JPH036150B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to benzoquinolidines, their preparation and uses. British Patent No. 1513824 describes the formula [In the formula, R ¹ and R ² are the same or different,
hydrogen, lower alkyl, lower alkoxy or halogen, respectively; ^R3 is hydrogen, lower alkyl or aryl; ^{R4 is} _-SO2R5 (wherein ^R5 is lower alkyl or aryl), _-CONH2 or -
CXNHR ⁶ (X is oxygen or sulfur, R ⁶
It is disclosed that benzoquinolidines represented by aryl or arylCO-) and their pharmacologically acceptable acid addition salts generally exhibit antihypertensive activity in warm-blooded animals. The present inventors have discovered that some of the compounds literally included in the above compound [] (i.e., compounds not specifically disclosed in the above specification) and their pharmacologically acceptable acid addition salts are suitable for warm-blooded children. It was discovered that the compound has high presynaptic α-adrenergic receptor antagonistic activity in animals, and the present invention was completed. This activity is neither described nor suggested in the above specification. Therefore, it is an object of the present invention to satisfy the formula [wherein R ⁷ is lower alkyl, R ⁸ is methyl or ethyl, or R ⁷ is phenyl or naphthyl optionally substituted with one or more lower alkyl, lower alkoxy or halogen; ⁸ means methyl] The present invention aims to provide a benzoquinolidine or a pharmacologically acceptable acid addition salt thereof. Here, "lower" refers to a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; for example, lower alkyl includes methyl, ethyl, propyl, or butyl, and lower alkoxy includes methoxy , ethoxy, propoxy or butoxy.
Specific examples of halogen include fluorine, chlorine and bromine. When R ⁷ is lower alkyl, methyl or propyl is preferred. R ⁸ is preferably methyl. A preferred compound [] is N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)methanesulfonamide, N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)propane-1-sulfonamide, N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)benzenesulfonamide and pharmacologically acceptable acid addition salts thereof. The presynaptic α-adrenergic receptor antagonistic activity of the compounds of the present invention against field-stimulated rat vas deferens preparations was determined by Drew, Eur. J. Pharmac.
1977, 42, pages 123-130. The method is described below. Desheathed ring vas deferens from adult rats are suspended in a 6 ml organ bath in Krebs solution at 37° C. and bubbled with 5% CO ₂ in oxygen. Platinum ring electrodes are placed above and below the tissue for field stimulation. Stimulation parameters are 0.1Hz/0.1Hz below the supermaximal voltage.
The pulse width is 1ms. Twitch responses were recorded isotically with a 0.5 g load. Clonidine hydrochloride is used as the α-adrenoceptor agonist and cumulative concentration-response curves are constructed for the spasm inhibition obtained with clonidine from 0.125 to 4 ng/ml. After washing out the clonidine, the convulsive response quickly recovered and the antagonist was introduced into the Krebs reservoir. Introduction of antagonist
After 90 minutes, the clonidine concentration-response curve could be repeated. Obtain a clonidine concentration that provides 50% inhibition of spasms before and after introducing the antagonist, and determine the dose of clonidine -
Calculate ratios. Various concentrations of antagonist are used. Arunlakshana & Schild, Br.J.Pharmac.
These results are plotted according to the method described in Chemother., 1959, 14, pages 48-58. Calculate _the ^pA2 value and slope. The compounds of the present invention have potent presynaptic α-adrenergic receptor antagonistic activity with a p ^A _{2 of} 7.5 or more, which is considerably greater than other compounds in [ ] as shown in the table below.

[Table] Sulfonamide

Table: The compounds of the present invention have been found to antagonize presynaptic alpha-adrenergic receptors to a greater extent than post-synaptic alpha-adrenergic receptors.
Postsynaptic antagonistic activity can be assessed in a variety of ways. One method involves assessing activity on isolated anococcygeus muscle. This method is
Gillesple, Br.J.Pharmac., 1972, 45, 404-416
It is based on the method described on page. In this method, male rats (250-360 g) are sacrificed and the two anal muscles superior to the upper coccygeal vertebrae are separated in the central part of the pelvic cavity. Put this muscle in a 5ml organ bath.
Suspend in Krebs solution containing 10 ^-4 M ascorbic acid to prevent oxidation by chemicals. The tissue was placed in a mixed gas atmosphere of 95% oxygen and 5% carbon dioxide at 37°C.
maintain it. Longitudinal muscle contractions are recorded using an isotonic transducer. Cumulative dose-response curves are obtained for the presynaptic alpha-adrenoceptor agonists phenylephrine and methoxamine. Phenylephrine and methoxamine were used at concentrations ranging from 0.02 to 0.8 μg ml ⁻¹ . The agonist is washed away from the bath and the test drug is added to the bath solution at a concentration of 10 ^-6 M. After 30 minutes, when equilibration of the test drug is reached, a further dose of agonist is applied.
