Method of producing derivatives of pyrazolo[3,4]quinoline or pyrido[2,3]quinazoline, or their salts

专利摘要:
7- or 8-Substituted, partially hydrogenated pyrazolo[3,4-g]quinoline, thiazolo[4,5-g]quinoline, oxazolo[4,5-g]quinoline, and pyrrolo[3,4-g]quinoline derivatives, and 8- or 9-substituted, partially hydrogenated pyrido[2,3-g]quinazoline derivatives of formula: <CHEM> wherein: <CHEM> represents <CHEM> <CHEM> <CHEM> <CHEM> <CHEM> or <CHEM> are D-2 dopamine agonists. 6-Oxo-1-substituted-octahydroquinolines and 6-oxo-1-substituted-decahydroquinolines which are additionally substituted in the 3- or 4-position are intermediates useful in preparation of the dopamine agonists. Acetals of 4,6-dioxo-1-substituted-decahydroquinoline 3-carboxylic acid esters enable synthesis of the foregoing compounds.
公开号:SU1644718A3
申请号:SU874202773
申请日:1987-06-15
公开日:1991-04-23
发明作者:Линн Хьюзер Диана；Менерт Шаус Джон
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing tricyclic ergoline analogs used as dopamine agonists.
The purpose of the invention is to obtain new pyrazolo derivatives 3,4-8 quinoline or pyrido-2,3-1-quinazoline or their salts, exceeding in their biological activity the known tricyclic analogues of ergoline.
Example 1. 7- (5-Propyl-trans-4,4a, 5,6,8a, 9-hexahydro-2H pyrazolo Ј 3,4-§ | -quinoline) methanol
ten
1.2 g (6.7 mmol) of guanidine carbonate in 75 ml of ethanol. The mixture was heated under reflux for 3h, left to stand overnight at room temperature, and then drunk into water. The product is extracted from aqueous CHC13 / iso-Phon (3: 1). The organic solvent is distilled off to give a brown semi-solid product, which is left overnight in a vacuum desiccator. The mass of the obtained product is 1.9 g. It is passed through a column of silica gel with a solution of 1.8 g (15.7 mmol) of tert-15 lei, using 10% MeOH / CHg / g, potassium co-butylate in 20 ml of THF to cool the traces. Fractions, dl
to 0 ° C0. A solution of 1.3 g (5.8 mmol) of a3-hydroxymethyl-1 is added to it. TLC shows the presence of the product, combined to give 0.5 g of propyl-trans-1, 4, 4a, 5.6, 7,8a-octahyd-yellow solid. His selected quinolin-6-one, 1.7 g (23.3 mmol) 20 They bore into a mixture of methanol and methylene chloride ethyl formate and 40 ml of THF. MixtureRead. The solution is evaporated and added
The mixture is heated to room temperature and stirred for 3 hours, after which 4 ml of hydrazine is added and the concentration of hydrogen ions is adjusted to pH 9-10. 25 are filtered, dried in a vacuum. The mixture is stirred overnight at a nominal desiccator. 0.4 g of the desired temperature is obtained and then poured into water. The product is extracted into a solution of CHC13 / iso-phon (3: 1), which is then evaporated to give 1.3 g of brown gum. It is purified on a silica gel column using 10% MeOH / CH2Cl2 containing traces, which gives 400 mg of material which is dissolved in CHClI. From a solution of Chris-35 1030 cm, a solid is precipitated and, for the example, 8-Methoxymethyl-6, the crystallization of the product, dopropyl-trans-5.5a, 6,7,9a, 10-hexahydb hexane. After filtering ropirido 2,3-3 quinazolin-2-amik0
390 mg of crystals are obtained, the Identification Target Product is obtained using the trichloromethane compound used in accordance with the procedure of Example 2 from the 3-melex of the target compound, m.p. 112-toxymethyl-1-propyl-trans-1,2,4a, 5,6,
7,8,8a-octahydroquinolin-6-one as starting material.
Calculated,%: C, 66.64; H 8.39; 45 N 19.43.
Found,%: C 66.76; H 8.20; N 19.52.
Mass spectrum: 287, 259, 243, 198, 166, 136.
ethyl acetate until the formation of crystals begins. The solution is cooled and the solid is sobivogo product.
Calculated,%: C 65.67; H 8.07; N 20.42,
Found,%: C 65.44; H 7.80; N 20.29.
Mass spectrum: 287, 273, 245, 198, 166, 152, 122. IR spectrum (KBG): 3380, 3316, 3192, 1642, 1593, 1562, 1476,
 ™
115 ° C
Calculated,%: C 49.08; H 6.05; N 11.51; C1 29.00,
Found,%: C 49.46; H 5.67; .N 11.53; C1 28.83.
Mass spectrum: 246,218,152,118.
Example 2 „8- (2-Amino-6-propyl-trans-5.5a, 6.7.9a, 10-hexahydropyrido
2, 3 quinazoline) methanol.JQ
To a solution of 1.5 g (6.7 mmol) of 3-hydroxypropyl-4,4a, 5,6,8a, 9-trans-hexaroxymethyl-1-propyl trans-1, 2.4a, 5,6, hydro-2H-pyrol ash 3,4-g quinoline.
7,8,3a-octahydroquinolin-6-one in 100 ml
toluene is added 4.5 ml (16.9 mmol)
Tris (dimethylamino) methane “Mixture bale - 556,7,8,8a-octahydroquinolin-6-one in
1 t under reflux. 50 ml of toluene add 1.3 g
Toluene is distilled off and get korich- (9.0 mmol) tris (dimethylamino) methane
nevy oil To a solution of this oil and heat under reflux to tev 75 ml of ethanol is added suspension for 2 hours, then toluene is distilled off, and an example of a 4-methoxymethyl-5K solution of 850 mg (3.6 mmol) of 3-methoxymethyl-1-propyl -trans-1,2,4a, 5,
