Method of producing benz-condensed cycloalkatrans-1,2-diamine derivatives as enantiomers or racemate

专利摘要:
Benzo-fused cycloalkane and oxa- and thiacycloalkane trans-1,2-diamine compounds of the formula: <CHEM> wherein A, B, C, D, n, X, Y, R, R<1>, R<2> and R<3> are as defined in the specification, e.g., trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy 1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide, and the pharmaceutically acceptable salts or N-oxides thereof, are useful as analgesics and/or diuretics.
公开号:SU1582984A3
申请号:SU874203411
申请日:1987-09-09
公开日:1990-07-30
发明作者:Пеннев Пенио；Раджагопалан Партасарати；Меррилл Скрибнер Ричард
申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to organic chemistry, namely to a method for the preparation of new benzofused condensates of cycloalkanthrans-1,2-diamine derivatives - NBM of the general formula
R-N-COCH2 as enantiomers or racemates, where B is H, OH, OOS2H5, OOS (H5 OR,
C - H, OR, OH; R - C C alkyl;
X and Y - C1 or together with the benzene ring form the group:
Ry - Su-S, -alkyl,
or their pharmaceutically acceptable salts, which have analgesic and diuretic effects and can be used in medicine.
The aim of the invention is to develop a process for the preparation of compounds of the formula I having high analgesic activity.
The invention is illustrated by the following examples.
Example 1. trans-3,4-dichloro-K-methyl -N- - (pyrrolidin-1-yl) -5-methoxy-1,2,3,4-tetrahydronaph-1-yl J benzenecetamide and its hydrochloride salt.
1.1. 5-Methoxy-1-tetralol.
5-methoxy-1 tetralone (100.0 g, 0.57 mol) was introduced into a 1 l round-bottom flask, ethanol (400 ml) was introduced, and the resulting suspension was stirred at room temperature. Sodium borohydride (17 g, 0.45 mol) is added in separate portions for about 20 minutes. When the reaction mixture becomes warm (about 40 ° C), it is quenched in an ice-water bath to about room temperature. The resulting clear solution is stirred for 4-5 hours after stopping the injection and then about 1/2 volume of ethanol is evaporated under reduced pressure in a rotary evaporator. The remaining mixture is stirred with water (approximately 1.5 liters) and extracted (three times) with these acetate. The ethyl acetate extracts are mixed and washed with water (twice), and then with saturated NaCl, dried over MgSO4 and evaporated, the result is 5-methoxy-1-tetralol (approximately 100 g), i.e. 75-76 ° C. Thin layer chromatography (ethyl acetate-hexhexane 2: 1): Rf 0.6, 1 spot. IR spectrum showed no peak
50
1.2. 8-Methoxy-1,2-dihydronaphlin.
The above product (about 100 g) in dimethyl sulfoxide (350 ml) is heated in an oil bath at 170 ° C with simultaneous stirring for 12 hours. The mixture is cooled to room temperature and poured into H2O (3 l). A mixture of water - dimethylsulfoxide55 is extracted with ether (3 times). The ether layers are combined and washed with water (2 times), then with saturated NaCl
0
five
0
five
0
five
0
five
0
five
(1 time) and dried over anhydrous K2CO3, the ether is evaporated and the remaining liquid is distilled from the flask into the flask, and 8-methoxy-1,2-β-dihydronaphthalene (approximately 80 g) is obtained, b.p. approximately 117-123 ° / V, 5-5 mm, (thin layer chromatography: Rf 0.8 (ethyl: hexane 1: 1).
1.3.1.2-Epoxy-5-methoxy-1,2,3,4-tetrahydronaphthalene.