Obtain the reaction curve. test drug at 10 ^-5 M and
Repeat the washing, equilibration and agonist addition operations using a concentration of 10 ⁻⁴ M. Arunlakshana &
Schild, Br.J.Pharmac.Chemother.1959, 14
Estimated p ^A ₂ values of test drugs as antagonists of phenylephrine or methoxamine were determined from agonist dose ratios by the method described in Vol., pp. 48-58. p ^A ₂ of post-synaptic antagonistic activity of the compounds of the present invention
and presynaptic selectivity (p ^A ₂ pre-synaptic antagonistic activity/p ^A ₂ post-synaptic antagonistic activity) are shown in Table 1.

[Table] Compounds with good presynaptic α-adrenergic receptor antagonism, especially high presynaptic selectivity, can be used, for example, as antidepressants, in the treatment of peripheral vascular diseases, in the treatment of diabetes, in the inhibition of platelet aggregation, etc. It is useful for That is, as already mentioned, the compounds of the invention have presynaptic adrenergic receptor antagonist activity. This is more commonly referred to as alpha ₂ antagonist activity. The compounds of the invention have high alpha ₂ antagonist selectivity and are therefore of use in diseases where selective antagonism of alpha ₂ -adrenoceptors is desired. Agents that selectively antagonize α ₂ -receptors suppress the negative feedback mechanism in nerve terminals that inhibits noradrenaline release (SZ Langer, British Journal of Pharmacology, Br. .J.Pharmac.),
1977, 60 , 481), and as a result, synaptic concentrations of noradrenaline increase. Depression is related to a lack of noradrenaline within the central nervous system (JJ Schildkraut).
American Journal of Psychiatry (Am.J.Psychiat.), 1965, 122 , 509 and A.
A. Copper et al., Lancet 1963(i), 79), thus suggesting that α ₂ -antagonists can be used as antidepressants. It is also known that human platelets aggregate when exposed to adrenaline and noradrenaline, and this response has been shown to be mediated by α ₂ -receptors (Grant and Scrutton). , Nature, 1979, 277 , 259). Representative compounds of the invention, such as N-methyl-N-(1,3,4,6,
7,11bα-hexahydro- 2H -benzo[a]
quinolidin-2β-yl)-methane-sulfonamide and N-methyl-N-(1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)propane-1-sulfonamide has been shown to inhibit adrenaline-induced in vitro aggregation of human platelets.
α ₂ -antagonists are therefore of value in diseases where excessive platelet aggregation occurs, such as atherosclerosis and migraine. Test examples of platelet aggregation inhibition are shown below. Evaluation of adrenaline and selective alpha ₂ -agonists
UK14304 [5-bromo-6-(2-imidazolin-2-ylamino)quinoxoline; performed against a sufficient agglutination response induced by Pfizer. A proaggregatory response induced by methoxamine was also performed to obtain selectivity ratios. Methods Blood (20-30 ml) was obtained by antenatal venipuncture from normal donors who had not taken any medications for the previous 14 days. Blood was added to 0.1 volume of dextrose with citrate (10mM) as an anticoagulant and leukocytes were removed by centrifugation at 200G for 20 minutes at room temperature. Platelet-rich plasma was stored at 37° in tightly stoppered test tubes and used within 3 hours of venipuncture. Payton Instruments connected to a 2-channel potentiometer recorder.
-nts) Agglomeration was evaluated using the Model 300ED Dual Cianel Aggregation Module. The device is heated to 37℃
It is possible to measure the change in absorbance in a cloudy solution that is maintained at a constant rate of 700 rpm and stirred at a constant speed (700 rpm). The aggregation response to adrenaline and the selective α ₂ -adrenoceptor agonist UK14304 was quantified based on the initial rate of absorbance decrease observed following addition of the agonist. The preaggregation response to methoxamine observed in the presence of suboptimal concentrations of ADP was quantified by measuring the initial phase change in absorbance. Data Data are expressed as K〓 values. where: K _I = IC ₅₀ / (I + [A] / K _D ) IC ₅₀ = Molar concentration that gives 50% inhibition of aggregation [A] = Concentration of the agonist used K _D = ED ₅₀ concentration of the agonist Effects of benzoquinolidine and standard alpha on adrenaline- and UK14304-induced platelet aggregation
- The average values for the effects of adrenergic receptor antagonists as well as the proaggregation response induced by methoxamine are listed in the table below. With yohimbine and rauolsine, as shown by the lower K _I values obtained for aggregation induced by adrenaline or UK14304 compared to that obtained for methoxamine.