1.2 g (6.7 mmol) of guanidine carbonate in 75 ml of ethanol. The mixture was heated under reflux for 3h, left to stand overnight at room temperature, and then drunk into water. The product is extracted from aqueous CHC13 / iso-Phon (3: 1). The organic solvent is distilled off to give a brown semi-solid product, which is left overnight in a vacuum desiccator. The mass of the obtained product is 1.9 g. It is passed through a column of silica gel by filtration and dried in a vacuum desiccator. Obtain 0.4 g of target-1030 cm. EXAMPLE 3 3-Methoxymethyl-6 ethyl acetate until the formation of crystals begins. The solution is cooled and the solid is collected by filtration, dried in a vacuum desiccator. 0.4 g of 1030 cm is obtained. EXAMPLE 3: 8-Methoximethyl 6th product.
Calculated,%: C 65.67; H 8.07; N 20.42,
Found,%: C 65.44; H 7.80; N 20.29.
Mass spectrum: 287, 273, 245, 198, 166, 152, 122. IR spectrum (KBG): 3380 3316, 3192, 1642, 1593, 1562, 1476,
 ™
Example 4 „4-methoxymethyl-5hydro-2H-pyri sol 3,4-g quinoline.
To a solution of 850 mg (3.6 mmol) of 3-methoxymethyl-1-propyl-trans-1,2,4a, 5,
516
The sample is taken in 50 ml of ethanol, 2 types of hydrazine are added and the mixture is stirred overnight at room temperature. The mixture is then poured into water and the product is extracted with methylene chloride. The extract was dried with sodium sulfate and evaporated to give 950 mg of a light brown oil. It is passed through a bag of heaps using 5% MeOH / CH / Clg f containing traces. Fractions for which TLC indicates the presence of the target compound are combined to give a yellow oil that crystallizes upon standing. It is recrystallized from EtOAc / hexane to give 550 mg of the title compound.
Calculated,%: C 68.93; H 8.87; N 16.08.
Found,%: C 68.99; H 8.64; N 16.11.
Mass spectrum: 260, 232, 216, 166, 136.
EXAMPLE 5 7-Methylthiomethyl-5-propyl-trans-4,4a, 5,6,8a, 9-hexahydro-2H-pyrazolr, 4-quinoline.
The title compound is prepared according to the procedure of Example 1, from 3-methylthiomethyl-1 propyl trans-1,2,4a, 5,6,7,8,8a-octacroquinolin-6-one as a starting material. M.p. 133-134 ° C.
Calculated,%: C 64.94; H 8.36; N 15.15; S 11.56.
Found,%: C 65.26; H 8.26;
N 14.91; S 11.30.
Mass spectrum: 276, 248, 230. 182, 136, 94. IR spectrum (CHC13): 3466, 3240, 2964, 1375, 1136. Proton NMR spectrum (CDClj) 270 MHz: 7.34 (s, 1H ), 5.46 (s, 1H), 2.02 (s, ZN), 0.93 (t, ZN),
EXAMPLE 6. 7-Methylsulfinylmethyl-5-propyl-trans-4,4a, 5,6,8a, 9-hexahydro-2H-pyrazole GZ, 4-rL quinoline.
To a solution of 480 mg (1.7 mmol) of 7- (methylthiomethyl) -5-propyl-trans-4,4a, 5,6,8a, 9-hexahydro-2H-pyrazole 3,4-gl quinoline (Example 5) in 50 ml of methanol was added a solution of 740 mg (3.5 mmol) of sodium metaperiodate in 20 ml of water. The mixture was stirred for 1 hour at room temperature and then poured into water. The concentration of hydrogen ions is adjusted to pH 11, after which the product is extracted with CHC1 / iso-phon (3: 1). The solvent is evaporated to obtain 0.47 g of product which is passed through a column of silica gel,
186
using 7-10% MeOH / CH2Cl2 containing traces of NHjOH. The fractions for which TLC indicates the presence of the target compound are combined to give 230 mg of penny. Proton NMR spectrum (CDC13) 270 MHz: 7.34 (s, 1H); 5.72 (s, 1H); 2.62 (s, 3N); 0.93 (t, 3N). Mass spectrum: 292, 261, 247, 230, 218, 200, 170, 152, 136.
Example 7. 8-Methylthiomethyl-6-propyl-trans-5.5a, 6,7.9a, 10-hexahydropyrido 2,3-pfJ quinazolin-2-amine.
The target compound was prepared according to the procedure of Example 2, using the compound of Example 5 as the starting material. Mass spectrum: 303.275.257, 227.313.198.182. IR spectrum (SNSCO: 3422, 2936, 1607, 1562, 1457. Proton NMR spectrum (SPS13) 270 MHz: 8.08 (s, W), 5.48 (s, III), 4.89 (s, 2H), 2.01 (s, 3N), 0.94 (t, 3N).
The maleic acid salt is obtained from 400 mg portions of the desired compound. The salt is recrystallized from MeOH / EtOAc to give 270 mg of product, which is then dissolved in warm MeOH. Activated charcoal is added and the mixture is filtered while hot. The residue is recrystallized to give 90 mg of the maleate of the title compound as yellow crystals, m.p. 208 ° C.
Calculated,%: C 57.12; H 6.71; 13.32.
Found,%: C 57.35; H 6.84; N 13.32.
Example 8. 8-Methylsulfinylmethyl-6-propyl-trans-5.5a, 6.7.9a, 10-hectare sagidropirido 2,3-j jin-azoline-2-amine.
The title compound was prepared according to the procedure of Example 6, using the compounds of Example 7 as the starting material. Proton NMR spectrum (DMSO-c1b) 270 MHz: 8.02 (s, 1H), 5.64 (s, 1H), 2.32 (s, ZN), 0.87 (t, ZN) Mass Spectrum: 273, 256, 245, 227, 152, 136.
PRI me R 9. rac- (4a / 3, 3/5, 8ab6) - 5-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyra zol rZ, 4 quinoline-8-ol.
Prepare a solution of 1.4 (12.8 mmol) potassium t-butoxide in 20 ml of tetrahydrofuran and up to O C. To the solution add 1.0 g (4.7 mmol) rac- (4 p, 4aoi,) -4-hydroxy-1-propyl-dekagidrokhinolin-6-one, 1.4 g |
