JPS6022711B2 - Trans-decahydroquinoline derivatives, their production methods, and pharmaceuticals containing the same - Google Patents

Description

[Detailed description of the invention]

The present invention relates to heterocyclic compounds, and more particularly to 4-aminotrans-decahydroquinoline derivatives, methods of preparing these derivatives, and pharmaceutical compositions containing them. The compounds of the present invention are compounds represented by the following general formula and pharmacologically acceptable acid addition salts thereof. Here, RI represents a branched or straight alkyl group having 1 to 4 carbon atoms, an alkoxy group, or a pyridyl group, and R
2 represents a phenyl group, a methoxyphenyl group, or a cyclohexyl group, R3 represents a group represented by the general formula, R4 represents a hydrogen atom or a fluorine atom, and n represents 3 or 4.
shows. The compound of general formula (1) in which RI is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, or a pyridyl group can be prepared by the following general formula [wherein R2 and R3 are the same as in general formula (1)]. 1-substituted-4-aminotrans-deca/
- Hydroquinoline is preferably prepared in an inert solvent such as dichloroethane, methylene chloride, benzene or toluene by the following general formula: where RI has the meaning as defined above. It can be obtained by refluxing the compound represented by the following formula in the presence or absence of a base such as triethylamine, trimethylamine or pyridine. R
The compound of general formula (1) in which I is an alkyl group having 1 to 4 carbon atoms or a pyridyl group can be prepared by using the general formula (1) instead of the above method.
m), preferably in dichloromethane,
In an inert organic solvent such as methylene chloride, benzene or toluene, a compound of the general formula [where RI has the meaning as defined above] is prepared. ] may be synthesized by refluxing in the presence or absence of an acid such as P-toluenesulfonic acid or sulfuric acid. General formula (1
) can be converted into a pharmacologically acceptable acid addition salt depending on the respective acid by treatment with an appropriate acid according to known methods. The compound of general formula (m) is 4-aminotrans-decahydroquinoline of the general formula,
It can be obtained by reacting with a halide of the general formula 1-R3 (K). Here, ya1 represents a chlorine, bromine or iodine atom, and R3
represents the same substituent as in general formula (1). This reaction is preferably carried out in a liquid medium, and examples of liquid soot include benzene, toluene, xylene, dichloroethane,
An inert organic solvent such as tetrahydrofuran, or an alcoholic solvent such as e.g. butanol, aqueous ethanol, or a ketone such as acetone, methyl ethyl ketone can be used, and the reaction is preferably carried out with an acid acceptor, e.g. potassium carbonate. , preferably in the presence of an alkali metal carbonate such as sodium bicarbonate. The reaction is accelerated using a small amount of potassium iodide,
Further, it is preferable to carry out the reaction at the reflux temperature of liquid soot. The compound of the general formula (K) is already known, but the compound of the general formula (Vm) is a combination of the known compound 4-oxotrans-decahydroquinoline, for example, p-toluenesulfonic acid, trifluoroboronate. ether salt of zinc chloride,
In the presence of a catalyst such as titanium tetrachloride, preferably in an inert organic solvent such as hexane, benzene or toluene and at the reflux temperature of the solvent, the general formula R2-N ratio
(X) can be obtained by reacting with an amine. Here, R2 is the same substituent as in general formula (1),
The water produced by the reaction is removed by co-distillation. The resulting imino derivatives are hydrogenated with sodium borohydride in methanol or with lithium hydride in tetrahydrofuran. This hydrogenation can be carried out over a wide temperature range. According to the above method, the compound of general formula (W) is produced in the form of a mixture of axial and ecutorial isomers. This mixture is divided into two parts by exploiting the different solubility of each isomer in hydrochlorination in aqueous solution at pH 3 or by chromatography.