Benzoquinolidines A and C were selective for platelet α ₂ -adrenergic receptors. In contrast, indolamine and prazosin were better inhibitors of methoxamine responses than that of adrenaline. In all cases, the K _I values obtained for adrenaline were very similar to those for UK14304. Table K _I values for inhibition of human platelet aggregation induced by adrenaline, UK14304 and methoxamine KI (μM) ± SEM Compound Adrenaline
UK14304 Methoxamine A in the presence of ADP 0.57±0.1 0.42±0.1 16.1±1.6 C 0.56±0.2 0.52±0.2 12.6±1.6 Yohimbine 0.35±0.07 0.30±0.05 >25 Rauolsine 0.01±0.15 1.24±1.2 1 >25 Indolamine 29.3±2.0 − 1.8±0.3 Prazosin 35.3±4.1 − 3.7±0.8 Furthermore, stimulation of α ₂ -receptors induces hyperglycemia and therefore selective α ₂ -antagonists can be used in diabetes. Representative compounds of the invention, e.g., N-methyl-N-(1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)
Methanesulfonamide and N-methyl-N-
(1,3,4,6,7,11bα-hexahydro-2
H-benzo[a]quinolidin-2β-yl)benzenesulfonamide, when administered to rats at 10 mg/Kg, suppressed the hyperglycemia induced by a 15 μg/Kg subcutaneous injection of the alpha ₂ agonist clonidine. Next, we present toxicity data that can be derived from acute pharmacological studies. used in an acute (single dose) technique;
The highest oral doses found to produce no effects are shown below. Table Compound Example No. Maximum non-observable dose Species (mg/Kg) 2 127 mice 3 >50 rats 4 127 mice 5 >50 rats 6 >50 rats 7 >50 rats 8 >50 rats 9 >50 rats 12 > In addition, the compound of Example 4 was subjected to several specific toxicity tests. In a 6-month oral experiment in rats, 20 mg/Kg/day did not produce any effects. Higher doses (63.2 and 200mg/
Kg/day) caused various side effects and disorders, and this was also true at doses above 2 mg/Kg/day in a 6-month study in dogs. Note that the antihypertensive effect of the compound is an undesirable side effect for the above-mentioned uses. The inventors
Surprisingly, some of the compounds of the invention (e.g. Compound A) were found to have no such effect in standard pharmacological tests using rats induced to develop hypertension by implantation of deoxycorticosterone acetate. Ta. The compound of the present invention is a reactive derivative of sulfonic acid represented by the general formula R ⁷ SO ₂ OH [] (wherein R ⁷ is the same as above), which is 2β-ethylamino- or methylamino-1,3,4 ，
6,7,11b-hexahydro-2H-benzo[a]
It is prepared by reaction with quinolidine and optionally converting the free base to a pharmacologically acceptable acid addition salt. Reactive derivatives of the sulfonic acid include, for example, acid halides or acid anhydrides. Preferably it is a halide, ie a compound represented by the formula R ⁷ SO ₂ X (wherein R ₇ is as defined above and X is halogen, preferably chlorine). The reaction is preferably carried out under basic conditions, for example in the presence of a tertiary amine such as triethylamine. In the above method, when the compound of the invention is obtained in the form of an acid addition salt, the free base is obtained by making the solution basic. On the other hand, if it is obtained as a free base, it can be dissolved in an appropriate organic solvent and treated with an acid to form the acid addition salt using a conventional method of making an acid addition salt from a basic compound.
In particular, it is directed to pharmacologically acceptable acid addition salts. Examples of acid addition salts include sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid,
Mention may be made of those derived from organic or inorganic acids such as p-toluenesulfonic acid. 2β-ethylamino- or methylamino-1,3,4,6,7, which is the starting material for the above method;
11b-hexahydro-2H-benzo[a]quinolidine was prepared by the method described in British Patent No. 1513824.
Prepared from the corresponding 2-oxo compound. Alternatively, the 2-methylamino compound is
It is obtained by reacting the -amino compound with an alkyl haloformate or formic acid and then reducing the resulting 2- _NHCO2alkyl or 2-NHCHO intermediate with a hydrogenating agent such as lithium aluminum halide. The present invention further provides a pharmaceutical composition comprising a compound of formula [] or a pharmacologically acceptable acid addition salt thereof and a pharmacologically acceptable carrier. Known carriers are used in the preparation of this pharmaceutical composition and include solid or liquid or mixtures thereof. Solid compositions include powders, granules, tablets,
Includes capsules (hard and soft gelatin capsules), suppositories and inserts. Solid carriers include one or more substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, compression molding agents, compression aids, binders, tablet disintegrants, etc. is included. Also included are encapsulating agents.