(19.0 mmol) ethyl formate and 20 ml of tetrahydrofuran. The mixture is stirred for 1 hour at room temperature to form a suspension. Then add 3 ml
hydrazine, the concentration of hydrogen ions is adjusted to pH 9, and the mixture is stirred for another 2 hours. Then the mixture is drunk on ice, the product is extracted with methylene chloride, dried with sodium sulfate and evaporated to obtain 400 mg of product. The remaining portion of the product in the aqueous layer is extracted with CHC1 / izo-RgOH (3: 1), mixed with sodium sulfate, after evaporation, an additional 680 mg of product is obtained. The combined portions are passed through a silica gel column using 20% MeOH / CH Cl containing (traces. Fractions for which TLC indicates the presence of the product are combined to give 850 mg. The free base is recrystallized from MeOH / EtOAc to give 270 mg of the desired product in white powder, mp, 153-154 ° C. Mass spectrum: 235, 219, 206, 159, 119, 107. UV spectrum (EtOH): fltfQKo 222 nm. Proton NMR spectrum (CSC) 270 MHZ: 7.34 (s, 1H), 4.34 (d, 1H), 0.88 (t, 3N). IR spectrum
(SNSC): 3450, 3225, 2947, 2875, 1078.
Example 10. rac (4AЈ, 8 (/, 8a "0-5-Propyl-4.4A, 7.8,8a, 9-octagndro-2H pyrazole 3,4 -} Lhinolin-8-ol„
The expected product is obtained according to the procedure of Example 9 using rac (4o (, 4th, 8a6) -4-hydroxy-1-propyl deca-hydroquinolin-6-one. IR spectrum (CHCl j): 3570, 3234, 1084. Proton NMR spectrum (CDCLj) 270 MHz: 7.28 (d, 1H), 0.89 (t, 3N) Mass spectrum: 235, 206, 140, 124 o
Example 11, rac methanesulfonate (4a | 5, 8ft, 8aOO-2-amino-6-propyl-5.5a, 6,7,8,9a, 10-octahydropyrido Ј2, W-gJ quinazolin-9-ol (1: 2) „
To a solution of 1.1 g (5.2 mmol) rac- (4 {J, 4ao (, 8a (b) -4-hydroxy-1-propyl-decahydroquinolin 6-one) in 60 ml of toluene is added t, 9 g (13.0 mmol) of tris- (dimethylamino) methane. The mixture is heated under reflux for 1 hour and then evaporated to a brown residue and 50 ml of ethanol are added. The mixture is added to a suspension of 0.95 g (5). , 2 mmol) of guanidinecarbonate in 50 ml of ethanol. The mixture is boiled under reflux for 4 hours, then cooled and poured into water. The product is extracted with CHCl 3 / / iso-RhOH (3: 1), combined with sodium sulfate, evaporated and get 1.3 g dark yellow th gums
through a silica gel column using 10% MeOH / CH 2 Cl g containing traces. The fractions for which TLC indicates the presence of the target material are combined to obtain 0.63 g of a yellow solid. Salt is obtained by adding methanesulfonic acid and recrystallizing from MeOH / EtOAc to obtain 450 mg of the desired product as a yellow powder, mp. 238-239 ° Co. IR spectrum (KBr): 3304, 3165, 2954, 1661, 1602, 1569, 1496. Mass spectrum: 261, 244, 234, 215, 153.
Example 12. Rac dihydrochloride (4a {3, 8, 8аоО-2-amino-6-propyl - 5, 5а, 6,7,8,9a, 10-octahydropirido 2, 3-pf quinazolin-9-ol.
The free base of the title compound was prepared according to the procedure of Example 11, using the compound obtained according to Example 10 as starting material. Mass spectrum: 262, 244, 215, 153. IR spectrum (KBr): 3380, 3320, 3166, 2980, 1653, 1599, 1565, 1487. Proton NMR spectrum (SPCS, DMSO-e) 270 MHz: 8.00 (s, 1H), 0.90 (t. MN). UV spectrum (EtOH): ftMClKC 229. Then get the hydrochloride salt, so pl. 29b-298 ° C.
Calculated,%: C 50.15; H 7.22; N 16.71; C1 21.15.
Found,%: C 50.36; H 7.45; N 16.76; C1 21.15.
Example 13. rac- (4a | $, 8tf, 8aoЈ) - 8- (dimethylaminosulfonylamino) -5-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazole 3,4 d quinoline ethanolate.
To a solution of 1.0 g (3.1 mmol) rac- (4o (, 4aoЈ, 8a6) -4- (dimethylaminosulfonyl-amino) -1-propyl-trans-decahydroquinolin-6-one in 100 ml of toluene is added 1.1 g (7.9 mmol) tris (dimethyl amino) methane The mixture is heated under reflux for 45 minutes, then toluene is removed and the residue is taken up in 100 ml of ethanol. To this is added 3 ml of hydrazine. the mixture is stirred overnight at room temperature and then poured into water.The product is extracted with methylene chloride, dried with sodium sulfate, evaporated and 1 g of substance is obtained t. It is passed through a column trays containing 7-10% MeOH / CH2G, 12. Fractions for which TLC indicates that they are a product are combined to produce a yellow foam. Mass spectrum: ha / e 341. UV spectrum: mchs 219, Ј 6278.3
After recrystallization from EtOH (EtOH) O, 360 mg of the desired solvate is obtained. M.p. 154-156 ° C.
Calculated,%: C 52.69; H 8.58; N 18.07.
Found,%: C 52.44; H 7.28; N 18.02.
Example 14. rac- (5a, 8 (X, GaoO 9- (Dimethylaminosulfonylamino) -6-propyl-trans-5.5a, 6.7.9.9a, 10-octahydro-pyridor, 3-1 chinazolin-2 -amine,