A solution of the above product (80 g, 0.5 mol) in CH2Cl2 (300 ml) is stirred in a 5-liter 3-neck round bottom flask at 0-3 ° C in an ice-water bath. A solution of 3-chloradoxibenzoic acid (97 g, 0.50 mol) with a purity of 85% in CH2Cl2 (2 L) is added dropwise with simultaneous cooling for 3 hours (approximately 13 ml / min) and then with continued cooling. stir for more than 3 hours at 0 ° C. Then a 10% aqueous solution of Na2CO3 (750 ml) was introduced into the cold reaction mixture with simultaneous stirring. The mixture was sent to a separatory funnel and the lower layer of CH2Cl2 was removed. The CH2Cl2 layer was washed with a 10% aqueous solution of Na2C03 (2x75 ml) and once with water. The CH2Cl2 solution is analyzed with reactive paper moistened with starch iodide in the absence of peroxide. This solution is dried over MgSO4 and evaporated at 45 ° C, resulting in 1,2-epoxy-5-methoxy-1,2,3,4-tetrahydronaphthalene (95 g).
1.4.trans-1- (Pyrrolidin-1-yl) -2-oxy-5-methoxy-1,2,3,4-tetrahydronaphthalene.
I
In a flask containing the above epoxy compound (17.6 g, O, 1 mol), j is added dropwise with simultaneous stirring for about 10 minutes pyrrolidine (10 ml, 0.12 mol) in ethanol (5 ml). The mixture is stirred at room temperature for about 18 hours and then heated at 50 ° C for about 1 hour. After cooling, the solid is recovered by filtration and recrystallized from absolute ethanol. The crystalline product trans--1- (pyrrolidin-1-yl) -2-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene (14.5 g, yield) is recovered by filter-; washed with cold ethanol and air dried. M.p. 113 115 ° C. Thin layer chromatography
(ethyl acetate: hexane 2: 1), Rf e 0.33.
1.5.trans-1- (Pyrrolidin-1-yl) -2- -oxy-5-methoxy-1,2,3,4-tetrahydronaphthalene-0-sulfonic acid.
A solution of the above pyrrolidinoic alcohol (47 g, 0.19 mol) in CH2Cl2 (250 ml) is stirred under a nitrogen atmosphere and cooled in an ice-water bath with simultaneous addition of chlorosulfonic acid (12.7 ml, 22, 2 g, 0.19 mol) in CH2Cl2 (250 ml). After stopping the addition, the mixture is stirred at 0-5 ° C for 2 hours and then at room temperature overnight. The solid product is recovered by filtration and air-dried, resulting in trans-1- (pyrrolidin-1-yl) -2-oxy-5-methoxy-1,2,3,4-tetrahydron-phthaline-0-sulfonic acid (62 g, 100%), so pl. 213-215 ° C (with decomposition),
1.6. Trans-1-methylamino-5-methoxy--2- (pyrrolidin-1-yl) -1,2,3,4-tetrahydronaphthalene.
In the Parr bottle, intended for hydrogenation, the above-mentioned dry sulfonate salt (62 g, 0.19 mol) and 33% CH 3 H 2 - ethanol (120 g, 1 mol) are introduced. The skull is sealed with a rubber stopper, held in place with the help of the claws, and heated in an oil bath for 20 h with simultaneous stirring. The mixture is cooled to room temperature and evaporated in a rotary evaporator, with most of the ethanol being removed. Ethyl acetate was added to the evaporation residue, followed by a 5% aqueous solution of NaOH (100 ml). The ethyl acetate layer is removed, and the aqueous phase is extracted with ethyl acetate. The organic extracts are dried over K2C03. After evaporation of the solvent, the crude diamine is obtained in the form of trans-1-methylamino-5-methoxy-2- (pyrrolidin-1-yl) -1,2,3, 4-tetrahydronaphthalene (49 g) free base.
This free base is dissolved in toluene, and the solution is evaporated in order to remove traces of water and ethanol until the next step. This diamine can also be obtained by chemical interaction of trans-1- (pyrrolidin-1-yl) -2-OXI-5- methoxy-1,2,3,4-tetrahydronaphthalene with methanesulfonyl chloride in the presence of ™.


