Method of producing derivatives of carbostyryl or hydrogenhalide salts thereof

专利摘要:
A piperazinylcarbostyril compound of the formula (I) <IMAGE> (I) wherein R1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R2 represents a hydrogen atom or a lower alkoxy group; R3 represents a hydrogen atom, a lower alkanoyl group, a furoyl group, a pyridylcarbonyl group, a lower alkanesulfonyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenylsulfonyl group which may be substituted with a lower alkyl group on the benzene ring thereof, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a phenylcarbonyl group, a phenyl-lower alkyl group or a phenyl-lower alkanoyl group where each of said phenylcarbonyl group, phenyl-lower alkyl group and phenyl-lower alkanoyl group may be substituted with 1 to 3 of a lower alkoxy group, a halogen atom, a lower alkyl group, a cyano group, a nitro group, an amino group, a hydroxy group, a lower alkanoylamino group, a lower alkylthio group and a lower alkanoyloxy group, or with a lower alkylenedioxy group on the benzene ring thereof; and the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; or its pharmaceutically acceptable salt, useful as a cardiotonic agent.
公开号:SU1426452A3
申请号:SU813349303
申请日:1981-10-29
公开日:1988-09-23
发明作者:Томинага Митяки；Янг Юнг-Хсиунг；Огава Хиденори；Накагава Казуюки
申请人:Оцука Фармасьютикал Ко., Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of carbostyryl compounds or their halohydrogen salts of the general formula
- /
e R is hydrogen, methyl, allyl, pro 5 pargyl, benzyl;
Rj is hydrogen, methoxy;
Rj is a hydrogen, lower alkanoyl group, cC-Fzphoipnna group, p-pyridylcarbonyl-20 group, methanesulfonyl group, ethoxynarbonyl-group, ethoxycarbonylmethyl group, para-tolylsulfonyl group, low-25-alkyl group, a lower alkenyl group, a pro-pargyl, benzoyl group, possibly substituted by 1–3 methoxy groups, 1–2 nitro – Z groups, ethoxy group, 12 chlorine atoms, methyl or ethyl group, or a bromine atom, cyano, amino, acetylamino methylthio-, acetyloxy-, 3,4-methycdioxy-sgruppa or hydro igrup- sing;
n RJ is phenyl C-C-alkyl group, benzyl group, substituted by 1-2 methoxy groups, 1-2 chlorine atoms, methyl group, cyano group, nitro group, amino group, 3,4-methylenedioxy- group, or hydroxy group,
whether an EZ is a phenylpropanoyl group, a phenylacetyl group substituted by a methoxy or hydroxy group, a bond between
3 and 4 of the positions of the carbostyrene core are single or double bond; moreover, if R is a methoxy group, then R, is hydrogen, and RJ is benzoyl, substituted by a dimethoxy group, and if between positions 3
0
five
0 5 o
,
d
and 4 carbostyril core there is a double bond, then R is hydrogen,
or their halogen salts with cardiotonic properties.
The purpose of the invention is to obtain new carbostyril derivatives, which have a degraded cardiotonic effect in comparison with the known analogue.
Example 1, A mixture of 9.36 g of 6-amino-3, 4-dihydrocarboxyate, 18 g of monobromohydrate. Bis (-bromostip) amine and 70 ml of methanol are heated under reflux for 15. h with stirring. After cooling, 3.06 g of sodium carbonate was added and the resulting mixture was heated under reflux for 8 hours while stirring. The reaction mixture is cooled, as a result of which crystals are precipitated, which are then collected by filtration, and the crystals are washed with methanol, resulting in 9.1 g of 6- (1-piperazinyl) -3,4-dihydrocarostyryl hydrobromide, t pl, (with dec.) 289- (methanol-water), colorless needles.
Calculated,%: C 50.00; H 5.77; N 13.46.
Found,%: C 49.95; H 5.82; N 13.50.
Example 2. Carrying out the processes in the same manner as in Example 1, monochlorine monohydrate is obtained - 5- (1-piperazinyl) -3,4-dihydrocarbostyril hydrate, mp, 300 ° C (methanol), colorless needles.
Example 3. A mixture of 9.36 g of 6-α-amino-3,4-dihydrocarbostyril, 18.3 g of S, N- (di- -bromoethyl) -3,4-dimethoxybenzamide and 70 ml of methanol is heated under a back-flow counter for 15 hours with stirring. After cooling, 3.06 g of potassium carbonate is added and the mixture is heated under reflux for 8 hours while stirring. The reaction mixture is cooled, whereby crystals are precipitated, which are then collected by filtration. Recrystallization from ethanol-chloroform to give 8.5 g of 6-R- (3,4-dimethoxybenzoyl) -1-piperazinyl-3,4-dihydrocarbostyril, mp 238-239.5 C, colorless granules.
Calculated,%: C, 66.84; H 6.33;
N10.63.
Found,%: C 66.71; H 6.51j N10.52.
Examples 4-48. Carrying out the processes in the same manner as described in g. 3, the following compounds were prepared using the corresponding starting materials:
6-D- (4-methoxybenzyl) -1-piperazinsh1 -, 4-dihydrocarbostyryl, t.p. C 196-198 C (ethanol), colorless needles (Example 4);
(p-toluenesulfonyl) -1-piperazinyl-3,4-dihydrocarbyls1, t. pl. 302-304 C (dimethylformamide), colorless powder (example 5); .
hemihydrate of monohydrochloride 6- (4-. -butyl-1-piperazinyl) -3,4-dihydrocar-bostyril, t. pl. (from Rael.) 279 - 28 G C (methanol) (Example 6); 20
5- (4-benzoyl-1-piperazinyl) -3,4-dihydrocarbostyryl, m.p. 248-251 C (ethanol), colorless needles (example 7 /;
6- (4-benzoyl-1-piperazinyl) -dihydrocarbostyryl, m.p. 221-222.5 ° C (ethanol), pale yellow granules (Example 8);
5-1 4- (3,4-dimethoxybenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl,
5-C4- (3,4-dichlorobenzoyl) -1-pipera zinyl-3,4-dihydrocarbostyryl, mp 250-252 s (methanol), colorless powder (example 17);
5- 4- (3,5-dichlorobenzoyl) -1-piperazinyl-3,4-difincrocarbostil, t.p. 255-257 C (methanol - chloroform), colorless needles (example 18);
6-L4- (4-bromobenzoyl) -1-piperazi-, 4-dihydrocarbostyryl, m.p. 233-234.5 C (methanol-chloroform), colorless granules (example 19);
5-.4- (4-cyanobenzoyl) -1-piperazi-15, 4-dihydrocarboster, 1 t. Pl. 266-269 C (methanol - chloroform), colorless granules, (example 20);
(4-nitrobenzoyl) -1-piperazi-, 4-dihydrocarbostyryl, m.p. 235-236, (methanol - chloroform), yellow flakes (Example 21); .
(3,5-dinitrobenzoyl) -1-pipa razinyl-3,4-dihydrocarbostyryl, mp, 262-264 ° C (methanol - chloro-25 forms), reddish-black needles (about measures 22);
(4-aminobenzoyl) -1-piperazioyl-3,4-dihydrocarbostyryl, mp 244-246 0 (ethanol), pale yellow
t, pl, 2SG7-208 C (ethanol), colorless 30 needles (example 23); powder (Example 9) (4-hydroxybenzoip) -1-piperazi-4- (3, A.5-trimethoxybenzoyl) -1-nyl-3,4-dihydrocarbylin 1, t, pl. piperazinyl-3,4-dihydrocarboxyryl,
m.p. 250-251.5 ° C (isopropanol), colorless granules (Example 10);
(3,4,5-trimethoxybenzoyl) -1- piperazinsh1-3,4-dihydrocarbostyryl, m.p. 180-182 C (isopropanol), colorless granules (example P);
hemihydrate (4-methoxybenzr-sp) -1-piperazinyl J-3,4-dihydrocarbog. styryl, m.p. 212-213 ° C (methanol), colorless needles (example 12);
6- (4-acetyl-1-piperazinyl) -3,4-di-hydrocarboster, m.p. 203-205 C (isopropanol), pale yellowish-brown needles (Example 13);
6- (4-furoip-1-piperazinyl) -3,4-dihydrocarbostyryl, mp, 206.5-207, (ethanol), pale yellow granules (Example 14);
(2-propynyl) -1-piperazinyl-3,4-dihydrocarbostyryl, t, mp, 174-176 ° C (isopropanol) (Example 15);
6-14- (4-chlorobenzoyl) -1-pn1erazi-. , 4-dihydrocarboyl, t, pl, 233-235 C (methanol), pale yellow needles (Example 16);
above (methanol - chloroform), colorless granules (example 24);
(3,4-methylenedioxybenzoyl) -1-piperazine-1 -3, 4-dihydrocarboxyryl, m.p. 191-192,5 C (methanol), colorless, needles (example 25);
5- 4- (4-methipbenzoyl) -1-pshterazy
40nyl3-3,4-dihydrocarbostyril ,. t, hsh, 239.5-240 0 (chloroform - ester growth), colorless powder (example 26
(methanesulfonyl) -1-piperazinyl} -3,4-dihydrocarbostyryl, t, mp,
45,241.5-243 ° O (methanol), colorless granules (Example 27);
monohydrochloride 5- (4-etsh1-1-pipera zinil-) 3,4-dihydrocarbostyril, t, n (with razl,). 293-296 ° 0 (methanol), without gQ colored granules (example 28);
6- (4-allyl-1-piperazinyl) g3, 4-di-hydrocarboster, t, pl. 175-176 ° (chloroform - ether), colorless 5g scales (Example 29);
(2-propynyl) -1-piperazinyl--1,4-dihydrocarboxystyrene, m.p. pl, 225-226 ° O (chloroform), pale yellow po) oshk (example 30);
g t. Yu
-- 20
;
426452
5-C4- (3,4-dichlorobenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl, m.p. 250-252 with (methanol), colorless powder (example 17);
5- 4- (3,5-dichlorobenzoyl) -1-piperazinyl-3,4-difincrocarbostil, t.p. 255-257 C (methanol - chloroform), colorless needles (example 18);
6-L4- (4-bromobenzoyl) -1-piperazi-, 4-dihydrocarbostyryl, m.p. 233-234.5 C (methanol-chloroform), colorless granules (example 19);
5-.4- (4-cyanobenzoyl) -1-piperazi-15, 4-dihydrocarboster, 1 t. Pl. 266-269 C (methanol - chloroform), colorless granules, (example 20);
(4-nitrobenzoyl) -1-piperazi-, 4-dihydrocarbostyryl, m.p. 235-236, (methanol - chloroform), yellow flakes (Example 21); .
(3,5-dinitrobenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl, mp, 262-264 ° C (methanol - chloro-25 forms), reddish-black needles (about measure 22);
(4-aminobenzoyl) -1-piperaziyl-3,4-dihydrocarbostyryl, mp, 244-246 0 (ethanol), pale yellow
, 4-dihydrocarboster1, t, pl.
above (methanol - chloroform), colorless granules (example 24);
(3,4-methylenedioxybenzoyl) -1-piperazine-1 -3, 4-dihydrocarboxyryl, m.p. 191-192,5 C (methanol), colorless, needles (example 25);
5- 4- (4-methipbenzoyl) -1-pshterasin-3, 4-dihydrocarbostyryl ,. t, gs, 239.5-240 0 (chloroform - ester growth), colorless powder (example 26);.