To a solution of 1.1 g (3.5 mmol) rac- (4 (X, 4ao (, 8p () - 4- (dimethylaminosulfonyl amino) -1-propyl decahydroquinolin-6-one in 100 ml of toluene is added 1.3 g (8.7 mmol) of tris (dimethylamino) methane and refluxed for 45 minutes, the toluene was removed and the residue was taken up in 100 ml of ethanol. 250 ml (4.2 mmol) of guanidine were added to it, and the mixture was stirred overnight at room temperature. Then another 240 mg (4.2 mmol) of guanidine is added and the mixture is heated at 50 ° C for 2 hours, after which it is poured into water. Extraction is carried out with CHCl 3 / iso-ROH (3 : 1), dried with sodium sulfate, evaporated and 1.2 g of product is obtained, it is passed through a sidicagel column using 5% MeOH / CH 2 Cl containing traces. The combined fractions for which TLC indicates the presence of the product are evaporated to give 0.9 g of a substance from which Recrystallization from EtOH / EgO gives 380 mg of the ethanol solvate of the target compound. UV spectrum (EtOH): A / waicc 29 6 14,130. Mass spectrum:.
When heated at 110 ° C, the solvate decomposes and the ethanol is removed, leaving the target compound.
Calculated,%: C 52.15; H 7.66; N 22.81.
Found,%: C 52.33; H 7.57; N 22.65.
M.p. 201 ° C (decomp.).
Example 15. rac- (, 8txf, 8arС) 8-Acetylamino-5-propyl-4,4a, 5,6,7,8, 8a, 9-octahydro 2H-pyrazole P3, quinoline.
The target compound was prepared according to the procedure of Example 9 using rac- (4 (X-4a, 8a | 3) -4-acetylamino-1-propyldecahydroquinolin-6-one).
source material. M.p. 190 ° C. Mass spectrum:.
Calculated,%: C 46.76; H 7.85; N 14.54.
Found,%: C 46.50; H 7.12; N 14.78.
Example 16. rac- (4ar, 8a, 8a) - 5-Propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazole 3,4-p; | quinoline-8-amine.
The desired product is obtained by hydrolysis of the compound of Example 15. m.p. 197-199 ° C. Mass spectrum:. UV spectrum: Maca 221; g 5670. IR spectrum (KBr): 3270, 3245, 2900, 1680.
Example 17. rac- (4a | b, 3 (1,8aooO-8 Lcetylamino-5-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo 3,4-p, 1quinoline
The title compound was prepared according to the procedure of Example 9 using rac- (4ao (., 8aft) -4-acetylamino-1-propyldecahydrocnollin-b-she as starting material. Then the dihydrochloride salt is formed and recrystallized from MeOH / EtOAc. Mp 230 ° C.
Mass spectrum:. I
Calculated,%: C, 51.58; H 7.50;
N 16.04.
Found,%: C, 51.32; H 7.38; N 15.81.
Example 18. rac- (, 8 |}, 8a5 5-propyl-4,4a, 5,6,7,8,8a, 9 octahydro-2H-pyrazolor, 4-1 quinoline-8-amine.
The desired product is obtained by acid hydrolysis of the compound of Example 17. A trihydrochloride salt is then formed and it is recrystallized from MeOH / EtOAc. Mass spectrum: 235, 215, 149, 80.
Example 19. 7- (2-Methyl-5-propyl-trans-4, 4a, 5,6,8a, 9-hexahydro-2H-pyrazolo Q3,4-p7 | quinoline methanol and 7- (1-methyl-5- propyl-trans-4,4a, 5,6, 8a, 9-hexahydro-1H-pyrazolo 3, quinoline) methanol.
A solution of 650 mg (5.8 mmol) of tert-potassium potassium in 10 ml of THF is cooled to O C. To it is added a solution of 480 mg (2.1 mmol) of 3-hydroxymethyl-1-propyl-trans-1,2 , 4a, 5,6,7,8,8a-octacroquinolin-6-one, 600 mg (8.5 mmol) of ethyl formate and 15 ml of TG &amp; The mixture is warmed to room temperature and stirred for 5 hours, after which 2 ml of methyl hydrazine is added and the concentration of hydrogen ions is adjusted to pH 9 while the mixture is kept in a cooled state. The mixture is stirred over night at room temperature.
111644718 f2
10-octahydropyrido-2, 3-rLhinaeolin) methanol.
To a solution of 0.5 g (2.2 mmol) of rac- (, 4atf,) -3-hydroxymethyl-1-propyl hydrochlorphinolin-6-one in 50 ml of toluene is added 1.5 ml (5.6 mmol) of tris (dimethylamino) methane. The mixture was refluxed for 2 hours. Toluene is distilled off and a suspension of 130 mg (2.2 mmol) of guanidine in 50 ml of ethanol is added to a solution of the residue in 75 ml of ethanol. The mixture is heated under reflux for 1 hour, stirred at room temperature for
overnight and then drink into the water. The product is extracted from an aqueous mixture of CHC13 / i-RhOH (3: 1), extract with sodium sulfate and evaporated, polurazoloz, 4 ylquinoline) methanol, combined 590 mg of a yellow solid, ignite and get hydrochloride salt It is passed through a column silica gel using 7% MeOH / CH Cl containing traces,. The fractions, for co- (from MeOH / EtOAc), trapped according to TLC data, are shown as Example 20 rac- (4ar, 7o {, 8a5b25), combined and get 7- (5-Propyl-4,4a, 5,6 , 7,8,8a, 9-octa-215 mg of the target compound. M.p.
hydro-2H-pyrazolo 3,4-g quinoline) methanol.
To a solution of 0.47 g (2.1 mmol) of rac (Ze /, 4ao (, 8a) -3-hydroxymethyl-1-propyl-zo (DMSO- (16): 7.98 (s, 1SC 6.21 ( s, 2H), decahydroquinolin-6-one in 50 ml of toluo-0.82 (t, 3N) was added 1.4 ml (5.2 mmol) of tris (dimethylamino) methane. The mixture was boiled in reverse a refrigerator for 3 hours. Toluene is distilled off and 3 ml of hydrazine is added to a solution of this material in 50 ml of methanol. The mixture is stirred overnight at room temperature