In powders, the carrier is a finely divided solid powder which is in admixture with the finely divided active substance. In the case of tablets,
The active substance is mixed with a carrier having the necessary compression moldability in an appropriate ratio and compression molded into the desired shape and size. Powders and tablets contain up to 99% active ingredient, usually from 0.03 to 99%, preferably from 1 to 80%. Preferred solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugar,
These include lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low-melting wax, and ion exchange resin. Compositions also mean active substances encapsulated with encapsulating agents as carriers (with or without other carriers), and also include cachets. Examples of liquid compositions include solutions, suspensions,
Includes emulsions, syrups, elixirs, and pressurized liquefied compositions. In this case, the active ingredient is dissolved or suspended in a liquid carrier such as, for example, water, an organic solvent, a mixture thereof, or a pharmacologically acceptable oil or fat. Liquid carriers include other agents such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, permeation pressure regulators, etc. It may also contain pharmacologically acceptable additives. Preferred examples of liquid carriers for oral and parenteral administration are water (especially with the additives mentioned above, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric and polyhydric alcohols, e.g. glycerol, glycols) and their derivatives, oils (e.g. fractionated coconut oil,
including peanut oil). Parenteral administration also includes oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration. Liquid pharmaceutical compositions of sterile solutions or suspensions are used, for example, by intramuscular, intraperitoneal or subcutaneous injection. If the compound is orally active, it is administered orally in the form of a liquid or solid composition. The pharmaceutical compositions are preferably used in unit dosage form, such as tablets or capsules. In such dosage forms, the composition is divided into unit dosage forms containing appropriate quantities of the active component, and the unit dosage forms are packaged compositions. For example, it may take the form of a powder pack, vial, ampoule, filled syringe, or liquid-containing sachet. The unit dosage form may be, for example, a capsule or tablet, or the appropriate number thereof may be packaged in one package. The amount of active ingredient in a unit dose may vary from 0.5 mg or less to 750 mg or more, depending on its activity and particular needs. The present invention also includes the use of the compound alone in a unit dose without the use of a carrier. Next, the present invention will be explained with reference to Examples. Example 1 2β-methylamino-1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidine (a) 2β-amino-1,3,4,6,7,11bα-
Hexahydro-2H-benzo[a]quinolidine
17.7 g is ice-cooled to 0° C. and carefully treated with 100% formic acid (100 cm ³ ). The mixture was stirred until homogeneous and slowly treated with 10.0 g of acetic anhydride at 0° C. for about 1 hour. After stirring for an additional hour, the mixture is heated to reflux for 2 hours. After cooling, excess solvent is evaporated in vacuo. The remaining oil is made basic with 10% aqueous Na ₂ CO ₃ (approximately 500 cm ³ ) and extracted with dichloromethane (3×100 cm ³ ). Combine the extracts, wash with 100 cm ³ of brine, and dry (MgSO ₄ ). At this stage, the reaction is incomplete (approximately 50%)
Therefore, repeat the whole cycle with fresh formic acid and acetic anhydride. Evaporation of the organic extract yields 16.4 g of a mixture of solid and oil. Ethanol - 7.12 g of pure N-[1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl]formamide crystallized from 60/80 gasoline into off-white fine needles. Obtained as crystal. Melting point 162-164℃ (partially decomposes above 147℃). (b) 7.3 g of the compound obtained in (a) above are suspended in 80 cm ³ of dry THF, and a solution of 4 g of lithium aluminum hydride in 120 cm ³ of dry THF is gradually added thereto. The mixture was stirred and placed in a stream of dry nitrogen.
Heat under reflux for 24 hours, then add 4 cm ³ of water, 15%
4 cm ³ of NaOH aqueous solution and 12 cm ³ of water are added dropwise for decomposition. After evaporation, the solution was evaporated and the residue was taken up in dichloromethane and dried (MgSO ₄ ).
After filtration, evaporation yields 6.19 g of a reddish-brown oil. This material is pure by thin layer chromatography and solidifies on standing. Take 0.57 g of the sample and convert it to its hydrochloride salt with ethanolic hydrochloric acid in 7 cm ³ of ethanol. Cool it, collect the precipitated crystals, wash with ethanol-ethyl acetate (1:2), and vacuum dry to obtain pure 2β-methylamino-1,3,
0.67 g (88.2%) of 4,6,7,11bα-hexahydro-2H-benzo[a]quinolidine hydrochloride is obtained as colorless fine needles. Melting point 248-251℃
(Decomposition) (Decomposition starts at 200℃ or higher if heated quickly) Example 2 N-Methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)methanesulfonamide 2β-methylamino-1,3,4,6,7,
1.88 g of 11bα-hexahydro-2H-benzo[a]quinolidine and 0.90 g of triethylamine are dissolved in 10 cm ³ of ice-cold dichloromethane and treated with an ice-cold solution of 1.00 g of methanesulfonyl chloride in 5 cm ³ of dichloromethane. This clear solution was allowed to stand overnight, and the resulting mixture of crystals and solution was evaporated into dichloromethane.
