ethoxyphenyl) 1-piperazinyl i-propenyl-3,4 dihydro carbostyryl.
10. G4- (3 Methylphenyl b1 pipera zinyl -1-propenyl-354-dihydro
.carbostyril,
11. (4 Phenyl 1 Piperzinyl) -1 butenyl 3,4 dihydrocarbostyryl.
12. (2 Ethoxyphenyl) 1 pipa - razinyl-Ibutenyl - C54 dihydro-carbostyryl.
13.6- 3-- 4 (4 Chlorophenyl - 1 pipera zinyl 1-propenyl 3,4-dihydro carbostyryl.
14. (2 - Chlorophenyl) - 1-pipera - zinil-butsh1 354-dihydrocarbo styryl,
/ 15, 6–4–14 (–Ethoxyphenyl) rasinyl – butyl 3 J 4 dihydrocarbostyryl.
16.6 ° {3 - DM- (2 Ethoxyphenyl) 1 pipera zinyl-propyl-3, A- dihydrocarbo styryl,
17, .4 (2 Methoxyphenyl) -ipiprazinyl propnl | 3,4-dihydrocar bostyryl.
18,6- 3- (NIL-1-piper and zinyl) pro, 4-dihydrocarbostyryl,
19.6-3- (2 -Methoxyphenyl) -1 pipa razinyl-Proproyl-3, A-dihydrobrostyryl.
20.1 Metschg ° 6 1 oxo-3- (4 fensch 1-piperazinyl) propyl-3,4 dihydrocarbostyryl monooxalate.
21,1-Benzshg-6 3 4- (3 - methylphenyl) -1 -1 piperazinyl -1 prapenyl-3J4 gdihydrocarbostyryl monooxalate,
22, (4-Fensh1-1-piperidyl) -propyl-3 ,, 4-dihydrocarboxyryl,
23, (4-Methylphenyl) 1,2,5,6-tetrahydropyridyl-α-propenyl 1 -3,4-dihydrocarbostyryl,
24.6 1-Oxo-3- (4-benzyl-1-psh1eri-dil) -propyl-3 5 4-dihydrocarboxyr
25
6- 1-Oxo-4-G4- (4-chlorophenyl) -1,2,5, 6-tetrahydropyridyl butyl-3,4 - dihydrocarbostyryl, 6-1-Oxo-3-4- (4-methylphenyl) - -1,2,5,6-tetrahydropyridyl-pro-, 4-dihydrocarbostyryl, 6- {3- 4- (2-Metoxyphenyl) -1,2,5,6-tetrahydropyridyl -1-propenyl - 354-dihydrocarboxyryl mono-oxalate
6- 1 Oxo-4- (4 phenyl-1,2,5,6-tetrahydropyridyl) -butyl-3,4-dihydrocarbostyril,
6- (2-Methoxyphensh1) -1-piperidyl-propyl} -3,4-dihydrocarbostyryl monoxalate, (4 Fesh1l-1-piperazinyl) -but -carbostiryl, (2-Ethoxyphenyl) -1- piperazinyl - butenyl-carbostyryl, 6- 1-hydroxy-2- 4- (3-chlorophenyl) -1 -piperazinyl-butyl} -carbostyryl 7-3- (4-phenyl-1-piperazinyl) 1-ok- sopropyl-3,4-dihydrocarbostyryl 6- {4- 4- (3-Chlorophenyl) 1-piperazinyl -1-oxobutyl} -3,4-dihydrocarbostil,
g-, 4- (4-Chlorophenyl) -1-piperazinyl-oxybutyl} -3,4-dihydro-carboxyl,
6-4-C4- (4-Methylphenyl) -1-pipera zinyl -1-oxobutyl} -3,4-dihydrobrostyryl,
7-13- 4- (2-Ethoxyphenyl) -l-piperazinyl-1-oxopropyl-3,4-dihydroxycarbostyryl, 6-4-t4- (3,5-Dichlorophenyl) -1-piperazinyl-oxobutyl -3,4-dihydro- carbostyryl,
(2-Hpor-6-methylphenyl) -1- piperazinyl -1-butenide} -3,4-dihydrocarbostyryl; a lime preparation (2-chloro-C, K-dimethyl-10H-) was used as the reference compound. phenothiazine-10-propanamine).
A, Surrounding anesthetic activity of halothane.
The test group consisted of 10 mice (male strain ddy, weight about 20 g. Aqueous suspension of gum arabic (1 g) and test compound (80 mg) in 100 ml of physiological L-C1D diluent was orally administered to each mass in a dose of 16 l / kg of live weight After 1 h after injection, each mouse was placed in a chamber with a gas respirator (chamber size 13 x 13 x 24 cm),
26
27
28
29
thirty
31
32
33
34
35
36
37
38
39
35136785
Yes, gaseous oxygen containing 4% halothane (Z-poivr-Z-xjiop-l, 1,1-trifluoroethane) was supplied, with soon 2 liters / min for 3 minutes. The anesthetized mouse was removed from the chamber and the time between the administration of the anesthetic substance and the awakening was determined. Mice of the control group were orally administered 1% gum ara-Q biological saline at a dose of 0.1 ml / kg of body weight.
The results are shown
others
 Compound
2 3 4 5 6
Time, min
. 13.3
11.5
8.0
9.7
13.0
8.2
B. Methamphetamine and L-DOPA Induced Jumping Inhibitory Activity.
The mice (strain ddy, weight 17–25 g, a group of 6 individuals) were not given food for 24 hours. The test compound was orally administered. Forty minutes after the administration, 4 mg / kg of methamphetamine (d-N-c dimethylphenyllayin) was intraperitoneally administered, and 15 minutes after the administration of methamphetamine, 400 mg / kg of L-DOPA were intraperitoneally administered. 60 minutes after the administration of L-DOPA - 3- - (3,4-dioxyphenyl-alanic), mice
They put in a 2 l glass cup and counted the number of jumps for each pair.
Bouncing inhibition activity for test compounds was determined to be positive if the number of hops in the test subject was 10 or less.
Determine the effective dose () that causes a positive response in 3 of 6 children.
The number of hops in the control group, which, as a comparison, was injected with saline, was 150–200 per hour.
The results are shown below.
36
Chlorpromazine
20. 33
34