The compounds of general formula (1) and general formula (m) may therefore also be obtained in the form of a mixture of their axial and equatorial isomers, or in the form of axial or equatorial isomers. However, it is not yet clear whether the water-indestructible portion having a pH value of 3 is either an axial isomer or an equatorial isomer, and 3 is formed from a mixture of the two. The same can be said for the soluble portion. Taking this into consideration, the term "a-type" will be used hereinafter to refer to an isomer compound of formula (W) whose Rf corresponds to a certain thin layer chromatography assay (this will be referred to as , "b-type") is used to refer to a compound represented by the general formula (W) that is smaller than Rf. The results of the chromatographic analysis are shown in the drawings attached to this specification.
The details of the analysis are as follows. Holder: Silica gel 6
Price. 254 (manufactured by MERCK) Thickness: 0.25
solvent) (under ammonia atmosphere) hexane: 8
0' 2-propanol: 20'

[Technique: 13% positive addition (PosiG): 200% (chloroform solution) Color development: 2% OA of U.P. in iodine vapor. V. Irradiation t1
1 4-phenylamino-trans-decahydroquinoline (type a) '21 4-phenylamino-trans-decahydroquinoline (type b) Similarly, "a-type" and "
In the following description, the name "b-type" will be used when the starting material is the "a-type" of the compound represented by the general formula (W) or the "a-type".
General formula (m) and general formula (1
) is also used to refer to isomers of substances. Therefore, the above method for obtaining a derivative of general formula (1) using a derivative of general formula (W) as a starting material is a method for obtaining a derivative of general formula (W).
) can be equally applied to the synthesis of the corresponding isomer of general formula (1) using the "a type" or "b type" of the derivative of formula (1) as a raw material. The compounds of the present invention have been found to have useful pharmacological properties, in particular to have no morphine-like action and to have a strong analgesic action. The above properties are what endow such compounds with particular importance in the treatment of pain. Therefore, the present invention provides a method for alleviating pain in a patient in need of treatment by administering to the patient an effective amount of a suitable compound of general formula (1) or a pharmacologically acceptable acid addition thereof. Included in the scope. Analgesics are drugs that reduce pain by acting on the central nervous system and increasing the pain threshold without disturbing consciousness or changing other sensory states. Drugs used primarily for the relief of pain may be divided into two generic groups for ease of classification. '11 Narcotic analgesics such as opium derivatives Among these, morphine is one of the most important drugs,
It has many useful properties, with analgesia being one of its main effects. Other drugs are less overall useful in alleviating various categories of severe pain. Unfortunately, morphine causes euphoria and addiction;
Decrease respiratory function. If morphine or other similar compounds are administered over a long period of time, tolerance to the analgesic effect gradually increases and the dose must be increased periodically to achieve equivalent pain relief. It will not happen. For these reasons, it is generally accepted that morphine and its derivatives should not be used for pain when other analgesics are adequate. The analgesic compounds of the present invention do not have any morphine-like effects and therefore can be recommended for use in more cases than morphine derivatives. {2} Non-narcotic analgesics, such as salicylates. These are generally less active than narcotic analgesics, while not depressing respiratory function and causing no or only minimal addiction. It will be seen that the analgesic compounds of the present invention compare very favorably to the most widely used non-narcotic analgesics. In addition to the above, some of the compounds