Dilute with 10 cm ³ and 5 cm ³ of water and extract with water (2x
^20cm3 ). The organic layer is separated and dried (MgSO ₄ ). After filtration, evaporation gives 2.37 g of a pink gummy substance. The hydrochloride salt is prepared using ethanolic hydrochloric acid and recrystallized from ethanol-ethyl acetate to yield 1.45 g of the hydrochloride salt of the title compound as off-white fine needles. Melting point 198-200℃ (decomposition). Example 3 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolizin-2β-yl)ethanesulfonamide A solution of 1.45 g of ethanesulfonyl chloride in 20 cm ³ of dichloromethane was added to 2β-methylamino-1,
3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidine and triethylamine
Add 1.2 g (0.0119 M) slowly to an ice-cold solution in 30 cm ³ of dichloromethane. After stirring the clear mixture slightly, it is stored at room temperature for 7 days. Confirm that the reaction is complete by thin layer chromatography. This is washed with water (2 x 25 cm ³ ) and dried (MgSO ₄ ). After filtering, evaporate to a yellow-orange syrup.
Obtain 3.13g. Dissolve this in 5 cm ³ of hot ethanol, acidify with ethanolic hydrochloric acid, and add ethyl acetate.
Dilute with 15 cm ³ and cool. The precipitated sticky crystals were collected, washed with ethanol-ethyl acetate (1:3), and recrystallized twice from ethanol-ethyl acetate (1:1) to obtain the hydrochloride of the title compound.
0.97 g is obtained as colorless crystals. Melting point 207~212℃
(Decomposition) (Partial melting due to decomposition at 180° or more) Example 4 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)propane-1-sulfonamide 2β-methylamino-1,3,4,6,7,
An ice-cooled stirred solution of 2.16 g of 11bα-hexahydro-2H-benzo[a]quinolidine and 1.1 g of triethylamine in 25 cm ³ of dichloromethane was mixed with n-
Treat slowly with a solution of 1.43 g of propanesulfonyl chloride in 25 cm ³ of dichloromethane. The clear solution is kept at room temperature for 72 hours. Confirm that the reaction is complete by thin layer chromatography. This mixed solution was washed with water (2 x 25 cm ³ ), dried (MgSO ₄ ),
After filtration, evaporation gives 3.09 g of a sticky pale yellow oil. This is dissolved in 7 cm ³ of hot ethanol, acidified with ethanolic hydrochloric acid, diluted with 25 cm ³ of ethyl acetate, and cooled while rubbing the walls. The slowly precipitated crystals were collected, washed with 20% ethanol-ethyl acetate, and recrystallized from methanol to obtain 1.98 g of the hydrochloride of the title compound as colorless plate-like crystals. Melting point: approximately 222-240°C (decomposition) (decomposes violently without melting at approximately 200°C) Example 5 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)benzenesulfonamide 2β-methylamino-1,3,4,6,7,
11bα-Hexahydro-2H-benzo[a]quinolidine and 0.7 g of triethylamine dissolved in 25 cm ³ of dichloromethane were added to an ice-cooled stirred solution of 1.2 g of benzenesulfonyl chloride in 25 cm ³ of dichloromethane.
Gradually treat with medium solution. The clear solution at room temperature
Hold for 72 hours. Confirm that the reaction is complete by thin layer chromatography. This mixed solution was washed with water (2 x 25 cm ³ ), dried (MgSO ₄ ), and filtered.
Evaporation yields 2.44 g of off-white glassy material. This was dissolved in 7 cm ³ of hot ethanol, acidified with ethanolic hydrochloric acid, diluted with 10 cm ³ of ethyl acetate, and cooled. The precipitated crystals were collected and washed with ethanol-ethyl acetate (1:1) to obtain 2.32 g of the hydrochloride of the title compound as colorless needles. Melting point approx. 225
~228℃ (decomposition) (partially decomposed above 193℃) Example 6 N-ethyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)methanesulfonamide 2β-ethylamino-1,3,4,6,7,
An ice-cooled stirred solution of 1.35 g of 11bα-hexahydro-2H-benzo[a]quinolidine and 0.60 g of triethylamine in 50 cm ³ of dichloromethane is treated with stirring with a solution of 1.02 g of dimethyl anhydride in 25 cm ³ of dichloromethane. The mixture is stirred for an additional 2 hours and then kept at room temperature until the reaction is confirmed to be complete by thin layer chromatography (approximately 11 days). The mixture is washed with water (2×25 cm ³ ), dried (MgSO ₄ ), filtered and evaporated to give 1.59 g of oil.
