JPS609500B2 - 1,3,4-trisubstituted-4-arylpiperidines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel aryl piberidine derivatives, particularly 1.2.
The present invention relates to 4-trisubstituted-4-arylpiveridine derivatives.

The compounds of the invention are useful as intermediates in the synthesis of pharmaceuticals or other piverdine derivatives.

The compounds provided herein are particularly useful as anti-narcotic analgesics (Cape rcotica nisba MIgesics) and narcotic anti-analgesics (Mrcoticanta nisba MIgesics).

Extensive research has been conducted with the aim of finding pain-relieving drugs and their manufacturing methods. Recently, there has been a growing interest in compounds that exhibit anti-narcotic effects for two main reasons. The first reason is that there is a desire for anti-narcotic compounds that exhibit analgesic effects while at the same time significantly reducing the potential for abuse, and the second reason is that compounds useful in the treatment of drug addiction are desired. This is because it is desired. N-allylnorcodeine was probably the first anti-narcotic drug to be synthesized and investigated. This item is 191 Pu Miko Jay Paul (J.
Synthesized by Pohl). Several additional similar compounds have been synthesized with the aim of providing long-acting oral antagonists. The general characteristics of all these compounds are a relatively short duration of action, low oral activity and different agonist effects. On the other hand, it has been discovered that several compounds of the piverizine family exhibit interesting analgesic activity, some of which exhibit varying degrees of anti-inflammatory activity (e.g.
．． Ha secretion. Japan J. Pharmcol.
23, 743 (1973)). U.S. Patent No. 30438
Looking at No. 45 and No. 2892842, many 1.
2,3-Trialkyl-3-arylpiverizines have been produced and evaluated as analgesics. Lambeen et al. (
Buddhism ein. et al. , Narcotic A
nta paddy nis$. Advances l
nBiochemicaIPpsycho
phannacology. Vol. 8. Raven
Press. New York-1974, pp157-
(165) describe that a group of 1,4-disubstituted-4-arylpiveridines exhibits very interesting anti-inflammatory activity. Furthermore, McE1vain has synthesized several types of 1-methyl-4-alkyl-4-1-(3-hydroxyphenyl)piverizines and is evaluating them as analgesics (US Pat. No. 2,892,842). but,
The synthesis of 1,3,4-trisubstituted-4-arylpiberidine has hardly been studied, probably because its synthesis is difficult.

McKelvain et al. is a byproduct of synthesizing 1,3,4-arylpiveridine as a byproduct of synthesizing 1,4-dialkyl-4-arylpiveridine.
・The synthesis of 4-trimethyl-4-(2-methoxyphenyl)piveridine has been reported (J. Am. Ch.
em. Soc. 80, 3918 (19 spots)). The ortho- or para-methoxy on the phenyl group is said to cause the compound to lose its overall analgesic activity. Also, Jansen (
Janssen) synthesized 1-aroyl-3,4-dialkyl-4-aryl piberidine derivatives useful as central nervous system depressants (US Pat. No. 3,080,372).
issue). The object of the present invention is to provide 4-arylpiveridines having alkyl or alkenyl groups in the 1, 3 and 4 positions.

Furthermore, another purpose is to exert a useful analgesic effect,
Another object of the present invention is to provide piberidines useful as strong anti-narcotic agents. Furthermore, another object of the present invention is to provide a novel intermediate useful in the production of novel piverizines. The compounds of the present invention provided to achieve the above objects are represented by formulas 1 and 1'.

The compound represented by formula 1 is obtained by hydrogenating the compound represented by formula 1', and if necessary, the hydrogenated product is subjected to i) modification reaction of the N-position substituent and/or...substituent at the 3-position on the benzene ring. It is produced by carrying out the modification reaction of Furthermore, the compound represented by formula 1 is
The compound represented by is reacted with an alkylating agent, the product is reacted with diazomethane to form a compound represented by formula 2, which is thermally decomposed to form a compound represented by formula 1', which is then treated by the above method. It can also be produced by converting into a compound represented by formula 1.

Here, the "alkylating agent" that acts on the compound represented by formula (b) includes not only alkylating agents in the narrow sense, but also (cycloalkyl) alkylating agents, benzylating agents, and the like.

In addition, the modification reaction of the N-position substituent is, for example, a reaction in which the N-position substituent is once removed and then another substituent is introduced (first, the N-position is acylated, and then the carbonyl of the acyl group is reduced to methylene). (including indirect methods such as ) and reactions to reduce the N-position substituent when it has a reducible component.