of general formula (1) have been found to have beneficial pharmacological properties that offer great utility in the treatment of disorders of the vasculature characterized by hypertension. Ta. Accordingly, another object of the present invention is to treat the arteries of a patient in need of treatment by administering to the patient at least one suitable compound of general formula (1) or a pharmacologically acceptable acid addition salt thereof. There are ways to treat pathological disorders of blood pressure, especially hypertension. Although there are many types of hypertension, there is currently no known universal treatment capable of combating these various types of disease, and the response to various drugs varies widely in individual cases. Therefore, there are many antihypertensive agents that are used to treat different types of hypertension. Some of these compounds are known to exhibit ganglionic blocking effects, such as blocking sympathotonic stimulation and thus causing relaxation of blood vessel walls. Others are characterized by a slightly narrower range between their therapeutic and toxic doses. Furthermore, it is known that some antihypertensive agents exhibit very rapid and strong antihypertensive effects, making it difficult to control their effects. The antihypertensive compounds of the present invention have these drawbacks. The following pharmacological tests were conducted to prove the analgesic or antihypertensive effects of the compounds of the present invention. Q' Key Effect The following compounds of the invention have been found to be particularly useful as analgesics. 4-[(N-phenyl-N-acetyl)-amino]-1
-[3-(4-fluorobenzoyl)-propyl]-trans-1decahydroquinoline (Compound A) 4-[(N
-Phenyl-N-propionyl)-amino]-1-[3
1(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline (Compound B) 4-[(N-phenyl-N-butyryl)-amino]111[3-(4-fluorobenzoyl)-propyl]-trans-decahydro Quinoline (Compound C) 4-[(N-phenyl-N-valeryl)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline (Compound D) 4-[(N-14- methoxyphenyl-propionyl)-ami/]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decanohydroquinoline (compound E) 4-[(N-nicotinoyl-
N-phenyl)-ami/]-1-[3-(4-fluoro
benzoyl)-propyl]-trans-decahydroquinoline (compound G) 4-[(N-isonicotinoyl-N
-phenyl)amino]111[31(4-fluorobenzoyl)propyl]-trans-decahydroki/phosphorus (compound H)41[(N-phenyl-N-propionyl)-amino]111(3- penzoylpropyl)-trans-deca/hydroquinoline (compound J) 4-[(
N-acetyl-N-phenyl)-amino]-1-[4-(4-fluorobenzoyl)-butyl]-trans-decahydroquinoline (compound K) 4-[(N-cyclohexyl-N-propionyl)-amino]-1 1 [31 (
4-fluorobenzoyl)-propyl]-trans-deca/hydroquinoline (Compound L) The first test was performed using the KOSTER method (Fed.PrM.18).
412, 1959) on groups of 20 mice that had been deprived of food for 18 hours. Each group of mice, apart from control mice, received intragastric administration of the compound to be tested, with increasing doses being administered for each group. Thirty minutes after administration, 0.2 screams of 0.25% acetic acid solution were intraperitoneally administered to mice in each group along with control mice weighing 10 pounds. The number of mice making characteristic torsions during the 20 minutes following acetic acid injection was recorded. If the mouse does not show any torsion, it is considered to be under the influence of analgesia. The AD50, ie the dose of the compound to be tested which causes asymptomatic symptoms in half of the handled mice, was recorded. The results of this test are shown in the table below. - The same study was conducted on five commonly used analgesics with the following results: The second test in Table 2 is the NILSEN method (
ActaPha dish aC. XiC of I,et. 1, I & IQ I96I) on groups of 10 mice. The mouse was connected to a current source by two electrodes inserted into the tail. The threshold voltage, ie the minimum voltage at which the mouse would make a cry at least once out of two during two consecutive shocks, was then determined. After this, the compound to be tested was administered intragastrically.