Apply this to silica gel chromatography for 5 to 10 minutes.
Elution with % ethanol-ethyl acetate yields 0.88 g of pure product. This is acidified with ethanolic hydrochloric acid, the solvent is evaporated and crystallized from isopropanol. The crystals are recrystallized from 3 cm ³ of boiling ethanol and 5 cm ³ of ethyl acetate are added to give 0.55 g of the pure hydrochloride quarter hydrate of the title compound as colorless crystals. Melting point 217-223°C (decomposition) (sublimation and partial decomposition above 200°C) Example 7 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)toluene-4-sulfonamide 2β-methylamino-1,3,4,6,7,
An ice-cold, stirred solution of 2.16 g of 11bα-hexahydro-2H-benzo[a]quinolidine and 1.1 g of triethylamine in 25 cm ³ of dichloromethane is treated with a solution of 1.91 g of tosyl chloride in 25 cm ³ of dichloromethane. The clear solution was kept at room temperature for 6 days, washed with water (2 x 25 cm ³ ), dried (MgSO ₄ ),
After filtration, evaporation yields 3.69 g of a red-orange glassy substance. This is crystallized from 10 cm ³ of hot ethanol.
After cooling, the crystals are collected and washed with ice-cold ethanol to obtain 4.43 g of the title compound as cream-colored crystals.
Melting point 161-164℃. Trituration with boiling ethanol, acidification with ethanolic hydrochloric acid (reprecipitation after dissolution), stirring to break up any lumps, and filtration yields the pure hydrochloride salt 3.39
g is obtained as slightly dull yellow rod-shaped crystals. Melting point 258
~261℃ (decomposition) (decomposition above 220℃) Example 8 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)-4-methoxybenzenesulfonamide 2β-methylamino-1,3,4,6,7,
An ice-cooled stirred solution of 2.16 g of 11bα-hexahydro-2H-benzo[a]quinolidine and 1.1 g of triethylamine dissolved in 25 cm ³ of dichloromethane was added to p-
Treat with a solution of 2.07 g of methoxybenzenesulfonyl chloride in 25 cm ³ of dichloromethane. The solution was kept for 7 days, washed with water (2 x 25 cm ³ ), dried (MgSO ₄ ), filtered and evaporated to give a residue of 3.61 g.
This is crystallized from 15 cm ³ of ethanol to give the title compound as cream colored crystals. Melting point 154-156 ° C. This base is tritiated with 10 cm ³ of boiling ethanol, acidified with ethanolic hydrochloric acid (reprecipitation after partial dissolution) and, after cooling, stirred to break up any lumps. This gives off-white crystals. This was thoroughly tritiated with a boiling mixture of ethanol-methanol-water, and after cooling, the crystals were collected and thoroughly washed with ethanol to yield 2.62 g of the hydrochloride of the title compound.
is obtained as pale yellow crystals. No clear melting point (decomposes above 220°C) Example 9 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro-2H-benzo[a]quinolidin-2β-yl)-4-chlorobenzenesulfonamide 2β-methylamino-1,3,4,6,7,
An ice-cooled stirred solution of 1.08 g of 11bα-hexahydro-2H-benzo[a]quinolidine and 0.55 g of triethylamine dissolved in 25 cm ³ of dichloromethane was added to 4-
Treat with a solution of 1.06 g of chlorobenzenesulfonyl chloride in 25 cm ³ of dichloromethane. The solution was kept at room temperature for 7 days, washed with water (2 x 25 cm ³ ), dried (MgSO ₄ ), filtered and evaporated to yield the title compound.
1.64 g are obtained as a brown semi-crystalline gummy material. This is crystallized from 5 cm ³ of hot ethanol to give pale yellow crystals. Melting point: 50-53°C (decomposition) The crystals are taken in 10 cm ³ of hot ethanol, acidified with ethanolic hydrochloric acid (re-precipitated after partial dissolution), cooled, and stirred well. The pale pink crystals obtained by filtration are tritiated with a hot ethanol-methanol-water mixture, cooled, filtered, and washed with ethanol to yield 1.10 g of the hydrochloride of the title compound as colorless short plate crystals. No clear melting point (decomposes above 230°C). Example 10 N-methyl-N-(1,3,4,6,7,11bα
-Hexahydro-2H-benzo[a]quinolidin-2β-yl)-2-methylbenzenesulfonamide production: 2β-methylamino-1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidine (1.84 g) and triethylamine (0.9 g)
An ice-cold stirred solution in dichloromethane (25 ml), O
- Treat slowly with a solution of toluenesulfonyl chloride (1.62 g) in dichloromethane (25 ml).