582984
of triethylamine followed by treatment of methanesulfonate with methylamine using the procedure described below in Example 2.2.
1.7. Trans-3,4-Dichloro-No-methyl-M- (pyrrolidin-1-yl) -5-methoxy-1,2, 3,4-tetrahydronaph-1-yl-7 benzene-amide.
10 To a solution of 3,4-dichlorophenylacetic acid (51.6 g, 0.25 mol) in dry tetrahydrofuran (300 ml) under N atmosphere, injected with simultaneous stirring 1.1-carbonyldiimidazole (40.8 g, 15 0, 25 mole). The reaction mixture is stirred for 2 hours at room temperature. temperature and then a solution of the diamine obtained in 1.6 is added dropwise.
20
25
(54.6 g, 0.21 mol), in dry tetrahydrofuran (110 ml). The mixture is stirred overnight at room temperature under N2. Then the solvent is evaporated in vacuo. The evaporation residue is dissolved in ether (1 L) and the solution is washed with a 5% aqueous solution of NaOH (2x250 ml), then with water, dried over MgSO4 and evaporated to give trans-3,4-di 30 chloro-S -methyl-M- 2- (pyrrolidin-1-yl) -5-methoxy-1,2,3,4-tetrahydronaphth-1-yl benzene-acetamide (89 g).
1.8. Trans-3,4-dichloro-Y-methyl-M-2- (pyrrolidin-1-yl) -535-methoxy-1,2,3,4-tetrahydronaphth-1-pc benzene-acetamide hydrochloride.
The above crude amine in the form of amide (free base, 89 g) paj is dissolved in tetrahydrofuran (400 ml) and this solution is introduced into a simple ether (1 liter) containing dissolved gaseous HCl, resulting in the precipitation of a gummy hydrochloride salt. Ether (500 ml) is added to this mixture and the resin is triturated. The liquid is decanted, a fresh portion of ether (700 ml) is introduced, resulting in the formation of a solid. The ether was decanted and acetone (400 ml) was added to the resulting solid. The acetone mixture is boiled for 10-15 minutes, kept at room temperature for 1-1.5 hours, and filtered to obtain a solid hydrochloride salt (32 g). After recrystallization from isopropanol-methanol (1: 1, 400 ml) using bleach charcoal and aging overnight
40
45
50
55
at room temperature, chlorohydrin. trans-3,4-dichloro-M-methyl- (pyrrolidin-1-yl) 5-methoxy--1,2,3,4-tetragicyronoft-1-ylLbenzacetamide is obtained as white crystals (21.6 g), m.p. 230-232 ° C (with decomposition) ". The acetone filtrate, from which 32 g of the crude product is separated, is evaporated and an oil (55 g) is obtained.
Boiling the residual oil with a portion of acetone and then evaporating the acetone in a rotating evaporator is repeated three times, to remove traces of the solvent, sate the product crystallizes from isopropanol and acetone and get a second portion of the product (about 9 g) with .pl. 225-227 C. Sometimes a third portion of the product can be allocated in even smaller quantities,
Example 2. Trans-3,4-dichloro-N-methyl-No. 2- (pyrrolidin-) -1,2,3,4-tetrahydronaph-1-yl benol acetamide hydrochloride.
2.1, trans-I, 2,3,4-tetrahydro-2-hydroxy-1-pyrrolidin-1-yl} naphthalene "
A mixture of 1,2-ethoxy-1,2,3,4-tetrahydronaphthalene (19.8 g), pyrrolidine (15 ml) and ethanol (75 ml) is stirred at reflux for 2 hours and reduced under reduced pressure. pressure to remove volatile. Residual evaporation product is dissolved in ether and the solution is extracted with 1N hydrochloric acid (200 ml), the acidic extract is washed with ether and basified with 1N aqueous sodium hydroxide solution with simultaneous cooling. The mixture is extracted with ether (twice) and the combined ether extracts are washed with water, dried over magnesium sulfate, and dried under reduced pressure. The residual viscous oil is distilled off in vacuo to give trans-1,2,3,4-tetrahydro-2-hydroxy-1- (pyrrolidine-1-i p) naphthalene (16.5 g) t cues. 128 -, 25 mm Hg
2.2.trans-1,2,3,4 Tetrahydro-1- -methylamino-2- (pyrrolidin-1-yl) -n.