C. Activity against epinephrine.
The test group consisted of 10 males of the smaller ddy strain weighing 17 ° - 20 g, and the mice were not given food for 24 hours. Compounds to be tested were administered orally. One hour after the administration, intraperitoneal but 40 mg / kg epinephrine was injected. After 24 h, the number of surviving mice was counted, and the dose of the test compound was calculated, which allowed half of the animals to survive (, kg / kg} All 10 mice of the control group, injected with saline, died a few minutes after the first male mice strain ddy weighing 18- epinephrine injection ... 20 g. My moms were not given food for
The results are shown 24 hours. The compounds to be tested are 20.
25
D. Test the lowering of the century in mice. The test group consisted of 10
nor administered orally at a dose of 0.64 mg / kg.
below.
Yu male male strain ddy weighing 18 to 20 g. Misham was not given food for
D. Test the lowering of the century in mice. The test group consisted of 10
24 h. The compounds to be tested were orally administered at a dose of 0.64 mg / kg.
E. Test for antihistamine activity.
The antihistamine activity of the compounds of formula I was assessed by the following procedure.
Male guinea pigs weighing 300 - 500 g were killed, releasing blood. The ileum, 15 cm long, exfoliated from the ileum, was immersed in a solution of Tyrol containing, g: NaCl 8; KS1 0.2; CaClz 0.2; glucose 1.0; NaHCGj 1.0; NaHP04 2H20 0.065; MgCl-eHjO 0.2135 water up to 1000, Then the tissue of the intestine was cut: into pieces 2.5-3.0 cm long and suspended in a bath filled with 30 ml of Tyrol solution, the temperature in the bath was maintained at about 36 ° C and blown with a mixture of gases consisting of 5% CO and 95% Oj. After 10 minutes of purging, histamine was added to the bath to determine the sensitivity of the tissue and the reaction (control) curve relative to the histamine dose was determined. After the dose of the reaction curve of histamine (control) became constant, 10 g / ml of the test compound was added to the bath after 5 minutes to obtain a dose-response curve and. The isotonicity reaction was recorded on the recorder through an isotonic transducer (TD-112).
The antihistamine activity of the dough compound was defined as the value of RA according to the Van-Rossam method in terms of the maximum {ial reduction: the ileum caused by histamine, depicted in the control curve as 100.
The results are shown
below.

Connection 20
21
. 22 23 24
RA 1 7.58
7.31 7.01 7.81 7.23
JO-30
25
F, Acute Toxicity Test.
Each of the test compounds of general formula 1 was administered orally to male rats to determine acute toxicity (),
Studies have shown that for compounds 1-32, LD is 500 mg / kg, °
Thus, the proposed compounds have high antihistamine activity and the ability to regulate the activity of the central nervous system.