and then poured into water. The product is extracted with CHCl3 / i-PrOH (3: 1), then the solvent is distilled off to obtain 560 mg of the product presented on TLC with two spots. The two isomers were separated on a silica gel column using 7% MeOH / CH Cljj containing traces. Fractions for which TLC indicates the presence of 7- (2-methyl-5-JQ propyl-trane-4,4a, 5,6,8a, 9-hexahydro-2H-pyrazolo 3,4- {L quinoline) methanol , combine and get the tosylate salt of this product in the form of a yellow solid. M.p. 232- 233 ° C (from MeOH / EtOAc).
The fractions for which TLC indicates the content of 7- (b1-methyl-5-propyl-trans-4,4a, 5,6,8a, 9-hexahydro-1H-pyto product in the form of a light yellow solid, mp 215-216 ° C
235 ° C (from MeOH / EtOAcj. Mass spectrum: 276, 247, 204, 168, 154, 146, 136, 126. Proton NMR spectrum (360 MHz)
35
Example 22. rac- (4a / 3, 7p (, ZaoO 7-methoxymethyl-5-propyl-4,4a, 5,6,7,8, 8a, 9-octahydro-2H-pyrazolo 3,4-th quinoline.
The desired product is obtained according to the procedure of Example 20, using rac- (Zo (, 4ar {, 8aY) -3-methylthiomethyl-1-propyldecahydroquinolin-6-one).
The desired product is obtained according to the procedure of Example 20, using rac- (Zo (, 4ar {, 8aY) -3-methylthiomethyl-1-propyldecahydroquinolin-6-one).
temperature and then drink into the water.
The product is extracted from an aqueous mixture of 40 starting material, “It is converted
CHCl3 / i-PrOH (3: 1), dried with sodium sulfate and evaporated to give an orange semi-solid product, which is passed through a column of silica gel using 5-7% MeOH / containing traces. The fractions for which TLC indicates the presence of a product are combined to give 300 mg of the desired compound. It is converted to the hydrochloride-50 12.42, a salt. T „pl. 224-228 ° C (from MeOH / / EtOAc),
to the dihydrochloride salt and recrystallized using MeOH / CH2Cl, to obtain a golden brown solid. M.p. 229-230 ° C. 45, Mass spectrum: 263, 248, 234, 169, 154, 140, 119, 71.
Calculated, -%: C 53.57; H 8.09; N 12.49.
Found,%: C 53.53; H 7.90;
PRI me R 23. rac- (5a / 5, Stf, 9aO 8-methoxymethyl-1-propyl-5,5a, 6,7,8, 9, 9a, 10-octahydropyrido JJ2,3-gJ quinazo- lin-2-amine.
Calculated,%: C 52.18; H 7.82; N 13.04.
Found,%: C 52.07; H 7.92;
The expected product is obtained in accordance with the procedure of Example 21 using rac- (3oЈ, 4a #, Ya | 5) -3-methoxymethyl-1 -propylN 13.07.
Example 21. rac- (5a, 8C, 9aY) decahydroquinolin-6-one as 8- (2-Amino 6-propyl 5.5a, 6.7.8.9.9a, starting material. Its recrystalline product, combined and 215 mg of the title compound were obtained. mp.
 (DMSO- (16): 7.98 (s, 1SH 6.21 (s, 2H), 0.82 (t, 3N).
235 ° C (from MeOH / EtOAcj. Mass spectrum: 276, 247, 204, 168, 154, 146, 136, 126. Proton NMR spectrum (360 MHz)
(DMSO- (16): 7.98 (s, 1SH 6.21 (s, 2H), 0.82 (t, 3N).
Example 22. rac- (4a / 3, 7p (, ZaoO 7-methoxymethyl-5-propyl-4,4a, 5,6,7,8, 8a, 9-octahydro-2H-pyrazolo 3,4-th quinoline.
The desired product is obtained according to the procedure of Example 20, using rac- (Zo (, 4ar {, 8aY) -3-methylthiomethyl-1-propyldecahydroquinolin-6-one).
 12.42,
to the dihydrochloride salt and recrystallized using MeOH / CH2Cl, to obtain a golden brown solid. M.p. 229-230 ° C. , Mass spectrum: 263, 248, 234, 169, 154, 140, 119, 71.
Calculated, -%: C 53.57; H 8.09; N 12.49.
Found,%: C 53.53; H 7.90;
 12.42,
PRI me R 23. rac- (5a / 5, Stf, 9a-8-methoxymethyl-1-propyl-5.5a, 6,7,8, 9, 9a, 10-octahydropyrido JJ2, 3-gJ quinazo - lin-2-amine.
The desired product is obtained according to the procedure of Example 21, using rac- (3oЈ, 4a #, Ya | 5) -3-methoxymethyl-1-propyldecahydroquinolin-6-one as the starting material. His recrystal1J16
lick from MeOfl / EtOAc, t.pcs 130 ° C. Mass spectrum: 290, 275, 261, 245, 218 179, 163, 154, 136, 122, 71.
Calculated,%: C, 66.17; H 9.09; N 19.29.
Found,%: C 66.41; H 9.25; N 19.39.
Example 24. rac- (4a /}, 7c (, 7-methylthiomethyl-1-propyl-4, 4a, 5.6, 7, 8.8a, 9-ok gagidro-2H-pyr, 4-pQ quinoline.
The desired product is obtained according to the procedure of Example 20 using rac (ZoЈ, 4ao (, 8a | 3) -3-methylthiomethyl-1-propyl-decahydroquinolin-6-one as starting material. Then the dihydrochloride salt is obtained and recrystallized from MeOH / EtOAc, mp. 230-234 ° C. Mass spectrum: 279, 264, 250, 232, 185, 170, 119, 87., Example 25 rats- (5a | 3, 8oi, 9aooO 8-methylthiomethyl-6-propyl-5,5a, 6,7,8, 9,9a, 10-octahydropyrido-2, 3-fQ quinazolin-2-amine.
The target compound was prepared according to the procedure of Example 21, using the same compound as the starting material as in Example 24
Calculated,%: C 62.71; H 8.55;
N 13.28.
Found,%: C 62.40; H 8.73; N 18.38.
M ss-spectrum: 306, 292, 277, 259, 245, 198, 184, 170, 146, 122.
Example 26. rac- (5a / 3, 8 (5, 9аоЈ 8-2-Amino-6-propyl-5,5а, 6,7,8,9,9a, 10-octahydropyrido-p, 3-p / quinazoline a) methanol.
The title compound was prepared according to the procedure of Example 21, using rac- (SJ, 4aoЈ, 8th) -3-hydroxymethyl-1-propyldecahydroquinolin-6-one as starting material. Then get