A solution of methanesulfonyl chloride (10.3 g) in methylene chloride (50 ml) was quickly added dropwise to a solution of trans-1,2,3,4-tetrahydro-2-hydroxy-1 that was stirred and cooled to 0 ° C5 ° C
five
0
five
0
five
0
five
0
- (pyrrolidin-1-yl) naphthapine (10.3 g) and triethylamine (10 g) in methylene chloride (100 ml). After stopping the addition, the mixture is stirred at room temperature for 3 hours and then boiled under reduced pressure. The evaporation residue is thoroughly treated with a 33% solution of methylamine in ethanol (125 ml) and the mixture is stirred at reflux for 2 h, after which the solvent is evaporated under reduced pressure. The evaporation residue is treated with water and extracted twice with ether. The combined ether extracts are washed with 2N sodium hydroxide and then with water, dried over magnesium sulphate and evaporated under reduced pressure. The residual viscous liquid product is distilled off in vacuo to give trans-1,2,3,4-tetrahydro- 1-methylamino-2- (pyrrolidin- 1 -yl) naphthalene (6.2 g) with bp, J26-1340C / 0.25 mm Hg
2.3, trans-3,4-dichloro-K-methyl-H-C2- (pyrrolidin-1-yl) -1,2,3,4-tetrahydronaphth-1-yl benzene-acetamide hydrochloride.
A solution of dichlorophenylacetyl chloride (1.1 g) in methylene chloride (25 ml) was introduced into a solution of the above diamine (1.1 g) in methylene chloride (50 ml), the resulting solution was stirred with an aqueous solution of sodium bicarbonate (75 ml) for 2 h at room temperature. The organic layer is separated and washed with an aqueous solution of sodium bicarbonate, then with water, dried over MgSO4 and evaporated to give an oil (.1.5 g) of crude final product, which is dissolved in tetrahydrofuran and introduced into the HCl solution in ether . The precipitated hydrochloride salt is washed with ether and air-dried. The crude salt is crystallized from acetone. After recrystallization from isopropanol, a clear hydrochloric mud of the final compound with mp. 234 C (with decomposition).
23
Example 3. trans-3,4-dichloro-N-methyl-K-2 - (pyrrolidin -1 -yl) -6-to-toxi-1,2,3,4-tetrahydronapht-1-yl benzene-acetamide and its hydrochloride salt.
3.1. Trans-2-bromo-1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthalene.
To a solution of 6-methoxy-1,2-dihydron phthaline (44.8 g, 0.28 mol) in dimethyl sulfoxide (450 ml) is added while simultaneously mixing H20 (1 ml). Into the stirred mixture are introduced in the form of five portions of N-bromosuccinimide (99.7 g, 0.56 mol) while controlling the exotherm using an ice bath. The mixture is stirred at room temperature for 3 hours. Water (approximately 1 L) is added and the mixture is extracted with ether (3 times). The combined extracts were washed twice with water, then with 5% NaHC03, dried over Cr03, filtered and evaporated, and an oil was obtained. After removing all of the solvent, a crystallized oil is obtained. This oil is recrystallized from a mixture of hexane - ethyl acetate, and trans-2-bromo-1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthalene is obtained with m.p. 80-82 ° C, chromatography on silica gel using ethyl acetate: Rf 0.85, second portion of product, obtained from the filtrate, 13 g, m.p. 80-81 ° C.
3.2. Trans-2-hydroxy-1- (pyrrolidin-1- -yl) -6-methoxy-1,2,3,4-tetrahydronaphthalene.
In the above bromohydrin (30.8 g, 0.12 mol), cooled in a water bath, pyrrolidine (240 ml) and water (47 ml) are added simultaneously. The mixture is cooled for 10 minutes and then kept at room temperature for 22 hours. Excess pyrrolidine is evaporated in a rotary evaporator. Aqueous 10% Na2CO3 was added and the mixture was extracted with ethyl acetate (three times). The extract is dried over MgSO4 and evaporated to give trans-2-hydroxy--1- (pyrrolidin-1-yl) -6-methoxy--1,2,3,4-tetrahydronaphthalene, which is crystallized from isopropanol. The first portion of the product is 17 g (mp. 79 - 80 ° C), the second portion is 7 g (mp, 78 - 79 ° C).