Four successive shocks were given at the previously determined threshold voltage at various times after administration. An animal was considered protected if the mouse made no vocalizations after every shock. The test results are shown in the table below. In addition, the feed compounds are the aforementioned compounds A, B, and C, and the following two types of compounds. 41 [(N-carboethoxy N
-phenyl)-amino]-11-[3-(4-fluorobenzoyl]-propyl]-trans-decahydroquinoline (type a) (compound F) 4-[(N-rubomethoxyN-phenyl)-amino]-1 -[3-(4-Fluorobenzoyl)-propyl]-trans-decahydroquinoline (form a) (Compound M) Notes to Table 3 [11] Dosage to obtain maximal efficacy in which at least 80% of animals are protected. The maximal effect was also obtained at a dose of 9/[9 of 50. Identical tests were carried out with three known analgesics and the following results were obtained. is the compound of the present invention, i.e. 41 [
(N-phenyl-N-propionyl)-amino]-1-
A study was conducted to determine the analgesic effect of [3-(4-fluoropennzoyl)-propyl]-trans-decahydroquinoline (Compound B). The first test was carried out according to the KOSTER method described above, but in this case a subcutaneous injection of the product to be tested was performed. Compound B was compared with two major analgesics and the following results were obtained. The second test in Table 5 was carried out according to the method of NILSEN, supra, but in this case subcutaneous injection of the compound to be tested. Compound B was compared with two known analgesics, vetidine and pentazocine, and the following results were obtained. The third test in Table 6 was conducted by Sigmund et al. (Pr ratio.S ratio.Exp
．． Biol. Med. 95 729, 1957) in groups of 10 male mice. Mice were injected intraperitoneally with a 0.25M aqueous solution of 0.02% 2-phenyl-1,4-benzoquinone (phenylbenzoquinone) to develop the typical syndrome. The syndrome is characterized by intermittent retraction of the abdomen, rotation of the trunk, and elongation of the posterior side. Records were taken for the number of movements over 3 periods starting 19 minutes after the injection of phenylbenzoquinone. The compound to be tested was injected 3 minutes before the phenylbenzoquinone injection and the dose was increased from group to group. Control mice received only phenylbenzoquinone. A.D.
50, i.e. doses of the substance at which the number of births in half of the mice was reduced by at least half, were recorded in comparison to the number of births observed in control mice. The following results were obtained. 7 The fourth test was conducted by CHARLmR et al.
．． int. Phanac's beating, 134, 306, 19
The experiments were carried out on groups of 10 rats according to the method of 61). The rat was connected to the current source by two electrodes, one attached to the tail and the other to the rectum. A current of 2 volts was then passed, increasing in 1 volt increments until the rat made a whimper, and the threshold voltage of pain was determined for each rat. This control test was repeated three times at 15 minute intervals. The compound to be tested was then administered intragastrically and, starting from the previously determined threshold voltage, the voltage at which the rat began to make a hoarse sound was recorded every 1 minute for 2 hours. The results are Winter (WmTER) and Flataker (FL).
ATAKER) scale (J.PMrmcol.Exp.Themp.Inhalation 3051950)
The AD50 obtained is shown in the table below. At the end of Table 8, D'AMOUR and Smith (Shada TH)
) (J, P rm, Exp, Thete. 72, 74, 1
Tests were carried out on groups of 10 rats weighing approximately 200 kg according to method 1). The heat point of the heating bulb was aligned with the tip of the rat's tail at a distance where a typical oick-nail could be seen after 4 to 6 seconds of irradiation with a 300 watt heating bulb. Ta. Rats, with the exception of the control group, were administered subcutaneously the compound to be tested, and records were taken of the time elapsed from the start of irradiation to the rat's first response (reaction time) compared to the reaction time of control rats. . The AD50s obtained are shown in the following table. Table 9 From the above tests, it can be concluded that the compounds of the present invention have extremely superior properties compared to the three most common analgesics. [21 Antihypertensive action General formula in which RI is a branched or straight-chain alkoxy group (
It has been found that the compounds of 1) have such beneficial antihypertensive effects that they can be of great utility in the treatment of hypertension in humans. As far as the treatment of hypertension is concerned, the compounds of the present invention are preferably: 4-[(N-phenyl-N-carboethoxy)-amino]-11-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline (Compound F) Pharmacological tests revealed the antihypertensive effects of Compound F. was done to show. This test was conducted by Okamoto and Aoki (Jap.Ci (c mountain. J.27).