(methanesulfonyl) -1-piperazinyl} -3,4-dihydrocarbostyryl, t, mp,
241.5-243 ° O (methanol), colorless granules (Example 27);
monohydrochloride 5- (4-etsh1-1-piperazinyl-) 3,4-dihydrocarbostyril, t, pl. (with dec,). 293-296 ° 0 (methanol), colorless granules (Example 28);
6- (4-allyl-1-piperazinyl) g3, 4-di-hydrocarboster, t, pl. 175-176 ° (chloroform - ether), colorless scales (Example 29);
(2-propynyl) -1-piperazinyl--1,4-dihydrocarboxystyrene, m.p. pl, 225-226 ° O (chloroform), pale yellow po) oshk (example 30);
514264526
(2-butenyl) -1-piperazilyl monohydrochloride monohydrate, 4-dihydrocarbostyryl, m.p.- (3,4-dichlorobenzide) -1-piperazinyl (with dis.) 242-245 s (Example 31); - 3, 4-dihydrocarboster, t. Pl.
1-benzp-6- 4- (3,4-di- 5 dec. hemihydrate) 298.5-300 0 (methanol), methoxybenzoyl) -1-piperazinyl-3,4-colored granules (Example A5);
- dihydrocarbostyril, t. pl. 131, (4-nitrobenzsh1) -1-piperazinyl
132, (ethanol), yellow powder-3,4-dihydrocarbostyryl, so pl. (with
(Example 32); decomp.) 268-271 C (methanol), pale hemihydrate 1-allyl-3- 4- (3,4-dime - 10 yellow powder (example 46), toxibenzoyl) -1-piperazinyl-3, 4-di-monohydrate dihydrochloride (4-,
hydrocarbonyl, t. pl. 120-122 C-aminobenzyl) -1-piperazinyl-3,4-di (methanol: ether), colorless hydrocarbostyril, t. Pl. (with dec.) granules (Example 33); 224-227 with (methanol - ether),
- 1- (2-propinsh1) (3,4-dimethok-15 yellow granules (example 47); ribekzoyl) -1-piperazinyl-3,4-dihydrochloride (4-methylbenzsh1) | rocarbostiril, so pl. 152-154 C (eta--1-piperazinyl-3,4-dihydrocarbyl-nol), pale yellow needles (Example 34); Rila, so pl. Cc decomp.) 272-273 C
1-metsh1-6-4- (3,4-dimethoxybenzo- (methanol - water), colorless powder
-1p) -1-psh1erazinyl) -3,4-dihydrocarbo-20 (Example 48);
gtiril, so pl. 146.5-147, (isopro-dichlorohydrate 5- (T- (3,4-dimethoxy: anol), pale yellow granules (at-benzyl) -1-piperazinyl7-3,4-dihydromer 35) ;. carbostyril, mp. (with different). 2708-methoxy-6-4- (3,4-dimethoxyben. (Example 49);
} oyl) -1-piperazinsh12-3,4-dihydrocar- 25 6- (4-ethoxycarbonyl-1-pn1erazinyl) | 5stiril, so pl. 162.5-163.5 ° e (iso-booster, pl. 223-224 C (metalpropanol), colorless needles (Zb example), zero), yellow needles (Example 50); I (3-chlorobenzosh1) -1-piperazi- (3-chlorobenzoyl) -1-piperaziyyl-3, 4-dihydrocarbostyryl, mp, nil carbostyryl, mp. 250.5-252 С
t95-197,5 С (methanol), colorless30 (methanol - chloroform), yellow powder
| Scraps (example 37); . (example 51);
I 5-G4- (4-methoxybenzosh1) -1-pipera-6-4- (4-chlorobenzoyl) -1-piperazi 1in-3, 4-dihydrocarbostyryl, t. Pl. .nil carbostyril t. pl. € 265-2.66; 19-220 ° C (methanol - chloroform), bes- (methanol - chloroform), colorless colored needles (Example 38); 35 powder (Example 52);
5- (4-ztoxycarbonylmethyl-1-pipera-6-4- (4-methoxybenzoyl) -1-pipera ynyl) -3,4-dihydrocarbostyryl, m.p. zinyla carbostyr silt, t. pl. 230-233 С 06-208 С (methanol), colorless needles (methanol - chloroform), yellow needles
(Example 39); (Example 53);
(4-formyl) -1-piperazinyl-3.4-40 (3,4-dimethoxybenzoyl) -1-pydihydrocarbostyril, m.p. 263-265 with perazinyl-carbostil, so pl. (c (methanol), colorless granules (by-decomp.) 265-266.3 s (methanol - chloroHiep 40); forms), yellow granules (example 54);
6- (4-ethoxycarbonyl-1-piperazinsh1) (3,4,5-trimetho | sibenzoyl) -1-3, 4-dihydrocarbostyryl, t. Pl. 182.5-45 piperazinyl carbostyryl, m.p. . 184 C (isopropanol), colorless needles 249.5-250 ° C (methanol - chloroform),
(Example 41);. Yellow needles (Example 55);
(4-methoxybenzyl) -1-piperazi-6-4- (4-cyanobenzoyl) -1-piperaziNil-3, 4-dihydrocarbostyryl, t. Pl. Or nyrobirocil, t. Pl. (with different)
194-1.9b with (methanol), colorless needles 50 300-301 0 (methanol - chloroform), (seller 42); yellow powder (example 56);
monohydrochloride (2-phenethyl) -6- | 4- (3,4-methoxy-1-Dioxybenzoyl) 1-piperazinyl-3, 4-dihydrocarbosty - 1-piperazinyl Carbostyryl, m.p.
Rila, so pl. Cc decomp.) 274–276 ° C (me; (decomp.) - 266–267 ° C (methanol – chlorotanol), colorless powder (example 43); 55 roform), yellow powder (example 57); ,
(4-Chlorobenzyl) -1-piperazinyl-6-4- (4-nitrobenzosch1) -1-piperazi-3, 4-dihydrocarbostyryl, mp, 190-nil carbostyryl, mp. (with decomp.) 265191, 5 ° С (chloroform - methanol), bes-266 ° С (methanol - chloroform), yellow
colored needles (example 44); needles (example 58);
71A26A528
(4-aminobenzoyl) 1-piperaz- (ethanol), colorless scaly-N-carbostyryl, t. Pl. 287-290 C (chloroform - methanol), yellow powder
.five
(example 59);
 (A-benzoyl-1-piperazinyl) carbostyryl, m.p. 26A-265 C (ethanol - chloroform), yellow needles (example 60);
(4-acetylaminobenzoyl) -1-piperazinyl 1-3, A-dihydrocarbostyri.p, so pl. above (chloroform - methanol), colorless powder (example 61);
(A-formyl) -1-piperazinyl carbostyryl, m.p. 286.5-288 s (meta10
Ki (example 7A);
8- A- (3, A-dimethoxybenzoyl) -1-piperazinsht-3, A-dihydrocarbostyryl, t. Pl. liS-lAB C (ethanol), colorless scales (Example 75);
8- A- (A-methylthiobenzoyl) -1-piperazinyl-3, A-dihydrocarboxyryl, m.p. 178-179.5 C (ethanol), colorless granules (example 76);
(2-Chlorobenzoyl) -1-piperazinyl-3, A-dihydrocarboxyrip, t. Pl. 19A- 195, (methanol), colorless needles
nol), yellow scales (Example 62); 15 (approx. 77);
(A-methylthiobenzoyl) -1-pipera-7- A- (3-chlorobenzoyl) -1-piperazinyl
Zinil carbostyril, so pl. 2A7.5 - 2A9.5 ° C (chloroform - methanol), yellow needles (Example 63);
(Z-pyridylcarbonate) - piperazinyl-3, A-dihydrocarbostyryl, t. Pl. 250-252 C (ethanol), yellow needles (example 6A);
(A-methoxyphenylacetyl) -1-piperazinyl 1-3, A-dihydrocarbostyryl, so pl. 266-268, (methanol), yellow powder (Example 65);
6- (A-phenylpropionyl-1-piperazinyl) -3, A-dihydrocarboxyryl, m.p. 189.5-191 С (chloroform - methanol), yellow granules (example 66);
8; 1.A-benzryl-1-piperazinyl | carbostyryl, m.p. 2AA-2A5 C (ethanol), colorless powder (Example 67); 8-A- (A-chlorobenzoyl) -1-piperazinyl carboxyl, m.p. 255.5-257 ° C (ethanol - chloroform), colorless powder (example 68);
(Z-chlorobenzoyl) -1-piperazinyl} carbostyryl, m.p. 208-209 ° C (ethanol), colorless granules (example 69);
8- A- (2-chlorobenzoyl) -1-piperazinyl carbostyryl, t. square 239-2AO, 5 C (ethanol), colorless needles (example 70);
(A-methoxybenzoyl) -1-piperazine carbostyril, m.p. 208-210 s (ethanol), colorless nonshuyki (example 71);
-3, A-dihydrocarbostyril, t. Pl. 136.5-138, (ethanol), colorless powder (Example 78);
(3, A-dimethoxybenzoyl) -1-pi-.50 (Example 85);
207-1 A- (A-chlorobenzoyl) -1-piperazi--:
, A-dihydrocarbostyril, t. Pl. 289-291 ° C (chloroform-methanol) colorless powder (Example 79);
7-C-methoxybenzoyl) -1-pipera-. 25 zinilJ-3, A-dihydrocarbostyril, t. Pl. 231-233 C (ethanol), colorless needles (Example 80);
(3, A-methylenedioxybenzoyl) -1 -1 piperazinyl-3, A-dihydrocarbosti-30ril, so pl. 207-208 ° C (ethanol), colorless powder (Example 81);
7- CA- (A-nitrobenzoyl) - -piperazine-3}, A.-dihydrocarbostyril, t. Pl. 2AO-2A2 C (chloroform - methanol), yellow granules (example 82);
(3, A.5-trimethoxybenzoyl} -1- β-pepep (azinylJ-3, A-dihydrocarbostyryl, m. N. 195-196, (methanol), 4o colorless diamond crystals: (Example 83);
7-fA-benzoyl-1-piperazinyl-3, A- -dihydrocarbostyryl, t. Pl. 26A, 5 - 265, (chloroform - methanol), needleless, colored needles (Example 8A); 45 G4- (3, A-dimethoxybenzoyl) -1-piperazinyl-3, A-digicrocarbosterine1, t. Pl. 118-120 C (ethanol), dried under reduced pressure at 80 C for 5 hours; colorless granules.
perazinyl carbostyryl, mp, 197 - 198 ° C (ethanol - ether), bes7-4- (A-methylthiobenoyl) -1-piperazinyl-3, A-dihydrocarbostyryl. m.p. 258-260 C (chloroform - methanol), colorless flakes (example 72);
(3, A-methylenedioxybenzoyl) -1-colored diamond-shaped crystals (at-piperazinyl-3, A-dihyd rocarbostyryl, 55 P 6);
m.p. 95-G97 with (ethanol), colorless 7- {A-phenylpropionyl-1-piperazinyl
scales and (example 73); .. -3, A-dihydrocarbostyril, so pl. 1838- A- (3-chlorobenzoyl) -1-piperazi-18A ° C (ethanol), colorless needles
, A-dihydrocarbostyril, t. Pl. (Example 87);
 (ethanol), colorless scales
Ki (example 7A);
8- A- (3, A-dimethoxybenzoyl) -1-piperazinsht-3, A-dihydrocarbostyryl, t. Pl. liS-lAB C (ethanol), colorless scales (Example 75);
8- A- (A-methylthiobenzoyl) -1-piperazinyl-3, A-dihydrocarboxyryl, m.p. 178-179.5 C (ethanol), colorless granules (example 76);
(2-Chlorobenzoyl) -1-piperazinyl-3, A-dihydrocarboxyrip, t. Pl. 19A- 195, (methanol), colorless needles
(Example 77);
7- A- (3-chlorobenzoyl) -1-piperazinyl
-3, A-dihydrocarbostyril, t. Pl. 136.5-138, (ethanol), colorless powder (Example 78);
(example 85);
(A-chlorobenzoyl) -1-piperazi--:
, A-dihydrocarbostyril, t. Pl. 289-291 ° C (chloroform-methanol) colorless powder (Example 79);
7-C-methoxybenzoyl) -1-pipera-. ZinilJ-3, A-dihydrocarbostyril, t. pl. 231-233 C (ethanol), colorless needles (Example 80);
(3, A-methylenedioxybenzoyl) -1 -1 piperazinyl-3, A-dihydrocarboxyryl, m.p. 207-208 ° C (ethanol), colorless powder (Example 81);
7- CA- (A-nitrobenzoyl) - -piperazine-3}, A.-dihydrocarbostyril, t. Pl. 2AO-2A2 C (chloroform - methanol), yellow granules (Example 82);
(3, A.5-trimethoxybenzoyl} -1- β-pyper (azinylJ-3, A-dihydrocarbostyryl, m. Nn, 195-196, (methanol), colorless diamond-shaped crystals, example 83);
7-fA-benzoyl-1-piperazinyl-3, A- -dihydrocarbostyryl, t. Pl. 26A, 5 - 265, (chloroform - methanol), colorless needles (Example 8A); G4- (3, A-dimethoxybenzoyl) -1-piperazinyl-3, A-digicrocarbosterine 1, so pl. 118-120 C (ethanol), dried under reduced pressure at 80 C for 5 hours, colorless granules.