3.3. trans-2-hydroxy-1- (pyrrolidin-1- -yl) -6-methoxy-1,2,3,4-tetrahydronaphthalene-0-sulfonic acid.
A solution of the above amino acid alcohol (7.4 g, 30 mmol) in methylene chloride (30 ml) is cooled in ice and at the same time a solution of chlorosulfonic acid (2 ml) is added dropwise to
0
Q e 5
0
Q
methylene chloride (60 ml). The mixture was stirred under nitrogen for 2 hours while cooling and then at room temperature overnight. The precipitated white product is recovered by filtration, washed twice with a fresh portion of methylene chloride and dried, the result is trans-2-ox-1- (pyrrolidin-1-yl) -6-meto--1,2,3 , 4-tetrahydronaphthalene-O-sulfonic acid (8.7 g) with m.p. 2U-212 ° C (with decomposition).
„3.4. trans-1-methylamino-2- (pyrrolidin-1-yl) -6-methoxy-1,2,3,4-tetrahydronaphthalene.
The above 0-sulfonic acid salt (8.6 g) and 30% methylamine in ethanol (20 ml) are heated in a hermetically sealed Parr flask at 50 ° C for 3-4 hours and then at 70 ° C for nights The mixture was evaporated in vacuo and ethyl acetate was added to the evaporation residue. An aqueous 5% solution of sodium hydroxide was added and the mixture was quickly extracted with ethyl acetate (3 times). The ethyl acetate extract is dried over anhydrous potassium carbonate, then evaporated to give trans-1-methylamino-2- (pyrrolidin-1-yl) -6-methoxy-1,2,3,4-tetrahydronaphthalene (3.5 g ) in the form of oil. The aqueous layer is further extracted with methylene chloride and an additional amount of product (0.5 g) is obtained.
3.5. Trans-3,4-dichloro-N-methyl-M-2-2 (pyrrolidin-1-yl) -5-methoxy-1,2, 3,4-tetrahydro-1-yl enzene-acetamide hydrochloride.
The above diamine is converted to the corresponding 3,4-dichlorobenzene-acetamide by treatment with 3,4-dichlorophenylacetic acid (3.37 g), which has been treated with N, N-Kap6o-nylimidazole (2.6 g) in tetrahydrofuran in a manner similar to that described in example 1.7.
The result is an aminoamide, which is converted to its hydrochloride salt by the method described in Example 1.8. The salt is recrystallized from isopropanol – methanol. This salt was washed with acetone and recrystallized from isopropanol-methanol to obtain analytically pure product, trans-3,4-dichloro-M-methyl-M- 2- (pyrrolidine) hydrochloride.
-1-yl) -6-methoxy-1,2,3,4-tetrahydro-1-shObenzenecetamide, m.p. 245 - (with decomp.).
Example 4 trans-3,4-dichloro-M-methyl-N-2- (pyrrolidin--1-yl) -6-hydroxy-1,2,3,4-tetrahydronaph--1 -itnjf benzene acetamide hydrochloride .
TRANS-3,4-Dichloro-P-methyl-M-C2-1tir-rolidin-1-yl) -6-methoxy-1,2,3,4-tetrahydronaph-1-shObenzenecetamide is treated with six molar equivalents of tribromide boron in CH, C1 at -78 ° C. The reaction mixture is slowly warmed to room temperature and stirred at room temperature for 2 hours. “This reaction mixture is then treated with methanol and then with aqueous 5% NaHC03 solution. Extraction of the CHjCl gives the desired product as a free base. This free base is dissolved in tetrahydrofuran and treated with a mixture of HC1 - ether, the result is a target compound with so pl. 238-240 ° C
Example 5
A. (+) trans-3,4-Dichloro-M-methyl-and- (pyrrolidin-1-yl) -1,2,3,4-tetrahydronaph-1 yl benzenecetamide and its hydrochloride salt.
Chlorohydrate (d, I) 3,4 dichloro-K-methyl-N-2- (pyrrolidin-1-yl) -1,2,3,4-tetrahydronaph-1-yl benzene-acetamide, prepared as described in Example 2, is converted to its free base with an aqueous solution of potassium carbonate.
A solution of this free base (1.10 g, 2.64 mmol) in hot acetonitrile (5 ml) is introduced into a solution of (-) - dibenzoyl tartaric acid, H20 (0.90 g, 2.4 mmol, obtained from neutral