, 282, 1963) on male rats belonging to a species specifically created to have high blood pressure. The animals used were approximately IG weeks old;
His blood pressure was around 180 Hg. This test was divided into two series. In the first series, each rat received only one intracranial administration of the compound to be tested, and the rats' arterial blood pressure was measured every hour after administration for 6 hours. In the second series, the compound to be tested was administered intragastrically every day for 11 consecutive days, and arterial blood pressure was measured daily during this period. For the first series of tests, the amount of compound administered varies for each rat. The following results were obtained. Table 10 From these results, it can be concluded that Compound F has a strong antihypertensive effect. '31 Acute Toxicity Acute toxicity studies were conducted on rats and mice that were kept under observation for 12 days after a single dose. The following results were obtained. a) Compound B b) Compound F These numbers are highly favorable compared to the active doses whose effects are shown above;
and shows a very wide safety range between toxic and therapeutic doses of the preferred compounds of the invention. For therapeutic use, the compounds of the invention may have the general formula (
The compound of 1) or at least one of its pharmaceutically acceptable acid addition salts is usually administered in the form of a pharmaceutical composition containing a pharmaceutical carrier and/or excipient. For clinical use, the compositions may be formulated into dosage units appropriate for the intended mode of administration. For example, they may be coated or uncoated tablets, hard or soft gelatin capsules for oral administration, solutions for injection, and suppositories for rectal administration. Regardless of the form the composition takes, the pharmaceutical composition may contain at least one or more of, for example, milk, sugar, starch, talc, magnesium stearate, polypynylphyzlolidone, alginic acid, colloidal silicic acid or flavoring. It usually contains at least one compound of general formula (1) or a pharmaceutically acceptable addition salt thereof, together with a suitable pharmacological diluent or excipient. Z Next, the present invention will be explained with reference to Examples. Example
1 4-[(N-phenyl-N-propionyl)-amino]
-1-[3-(4-fluorobenzoyl)-propyl]
-trans-decahydroquinoline hydrochloride (type a) [a
l Synthesis of 4-phenylamino-trans-decahydroquinoline 76.8 units (0.5 mol) of 4-oxo-trans-decahydroquinoline and 1.0 units of p-toluenesulfonic acid were combined with 350 units of [ The solution in hexane was refluxed in a 1 liter flask and heated to 46.3 min (0
．． 5 mol) of aniline was added. The resulting water is Dean-Stark system (Dean-Stark system).
Refluxing was continued until complete removal by system), and 140' of hexane was distilled off. The solution was cooled and 250' of benzene was added. The reaction solution was washed first with water, then with a dilute solution of sodium hydroxide and finally with water again. This solution was dried with anhydrous sodium sulfate,
Filtration and removal of the solvent gave 102.4 hours of crude 4-phenyliminotrans-deca/hydroquinoline. (
(yield: 89%) 102.4 ml of the 4-phenyliminotrans-decanohydroquinoline thus obtained was dissolved in 190 ml of methanol containing 200 M of sodium hydroxide.
The solution was dissolved in the flask and the temperature of the solution was maintained at approximately 20°C. After adding a solution of 2M sodium borohydride to 60cm of methanol stabilized with 60cm of sodium hydroxide, the temperature of the reaction solution was kept at 20°C to 20°C for 2 to 3 hours. I kept it. Finally, the solution was heated to 4°C for 8 hours and then cooled. The solvent was removed and the residue was added to 150 °C of benzene and 250 °C of water. The mixture was decanted and the aqueous phase was extracted with benzene. The organic phase was then extracted with 240' of state hydrochloric acid. The mixture was decanted and sodium hydroxide was added until the pH was 3. This was heated in a furnace to obtain an aqueous acidic solution and a precipitate, and this precipitate was dried to give 4-phenylamino-trans-deca/hydroquinoline hydrochloride (type a) at 43.8 days.