(example 85);
(A-methylthiobenoyl) -1-piperazinyl-3, A-dihydrocarbostyryl. m.p. 258-260 C (chloroform-methanol), colorless diamond-shaped crystals (at 6-4- (4-methoxyphenylacetyl) -1-piperazinyl carbostyryl, mp 224-225 C (ethanol), yellow needles (example 88);
(4-hydroxyphenylacetyl) -1-piperazinyl carbostyryl, mp, above 300 ° C (dimethylformamide) yellow powder (Example 89);
5- 4- (4-: nitrobenzoyl) -1 piperazi-, 4-dihydrocarbostyryl, m.p. (with dec.) 292-294 0 (methanol - chloroform), yellow granules (example 90);
5- (4-aminobenzoyl) -1-piperazi-, 4-dihydrocarbostyryl, t, pl. (with dec.) 285-287 with (methanol - chloroform), yellow granules (example 91).
Example 92. 6- (1-piperazinyl) -3,4-dihydrocarbostyryl monobromide (3.5 g) is suspended in 40 ml of dimethylformamide (DMF). After addition of 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes in order to convert the starting compound to 6- (1-pipa razinyl) 3,4-dihydrocarbostyryl. Then, 2.34 ml of triethylamine is added to the mixture and stirred at room temperature while slowly adding 1U ml of DMF solution containing 2.9 g of 3,4-dimethoxybenzoyl chloride in drops. After the addition is complete, the reaction mixture is stirred for 30 minutes, poured into a large amount of brine and extracted with chloroform. The extract is washed with a saturated sodium bicarbonate solution, then with water and dried over anhydrous sodium sulphate. Chloroform was distilled off and the remaining crystals were recrystallized from chloroform-ethanol. As a result, 3.8 g of 6- (3,4 Dimethokeibenone) -I-piperazinyl-3,4-dihydrocarbatiryl were obtained, mp 238-239.5 C, colorless granules.
Calculated,%: C, 66.84; H 6.33; N 10.63.
Found,%: C 66.69; H 6.49; N 10.51.
Carrying out the processes in the same manner as described in Example 92, and using the appropriate starting materials, the same compounds are obtained as in Examples 7-14, 32-36, 41, 50-61 and 63-91.
Example 93. 6- (1-piperazinyl) -3,4-dihydrocarbo-C | Tyril monobromide (1 g) is suspended in 15 ml
DMF. After the addition of 296 mg of sodium carbonate, the suspension is stirred at room temperature for 30 minutes, with the aim of converting the starting compound to 6- (1-piperazinyl) -3,4-dihydrobrostyryl. Then, 0.62 ml of triethylamine is added to the mixture and stirring is carried out at room temperature while slowly adding 5 ml of DMF solution containing 532 mg of methachlorobenzononechloride in drops. After the addition is complete, the reaction mixture is stirred at room temperature for 1 hour, poured more into a large amount of water and extracted with chloroform. Extract washed us | Sodium bicarbonate solution and then water is dried over anhydrous sodium sulphate. Chloroform was distilled off and the remaining crystals recrystallized from methanol, resulting in 0.4 g of 6- | 4- (3-chlorobenzoyl) -1 -1 piperazinyl-3,4-dihydrocarbastryl, m.p. GS7-197,5 ° C, colorless scales.
Calculated,%: C 65.04; H 5.42; N 11.38.
Found,%: C 64.99; H 5.35; N P, 45.
Example 94. 6- (1-piperazinyl) -3,4-dihydrocarbostyryl monobromide (3.5 g) is suspended in 40 ml DMF. After the addition of 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes in order to be converted to 6- (I-piperazinyl) -3,4-dihydrocarbytyl. Then, 2.34 ml of triethylamine was added to the mixture and the mixture was stirred at room temperature while slowly adding 10 ml of a solution of DMF containing 2.5 g of 4-chlorobenzoyl chloride dropwise. After the addition is complete, the reaction mixture is stirred for 30 minutes, poured into a large amount of water and extracted with chloroform. The extract is washed with a saturated sodium bicarbonate solution and then with water and dried over anhydrous sodium sulphate. Chloroform was distilled off and the remaining crystals recrystallized from methanol, resulting in 0.7 g of 6-G4 - - (4-lorbenzoyl) -1-piperazinyl-3,4- -dihydrocarbostil, mp. 233 - 235 s, pale yellow needles.
Calculated,%: C 65.04; H 5.42; N 11.38.
eleven
Found,%: C 64.89; H 5.30; And 11.51.
Example 95. 5- (1 Piperazinyl) -3,4-dihydrocarbostyryl monobromide (2.6 g) and triethipamine (2.34 ml) are dissolved in 40 ml of DMF. The mixture is stirred at room temperature with a slow addition of 10 ml of a solution of DMF containing 2.5 g of 4-methoxybenzene chloride and dropwise. After the addition is complete, the reaction mixture is stirred for 30 minutes, poured into a large amount of water and extracted with chloroform. Extract washed with saturated sodium bicarbonate solution and then with water and dried over anhydrous sodium sulfate. Chloroform is distilled and the remaining Cree
15 N
12 Calculated,%: C 59.55; H 4.71;
C 59.43; H 4.83;
.
. Found,% 5 N 10.31.
Example 97 6- (1-Piperazinyl) -3,4-digidrocarbostyrip (2.6 g) and sodium bicarbonate (1 g) are added to 50 ml of dimethyl sulfoxide and the mixture is stirred while cooling with ice while slowly adding dropwise 20 ml of dimethyl sulfoxide solution containing 3.2 g of 4-bromobenzoyl chloride. At the end of the addition, the reaction mixture is stirred at a natal temperature of 60 minutes, poured into a large amount of water and extracted with chloroform.
the steels are recrystallized from 20 with a saturated solution of bicarbium and chloroform - methanol, resulting in 1.1 g of 5-G4 g of (4-methoxy-benzoyl) -1-piperazinyl-3,4-dihydrocarbostyrnla, m.p. 219-220 ° C, colorless needles.
N
N
Calculated,%: C 69.04; H 6.30; 13.15. Found,%: C 68.95;; H, 6.21;
13.24 ..
Example 96. 5- (1-Piperazinyl) -3,4-dihydrocarbostyryl monobromide (3.5 g) is suspended in 40 ml of DMF. After addition of 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes in order to convert the starting compound to 5- (1-piperazinyl) -3,4-dihydrocarbostil. Then, 2.34 ml of triethylamine is added to the mixture and the mixture is stirred at room temperature while slowly adding 10 ml of a solution of DMF dropwise containing 3.0 g of 3.5-dichlorobenzoyl chloride. After the addition is complete, the reaction mixture is stirred for 40 minutes, poured into a large amount of brine and extracted with chloroform. The extract is taken up with a solution of sodium bicarbonate and then with water and dried over anhydrous sodium sulphate. Chloroform is distilled off and the remaining crystals are recrystallized from methanol-chloroform, resulting in 1.8 g of 5-14- (3,5-dichlorobenzoyl) -1- piperazinyl1-3,4-dihydrocarboxyryl, m.p. 255-257 C, colorless needles.
sodium sodium and then water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the remaining crystals are recrystallized from 25 chloroform-methanol, resulting in 0.8 g of (4-bromobenzyl) -1-piperazinylJ-3,4-dihydrocarbostyryl. That pl. 233-234 ,, colorless granules ..
N
Calculated 10.14.
C, 57.97; H 4.83;
Found,%: C 57.79; H 4.71; N 10.23.
Example 98 5- (1-Piperazinyl) -3,4-dihydrocarbostyryl (2.6 g)
trimethylamine (2 ml) was added to 40 ml of DMF. The mixture is stirred at room temperature with a slow addition of 10 ml of a solution of DMF containing 2.4 g of dropwise.
4-cyanobenzoyl chloride. . By the end-. After the addition, the reaction mixture is stirred at 40-50 ° C for 30 minutes, poured into a large amount of water and extracted with chloroform. The extract is washed with a solution of sodium bicarbonate and then dried with water over anhydrous sodium sulphate. Chloroform is distilled off and the remaining crystals are recrystallized. Lick up from methanol-chloroform
obtaining 1.9 g of 5- (4-cyanobenzoyl) - -l-piperazini-IJ-3,4-dihydrokap batitil, m.p. 266-269 0, colorless granules.
Calculated,%: C 70.00; H 5.56; N 15.56.
Found,%: C 7p, 14; H 3.71; N 15.43.
Example 99 6- (1-Piperazinip) -3,4-dihydrocarbostyryl (2.6 g) and pyridine (2 ml) are added to 40 ml of DMF. The mixture is stirred at room temperature with a slow addition of Hiffl 10 ml of DMF solution containing 2.7 g of 4-nitrobenzoyl chloride dropwise. After the addition is complete, the reaction mixture is stirred at the same temperature for 30 minutes, poured into a large amount of water and extracted with chloroform. The extract is washed with sodium bicarbonate solution and then with water and dried over anhydrous.
sodium sulfate. Chloroform was distilled off 20 N 10.42,
/ and the remaining crystals recrystallize from methanol-chloroform, to obtain 2.4 g of 6-G4- (4-nitrobeisoyl) -1-pipersinil-3,4-dihydrocarbostyryl, m, pl, 235.5-236, 5 C,
Calculated,%: C 63.15; H 5.30; N 14.73,
Found,%: C 63.09; H 5.35; N 14.77.
Example 100. 6- (1-Piperazinyl) -3,4-dihydrocarbostyryl (2.6 g) and triethylamine (2.34 ml) are added to 40 ml of dimethyl sulfoxide and the mixture is stirred at room temperature while slowly adding dropwise 10 ml of dimethyl sulfoxide solution containing 3.3 g of 3,5-dinitrobenzoyl chloride. After the addition is complete, the reaction mixture is stirred at
Found,%: C 59.38; H 4.82; N 10.34,
Example 102, 6- (l-Pipepazinyl) -3, 4-dihydrocarbostyryl (2.6 g)
25 and triethylamine (2.34 ml) are added to 40 ml of DMF. The mixture is stirred at room temperature while slowly adding 10 ml of a solution of DMF containing 2.7 g of 3,4-methylene 30 dioxybenzoylchloro in drops. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes, pour it into a large amount of water and extract with chlorofor. The extract is washed with sodium bicarbonate solution and then with water and dry dried over anhydrous sodium sulfate. Chloroform is distilled off and the remaining crystals are recrystallized from a smekomnatnoy temperature for 30 minutes, pouring 40 x methanol-chloroform to obtain 1.6 g of it in a large amount of water and (3,4-methylenedioxybenzene 1) -1- extracted with chloroform. The extract of α-piperazinyl-3,4-dihydrocarbostyri is washed with a saturated bicarc solution, t, mp, 191-192.5 colorless sodium bonate and then water and the needles are dried. . .