1582984 2
tartaric acid) in hot acetonitrile (5 ml), the resulting solution is heated
15

n 25
l
35
The solution, the oil that is formed, is then slowly cooled with the seed of the crystals from the material previously formed in a similar experiment. The next day, the crystalline solid was recovered, washed with a fresh portion of acetonitrile (5 ml) and dried at 55 ° C under vacuum, resulting in a split salt (0.92 g) with mp, 157-158 ° C, split salt, obtained from (-) - dibenzoyl tartaric acid, again converted into the free base and then into the hydrochloride salt of the final compound with m.p. 222-223 ° С, fcOjf +63.0 ± 0.8 ° (с 1.0, ethanol).
B. (-) trans-3,4-Dichloro-No-methyl- (pyrrolidin-1-yl) -1,2,3,4-tetrahydronaph-1-yl benzenecetamide and its hydrochloride salt.
The mother liquors from the crystallization process described in paragraph A are treated with an excess of an aqueous solution of K2C03, and the free base thus obtained is treated with (+) - dibenzoyl tartaric acid, H20 obtained from artificial tartaric acid, and the resultant enantiomer salt (0.616 g ) with so pl. 157 - 158BC. This salt is converted into the free base and then into the hydrochloric salt of the final compound with m.p. 221-222 ° С,, 6 (с 1.0, ethanol).
 Compounds, examples 1-5,
obtained according to other compounds
obtained by the described method are presented in table. one.
Table 1
13
Test method for analgesic action.
The standard procedure for determining and comparing the analgesic effect of the compounds is to conduct a test for phenylquinoline-induced paralysis syndrome (PQW).
The compounds to be tested are dissolved in saline or distilled water using diluted lactic acid as necessary or suspended in an aqueous vehicle containing 2% by volume of Twi. 80® - pharmacological dispersing agent (Fisher-Scientific Company), containing 100% polysorbate 80 and 0.25 wt.% of Methocel A15C powder - suspending agent.
1582984
14 Continued table. one
an agent (Dow Chemical Co) containing 100% methylcellulose. The test compounds were administered orally or subcutaneously into the body of starved (17-21 h) male white mice (CFI), 5-15 animals per calibrated dose, in an amount of 10 ml / kg body weight. After 5–25 minutes, intraperitoneal injection of aqueous 0.01% phenyl-parabeneoquinone, 0.125 mg / kg, is performed. After an additional 5 min., The mice are observed (10 min.), A tentative syndrome or
5 palsy syndrome, which is an indication of the pain caused by phenylquinone. Calculate the effective disinfectant, pouring dose in 50% of mice (AU) by the averaging method.
15
Test data are given in Table. 2
Table
 488H - trans-3-dichloro-N-methyl-M C2- (pyrrolidin-I-yl) ™ cyclohexyl} benzenecetamide,
As can be seen from the table. 2, the compounds obtained according to the proposed method have a strong anesthetic effect on warm-blooded animals. This analgesic effect has the same limits as morphine and the standard at-agonist analgesic - U-50, 488H,
As tests have shown, these compounds have a strong sedative effect caused by a dose of 3 times the greater anesthetic dose ED e-c. This soothing effect is characteristic. „
58298416
 for α-α-agonistic compounds such as U-50, 488H. Morphine and other compounds that are antagonistic β-agonist agents do not show a sedative effect when tested on mice. All compounds obtained by the proposed method, which show anesthesia
The Q effect on mice (Table 2) also has a strong sedative effect in their analgesic-effective dose limit, i.e. show selective activity of ae agonistic agents,
The standard technique used to confirm the opioid activity of the. Receptor is to induce polyuria in rats.
20 Known jf-agonist agents, such as U-50, 488H, cause a significant increase in urine flow. Painkillers / -agonists, such as morphine, are largely devoid of this property.
The polyuretic effect test was carried out on Sprague Dawley rats carrying approximately 200-300 g. Before use, rats were not subjected to preliminary starvation, but in the course of this study food and water were not supplied to them. The animals were acclimated for about 30 minutes in separate metabolic cells, then they were injected subcutaneously with the test compound with a dose of 1 ml / kg wAA. Spontaneously discharged urine was collected for the next 5 hours. The test compounds were prepared either in a distilled solution (solutions) or Suspension x Medetel® (tween®).
Population data in rats is given in gabl 3,. Table 3
50 330
 v
17
-50, 488H
orfin
one
4 16
0.0
0.33
one
3
9 27
0.0 0.063 0.25 1 4 16 0.0 0.1
one
20
 Slightly
P 0.05, significantly compared with the control and animals, which were injected only media.
As can be seen from the table. 3, the compounds obtained according to the proposed method lead to a significant increase in urine outflow, similar to that observed when using the standard anesthetic agent Ze-agonist U-50, 488H / v-Agonistic anesthetic agents (morphine) cause minimal polyuria in rats or not at all. These data confirm that the compounds obtained by the proposed method are anesthetizing G-agonistic agents.
All tested compounds exhibit low toxicity.
138298413
 Continued table. 3
#
8.76 10.9 8.64 1.40 0.96 2.24 3.08 6.36 8.56
2.44 3.48 2.84 5.44 10.5 13.6 0.93 1.38 2.41
oxy / 2/8 flesh)
995 1263 980
-31 60
120 354 511
43 16
123 330 457
#