the dihydrochloride salt and recrystallized from MeOH / EtOAc, so pl. 250 C, mass spectrum: 276, 247, 204, t68, 154, 146, 136, 126.
Calculated,%: C, 51.59; H 7.50; N 16.04; About 20.30.50
Found,%: C 51.31; H 7.79; K 15.91; About 20.17.
PRI me R 27. pan- (5af3,8fj, 9acO-8-methoxymethyl-6-propyl-5,5a, 6,7,8, 9, 9a, 10-octahydropyrido 7., 3-pQ hina- zolyn-2-amine.
The desired product is obtained according to the procedure of Example 21 and as the source14
rac- (ZG5, 8a) -3-methoxymethyl-1-propyldecagndroquinna-6-one is used for this material.
Calculated,%: C H 9.02; N 19.29.
Found,%: C 65.89; H 8.89; N 19.16.
PRI me R 20. parr (5a / i, 8D,) 8-methylthiomethyl-t-propyl-5,5a, 6,7,8, 9,9a, 10-octahydropyrdoЈ2,3-p1 chinazoline-2 -amine.
The title compound was prepared according to the procedure of Example 21 from rac- (3 |, 4th 8th) -3-methylthiomethyl-1-propyldecahydroquinolin-6-one. Mass spectrum: 306, 292, 277, 259, 245, 188, 146. The monohydrochloride salt is formed and it is recrystallized from m.p. more. Calculated,%: C 56.04; H 7.94; N 16.34.
Found,%: C 56.16; H 7.73; N 16.09.
Example 29 4-oxo-1-propyl-trans-spiroGdecagidroquinolin-6,2 - (1, 3-dioxolane) 1 -3-carboxylic acid ethyl ester.
To a potassium tert-butylate (61.6 g, 0.55 mol) was added THF (500 ml) and 8- (3-ethoxy-3-oxapropyl) propylamino -1,4-dioxaspiro ethyl ester was slowly added to this mixture. -4,5-decan-7-carboxylic acid (98.0 g, 0.27 mol), dissolved in 500 ml of THF. The mixture is then drunk on ice and the concentration of hydrogen ions is adjusted to pH 10. The product is extracted with methylene chloride, dried with sodium sulfate and evaporated to yield 87.2 g (97.7%) of the desired product.
Biological testing. Adult male rats of the Sprap.ue-Dawley race weighing about 200 g were kept in a controlled room with controlled lighting (the light was switched on from 6 am to 8 pm), fed and allowed to drink without restrictions. When conducting tests on re-resinized male rats, a dose was used (Test compound 50 µg / kg, and each rat received an intraperitoneal injection of 2.0 mg of reserpine in an aqueous suspension 18 hours before the administration of the test substance. Reserpine was administered with the goal of a uniform increase in the level of prolactin B in the tests on non-resuscitated male rats, at a dose of 1000 µg / kg of the test compound preceding 1516
Schedule procedure was not performed. Test compounds were dissolved in 10% ethanol and administered by intraperitoneal injection. Each compound was administered at each dosage level to a group of 10 rats, and a control group of 10 intact males received an equivalent amount of 10% ethanol. One hour after treatment, all rats were killed by decapitation and 150 μl aliquots of serum were analyzed for prolactin.
The difference between the level of prolactin for treated rats and the level of prolactin for control animals, divided by the level of prolactin for control animals, gives a number that, when multiplied by 100, represents the percentage inhibition of prolactin secretion characteristic of the compounds according to the invention. These indicators of percentage inhibition are given in Table. one.
It has been shown that premymine agonists affect the verticular behavior of rats affected by 6-hydroxydopamine during tests designed to detect compounds useful for parkinsonism treatment. In this test, nitroneostriatal rats prepared using the method of Ungerstedt I Arbuthnoff are used, Brain Res. A compound exhibiting dopamine-agonistic activity and the ability to penetrate the hemato-encephalic barrier into the striatum of the brain causes the rats to walk in circles to the opposite side of the p position wounds. After the latent period, the duration of which varies from compound to compound, is calculated the number of revolutions per 15-minute period.
It has been shown that dopamine agonists, which penetrate the blood-brain barrier and enter the brain, reduce the content of dopamine metabolites in the brain, such as 3,4-di-hydroxyphenyl acetic acid (DOPUK) and homovanillic acid (HVA). The tests described in Perry and Fuller, Soc. Neurosei. Abstr., Allow the assessment of the effect of compounds on the level of dopamine metabolites in the brain. The compounds according to the invention were tested according to these methods and the resultant
sixteen
Tables for representative compounds are given in Table. 2
Dopamine agonists, which enter the brain, lead to an increase in serum corticosterone levels. The compounds according to the invention were tested according to the method of Solem and Brink-Johnsen, Seand. J. Clin, Lab. Invest, to determine their effect on serum corticosterone levels.
The compounds of examples 1 and 11 are peripherally selective dopamine agonists. They are active and inhibit serum prolactin secretion by activating the dopamine receptors of the pituitary gland, a tissue that is not protected by the hemato-encephalic barrier. These ke compounds cause the verticular behavior of rats affected by 6-hydroxydopamine and do not cause changes in serum dopamine or corticosterone metabolite levels, which are types of activity mediated in areas of the brain that are protected by the hemato-encephalic barrier
The compounds according to the invention lower the blood pressure of spontaneously hypertensive rats, as demonstrated by the following experiment.
Adult male rats of spontaneously hypertonic (SGC) weighing approximately 300 g are anesthetized with pentobarbital-sodium (60 mg / kg, intraperitoneally). The trachea is cannulated and SGC breathes the room air. Pulsating arterial blood pressure is measured by the kankshirovanny carotid artery using a Statham sensor (P23 ID). Mean arterial blood pressure is calculated as diastolic blood pressure plus 1/3 pulse pressure. Drug solutions are administered intravenously through a catheter placed in the femoral vein. Arterial blood pressure is measured and recorded on a multichannel oscilloscope (Beckmann Company, Model R 511A). For balancing the drug after surgery for 15 minutes no action is taken.
Table 3 shows the results of this test for representative compounds according to the invention.
In tested doses of a compound according to the invention, signs of toxicity are not
Do they show and can be categorized as low-toxic
The compounds prepared according to the invention can be used to inhibit the secretion of prolactin, in the treatment of unnecessary lactation, such as postpartum lactation and galactoria.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining pyrazolo derivatives of 3,4-pPhinolin or pyrido Ј2,3-g quinazoline of formula
p (i)
R4
I Ko
with)
where R is a hydrogen atom or C3-C3 alkyl;
rings C and D are trans-condensed, R is C (-Cd-alkyl,, and R5 are defined below, if Rg is hydrogen atoms; K.Ј ™, CHLOSNp, CHrtSCHe,
, -СНг80гСН3,
provided that rac- (4ar, 7Y, 8aoi) -4, 4a, 5j6,7,8,9-oK rarHflpo-2H-pyrazolo 3,4-quinoline and rac- (4th,
7f5, 8aooO-4,4a, 5,6,7,3,9-octahydro-1H-pyrazolor, 4 quinolines; in the case when b .. - CHNOSH5, -CH2SCH3 Rg does not mean hydrogen; or Rz is SNGON, -CHNOSCH, -CHjjSCH, S-CH3,
eight
R-3 is hydrogen, a is R, and R is combined to form a double bond, or R2,
4 and% hydrogen atoms; R, -OH, -NH2-NHCORT, and -NHSOtNR4R8, where Ry and Rg independently mean C-C alkyl, or their salts, characterized in that the 7-dimethylaminomethylene-6-oxo-trans-quinoline derivative of the formula
ABOUT
(SN AN -SI
R, R,
RR4
R.
(ti)
40
,,
2d where R is RJ. have the indicated meanings, are reacted with hydrazine or a hydrazine derivative of the formula
NRjNHR
where Rg is hydrogen or C, -C3-alkyl, to obtain the pyrazolo derivative P (1 quinoline of Formula (I), in which ring B has the structure a) or b) or c) guanidine to obtain the pyrido derivative ,2, H-g of quinazoline 35 of the formula (I) in which ring B has the structure c), and / or, if necessary, a compound of formula (1) in which Rg - CH SCH-j is oxidized to give the corresponding compound of formula (I) in which Rg is CHg5CH -z, or connection0
formula (I), where R is NHCOR, is hydrolyzed underneath to give the corresponding compound of formula (I), where is RS NH, or the compound of formula (l) is converted to the salt
nineteen
164471820
Continuation of table 1
(1H) (2H)
14 62 83 27 7.2
84 84 94
83 84 70 37 89 39 89 92 35
 Percentage decrease relative to control for serum prolactin level after a 50 µg / kg dose was administered to re-mated rats to males;
 percent reduction relative to control for serum prolactin level after a dose of 1000 µg / kg to non-resuspended male rats.
Table
DOPA 3,4-dihydroxyphenylacetic acid; GVK homovanilic acid;
B Compound 8-methylthiomethyl-6-propyl-trans-5.5a, 6.7.9a, 10-hexahydropyrido 2, H-R quinazolin-2-amine.
80
33
ABOUT
ABOUT
100