I got it. Yield unevenness %, Kudzu point 265-270 hours C Isolated aqueous acidic solution of type b was made alkaline by adding sodium hydroxide, and extracted with benzene. The mixture was decanted and the organic phase was washed with water, dried over anhydrous sodium sulfate and filtered. The benzene was removed and Zeniza was added to 35' of ethyl ether. The solution thus obtained was cooled to a temperature of 0 to 5°C, filtered and washed with diethyl ether to give 4-phenylamino-trans-decahydroquinoline (form b) of 9.2 hours. Yield 7
%, melting point 118-12 pi○ The following listed compounds were synthesized following the same method using the appropriate starting materials. Compound Melting point ℃ 4-(4-methoxyphenyl) monoaminotrans-hydroquinoline 144-14
54-cyclohexylamino-trans-decahydroquinoline No crystallization [b] 1-[3-(fluorobenzoyl)-propyl]-4-phenyluamino-
Synthesis of trans-1-decano-hydroquinoline dihydrochloride (form a) A solution of 230 mg (1 mol) of 4-phenylamino-trans-decano-hydroquinoline (form a) dissolved in 920 M of n-butanol was sodium carbonate 10
The mixture was refluxed in a 4 liter flask in the presence of 0 ml. During reflux, 3-chloro1,1-ethylenedioxy-1-
(4-fluorophenyl)-butan 274 units (1.1
A solution of 2 mol) of n-butanol dissolved in 200' of n-butanol is added, and the resulting water
Refluxing was continued until complete removal by tarks. The solution was naturally cooled to 50% and the bound salts were removed by filtration. The solvent was removed from the solution under vacuum and the residue was dissolved in 2500ml of benzene. The solution is 250
was extracted with a solution of concentrated hydrochloric acid dissolved in 1250' of water. The resulting mixture was decanted, made alkaline with a hydrochloric acid solution for 3 hours, and then extracted with benzene. The obtained organic phase was washed with water, dried over anhydrous sodium sulfate, and heated in an oven to remove benzene. The obtained solution was dissolved in ethyl acetate, and a 2-propanol solution of hydrogen chloride gas was added thereto. The resulting precipitate was placed in an oven, washed with ethyl acetate, and dried. The target product obtained was recrystallized from a mixed solvent of ethyl acetate and methanol, and 1-[
3-(4-fluorobenzoyl)-propyl]14-phenylaminotrans-decahydroquinoline dihydrochloride (form a) was obtained. Yield 64.8%, melting point 204-2
06oo The following listed compounds were synthesized following the same method using the appropriate starting materials and melting points determined after recrystallization from the indicated solvents. Compound Δ Melting point °C 'c' 4 - Synthesis of [(N-phenyl-N-propionyl)-amino]111 [3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline hydrochloride 394 (1 mol) of 1-[3-(4-fluorobenzoyl)-propyl]-14-phenylaminotrans-decahydroquinoline (form a) was dissolved in 800 molar dichloroethane in a 2 liter flask. I let it happen. The solution was cooled to about 2° C. and a solution of propionyl chloride dissolved in dichloroethane 105 was added. The reaction solution was kept at 20°C for 1 hour, then 45°C for 16 hours.