45
over anhydrous sodium sulfate. Chloroform was distilled off and the remaining crystals were recrystallized. From methanol-chloroform, to give 0.3 g of 6-l4- (3,5-dinitrobenzoyl) -1-piperac% calculated: C, 66.49; H 5.54; N 1.08,
Found,%: C 66.35; H 5.67; N 10.94,
Example 103, 5- (1-Piperazizinyl-3, 4-dihydrocarbostyril, t, mp, 50 nile) -3,4-dihydrocarbostyrl (2.6 g)
262-264 C, reddish-black needles,
Calculated,%: C 56.47; H 4.47; N 16.47.
Found,%: C 56.34; H 4.61; N 16.35.
Example 101 5- (1-PiperazI-nyl) -3,4-dihydrocarbostyryl (2.6 g) and 1,5-diazabicyclo 5,4, about undepen-5 .4 ml) was added to 40 ml of DMF. Mixture
stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 3.0 g
3,4-dichlorobenzoyl chloride. After the addition is complete, the reaction mixture is stirred for 30 minutes, poured into a large amount of water and extracted with chloroform. The extract is washed with a solution of sodium bicarbonate and then with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the remaining crystals recrystallized from methanol, to give 1.2. g 5-G4- (3,4-dichlorobenzoyl) -1-piperazinsh1 -3,4- -dihydrocarbostyril, t, mp, 250-225 ° C, colorless powder ..,
Vmsleno,%: C 59.55; H 4.71;
Found,%: C 59.38; H 4.82; N 10.34,
Example 102, 6- (l-Pipepazinyl) -3, 4-dihydrocarbostyryl (2.6 g)
25 and triethylamine (2.34 ml) are added to 40 ml of DMF. The mixture is stirred at room temperature while slowly adding 10 ml of a solution of DMF containing 2.7 g of 3,4-methylene 30 dioxybenzoylchloro in drops. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes, pour it into a large amount of water and extract with chlorofor. The extract is washed with sodium bicarbonate solution and, then with water and dried, over anhydrous sodium sulfate. Chloroform is distilled off and the remaining crystals are recrystallized from a mixture,%: C, 66.49; H 5.54; 1.08,
Found,%: C 66.35; H 5.67; 10.94,
Example 103 5- (1-Piperazii triethylamine (2.34 ml) was added to 50 ml of chloroform. The mixture was stirred at room temperature while slowly adding 10 ml of solution of chloroform containing 2.3 g of 4-methylbenzoyl chloride After the addition is complete, the reaction mixture is stirred for 30 minutes. At the end of the reaction, 100 ml are added.
231A26L5224.
Calculated,%: C 56.98; H 7.03; recrystallization of the residue from ethanol
J5 11.73 ... 8 g are obtained (4-methoxybenzene 1) Found: C, 56.92; H 6.72; .- 1-piperazinyl-3,4-dihydrocarbyl N 11,77 / -sril, t, pl. i 96-198 C, colorless
Example 123, Mix 14.5 gig ..
6- | 6is (2-chlorobutyl), 4-dihydro-Calculated,%: C 71.79; H 7.12;
carbostyril, 8.0 g 4-methoxybenzyl-N 11.97 ..
amine and 70 ml of methanol are stirred. Found,%: C 71.91; H 7.01;
when heated to reflux-10N 11.86.
15 hours after cooling to reaction — Example 125. Mixture 2.7 g
3.06 g of carbono-6-amino-3,4-dihydrocarbosterine,
This sodium and the mixture are stirred at 5.9 g of N, N-Bic (2-oxyethyl) -3,4-dime by refluxing totoxybenzamide and 8.6 g of 85% phosphorus h. After cooling, precipitated t in reaction with
The dock crystals are collected by filter- .165-1 5 C for 4.5 hours with stirring.
recrystallization from ethano-After ohlakcene to the reaction mixture
la, giving 8.1 g of 6-14- (4-methoxyben-about 50 ml is added dropwise
3pc) -1-psh1erazinyl3-3,4 - dihydrocarbo-water to dissolve. Solution
steryl, t, pl. 196-198 b, colorless 20 neutralize with water 48% solution
needles .... sodium hydroxide and extracted
Calculated,%: C 71.79; H 7.12; chloroform. After with eyelets extract
N 11.97. .- potassium carbonate chloroform is recovered.
Found,%: C 71.62; H 7.25; After recrystallization of the residue from
N P, 82.25 mixtures of ethanol - chloroform receive
Example 24.4.7 g (3,4-dimethoxybenzoyl) -1a) A mixture of 81 g of 6-amino-3, 4-dihydro-piperaziksh1-3,4-dihydrocarboxyrylate and 82 g of ethylene chlorohydrinal, m.p. 238-239.5 C, colorless, stirred at approximately the temperature of a granule.
160 from 10 h. After cooling to the reaction: 30 Calculated,%: C, 66.84; H 6.33;
100 ml of water-N 10.63 are added to the mixture.
10 k. of NaOH solution for separation. Found:%: 66.95; H 6.23;
organic layer, which is then K 10,51.
| dried over KOH. After removal of KOH. Example 126. Anhydride mixture
by filtration, the mother liquor of acetic acid (1.22 ml) and the ants are distilled under reduced pressure; hydrochloric acid (0.5 ml) is stirred at
receiving 90 g. 6- {bis. (2-hydroxyethyl) amnn (-50-60 C 2 h. After the coolant: averaged to, 4-dihydrocarbostyryl. Formed reaction temperature to the reaction mixture
The compound of this compound is confirmed-added in portions of 1.0 g of 5-piperaz-infrared and NMR-spectral-40-nyl-3,4-dihydrocarbostyrene data, and the process of this operation occurs from the calculated%: C 62.40; H 7.20; product belief. By rzrazukitsims
N, 11.20. To the solids, add 5 ml of diNadeno,%: C, 62.27; H 7.09; chloromethane and the mixture is stirred at
N 11.34., 45 room temperature 2 hours. Then to
b) A mixture of water, aminr-3,4-dihydrocarbostyryl, is added to a mixture of 9 g (2-hydroxyethyl 1), 4.1 g of the mixture is extracted with chloroform. After 4-methoxybenzylamine and 7.6 g of polyphos — the extracts are hardly washed with water, dried fororic acid obtained from 3.8 gnad of anhydrous sodium sulphate with 160 races. Recrystallization of the residue from 170 ° C for about 6 hours. After cooling the methanol, 420 mg of the 5- (4-formyl-1k) reaction mixture are added, drop by drop, in a small amount of approximately 500 ml of water to give pl. 263-265 ° C, colorless grains. The solution is neutralized with water-ggula.
48% solution of the hydrate of oxide Calculated,%: C 64,84; H 6, bG;
sodium and extracted with chloroform. N 16.21.
After drying the extract over carbonate Found%: C 64.64; H 6.57;
potassium chloroform is distilled off. After ne-.j 16,22.
25142645226
Example 127. To a suspension of 1.9 g (3,4-methylenedioxybenzo-1.0 g of 6- (1-pinperazyl) -1-piperazinyl carbostyryl monobromide, t.p.
nyl) -3,4-dihydrocarbostyril in JO ml of DMF, add 296 mg of sodium bicarbonate and stir at room temperature for 30 minutes in order to prevent this compound in 6-piperaenyl-3,4-dihydrocarboxyrip, to which is added 0 , 62 ml of triethylamine. Then a solution of 605 mg of 4-acetyl oxybenzoyl chloride in 5 ml of DMF is added dropwise to the mixture slowly. After the addition is complete, the mixture is stirred at room temperature. Jh. 15 The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is successively diluted with &amp; 1 with an aqueous solution of sodium bicarbonate and soda, and then 20 is dried over anhydrous sodium sulfate. Chloroform is distilled off to give (4-α-acetyloxybenzoyl) -1-piperaoinyl-3,4-dihydrocarboxy.
Calculated,%: C 67.16; H 5.89; N10.68.
I Found,%: C 67.04; H 5.98; IN 10.49.
I Example 128. A mixture of 25 g of f6-aminocarbostyril, 50 g of bis-beta-bromoethylamine bromohydrate and DMF is stirred at 80-90 ° C for 3 hours. After cooling to room temperature, 8.2 g of sodium carbonate 266-2iJ7 is added to the mixture C (with dec.), Yellow powder. Example 130. A mixture of 23 g of 7-α-amino-3,4-dihydro-Carbostyril, 48 g of bis (beta-bromoethyl) amine bromohydrate and 200 ml of methanol is heated under reflux with stirring for 8 hours. After cooling to room temperature, 7 , 52 g of sodium carbonate, followed by heating under reflux with stirring, another 8 hours. After distilling off the methanol under reduced pressure, isopropanol was added to the residue. Cooling poile crystals that precipitate are collected by filtration and recrystallized from ethanol three times, giving 15 g of 7- (1-piperazinyl) 3-C, 4-dihydrocarbatir bromohydrate, m.p. 174-177 C, colorless granules.
Example 131. To a solution of 25,800 mg of hydrobromide 7 - (- piperazinyl) -3,4-dihydrocarbosterine in 10 ml of DMF was added 1.2 ml of triethylamine, and then a solution of 730 mg of 4- is added dropwise to the mixture while stirring. chlorobenzoyl chloride in 2 ml of DMF. After the addition is complete, the mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into b, a large amount of water. Crystals that
thirty
and the mixture is stirred at 80-90 ° C. gg formed, collected by filtration.
| 4 hours. After cooling to room temperature; temperatures The crystals that precipitated are collected by filtration, washed with ethanol and dried. Receive; 22 g of 6- (1-piperazinyl) 40 carbostyril bromohydrate, t, pl. higher than 300 ° C, pale yellow rhombic crystals (water - ethanble).
Example 129, 6- - (I-piperazinyl) -carbostyril hydrobromide (2.0 g) 45 -dihydrocarbostyryl (7.5 g, 46.2 mmol) is suspended in 20 ml of DMF. After the addition- and bromhydrate bis (beta-bromoethyl) amine.
rinse with water and exist. The crystals are purified by chromatography on a column filled with silica gel, and recrystallized from a mixture of chloroform-methanol to obtain 700 mg of chlorobenzoyl (1-piperazinyl) -3, hydrocarbatir, m.p. 289-291 C, colorless powder.
Example 132. 8-Amino-3.4; 2.34 ml of triethylamine; a solution of 1.43 g of 3,4-methylenedioxybenzoyl chloride in 2 ml, CMP, is added dropwise to the mixture. Upon completion of addition, the reaction mixture is stirred at room temperature 30 and poured kg in a large amount of water. The crystals that formed are collected by filtration and dried. The crystals are then purified by chromatography on a column filled with jilica gel, and the mixture is recrystallized, the chloroform is methanol, to give

 266-2iJ7 C (with decomp.), Yellow powder. Example 130. A mixture of 23 g of 7-α-amino-3,4-dihydro-Carbostyril, 48 g of bis (beta-bromoethyl) amine bromohydrate and 200 ml of methanol is heated under reflux with stirring for 8 hours. After cooling to room temperature, 7 , 52 g of sodium carbonate, followed by heating under reflux with stirring, another 8 hours. After distilling off the methanol under reduced pressure, isopropanol was added to the residue. Cooling poile crystals that precipitate are collected by filtration and recrystallized from ethanol three times, giving 15 g of 7- (1-piperazinyl) 3-C, 4-dihydrocarbatir bromohydrate, m.p. 174-177 C, colorless granules.