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING CARBOSTERILE DERIVATIVES of the general formula where R ₃ is a hydrogen atom, lower alkyl _; a group, a phenyl lower alkyl group, a lower alkenyl group, a lower alkynyl group;
A - group) C = 0,) CH-OH or R, R, 'I
-CH = C- —CH -CH- where R _{2 is} a hydrogen atom, a lower alkynyl group;
—— possible carbon-carbon bond,
B is a lower alkylene group;
1 ^a 1 if A is a group) C = 0 or 'CH-OH or 1 = 0 or 1 if A is a -CH group
Kg ί
or CH, —CH—;
Ζ is a group NR ₃ , where R ₃ is a phenyl or substituted phenyl group containing, from 1 to 3 substituents, a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group, a carboxyl group, a lower alkanoyl group, a lower alkylthio group, a hydroxyl nitroamino or cyano group or a lower alkylenedioxy group, phenyl lower alkyl, a 1,2,3,4-tetrahydronaphthyl group, or 14
Z - group where
R ₊ is a phenyl or substituted phenyl group containing, as a substituent, a halogen atom, lower alkyl. a lower group, a lower alkoxy group, or Ry ~ phenyl — a lower alkyl group, a lower alkyl group or a group of the formula
SU „.1367857 AZ or Ry is a hydrogen atom, ok is a group, lower alkanoyl, in case R _s is a hydrogen atom, the carbon-carbon bond in the position of the 3,4-piperidine ring can be double, and in the case of if
R _f is a hydrogen atom, a carbon-carbon bond at the position of the 3,4-carbostyryl skeleton is simple, in that the compound of the general formula
A- (B -X 'Oj-0
R, where R. ,, A, B, 1, --- have values;
X ~ halogen atom, these are reacted with a compound of the general formula
HN 2 where Z has the abovementioned meaning, at from room temperature to 200 C ^and subsequent isolation of the desired products.
ΪΙ ор ор и те те ри ри зн зн зн зн ак ам ам.. 03/06.80 A - group - С- or) СН — ОН / ί о
R ₃ is all values except the phenyl lower alkyl group, 08.20.80. A, - group —CH = C— /

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HU194233B|1988-01-28|Process for preparing 3,7-diazabicyclo/3.3.1/nonane derivatives and pharmaceuticals comprising these compounds

同族专利:

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公开号 | 公开日

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FR2477542A1|1981-09-11|

---

CA1155119A|1983-10-11|

---

MX6980E|1987-01-19|

---

RU1779249C|1992-11-30|

---

NL184364B|1989-02-01|

---

DK155282B|1989-03-20|

---

FI810669L|1981-09-07|

---

CH647775A5|1985-02-15|

---

ES509658A0|1983-04-01|

---

US4567187A|1986-01-28|

---

ES8305356A1|1983-04-01|

---

US4619932A|1986-10-28|

---

US4455422A|1984-06-19|

---

NL8101099A|1981-10-01|

---

ES8405782A1|1984-06-16|

---

PT72622B|1982-06-15|

---

ES518667A0|1984-06-16|

---

BE887800A|1981-09-07|

---

PH17194A|1984-06-19|

---

DE3107601A1|1982-02-04|

---

AT381307B|1986-09-25|

---

NO159531C|1989-01-11|

---

SE447255B|1986-11-03|

---

PT72622A|1981-04-01|

---

FI76323C|1988-10-10|

---

GB2071094A|1981-09-16|

---

IT1144315B|1986-10-29|

---

SE8101409L|1981-09-07|

---

DE3152880C2|1990-03-22|

---

NO159531B|1988-10-03|

---

ATA98481A|1986-02-15|

---

NO810765L|1981-09-07|

---

ES8301962A1|1982-11-01|

---

ES500137A0|1982-11-01|

---

IT8167311D0|1981-03-05|

---

AU523005B2|1982-07-08|

---

ES8306141A1|1983-05-01|

---

ES509659A0|1983-05-01|

---

DK99781A|1981-09-07|

---

US4460593A|1984-07-17|

---

NL184364C|1989-07-03|

---

FI76323B|1988-06-30|

---

FR2477542B1|1983-09-09|

---

GB2071094B|1984-09-26|

---

DE3107601C2|1989-07-20|

---

DK155282C|1989-08-07|

---

AU6797381A|1981-09-10|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP55028805A|JPS6325585B2|1980-03-06|1980-03-06|

---

JP55115022A|JPS6320430B2|1980-08-20|1980-08-20|

---