The solution was left at room temperature for 2 days and washed with water (2 x 50 ml).
After drying with _MgSO4 . After filtration and evaporation, orange syrup (3.37 g) was obtained. This is dissolved in hot ethanol (10 ml), acidified with ethanolic HCl and cooled. After 1 hour, the crystals were collected and washed with ethanol to obtain the title compound as the hydrochloride salt (2.88 g). Pearl cream colored crystals. ethanol/
Pure hydrochloride quarter hydrate (2.03g) recrystallized from water
Colorless needle-like crystals are obtained. Melting point 197-203℃ (decomposition)
(Decomposition occurs above 175℃). Example 11 N-methyl-N-(1,3,4,6,7,11bα
-Hexahydro-2H-benzo[a]quinolidin-2β-yl)-3,4-dichlorobenzenesulfonamide production: 2β-methylamino-1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidine (1.84 g) and triethylamine (0.9 g)
Stir the ice-cold solution in dichloromethane (25 ml),
Treat slowly with a solution of 3,4-dichlorobenzenesulfonyl chloride (2.09 g) in dichloromethane (25 ml) and leave the mixture at room temperature for 2 days. This is washed with water (2 x 50 ml) and dried with _MgSO4 . Filtration and evaporation gave an off-white solid (3.30 g), which was purified by trituration with hot ethanol to give the pure title compound. Melting point 191~
A suspension of the sulfonamide in boiling ethanol (10 ml) at 193° C. is acidified with ethanolic HCl and the clear liquid is cooled. After filtering and washing with ethanol, pearl cream-colored crystals of hydrochloride (3.03 g) were obtained. Pure hydrochloride recrystallized from ethanol/water 1/4
The title compound is obtained as a hydrate (2.71 g). Colorless crystals, melting point 195-197°C (decomposition). Example 12 N-methyl-N-(1,3,4,6,7,11bα
-Hexahydro-2H-benzo[a]quinolidin-2β-yl)-n-butanesulfonamide production: 2β-methylamino-1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidine (2.16g) and triethylamine (1.2g)
An ice-cold stirred solution of n-n in dichloromethane (25 ml)
Treat with a solution of butanesulfonyl chloride (1.57 g) in dichloromethane (25 ml). The clarified solution was left at room temperature for 4 days and washed with water (2 x 50 ml) with MgSO ₄
Dry with. Filtration and evaporation gave a dark gum (2.96 g) which was chromatographed on silica eluting with 10% ethanol-ethyl acetate.
A pearl yellow colored syrup (2.04 g) is obtained. Dissolve this in 5 ml of hot ethanol and make an ethanolic
Acidified with HCl, diluted with ethyl acetate (20ml),
Cooling. After a few hours, the precipitated crystals are collected, washed with ethyl acetate and dried at 60°/100 mm to give the title compound as the hydrochloride salt (2.25 g). Colorless fine platelet crystals, melting point 224-226°C (decomposition). Example 13 N-methyl-N-(1,3,4,6,7,11bα
-hexahydro- 2H -benzo[a]-quinolidin-2β-yl)naphthalene-2-sulfonamide 2β-methylamino-1,3,4,6,7,
11bα-hexahydro- 2H -benzo[a]quinolidine (2.16 g; 0.01 M) in dichloromethane (25
A solution of naphthalene-2-sulfonyl chloride (2.27 g; 0.01 M ⁾ in dichloromethane (25
cm ³ ) solution. The clarified solution was kept at room temperature for 7 days, washed with water and saline, and dried (MgSO ₄ ).