Example 131. To a solution of 800 mg of hydrobromide 7 - (- piperazinyl) - -3,4-dihydrocarbosterine in 10 ml of DMF was added 1.2 ml of triethylamine, and then a solution of 730 mg of 4-chloro was added dropwise to the mixture with stirring - benzoyl chloride in 2 ml of DMF. After the addition is complete, the mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into b, a large amount of water. Crystals that
formed, collected by filtration.
-dihydrocarbostyril (7.5 g, 46.2 mmol) and bis (beta-bromoxy) amine bromohydrate.
rinse with water and exist. The crystals are purified by chromatography on a column filled with silica gel, and recrystallized from a mixture of chloroform-methanol to obtain 700 mg of chlorobenzoyl (1-piperazinyl) -3, hydrocarbatir, m.p. 289-291 C, colorless powder.
Example 132. 8-Amino-3.4 (15.9 g, 50.8 mmol) is suspended in methanol and the suspension is heated under reflux with stirring at 9 hours. After adding 2.5 g of sodium carbonate, the reaction mixture is additionally heated at reflux for 8 hours with stirring and then stirred for
an ice bath I h. The crystals that precipitate are collected using ani o filters. The crude crystals thus obtained are recrystallized from methanol – ether.
chloroform followed by a large amount of water to separate the chloroform, and the chloroform layer is washed with sodium bicarbonate solution and then water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the remaining crystals were recrystallized from a mixture of chloroform-ether to give 1.8 g of (4-methyl 1-benzosh 1) -1 -1-pylerasinyl-3,4-dihydrocarburil, m.p. 239.5-240 ° C, colorless powder.
Calculated,%: C, 72.21; H 6.59; N 12.03.
Found,% N, 11.94.
Example 104. To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium carbonate and 20 ml of DMF were added 720 mg of 4-methoxybenzyl chloride and the mixture was stirred at 80 ° From 2.5 hours. The reaction mixture is poured into a large amount of sulphide 72.34; H 6.44;
one of the salt solution was extracted with tanrla to give 0.6 g of hydrochloride (2-phenylethyl). - 1-piperazinyl-3,4-dihydrocarbostyril, t. pl. (in terms of 274-276 C, colorless powder. Calculated,%: C, 67.82; H, 7.05;
chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by passing it through a chromatographic column filled with silica gel. After recrystallization from ethanol, 950 mg of 6- (4-methoxybenzyl) -1-mn-1-rasinil-3,4-dihydrocarboxyate, m.p. 196-198 C, colorless needles.
Calculated,%: C 70.00; H 7.22; N 11.67.
Found,%: C 69.91; H 7.15; N 11.71.
Carrying out the process in the same manner as described in Example 104, the same compound was obtained as in Example 44 using the appropriate starting materials.
Example 105, Mixture 1, O g of 5- (1-piperazinyl) -3,4-dihydrocarbaster, 1.11 g of potassium carbonate, 760 mg of 4-methoxybenzene chloride and 20 ml of DMF are stirred at 70-80 ° C for 4 hours. the mixture is poured into a large amount of water and chloro-4- (2-phenylethyl) is extracted. - 1-piperazinyl-3,4-dihydrocarbostyryl, m.p. (srazl 274-276 C, colorless powder. Calculated,%: C, 67.82; H, 7.05;
30 IN 11.30.
Found,%: C 67.85; H 6.93;
g} 11.39.
Example 107. To a mixture 1.2. G 5- (1-piperazinyl) -3,4-dihydrocarbo
steryl, 1.17 g of potassium carbonate and
85 ml of 3,4-dimethox ibenzyl chloride are added to 20 ml of DMF and the mixture is stirred at 70-80 t for 2 hours. The reaction mixture is poured into a large amount of
40 in water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by passing it through a chromatographic 45 column filled with silica gel. The residue is converted into the hydrochloride salt to give 610 mg of dichloro ;; - 5-14- (3,4-dimethoxybenzyl) -1-piperazinyl J -3,4-dihydrocarbatiri50 la, so pl. 270-272.5 X; (with different). Calculated,%: C 58.15; H 6.43;
by form. After flushing with water, extract N 9.25.
dried over anhydrous sodium sulphate. Found,%: C 58.08; H 6.51;
Chloroform was distilled off and the residue was purified N 9.14.
pass through the chromatographic 55 Example 108. To a mixture of 1.0 g
a column filled with silica gel. 6- (1-piperazinyl) -3,4-digndrocarbo After recrystallization from methanolastyryl, 1.11 g of potassium carbonate and
60 mg of (4-methoxybenzyl) -20 ml of DMF are obtained, 780 mg of 4-chloro-1-piperazinyl-3, 4-dihydrocarbosty-benzyl chloride are added and the mixture is stirred
Rila, so pl. 194-196 0, bes1; needles.
Calculated,%: C 71.79; H 7.12; N 11.97.
Found,%: C 71.84; H 7.05; N 11.89.
Example 106 o To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydrocarbaster, 1.17 g of potassium carbonate and 20 ml of DMF, 646 mg of 2-phenethyl chloride was added and the mixture was stirred at 80 - 2.5 hours. The reaction mixture is poured into a large amount of water and: extracted with chloroform. After washing with water, the extract is dried over non-aqueous sodium sulfate. Chloroform is distilled off and the residue is purified by passing through a chromatographic column filled with silica gel. After conversion of this product to the hydrochloride salt using methanol - hydrochloric acid, the product is recrystallized from 5
- Tanrla to give 0.6 g of hydrochloride (2-phenylethyl). - 1-piperazinyl-3,4-dihydrocarbostyril, m.p. (srazl 274-276 C, colorless powder. Calculated,%: C, 67.82; H, 7.05;
30 IN 11.30.
Found,%: C 67.85; H 6.93;
g} 11.39.
Example 107. To a mixture 1.2. G 5- (1-piperazinyl) -3,4-dihydrocarbo
steryl, 1.17 g of potassium carbonate and
85 ml of 3,4-dimethox ibenzyl chloride are added to 20 ml of DMF and the mixture is stirred at 70-80 t for 2 h. The reaction mixture is poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by passing it through a chromatographic 45 column filled with silica gel. The residue is converted to the hydrochloride salt to give 610 mg of dichlorine ;; - rata 5-14- (3,4-dimethoxybenzyl) -1- piperazinyl J- 3,4-dihydrocarbatiri50 la, so pl. 270-272.5 X; (with different). Calculated,%: C 58.15; H 6.43;
at 70-80 ° C for 4 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. Chloroform is distilled off and the residue is purified by passing g through it through a chromatographic column filled with silica gel. After recrystallization from a chloro-I-methanol mixture, 500 mg of 6-f4 I - (4 chlorobenzyl) -1-piperazine -3.4-o are obtained; - dihydrocarbostyril, t. pl. 190 - I 191 ,, colorless needles.
Calculated,%: C 67.51; H 6.23; N 11.81. . ..
Found,%: C 67.31; H N 11.85.
Example 109. To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium carbonate and 20 ml of DMF, 895 mg of 3,4-dichlorobenzyl chloride was added and the mixture was stirred at 60-70 ° C for 3 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform 1 is distilled off and the residue is purified by passing it through a chromatographic column filled with silica gel. After being converted into the hydrochloride salt 30, the product is recrystallized from methanol with a mixture of methanol and hydrochloric acid, resulting in 0.17 g; Monohydrochloride monohydrate - (3,4-dichlorobenzyl) -1 -piperazinyl - -3,4-dihydrocarboythryl, mp
{298.5-300 ° C, colorless granules.
Calculated% 5 C 54.00; H 5.44; Jj 9.45.
Found,% :. C 53.73; H 5.57; 9.29.
i Sample software. To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydrocarboethyryl, 1.17 g of potassium carbonate and jO ml of benzene was added 789 mg of 4-nitrobenzyl chloride and the mixture was stirred under heating at reflux. shok 4h. After completion of the reaction, the benzene was distilled off and the residue was dissolved in chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulphate. Chloroform is distilled off and the residue is purified, passed through
la, - That pl. 268-271 ° C (with dec,), pale yellow powder.
Calculated,%: C 65.57; H 6.01; N 15.30.
Found,%: C 65.43; H 5.89; N 15.42.
Example 111. To a mixture of I, 2 g of 5-C1-pipera.zinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium carbonate and 20 ml of dimetypsulfoxide was added 650 mg of 4-aminobenzyl chloride and the mixture was stirred at 80 ° C. 2.5 hours. The reaction mixture is poured into a large amount. water and extracted with chloroform. After washing with water, the extract is dried over anhydrous Hs sulfate, t. Chloroform is distilled off and the residue is purified by passing through a chromatographic column filled with silica gel. After conversion to the hydrochloride salt with methanol-hydrochloric acid, the product is recrystallized from methanol-ether mixture to obtain 0.4 g of 5- - (4-aminobenzyl) -1-piperazinyl-3,4--dihydrocarbostyryl dichlorohydrogen monohydrate, m. square 224 - 227 ° C (with decomp.), Yellow granules.
Calculated,%: C 56.20; H 6.60; N 13.11 ..
Found,%: C 56.19; H 6.57; N 13.31.
Example 112. To a mixture of 1.2 g
2g of 6- (1-piperazinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium carbonate and 20 ml of triamide-hexamethylphosphoric acid were added 651 mg of 4-hydroxybenzyl chloride and the mixture was stirred at 40–90 ° C for 2.5 h. The reaction the mixture is poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified on a chromatographic column filled with silica gel to obtain 0.8 g of 6-f4- (4-y-oxybenzyl) -I-piperazinyl-3,4-dihydrocarbostyril.
50 Calculated,% J C 14.24; H 6.82; N 12.46.
Found,%: C 14.33; n 6.74; N 12.37.
Example 113. To a mixture of 1.2 g
a chromatographic column filled with, gg 6- (I-piperazinyl) -3,4-dihydrocarbon silica gel. After recrystallization, 1.17 g of sodium bicarbonate from a mixture of chloroform-ether and 20 ml of DMF, 646 mg of 4-methyl-methyl 0.26 g of 3-14- (4-nitrobenzyl) -1-benzyl chloride and the mixture is stirred - piperazine 3-3,4-ihydrocarbatir- at 2.5 h. The reaction mixture

0
la, - That pl. 268-271 ° C (with dec,), pale yellow powder.
Calculated,%: C 65.57; H 6.01; N 15.30.
Found,%: C 65.43; H 5.89; N 15.42.
Example 111. To a mixture of I, 2 g of 5-C1-pipera.zinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium carbonate and 20 ml of dimetypsulfoxide was added 650 mg of 4-aminobenzyl chloride and the mixture was stirred at 80 ° C. 2.5 hours. The reaction mixture is poured into a large amount of 5. water and extracted with chloroform. After washing with water, the extract is dried over anhydrous Hs sulfate, t. Chloroform is distilled off and the residue is purified by passing through a silica gel filled column. After conversion to the hydrochloride salt with methanol-hydrochloric acid, the product is recrystallized from methanol-ether mixture to obtain 0.4 g of 5- - (4-aminobenzyl) -1-piperazinyl-3,4-β-dihydrocarboxyryl dichlorohydrogen monohydrate, m. square 224 - 227 ° C (with decomp.), Yellow granules.
Calculated,%: C 56.20; H 6.60; N 13.11 ..
Found,%: C 56.19; H 6.57; N 13.31.
Example 112. To a mixture of 1.2 g
g 6- (1-piperazinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium carbonate and 20 ml of triamide-hexamethylphosphoric acid are added 651 mg of 4-hydroxybenzyl chloride and the mixture is stirred at 90 ° C for 2.5 h. The reaction mixture poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform was stripped off and the residue was purified through a chromatographic column filled with silica gel, obtaining 0.8 g of 6-f4- (4-oxybenzyl) -I-piperazinyl-3,4-dihydrocarbostyryl.
Calculated,% J 14.24; H 6.82; N 12.46.
Found,%: C 14.33; n 6.74; N 12.37.