48 159

权利要求:
Claims (1)
[1]
Claims of production method for producing benzo-condensed cycloalkanthrans-1,2-diamine derivatives of general formula
R-N-COCH2
in the form of enantiomers or racemates, where B is H, OH, OCOC-jHj-,
CHa.ORt;
C - H, OR ,, OH; R is C1-Ce-alkyl;
X and Y - C1 or together with the benzene ring form a group
RT, - C, -C3 alkyl ,,
or their pharmaceutically acceptable salts, characterized in that the compound of formula
nossn
in the presence of cyclohexylcarbodiimide or carboxylic acid chloride in the presence of triethylamine or aqueous sodium bicarbonate, or acyl-imidazole, obtained by chemical interaction of the carboxylic acid with carbonyldiimidazole.

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US4301292A|1981-11-17|1-[2-|phenyl]-4-|cyclohexanol

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US2700041A|1955-01-18|6-benzyloxy-7-methoxy-1-methyl-3, 4-dihydroisoquinoline and its process of preparation

---

US5043350A|1991-08-27|Benzo-fused cycloalkane and oxa- and thia-, cycloalkane trans-1,2-diamine derivatives

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EP0209275A1|1987-01-21|Benz-trisubstituted 2-aminotetralins

同族专利:

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公开号 | 公开日

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PT85668A|1987-10-01|

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IE872406L|1988-03-10|

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FI873896A|1988-03-11|

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AT75223T|1992-05-15|

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HUT47076A|1989-01-30|

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KR960009421B1|1996-07-19|

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DK169071B1|1994-08-08|

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JPH0819065B2|1996-02-28|

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FI88298B|1993-01-15|

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DE3778463D1|1992-05-27|

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CA1341024C|2000-06-13|

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EP0260555A1|1988-03-23|

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DK470087A|1988-03-11|

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US4876269A|1989-10-24|

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IL83842A|1991-06-30|

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EP0260555B1|1992-04-22|

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FI873896A0|1987-09-09|

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NO873762D0|1987-09-09|

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JPS63146852A|1988-06-18|

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DK470087D0|1987-09-09|

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GR3004962T3|1993-04-28|

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IL83842D0|1988-02-29|

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AU7822487A|1988-03-17|

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PT85668B|1990-05-31|

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NO873762L|1988-03-11|

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ES2040721T3|1993-11-01|

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MX170515B|1993-08-27|

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NO172934B|1993-06-21|

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AU607935B2|1991-03-21|

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NZ221726A|1990-04-26|

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FI88298C|1993-04-26|

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HU198016B|1989-07-28|

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IE60423B1|1994-07-13|

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KR880003906A|1988-05-31|

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NO172934C|1993-09-29|

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法律状态:
2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20030910 |

优先权:

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申请号 | 申请日 | 专利标题

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US90554386A| true| 1986-09-10|1986-09-10|

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US07/071,028|US4876269A|1986-09-10|1987-07-16|Benoz-fused cycloalkane trans-1,2-diamine derivatives|

---