It was heated to 50 oo. The solution is then cooled to 10-15q0, resulting in 1-[
The precipitate of 3-(4-fluorobenzoyl)-propyl]-4-phenylaminotrans-decahydroquinoline dihydrochloride was removed by filtration. Excess propionyl chloride is
Hydrolyzed with 120 ml of methanol and the solution was evaporated to dryness. The resulting residue was dissolved in 150 tons of acetone and refluxed, and the solvent was distilled off. This operation was repeated two more times. This residue was dissolved in 150 ml of acetone at the reflux temperature of the solvent and a 2-propanol solution containing a small amount of hydrogen chloride gas was added. Crystallization was carried out from the resulting solution at room temperature, and the resulting precipitate was stirred, washed with acetone, and dried to obtain crude product 318. Ethylnomethanol acetate mixed solvent (volume ratio 2:1
) after recrystallization from 4-[(N-phenyl-N-propionyl)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decanoide. 263 pieces of quinoli hydrochloride (form a) were obtained. Yield 54%, melting point 158-160 DEG C. Using the appropriate starting materials, the compounds listed below were synthesized according to the same method and their melting points determined after reconsolidation from the indicated solvents. Compound Melting point °C Compound Melting point °C Quinorime hydrochloride (type a) Example 2 41 [(N-phenyl-N-propionyl)-amino]
111 [31 (4-fluorobenzoyl)-propyl]
-trans-decahydroquinoline hydrochloride (form a) 1-[(4-fluorobenzoyl)-propyl]-4-phenylaminotrans-decanohydroquinoline hydrochloride (form a) synthesized by the method of Example 1 ) 3.94 evening (0.0
(85 mol) was dissolved in 20' of dimethylformamide and 3.5' of propionyl chloride was added to the solution. The mixture was heated to 60-80 qo for 4 q hours and 5' of methanol was added. The reaction solution was distilled under vacuum at 80°C until the solution of 12' was distilled off, and the residue was added to dilute sodium hydroxide. The reaction solution was extracted with diethyl cable, and the organic phase was washed with water and treated with activated carbon. The solvent was removed and the residue was dissolved in 150M acetone at reflux temperature. A 2-propanol solution containing a small amount of hydrogen chloride gas was added and crystallization was effected from this solution at room temperature. The obtained precipitate is filtered,
Washing with acetone and drying gave 3.8 g of crude product.
Mixed solvent of ethyl acetate and methanol (volume ratio: 2:1)
After recrystallization from Obtained. 0 Yield 65.
1%, melting point 1 group-16000 Example 34-[(N-phenyl-N-propionyl)-amino]-111[3-(
4-fluorobenzoyl)-propyl]-trans-decahydrokitanoline hydrochloride (form a) 1-[3-(4-fluorobenzoyl)] synthesized by the method of Example 1
-Propyl]-4-phenylamino-trans-decahydroquinoline (type a) 6 (0.015 mol), 450% of propionic anhydride, and a small amount of P-toluenesulfonic acid. Heated at time 100:00. After cooling, methanol was added, and 4-[(N-phenyl)-N-propionyl]-amino-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline was prepared by the method described in Example 1 below. 4.5 hours of hydrochloride (type a) was obtained. Yield 61.6%, melting point 1-16 p○ Example 4 41 [(N-phenyl-N-propionyl)-amino]
-1-[3-(4-fluorobenzoyl)-propyl]
-trans-decahydroquinoline methanesulfonate (type a) 41[(N-phenyl-N-propionyl)-ami/]111[3-(4-
Fluorobenzoyl)-bropyl]-trans-deca/
- A benzene solution containing hydroquinoline (type a) Soyu (0.2 mol) was acidified with a 69.5% aqueous methanesulfonic acid solution containing 2-propanol for 30 minutes until the solution reached a solution of 3.5 to 4. The acidic solution was dried and dissolved in toluene 600. After removing 100' of toluene by Konada distillation, recrystallizing and filtration, 41[(N-phenyl-N-propionyl)-ami/]111[31(4-fluorobenzoyl)]
-propyl]-trans-deca/hydroquinoline methanesulfonate (form a) 104 times was obtained. Yield %, melting point 132-134°C Example 5 1-[3-(4-fluorobenzoyl)-propyl]-4-phenylaminotrans-decahydroquinoline (55%) synthesized by the method of Example 1. 0.14 mol) was dissolved in 200' of dichloroethane. 16 minutes of ethyl chloroformate was added dropwise while stirring, and the reaction mixture was heated to 50 to 60 minutes per field hour. The reaction solution was cooled to 20°C, and a 2-propanol solution of hydrogen chloride gas was added. After stirring for 2-3 minutes, the mixture was evaporated to dryness and the residue was dissolved in acetone. The reaction solution was cooled to 0° C. for 1 hour and excess 1-[3-(4-fluorobenzoyl)-propyl]-4-phenylamino-trans-decahydroquinoline was removed by filtration. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate. The organic solution was cooled to 0° C. for 1 field hour, and 4-[(N-ruboethoxyN-phenyl)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline hydrochloride ( Form a) was crystallized, filtered and recrystallized from ethyl acetate/methanol. Yield: 31%, melting point: 1 x 13. The following compounds were synthesized using the appropriate starting materials and following the same method. Compound Melting Point °C Example 6 Soft-gelatin capsules containing the following ingredients were prepared according to known drug manufacturing methods. Ingredients Weight Example 7 An injectable solution containing the following ingredients was prepared according to a known method.