Example 113. To a mixture of 1.2 g
nineteen
poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by passing through a chromatographic column filled with silica gel. After that, by means of methanol-hydrochloric acid, the product is recovered from the methanol-water mixture by means of methanol-hydrochloric acid to obtain 0.17 dichlorohydrate (methylbenzip) -1

- piperazinyl-3,4-dihydrocarbostyril, t. pl. 272-273 C (with diss.), 15 without
25
C, 61.91; H 6.63; C, 61.86; H 6.59;
colored powder.
Calculated,%: N 10.31.
Found,%: N 10.39.
Example 114. To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydrocarbaster, 1.17 g of potassium carbonate and 50 ml of benzene, 688 mg of 4-cyano-benzyl chloride are added and the mixture is stirred under heating reflux for 3 hours. The reaction mixture is poured into a large amount of brine and extracted with chloroform. After washing with water, the extracts are dried over anhydrous sodium sulfate. Chloroform is distilled off, and the residue is looking for a pass through a chromatographic column filled with silica gel to obtain 105 mg of (4-cyanobenzyl) -1.1-piperazinyl-3,4-dihydrocarbostil.
Calculated,%: C, 72.83; H 6.36; N 16,18.
Found,%: C 72.92; H 6.51;
16.07.
N
Example 115. To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydrocarbosteryl, 1.17 g of potassium bicarbonate and 20 ml of dimethylformamide, 785 mg of 3,4-methylenedioxybenzyl chloride was added and the mixture was stirred at 80-90 ° C 3.5 hours o The reaction mixture is poured into a large amount of saturated saline and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by passing it through a chromatographic column filled with silica agel, yielding 0.2 g (3,4-m-1-piperazinyl-3,4-dihydrocarbenyl).
N
N
6452
20 C 69.04;
H 6.30; C 68.89; H 6.43;
0
five
20
ZO
Calculated,%: 11.51.
Found 11.42.
Example 116. 5- (1-Piperazinyl) -3,4-dihydrocarbostyryl (1.0 g) is added to a mixture of 10 ml of dimethylformamide and 0.85 ml of trimethylamine and the mixture is stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 1.07 g of para-toluenesulfonyl chloride. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into a large amount of saturated cobalt, left solution. And extracted with chloroform. The extract is rinsed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the remaining crystals recrystallized from dimethylformamide to obtain 800 mg of - (p-toluenesulfonyl) -1-piperazi-25, 4-dihydrocarbostyryl, m.p.
35
40
45
50
55
302-304 C, colorless powder.
Calculated,%: C, 62.34; H 5.97; N 10.91.
Found,%: C 62.43; H 5.89; N 10.79.
Example 117. 6- (1-Piperazinyl) -3,4-dihydrocarbostyryl (1.0 g) was added to a mixture of 10 ml of dimethylformamide and 0.85 ml of trimethylamide and the mixture was stirred at room temperature while slowly adding 5 ml of dropwise DMF solution containing 440 mg of methanesulfonyl chloride. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroborm is distilled off and the remaining crystals are recrystallized from methanol to give 0.17 g of 6- (4-methanesulfonyl-1-piperazinyl) - - (3,4-dihydrocarbostyryl), m.p. 241-243 C, colorless granules.
Calculated,%: C 54.37; H 6.15; N 13.59.
Found,%: C 54.23; H 6.24; N 13.43.
Example 118. To a mixture of 1 g of 6- (1-piperazinyl) -3,4-dihydrocarbostyril, 30 ml of dimethylformamide and 900 mg of potassium carbonate, 2 ml of butyl bromide are added and the mixture is stirred
21
at 2.5 h. The reaction mixture is poured into a large amount of brine and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Then, chloroform is distilled off and the residue is purified by passing it through a chromatographic column filled with silica gel. After the hydrochloric acid salt was converted into a salt with methanol-hydrochloric acid, the product was recrystallized from methanol to obtain 700 mg of 6- (4- -butyl-1-piperazinyl) -3,4-dihydrocarboxyryl hemihydrate, hydrochloride, m.p. 279-281 C (with sect.).
Calculated,%: C, 61.46; H 7.53; H.52,65.
Found,% g C 61.34; H 7.45; fJ 12.51.
Carried out the same process
yum
as described in Example 114, the same compound is obtained as in the 15 and 39 fimers when used (|: the corresponding starting materials.
Example 119. To a mixture of 1 g of 5 (1-piperazinyl) -3,2-dihydro-1 botiryl, 20 ml of dimethyl sulfoxide and 1; 7 g of potassium carbonate are added 450 mg of ejpoMHCToro ethyl and the mixture is stirred with 70-100 s 4.5 h. The reaction mixture c) is drunk in a large amount of water and extracted with chlorine / form. After washing with water, the extract is dried over anhydrous sodium sulfate. After that, the hyuroform is distilled off and the residue is purified, p:) by lowering it through the chromatographic solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Then, the chloroform is distilled off; the yi residue is purified; it is passed through a chromatographic column filled with silica gel, and recrystallized from chloroform to obtain 0.1 g of (2-propynp) -I-piperazinyl-3,4-dihydrocarbenzene, t pl. 225-226.C, pale yellow powder.
Calculated,%: C 71.38; H 7.06; N 15.61.
Found,%: - C 71.23; H 7.14; N 15.48.
PRI me R 122. To a mixture of 1 g 6-
to; on a column filled with silica gel. , 40 - (1-piper azinyl) -3,4-dihydrocarbyl- After conversion to hydrochloride, 30 ml of dimethylformamide and 900 mg
HJTo salt via methanol - sodium chlorobitonate added 600 mg
Hydrosilicic acid, the product is re-3-methylallyl bromind and the mixture is stirred; K1 is converted from methanol, obtained at 100 ° C for 2.5 h. The reaction
 0.14 g of 5- (4-ethyl- 45 monohydrochloride mixture is poured into a large amount of -H-piperazinyl) -3,4-dihydrocarbyl-saturated brine and extreme, so pl. 293-296 with (with decomp.), Shave chloroform. After business
with water, the extract is dried over anhydrous sodium sulfate. Then, chloroform 50 is distilled off and the residue is purified by passing it through a chromatographic column filled with silica gel. After being converted into a hydrochloride salt, the color granules.
Calculated,%: C 61.01; H 7.46; N 14.24 ..-.
Found,%: C 61.08; H 7.41; S 14.19.
Example 120. To a mixture of 1 g of 6- - (I-piperazinyl) -3,4-dihydrcarbostyril, 15 ml of DMF and 1.82 g of potassium carbonate, 500 mg of allyl bromide was added and the mixture was stirred at room temperature for 2 hours. the mixture is poured into a large amount
by means of methanol - hydrochloric acid; 55 - the product is recrystallized,
Accepted from methanol, yielding 0.4 g, dichlorohydrazide: 6-4- (2-butenyl) -1 -Piperazinyl-3,4-dihydrocarbostyril, m.p. 242-245 C, colorless cheshchuyki

22
and extracted with chloroform. Pos
After washing with water, the extract is dried over anhydrous sodium sulfate. Then, the chloroform is distilled off and the residue is purified, passing it through a chromatographic column filled with silica gel, and recrystallized from a mixture of chloroform - ethanol, obtaining 0.43 g of 6- (4-allyl-1-piperazinyl) -3.4- dihydrocarbostyril, t. pl. 175-176 0, colorless scales. Calculated,%: C, 70.84; H 7.75;
N 15.50. :.
Found,% C 70.73; H 7.81; N 15.38.
Example 12U To a mixture of 1 f 5- (1-piperazinyl) -3,4-dihydrocarbastyl, 30 ml of DMF and 900 mg of sodium carbonate were added 491 mg of propargyl bromide and the mixture was stirred for 3 hours. The reaction mixture was poured into a large amount of valuable With
left solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate. Then, the chloroform is distilled off, the yi residue is purified, passing it through a chromatographic column filled with silica gel, and recrystallized from chloroform to obtain 0.1 g of (2-propynyl) -I-piperazinyl-3,4-dihydrocarboxytype, t pl. 225-226.C, pale yellow powder.
Calculated,%: C 71.38; H 7.06; N 15.61.
Found,%: - C 71.23; H 7.14; N 15.48.
PRI me R 122. To a mixture of 1 g 6-
by means of methanol - hydrochloric acid; 55 - the product is recrystallized,
Accepted from methanol, yielding 0.4 g, dichlorohydrazide: 6-4- (2-butenyl) -1 -Piperazinyl-3,4-dihydrocarbostyril, m.p. 242-245 C, colorless cheshchuyki
Obtain 2.4 g of 8- (1-piperazinyl) -3,4-dihydrocarboxytype hydrobromide, m.p. above, colorless needles.
Example 133. 8-Aminocarboxy with styryl (15.47 g, 96.6 mmol) and bromo-: Bis (beta-bromoethyl) amine hydrate (33 g, 106 mmol) is suspended in DMF and the suspension stirred at 70- 80 ° C 10h. After adding 5.1 g of carbonate to a mixture, stir the reaction mixture at the same temperature as above for 7 hours. After distilling off the solvent under reduced pressure, methanol is added to the residue to crystallize. The crude crystals thus obtained were recrystallized from methanol-ether to give 5.1 g of an 8- (1-piperazinyl) carbon bromohydrate, m.p. Vpep 300 ° C, colorless scales.
Example 134. 8- (1-Piperazinyl) carbostyryl (0.7 g, 2.26 mmol) and sodium bicarbonate (0.2 g) suspension. After recrystallization of the precipitate from ethanol, 3 g of 6- (1-piperazinyl) -3,4-dihydrocarbostyryl are obtained, m.p. 289-293 C, colorless needles.
Calculated,%: C 50.00; H 5.77; N 13.46.
Found,% g C 49.93; H 5.84; N 13.53.
Examples 136-141. In the same manner as described in Example 3, the following compounds were prepared from the corresponding starting materials:
(3-methoxy-4-hydroxybenzo-15-yl) -1-piperazinyl-3,4-dihydrocarbostyryl, m.p. 200-202 s, colorless granules (example 136);
(2,4-dimethoxybenzoyl) -1-piperazinyl J-3, 4-dihydrocarboxyrnl, m.p. 228-23f C., slightly colored red-yellow powder (example 137);
6-L4- (2-methoxybenzosh1) -1-piperazinyl-3,4-dsh ncrocarbostiril, mp 164-165.5 C, pale violet poro
dihydrate in 5 ml DMF and slurry suspension (Example 138);
6-4- (2,6-dimethoxybenzoyl) -1-pi30 is sewed at room temperature. Perazinyl-3,4-dihydrocarboxyethyl 1 is added to the resulting mixture,
0.4 ml of triethylamine and then
drop a solution of 0.47 g of 2-chlorobenzoyl. square 218-220 ° C, colorless needles (Example 139);
(4-eth1benzoyl) -1-piperazini-3,4-dihydrocarboxyrip, t, pl. 188-190 s, colorless granules (Example 140
chloride in 5 ml of DMF, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer is washed with water and then gg with saturated aqueous sodium bicarbonate and dried over sodium sulfate. After distilling off the solvent, ether is added to the residue for crystallization. Chris 6-4- (4-eth1benzoyl) -1-piperazinyl-3,4-dihydrocarboxyrip, t, pl. 188-190 s, colorless granules (Example 140
(4-ethoxybenzoyl) -1-piperazinyl-J-3,4-dihydrocarbacter, m.p., 232-233 s, pale yellow needles, (Example 141),
EXAMPLE 142. A mixture of 9.36 g of 6-amino-3, 4-dihydro-carbostyril.
talts thus obtained are converted to 26.1 g of bis- (iodoethyl) amine monohydrocrystallization from ethanol. Obtain 0.24 g of (2-chlorobenzoyl) -1- piperazinyl Tkarbostyril, t, pl, 239-240 ,, colorless needles.