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1644718A3|1991-04-23|Method of producing derivatives of pyrazolo[3,4]quinoline or pyrido[2,3]quinazoline, or their salts

---

KR960000852B1|1996-01-13|Quinoline type mevalonolactones

---

SU1560056A3|1990-04-23|Method of producing derivatives of 1,3,9,9a-tetrahydro-2n-imidazo/4,5-b/quinoline-2-on or their pharmaceutically acceptable salts

---

AU2003292320B2|2009-03-12|Pyridopyrimidinone compounds, method for production thereof and medicaments comprising the same

---

JPH0739346B2|1995-05-01|Antihistamine / antiallergic agent

---

CZ265096A3|1997-06-11|Thienoindole derivatives, their use, process of their preparation and pharmaceutical composition containing thereof

---

EP0125607A2|1984-11-21|Pyrido|benzodiazepinone derivatives and pharmacological activities thereof

---

PL164662B1|1994-09-30|Method of obtaining novel derivatives of 1-oxa-2-keto-3,8-diazospiro 4,5 decane

---

EP0133530B1|1989-03-15|1,6-naphthyridinone derivatives, process for their preparation, and medicaments containing them

---

KR101027977B1|2011-04-13|Quinoline Derivatives

---

US4758559A|1988-07-19|Pyrrolo[1,2-a] [4,1]benzoxazepine derivatives useful as calmodulin and histamine inhibitors

---

DK153149B|1988-06-20|METHOD OF ANALOGUE FOR THE PREPARATION OF HYDROXYAMINOEBURNAND DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OR OPTIC ACTIVALLY ISOMERATED ANGERA DERIVATED ANOSTERANE DERIVATED ANOSTERIVES

---

US4309348A|1982-01-05|Tricyclic indole derivatives

---

DK169948B1|1995-04-10|Intermediates for use in the preparation of pyrimido [4,5-g] quinoline derivatives or salts thereof

---

US4609657A|1986-09-02|Ergot peptide alkaloid derivatives, processes for their preparation and pharmaceutical compositions containing them

---

CA1300146C|1992-05-05|12b-substituted 1-hydroxymethyl-octahydroindolo¬2,3-a|- quinolizine derivatives, process for the preparation and pharmaceutical compositions containing them

---

FR2508457A1|1982-12-31|PYRROLO | QUINAZOLINES AND PYRIDO | QUINAZOLINES SUBSTITUTED, THEIR PREPARATION AND THEIR THERAPEUTIC USES

---

SU1189349A3|1985-10-30|Method of producing 6-substituted hexahydroindazolisoquinolines

---

US2858251A|1958-10-28|Indolo [2, 3-c] quinazo [3, 2-a] pyridine derivatives

---

US3983127A|1976-09-28|Pyrrolo[3,4-b]pyridines

---

US4621087A|1986-11-04|Anti-anoxic furo- or pyrrolo-pyridine compounds and pharmaceutical compositions containing them

---

CA2350560C|2006-10-31|Novel type condensed pyridazinone compounds

---

SAIGA et al.1987|Synthesis of 1, 2, 3, 4-Tetrahydro-β-carboline Derivatives as Hepatoprotective Agents. II. Alkyl 1, 2, 3, 4-Tetrahydro-β-carboline-2-carbodithioates

---

US4273780A|1981-06-16|Anti-allergic anti-9,10-dihydro-4-|-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10|-one oxime

---

US4146626A|1979-03-27|8-adamantylaminomethyl ergolene derivatives

同族专利:

---

公开号 | 公开日

---

DK299787D0|1987-06-12|

---

KR890005302B1|1989-12-20|

---

DK299787A|1987-12-17|

---

HUT44546A|1988-03-28|

---

NZ220650A|1989-11-28|

---

PT85061B|1990-03-30|

---

JPS62298589A|1987-12-25|

---

PH25132A|1991-02-19|

---

EP0250179A2|1987-12-23|

---

CN1016872B|1992-06-03|

---

HU197900B|1989-06-28|

---

CN87104651A|1988-01-13|

---

EP0250179A3|1989-08-23|

---

KR880000430A|1988-03-25|

---

CA1307526C|1992-09-15|

---

AU597073B2|1990-05-24|

---

MX6887A|1993-11-01|

---

ZA874137B|1989-01-25|

---

US4826986A|1989-05-02|

---

AT390061B|1990-03-12|

---

ATA263287A|1989-08-15|

---

AU7422987A|1987-12-17|

---

PT85061A|1987-07-01|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4230861A|1979-01-22|1980-10-28|Eli Lilly And Company|1-And/or 7-substituted-6-hydroxy -3-decahydroquinoline carboxylic acids|

---

US4198415A|1979-01-22|1980-04-15|Eli Lilly And Company|Prolactin inhibiting octahydro pyrazolo[3,4-g]quinolines|

---

JPS647072B2|1979-03-09|1989-02-07|Mitsui Toatsu Chemicals|

---

US4235909A|1979-04-19|1980-11-25|Eli Lilly And Company|Octahydro-2H-pyrrolo[3,4-g]quinolines|

---

US4647667A|1982-11-03|1987-03-03|Eli Lilly And Company|Octa- and deca-hydroquinoline intermediates|

---

ES8501395A1|1982-11-03|1984-12-01|Lilly Co Eli|Improvements in keto intermediates, their use and preparation.|

---

US4471121A|1982-11-03|1984-09-11|Eli Lilly And Company|Method of resolving trans-d alpha-1-n-propyl-6-oxodecahydroquinoline and di-p-toluoyltartaric acid salts thereof|

---

US4567266A|1982-11-03|1986-01-28|Eli Lilly And Company|Method of preparing octahydro-1H-pyrazolo[3,4-g]quinolines|

---

AU546346B2|1983-01-11|1985-08-29|Eli Lilly And Company|1,3 disubstituted-6 oxo-decahydro quinolines|

---

US4507478A|1983-09-26|1985-03-26|Eli Lilly And Company|2-Mercaptopyrimidohexahydroquinolines and related compounds|

---

US4501890A|1983-09-26|1985-02-26|Eli Lilly And Company|Trans--2,4,6-substituted-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinolines|

---

US4778894A|1983-09-26|1988-10-18|Eli Lilly And Company|6 oxo-decahydroquinolines|

---

FI78091C|1983-09-26|1989-06-12|Lilly Co Eli|ANALOGIFICATE FARING FOR THE PREPARATION OF SAUSOM DOPAMINOAGONISTER ANVAENDBARA PYRIMIDO / 4,5-G / KINOLINDERIVAT.|

---

IL73001D0|1983-09-26|1984-12-31|Lilly Co Eli|Improvements in and relating to 6-oxodecahydroquinolines|

---

US4528290A|1984-01-30|1985-07-09|Eli Lilly And Company|Stimulating dopamine D-1 receptors|

---

US4537893A|1984-04-27|1985-08-27|Eli Lilly And Company|Octahydrothiazolo[4,5-g]quinolines and use as prolactin secretion inhibitors|

---

GR851895B|1984-08-02|1985-12-03|Lilly Co Eli|

---

US4537965A|1984-08-03|1985-08-27|Eli Lilly And Company|Method of preparing 4aR,8aR-5-permissibly substituted-6-oxo-octahydro-1H-pyrazolo[3,4-g]quinolines, useful as intermediates|

---

US4659832A|1985-06-10|1987-04-21|Eli Lilly And Company|Process for the preparation of octahydro-oxazolo [4,5-G]quinolines|GR851895B|1984-08-02|1985-12-03|Lilly Co Eli|

---

US5134143A|1986-06-16|1992-07-28|Eli Lilly And Company|BCD tricyclic ergoline part-structure analogues|

---

US4977160A|1986-06-16|1990-12-11|Eli Lilly And Company|BCD tricyclic ergoline part-structure analogues|

---

US4743607A|1987-05-29|1988-05-10|Merrell Dow Pharmaceuticals Inc.|Cardiotonic tricyclic imidazolones|

---

US4977149A|1989-07-24|1990-12-11|Eli Lilly And Company|Pyridoquinoline dopamine agonists, compositions and use|

---

US4939259A|1989-07-24|1990-07-03|Eli Lilly And Company|2-oxo-pyrido[2,3-g]quinoline derivatives|

---

US5057515A|1989-07-24|1991-10-15|Eli Lilly And Company|Method for agonizing a dopamine receptor|

---

US5436344A|1990-11-29|1995-07-25|Pfizer Inc.|3-bromo-5-chloro-pyridines used as intermediates in the synthesis of azatetralones|

---

US5416090A|1991-01-31|1995-05-16|Eli Lilly And Company|Method of treating inflammation|

---

US6835841B2|2002-09-13|2004-12-28|Bristol-Myers Squibb Company|Asymmetric catalytic hydrogenation process for preparation of chiral cyclic β-aminoesters|

---

AR046172A1|2003-10-03|2005-11-30|3M Innovative Properties Co|PIRAZOLOPIRIDINAS AND ITS ANALOGS; PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THE INHIBITION OF THE BIOSYNTHESIS OF CITOCINES|

---

US7544697B2|2003-10-03|2009-06-09|Coley Pharmaceutical Group, Inc.|Pyrazolopyridines and analogs thereof|

---

TWI537274B|2011-03-14|2016-06-11|橘生藥品工業股份有限公司|Novel octahydrothienoquinoline derivatives, pharmaceutical compositions containing the same, and their uses|

---

JP6177061B2|2012-09-12|2017-08-09|キッセイ薬品工業株式会社|Novel dopamine D2 receptor agonist|

---

JP6166990B2|2012-09-12|2017-07-19|キッセイ薬品工業株式会社|Process for producing octahydrothienoquinoline derivative and its intermediate|

---

JP6242811B2|2012-12-10|2017-12-06|キッセイ薬品工業株式会社|Novel octahydropyridoquinazoline derivatives, pharmaceutical compositions containing them and their use|

---

WO2014112492A1|2013-01-17|2014-07-24|キッセイ薬品工業株式会社|Novel octahydroquinoline derivative, pharmaceutical composition containing same, and use thereof|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US06/874,741|US4826986A|1986-06-16|1986-06-16|6-Oxo-trans-octa- and decahydroquinolines|

---