did. A brown syrup is obtained by evaporation, which is 10%
Chromatography on silica eluting with ethanol-ethyl acetate gave a semi-solid yellow glass (3.60 g) which was crystallized from ethanol. The crystals were taken up in hot ethanol (10 cm ³ ), acidified with ethanolic HCl, and the clear solution was cooled. The precipitated crystals were collected by filtration and thoroughly washed with ethanol to obtain the pure title compound as a hydrochloride (3.27 g). Colorless crystals, melting point: 225-230°C (decomposed). Example 14 N-methyl-N-(1,2,3,4,6,7,
11bα-hexahydro- 2H -benzo[a]-quinolidin-2β-yl)naphthalene-1-sulfonamide 2β-methylamino-1,3,4,6,7,
11bα-hexahydro- 2H -benzo[a]quinolidine (2.96 g; 0.137 M) and _Et3N (1.5 g;
A stirred ice-cooled solution of 1-naphthalenesulfonyl chloride (3.1 g; 0.0137 M) in CH ₂ Cl ₂ (50 cm ³ )
The mixture was slowly treated with a solution of 20% in CH ₂ Cl ₂ (25 cm ³ ). The clear solution was kept at room temperature for 3 days, washed with water and brine, and dried (MgSO ₄ ). Obtain oil by evaporation,
This was chromatographed on silica, eluting with ethyl acetate containing up to 10% ethanol. The main component was obtained as a yellow syrup. The first eluate (1.27 g) was an unknown secondary product probably arising from impurities in the sulfonyl chloride. The second one (1.84g) is ethanolic HCl
Convert to hydrochloride salt with filtered ethanol (15 cm ³ )
-Hydrochloride, 4/3 hydrate (1.07 g) that strongly retains water of crystallization of the title compound by recrystallization from water (25 cm ³ )
obtained as. Colorless crystals, melting point: 180-190°C (decomposed).

Claims (1)

[Claims] 1 formula [wherein R ⁷ is lower alkyl, R ⁸ is methyl or ethyl, or R ⁷ is phenyl or naphthyl optionally substituted with one or more lower alkyl, lower alkoxy or halogen; ⁸ means methyl] A benzoquinolidine or a pharmacologically acceptable acid addition salt thereof. 2. The compound according to paragraph 1, wherein R ⁸ is methyl. 3 N-methyl-N-(1,3,4,6,7,
11. The compound according to item 1, which is 11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)methanesulfonamide or a pharmacologically acceptable acid addition salt thereof. 4 N-methyl-N-(1,3,4,6,7,
11b The compound according to item 1, which is α-hexahydro-2H-benzo[a]quinolidin-2β-yl)propane-1-sulfonamide or a pharmacologically acceptable acid addition salt thereof. 5 N-methyl-N-(1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)benzenesulfonamide or a pharmacologically acceptable acid addition salt thereof
Compounds described in Section. 6 N-methyl-N-(1,3,4,6,7,
11b The compound according to item 1, which is α-hexahydro-2H-benzo[a]quinolidin-2β-yl)ethanesulfonamide or a pharmacologically acceptable acid addition salt thereof. 7 N-ethyl-N-(1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)methanesulfonamide; N-
Methyl-N-(1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidine-2β-
yl) toluene-4-sulfonamide; N-methyl-N-(1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)
-4-methoxybenzenesulfonamide; N-methyl-N-(1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)-4-chlorobenzenesulfonamide; N-
Methyl-N-(1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidine-2β-
yl)-2-methylbenzenesulfonamide; N
-Methyl-N-(1,3,4,6,7,11bα-hexahydro-2H-benzo[a]quinolidine-2β
-yl)-3,4-dichlorobenzenesulfonamide, N-methyl-N-(1,3,4,6,7,
11bα-hexahydro-2H-benzo[a]quinolidin-2β-yl)-n-butanesulfonamide;
N-methyl-N-(1,3,4,6,7,11bα-
hexahydro-2H-benzo[a]quinolidine-
2β-yl) naphthalene-2-sulfonamide or N-methyl-N-(1,2,3,4,6,7,
11b The compound according to item 1, which is α-hexahydro-2H-benzo[a]quinolidin-2β-yl)naphthalene-1-sulfonamide or a pharmacologically acceptable acid addition salt thereof. 8 Reactive derivatives of sulfonic acids of the formula R ⁷ SO ₂ OH [wherein R ⁷ is lower alkyl or phenyl or naphthyl which may be substituted with one or more lower alkyl, lower alkoxy or halogen] 2β-ethylamino or 2β-methylamino-
1,3,4,6,7,11bα-hexahydro-2H
- by reaction with benzo[a]quinolizine, optionally converting the free base to a pharmacologically acceptable acid addition salt of the formula [wherein R ⁷ is lower alkyl, R ⁸ is methyl or ethyl, or R ⁷ is phenyl or naphthyl optionally substituted with one or more lower alkyl, lower alkoxy or halogen; ⁸ means methyl] A method for producing benzoquinolidines, which is characterized by obtaining a benzoquinolidine or a pharmacologically acceptable acid addition salt thereof. 9 formula [wherein R ⁷ is lower alkyl, R ⁸ is methyl or ethyl, or R ⁷ is phenyl or naphthyl optionally substituted with one or more lower alkyl, lower alkoxy or halogen; ⁸ means methyl] A presynaptic α-adrenergic receptor antagonist containing a benzoquinolidine or a pharmacologically acceptable acid addition salt thereof as an active ingredient.