Example 135. A mixture of 13.5 g of 45 6- (bis (2-bromoethyl amino) -3,4-dihydroburostyryl and 200 ml of methyl ammonium alcohol (saturated at 0 ° C) is reacted at 110-120 ° C for - a period of time of approximately gQ of 30 hours in a hermetically sealed vessel. After the reaction mixture was allowed to dry, about 500 ml of water was added dropwise to it to dissolve. Then the solution was neutralized with water. hydrateN solution
sodium oxide (48%) and extracted with chloroform. After drying the extract over potassium carbonate, chloro-N is distilled off.
roiodide and 70 ml of benzene are heated at 40 ° C for 30 hours with stirring. After cooling, 3.06 g of sodium carbonate is added and the resulting mixture is heated at reflux for 8 hours with stirring. The reaction mixture is cooled to precipitate crystals, which are then collected by filtration. These crystals combine with methanol to form 5.4 g of 6- (1-piperazinyl) -3,4-dihydro-1-bostyryl hydroiodide, t, pl. 289-293 C (with decomp.) (Methanol - water) colorless needles.%: C 43.46; H
Calculated 11.70.
C iHisNjO,
Found,%: C 43.35; H 5.11; 11.58.

forms. After recrystallization of the precipitate from ethanol, 3 g of 6- (1-piperazinyl) -3,4-dihydrocarbostyryl are obtained, m.p. 289-293 C, colorless needles.
Calculated,%: C 50.00; H 5.77; N 13.46.
Found,% g C 49.93; H 5.84; N 13.53.
Examples 136-141. In the same manner as described in Example 3, the following compounds were prepared from the corresponding starting materials:
(3-methoxy-4-hydroxybenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl, m.p. 200-202 s, colorless granules (example 136);
(2,4-dimethoxybenzoyl) -1-piperazinyl J-3, 4-dihydrocarboxyrnl, m.p. 228-23f C., slightly colored red-yellow powder (example 137);
6-L4- (2-methoxybenzosh1) -1-piperazinyl-3,4-dsh ncrocarbostiril, m.p. 164-165,5 C, pale purple poro
m.p. 218-220 ° C, colorless needles (Example 139);
(4-eth1benzoyl) -1-piperazinylJ-3,4-dihydrocarboxyrip, t, pl. 188-190 s, colorless granules (Example 140
(4-ethoxybenzoyl) -1-piperazinyl-J-3,4-dihydrocarbatir, m.p., 232-233 s, pale yellow needles, (Example 141),.
EXAMPLE 142. A mixture of 9.36 g of 6-amino-3, 4-dihydro-carbostyril.
 26.1 g bis (iodoethyl) amine monohydN
roiodide and 70 ml of benzene are heated at 40 ° C for 30 hours with stirring. After cooling, 3.06 g of sodium carbonate is added and the resulting mixture is heated at reflux for 8 hours with stirring. The reaction mixture is cooled to precipitate crystals, which are then collected by filtration. These crystals combine with methanol to form 5.4 g of 6- (1-piperazinyl) -3,4-dihydro-1-bostyryl hydroiodide, t, pl. 289-293 C (with dec.) (Methanol - water) colorless needles. From 43.46; H

43.35; H 5.11;
29
Example 143. A mixture consisting of 9.36 g of 6-amino-3,4-digipocap
Bostyril, 18.3 g of H, H- (di-, bromo ethyl) -3,4-dimethoxybenzamide and 70 ml of dimethylformamide are heated under stirring for 5 hours. After cooling, 3.06 g of potassium carbonate was added, and the mixture was heated under reflux for 8 hours with stirring. The reaction mixture is cooled to precipitate crystals, which are then collected by filtration. By recrystallization from ethanol-chloroform, 7.8 g of (3,4-dimethoxybenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl, m.p. 238-239.5 C, colorless granules.
four
Vyisleno,%; N 10.63
the dioxane and the suspension is stirred at 70 ° C for 5 hours. After completion of the reaction,
N
C, 66.82; H, 6.37;
20, the solvent was removed by distillation, ether was added to the residue, and the resulting crystals were removed by filtration. After concentrating the mother liquor, the residue is dissolved in
25 chloroform and chloroform solution are washed with water and saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate and the solvent is removed by distillation30
Found,%: C 66.72; H 6.50; 10.51.
Example 144. A mixture of 9 g of 6- (2-hydroxyethyl) amine 3-3,4-dihydrocarbostyril, 4.1 g of 4-methoxybenzylamine and 7.6 g of polyphosphoric acid obtained from 3.8 g of pentoxide phosphorus and 3.8 g of phosphoric acid, heated at 350 ° C for about 3 hours. After cooling, about 500 ml of water is added dropwise to the reaction mixture to dissolve. The resulting solution is neutralized with a 48% aqueous solution of sodium hydroxide and extracted with chloroform. After drying the extract over potassium carbonate, chloroform is distilled off. By recrystallization of the residue from ethanol, 4 g of p-6- (4-methoxybenzyl) -1-piperazinyl- is obtained.
-3,4-dihydrocarbostyril, t. Pl. 196- 98 ° C, colorless needles.
Included,%: C 71.77; H 7.17;
35
l cue. By recrystallization from ethanol, 330 mg of (3,4-dimethoxybenzoyl-1-piperazinyl) -3,4-dihydrocarbostyryl is obtained. Colorless granules, so pl. 238-239,
Example 147 (additionally), To 10 ml of gionyl chloride was added 5 g (30 mmol) of p-methylthiobenzoic acid. the lots and the mixture are heated under reflux for 1 hour, followed by distillation under reduced pressure to obtain crystals. 8 g (30 mmol) of 6- (1-piperazinyl) -3,4-dihydrocarbostyril bromohydrate and 12.4 g (90 Mmol) are dissolved in a mixture of 70 ml of acetoN 11.96.
.O
Found,%: N 11.84.
Prime
C, 71.89; H 7.02;
g 6-145. Mixture 9.
- bis (2-hydroxyethyl) amino-3,4-dihydrocarbostyril, 4.1 g of 4-methoxybenzylamine and 7.6 g of polyphosphoric acid prepared from 3.8 g of phosphorus pentoxide and 3.8 g of phosphoric acid It is heated at 100 ° C for 10 hours. After cooling, about 500 ml of water is added dropwise to the reaction mixture until dissolved. This solution is neutralized with a 48% aqueous solution of sodium hydroxide and extracted
ten
15 2645230
xporoform. After drying the extract over potassium carbonate, chloroform is distilled off. By recrystallization of the residue from ethanol, 5.3 g of 6- (4-methoxybenzyl-1-piperazinyl) -3,4-dihydroburostyryl are obtained, m.p. 196-198 C, colorless needles.
Calculated N 1G, 96.
C s-H gNjOt
Found%
C, 71.77; H 7.17;
7.03;
N
;
C 71.90; H 11.87.
Example 146. 1.2 g of 3,4-dimethoxybenzoic acid, 1.3 g of DCC and 1, T4 g of 6- (1-piperazinyl) -3,4-dihydrocarbostyril are suspended in 10 ml
and the suspension is stirred at 70 ° C for 5 hours. After completion of the reaction
l cue. By recrystallization from ethanol, 330 mg of (3,4-dimethoxybenzoyl-1-piperazinyl) -3,4-dihydrocarbostyryl is obtained. Colorless granules, so pl. 238-239,
Example 147 (additionally), To 10 ml of gionyl chloride was added 5 g (30 mmol) of p-methylthiobenzoic acid. the lots and the mixture are heated under reflux for 1 hour, followed by distillation under reduced pressure to obtain crystals. 8 g (30 mmol) of 6- (1-piperazinyl) -3,4-di- hydrobromide. bicarbostyril and 12.4 g (90 Mmol), dissolved in a mixture of 70 ml of acetone and 70 ml of water, and the resulting crystals are added to this solution, dissolved in 40 ml of acetone, cooled with ice and stirring.
After stirring for
The reaction mixture was poured into ice water for 30 minutes and the resulting crystals were separated by filtration and washed with water.
The resulting crystals are purified by chromatography on silica gel (ethyl acetate: methanol 100: 0-100: 5 by volume) and recrystallized from ethanol - dimethylformamide to give 4.0 g of 6- (4-methylthiobenzoyl) -1-piperazine-3, 4- dihydrocarbostyril in the form of (Pale brown powder, so pl. 211-211 ,.
Example 148 (optional) By the method described in examples 3, 92 131, 132, 133, 136, 139, 140 or 142, (4-methylthiobenzoyl) -1- piperazinylJ-3,4-dihydrocarbostyryl is obtained in the form of a pale brown powder, mp, 211-211, (recrystallized from ethanol-dimethylformamide).
Pharmacological testing.
The pharmacological activity of the compounds of the invention is determined as follows.
I. Preparations of an isolated sinus-atrial node with perfused blood.
The experiments were carried out on adult mongrel dogs of both sexes. Sinus atrial node preparations were obtained from dogs weighing 8–13 kg, anaesthetized with pentobarbital sodium (30 mg / kg intravenously) with heparin sodium (100 and / kg intravenous) and bloodless. The preparation consisted of the right atrium and placed in a cold Tyrode solution. 100 mm Hg Dogs used as donors had a body weight of 18-27 kg and were anesthetized with sodium pentobarbital (30 mg / kg intravenously). Heparin sodium was given at a dose of 1000 and / kg intravenously. The stress state developed by the right; auricle was measured using a strain gauge. A load of about 1.5 grams was applied to the right atrium. The sinus rate was measured using a cardiotachometer triggered by the developed voltage of the right atrium. Blood flow through the right coronary artery was measured with an electromagnetic flow meter. Using the ink recorder, graphical recording of the developed voltage, sinus rate, and blood flow was made. Compounds in the amount of lO-30 MKji were injected intraarterially after 4 hours. The inotropic effects of the compounds are expressed as the percentage of voltage developed before injection of the compounds.
The effect of the compounds on the sinus rate (number of heartbeats per minute) or on the blood flow (ml / min) is expressed as the difference between the values before and after the injection joints.
The results are presented in Table. one ,
The following are test compounds.
1) (3,4-Dimethoxybenzoche1) -1- piperazinylJ-4,4-dihydrocarbostyryl.
2) 6-4- (4-Methoxybenzoyl) -1-piperazium yl-3,4-dihydrocarbostyryl.
3) 6- (4-Acetyl-1-piperazinyl) -3,4-dihydrocarbostyryl.
4) (4-Methoxybenzyl) -1-pipo-1razinyl-3,4-dihydrocarbostyryl.
5) (3, L, 5-Trimethoxybenzoyl) -1 -1 piperazinyl-3,4-dihydrocarbostyryl.
6) (3,4,5-Trimethoxybenzoyl) -1 -1 piperazinyl-3,4-dihydrocarbostyryl.
7) (4-Chlorobenzoyl) -1-piperazinyl-3,4-digindrocarbostyryl.
8) 6- (1-Piperazinyl) -3,4-dihydrocarbostyryl.
9) (4-Nitrobenzoyl) -1-piperazinyl-3, 4-dihydrocarbostyryl.
10) (4-Aminobenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
11) (3,4-Methylenedioxybenzoyl) -1-piperazinylJ-3,4-dihydrocarbostyryl.
1 2) 6-.4- (4-Bromobenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
13) 6- 4- (4-Cyanobenzoyl) -1-piperazinyl-J-3,4-dihydrocarbostyryl.
14) (3.4-Dimethoxybenzoyl) -1 -1 piperazinyl-3,4-dihydrocarbostyryl.
15) 8-Methoxy-6- 4- (3,4-dimethoxy-benzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
16) 1-Methyl-6- 4- (3 4-dimethoxy-benzoyl) -1-piperazinyl | -3,4-dihydrocarbostyryl.