[Brief explanation of the drawing]

The accompanying drawings show the results of thin layer chromatography analysis of the a-form and b-form of 4-phenylaminotrans-decahydroquinoline.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ^2 represents a phenyl group, methoxyphenyl group, or cyclohexyl group, R^3 represents a group represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ where R^4 is a hydrogen atom or represents a fluorine atom, and n represents 3 or 4. A trans-decahydroquinoline derivative represented by the above formula, and a pharmacologically acceptable acid addition salt thereof. 2 Claims in which the trans-decahydroquinoline derivative is 4-[(N-phenyl-N-acetyl)-amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline The transformer described in item 1.
Decahydroquinoline derivatives and pharmacologically acceptable acid addition salts thereof. 3 The trans-decahydroquinoline derivative is 4-[(
N-phenyl-N-carboethoxy)-amino]-1-
Claim 1 which is [3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline
Trans-decahydroquinoline derivatives and pharmacologically acceptable acid addition salts thereof as described in 1. 4 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^2 represents a phenyl group, methoxyphenyl group, or cyclohexyl group, and R^3 is the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a group represented by Here, R^4 represents a hydrogen atom or a fluorine atom, and n represents 3 or 4. ] Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. [In the formula, R^1, R^2, and R^3 have the same meanings as above. ] A method for producing a trans-decahydroquinoline derivative represented by: 5. The method according to claim 4, wherein the compound of general formula (III) is refluxed together with the compound of general formula (IV) in an inert organic solvent. 6. The method according to claim 5, wherein the inert organic solvent is dichloroethane, methylene chloride, benzene or toluene. 7. The method according to claim 4, wherein the compound of general formula (III) is refluxed together with the compound of general formula (V) in the presence of a base. 8. The method according to claim 7, wherein the base is triethylamine, trimethylamine or pyridine. 9 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 represents a branched or straight-chain alkyl group having 1 to 4 carbon atoms, an alkoxy group, or a pyridyl group, and R^2 represents a phenyl group, Represents a methoxyphenyl group or a cyclohexyl group, R^3 is a general formula ▲ mathematical formula, chemical formula,
There are tables, etc. Represents the group represented by ▼. Here, R^4 represents a hydrogen atom or a fluorine atom, and n is 3
or 4. An analgesic agent comprising at least one of the trans-decahydroquinoline derivatives represented by the following formula and a pharmacologically acceptable acid addition salt thereof as an active ingredient. 10 4-[(N-phenyl-N-acetyl)-amino)-1-[3-(4-fluorobenzoyl-propyl]-trans-decahydroquinoline or a pharmacologically acceptable acid addition salt thereof) as an active ingredient 11. The analgesic according to claim 9 or 10, which is formed into a dosage unit suitable for oral administration. 12. The analgesic according to claim 9, which is suitable for administration by injection. The analgesic agent according to claim 9 or 10 formed into units. 13 4-[(N-phenyl-N-carboethoxy)-
An antihypertensive agent containing at least one of amino]-1-[3-(4-fluorobenzoyl)-propyl]-trans-decahydroquinoline and a pharmacologically acceptable acid addition salt thereof as an active ingredient. 14. The antihypertensive agent according to claim 13, which is formed into a dosage unit suitable for oral administration. 15. The antihypertensive agent according to claim 13, which is formed into a dosage unit suitable for administration by injection.