17) .6- (4-FUROIL-1-piperazinyl) -3,4-dihydrocarbostyryl.
18) 6- (4-Benzoyl-1-piperazinyl) -3,4-dihydrocarboxyryl
19) 1-Benzoyl-6- 4- (3,4-dimethoxy-benzoyl) -1-piperazinyl-3,4-dihydrocarstyryl hemihydrate.
20) Monohydrochloride (2-phenethyl) - -piperazinyl J-3,4-dihydrocarbostyryl.
21) 6- (Formyl-piperazinip) -3,4- -dihydrocarbostyryl.
22) 6 (4-Ethoxycarboxymethyl-1-piperazinyl) -3,4-dihydrocarbostyryl
23) 6- (4-Ethoxycarbonyl-l-piperazazinyl) -3,4-dihydrocarboxylate.
24 6- {4- (3-Chlorobenzoyl) -1 piperazinyl J-3,4-dihydrocarbostyryl,
25) 6- (4-Methanesulfonyl-1-piperazinyl) -3, 4-dihydrocarbostyryl,
26) (4-Methylbenzosh1) -1-piperazinyl-3,4-dihydrocarbostyryl.
27) (3,4-Dichlorobenzoyl) -1-piperazinyl-3,4-dihydrocarboxyryl monohydrate monohydrate.
28) (3., 4-Dinitrobenzoyl) -1- piperazinyl-3,4-dihydrocarboster
29) 6- (4-ALLSH1-1-piperazinyl) -3,4-dihydrocarbyl.
30) 5-4- (2-Propynyl) -1-piperazinyl-3, 4-dihydrocarbostyryl
; 31) Monohydrochloride 5- (4-ethyl-1- piperazine) -3,4-dihydrocarbostyryl
32) Hemihydrate of 1-allyl-5-4- (3,4-dimethoxybenzoyl) - piperazinyl-3, 4-dihydrocarbostyryl.
33) (2-Propinsh1) (3,. 4-di-Itoxybenzoyl) -1-piperazinylJ-3,4-dihydrocarbostyryl.
i 34) (para-Tolysulfonyl) -l | -piperzinylJ-3,4-dihydrocarbotyl.
35) (3-Pyridylcarbonyl) -1-piperazinyl J-3,4-dihydrocarbyl-pml.
36) (4-Methoxy-phenylacetyl) -1-piperazinyl-3,4-digi-ocarbosterine hemihydrate.
37) 6- (4-Phenylpropionyl-1-piperaionyl) -3,4-dihydrocar bostyril.
38) (3,4 D1shetoksibenzoyl) - 1-piperazinyl.} Carbostyril.
39) 5- 4- (4-hydroxybenzoyl) -1-pipera zinyl 3,4-dihydrocarbostyryl.
40) (3,4-Dimethoxybenzoyl) -1-piperazinyl .arbostyryl.
41) b-rch-SZ-Chlorobenzoyl) - -piperazinyl carbostyryl.
42 (3,4-MetnpenDioxybenzo-i-in) -1-piperazinyl carbostyryl.
43) (4-Nitrobenzoyl) -1: -pi-rasinil carbostyril.
44) (4-Cyanobenzoyl) -1-piperazinyl carbostyryl.
45) 6- (4-Benzoyl-α-piperazinyl) carbostyryl.
46) (4-Chlorbenzoyl) -1-pipera srshil carbostyril.
47) (3,4,5-Trimethoxybenzoyl -1-piperazinyl / k arbostil.
48) 5- (4-Ethoxycarbonyl-1-piperazinyl) carbostyryl.
49) (4-Aminobenzoyl) -1-piperazinyl carbostyryl.
50) (4-formyl) -1-piperazyl carbostyril,
51) Monohydrochloride 5- (4-benzsh1-1- -piperazinyl) -3,4-dihydrocarbostyr1
52) (3,4-Methylenedioxybenzoyl) -1-piperazinip-3,4-dihydrocarbostyryl.
53) (3,4,5-Trimethoxybenzoyl -1-piperazinyl J-3,4-dihydrocarbostyryl-.
54) (2-Chlorobenzosh1) -1-piperazinyl J-3,4-digshch1, rocarbostiril.
55) 7-4-Fenilpropionyl-1-piperazinyl J-3,4-dihydrocarbstyryl.
5b3 7-L4- (3,4-Dimethoxybenzoyl) -1 piperazinyl-3,4-dihydrocarbostyryl.
57) Papaverine (for comparison).
58 Amrinon (for comparison) ..
59) (4-Metsh1 Yenzoip) -1-piperazinyl-3,4-dihydrocarbostyryl.
60) (4-Acetylaminobenzoyl) -1 -1 piperazinyl-3,4-dihydrocarbostyryl.
61) (4-Acetyloxybenzosh1) -1- piperazinyl-3,4-dihydrocarbostyryl.
62) 5- L4- (4-Cyanobenzyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
63) 5-C4- (4-Nitrobenzsh1) -1-piperazinyl-3,4-dihydrocarbostyryl.
64) (4 - Aminobenzyl) -1-riper zynyl-3,4-dihydrocarboxyr 1S dihydrochloride monohydrate.
65) (4-Hydroxybenzyl) -1-piperazinyl-3,4-digvdrocarbostyryl.
66) 6- | 4- (3,4-methylenedioxybenzyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
67) (4-Hydroxyphenylacetyl) - -1-piperazinyl} -carbostyryl.
68) (3-Methoxy-4-hydroxyben zoyl) g 1-piperazinyl-3,4-dihydroxy-carbostyryl.
69) (2.4-Dimethoxybenzoyl) -1 -1 piperazins IJ-3,4-dihydrocarbostyryl.
70) 6-C4- (2-Methoxybenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
71) 6-f4- (2,6-Dimethoxibenzoyl) -l-piperidinyl-3,4-dihydrocarbostyryl.
72). 6-L4- (4-Ethylbenzoyl) -l-piperidazinyl-3,4-dihydrocarbostyryl,
73) (4-Ethoxybenzoyl) -1-piperazinyl-3,4-dihydrocarbostyryl.
74) (3,4-Dichlorobenzyl) -1-piperazinyl J-3,4-dihydrocarbostyryl monohydrochloride monohydrate.
75) 5-C4- (3,4-Dimethoxybenzyl) -1- piperazinyl-3,4-dihydrocarbostyryl dihydrochloride.
76) 6-C4- (2-Butenyl) -1-piperazi-, 4-dihydrocarbostyrip dihydrochloride.
Table 1
Ii. Preparations of isolated papillary blood with perfused blood.
Experiments were carried out on adult mongrel dogs of each sex. Papillary muscle preparations were obtained from dogs weighing 8–13 kg, anesthetized with pentobarbital sodium (30 mg / kg intravenously) and exsanguinated. The preparation is a posterior papillary muscle, excised together with the interventricular septum, and placed in cold Tyrode solution. The preparation was placed in a glass vessel with a water jacket (water temperature about 38 ° C) and blood was circulated through it using the cannulated artery of the posterior septum from the donor dog at a constant pressure of 100 mm Hg. The dogs used as donors had a weight of 18-27 kg and were anesthetized with pento barbital sodium (30 mg / kg intravenously). They were given heparin sodium at a dose of 1000 and / kg intravenously. Paplplarny muscle was set in motion by a direct-impulse carbon impulse equal to one and a half times threshold voltage (0.5–3 V) with a duration of 5 m / s at a constant speed of 120 jolts per minute using bipolar stepped electrodes. The voltage created by the papillary muscle is measured with the help of a strain gauge. The weight was loaded with a weight of about 1.5 g. The blood flow through the artery of the posterior septum was measured using an electromagnetic flow meter. The recording of the developed voltage and blood flow was done graphically using an ink-south recorder. Compounds with a volume of 10-30 µl were injected intraarterially after 4 s.
The inotropic effects of the compounds are expressed as the percentage of stress developed prior to the injection of the compounds. The effect of compounds on the blood duct is expressed as the difference (ml / min) between the values before and after the injection of the compounds. The results are shown in Table. 2
Data on acute toxicity are given; in tab. 3. Each of the test compounds was orally administered to male rats for the purpose of determining acute toxicity.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing carbostyril derivatives of the general formula
.
de
RI is hydrogen, methyl, allyl, pro-pargyl, benzyl; hydrogen, methoxy; hydrogen, lower alkanoyl group,. i-furoyl group, j-pyridylcarbonyl group, methanesulfonyl group, ethoxycarbonyl group, ethoxycarbonyl methyl group, parathyryl sulfonyl group, lower alkyl group, lower alkenyl group, propargylanyl group, , benzoyl group, possibly substituted by 1–3 methoxy groups, 1–2 nitro groups, ethoxy group, 1–2 chlorine atoms, methyl or ethyl group or bromine atom, cyano, amino, acetyl amino, methylthio -, acetyl- oxy-, 3,4-methylenedioxy- group or hydroxy ruppoy;
Cd is a phenyl-C-C alkyl group, a benzyl group substituted by 1-2 methoxy groups, 1-2 chlorine atoms, a methyl group, a cyano group.
sing, nitro, amino, 3,4-methylenedia) xi-group, or hydroxy group; 10
Rj is a phenylpropanoyl group, a phenylacetyl group substituted by a methoxy or hydr-B group by an ox-group, the bond between the 3 and 4 positions of carbostyril is
new dra; is a single or double bond, and if RZ is a methoxy group, then Rj is hydrogen, and RJ is benzoyl, 20 is a substituted dimethoxy group, and if there is a double bond between positions 3 and 4 of the carbostyryl core, then R ,, - hydrogen, 25
their hydrogen halide salts, such as What, a compound of the general formula
where r and
. TTt
A - NH or
a halogen or guide is subjected to a common photo
Where r has yk
where X has yk provided that, to
/СНСН
-.
Group
na
t.
 Sn, SnGH at 40-120 C, preferably in a precursor of potassium agonate or hydroxide;
(Ii) 30
where R and Rj have the indicated meanings;
. - L LSNHH
A - NH or N,
SNACH X
halogen or hydroxy; exposed to the general formula
where X is connected
(Iii)
B - group
R has the indicated meanings;
N fX
or cnz
 B - group
CHjXJH X
where X has the indicated meanings, provided that when A is NH, then B / CH.
-.
Group
and when A is a group
na
t. then B - NH
 SN, CNHC at 40–120 C for 5–30 h, not necessarily in the presence of a basic condensing agent, such as potassium carbonate or sodium, bicarbonate hydroxide, lower sodium allogolate, triethylamine, pyridine, for 350 s 3-10 h of dehydrocondensation, such as polyphosphoric acid, when X is a hydroxy group, if necessary, followed by the interaction of the obtained compound of the general formula (I), where RJ is H,
or at I00 - in the presence of an agent of such a general formula R. X,
Where
compound X C1, Br,
HE.
Table 1

1.2 0.8 0.8
1.6 0.8
39
100 100 300 100 300, 300 300
1000 300 100 300 300 500 100
1000 100 100 100 100 300 300 100 100 100
 zso
300 300
1426452 0
Continued table.
5.7. 0
0.0 6.9 3
3.2. 5.9 25
10.7 3.8 0 17.9 18.5 22.2 15.3 25.0 37.1 24.1 19.0 20.0 14.3 20.3 21.4 20.7 3 12 42
0.4 1.0
1.2
1.6
1.6
0.6
1.0
1.2
2.0
1.2
1.6
2.0
0.8
0.4
0.4
0.4
0.2.
0.3
0.2
0.2
1.4
0.2
0.3
0.2
1.2
0.8
1.1
41
1426452 2
Continued table. I
table 2
43
1426452, 44.
Yrodolzhenie tab. 2
Table
7000 7000 7000 7000
7000 7000 7000 7000

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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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JP55154071A|JPH0143747B2|1980-10-31|1980-10-31|

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