Furthermore, the modification reaction of the substituent at the 3-position on the benzene ring includes, for example, a reaction in which R'4 is alkylated when it is hydroxy, a reaction in which it is hydrolyzed when R'4 is alkoxy, and a reaction in which R'4 is hydrolyzed when it is alkoxy. It refers to a reaction in which water scales are followed by alkylation to introduce another alkyl group. The target compounds of the present invention also include pharmaceutically acceptable acid addition salts and quaternary ammonium salts of the above-mentioned piverdine derivatives.

In the above formula, R is hydrogen, alkyl having 1 to 8 carbon atoms, alkenyl having 3 to 8 carbon atoms, (cycloalkyl)alkyl having 4 to 8 carbon atoms, or a formula (where n is 1, 2 or 3; m is 0 or 1 (however, when n is 3, m is 0); X is C0, CHOH or CH=CH:R
5 is hydrogen, alkoxy having 1 to 3 carbon atoms, nitro, amino or hydroxy.

) represents a group represented by "Alkyl having 1 to 8 carbon atoms" means a straight chain or branched alkyl having 8 or less carbon atoms, and specific examples include methyl, ethyl, isopropyl,
Examples include isobutyl, bentyl, 3-methylheptyl, and octyl. “Alkenyl having 3 to 8 carbon atoms” means the formula CH
2A (where A is alkenyl having 2 to 7 carbon atoms), specifically allyl, 3-butenyl, 3-methyl-2
-butenyl, 2,3-dimethyl-2-butenyl, 5-octenyl, etc. A typical example of "(cycloalkyl)alkyl having 4 to 8 carbon atoms" is Sik. Bropylmethyl, 1-cyclop. Examples include pylethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylpropyl, (2-methylcyclobutyl)methyl, and 2-cyclohexylethyl. "Specific examples of phenyl-substituted alkyl represented by the above formula include benzyl, 3
-Phenylpropyl, benzoylmethyl, 3-hydroxy-3-phenylpropyl, 3-phenyl-2-probenyl, 3-(4nitrophenyl)propyl, (3-aminophenyl)methyl, 2-(3-hydroxyphenyl)ethyl, etc. . In the above formula, R2 is hydrogen or alkyl having 1 to 4 carbon atoms. Carbon number 1-4
Examples of alkyl include methyl, ethyl, isobutyl and n-butyl. In the above formula, R3 is alkyl having 1 to 4 carbon atoms. In the above formula, R4 is hydrogen, hydroxy, or alkoxy having 1 to 3 carbon atoms.

Alkoxy having 1 to 3 carbon atoms includes methoxy, ethoxy, propoxy or isopropoxy. In the above formula, R' is a subgroup of R, and represents alkyl having 1 to 8 carbon atoms, (cycloalkyl)alkyl having 4 to 8 carbon atoms, or pendyl, and R'4 has the same meaning as R4. have

The piveridine compounds of the present invention can be conveniently produced by the methods described below, but particularly preferred are substituents that are not modified at any stage of the reaction process and that readily provide the desired compound or intermediate. The method is to use a pyrroline compound with

In particular, the method of the present invention is most preferably carried out by alkylating the pyrroline compound such that the group represented by R' as a subgroup of R in the above formula is alkyl, (cycloalkyl)alkyl or pendyl. Ru. According to the present invention, a piverdine compound of the formula is prepared from a pyrroline starting material with appropriate substituents.

In this step, either a piberidine compound which is itself a useful drug is produced, or the piberidine obtained here is converted into another useful piberidine compound. For example, this step can be carried out to provide a piveridine compound where R' is an easily removable group (e.g., methyl, benzyl) and R'4 is an easily modifiable group (e.g., methoxy). I can do it. Methyl or pendyl can be removed by conventional methods; methoxy can be converted to a hydroxyl group. Thus, an important intermediate, 3,4-di-substituted-
4-(3-hydroxyphenyl)piveridine is obtained,
This product can be converted into other target substances of the present invention by conventional methods (eg alkylation). As is clear from the above formula,
Stereoisomers occur in the piveridine compound of the present invention due to the substituents at the 3- and 4-positions. In particular, for example, the alkyl at the 3-position is in the cis or trans position with respect to the alkyl at the 4-position,
You can take layers. Generally, in the above formula R2
Cyspiveridine compounds, in which CH2 and R3 are mutually cis-type, have anti-narcotic analgesic activity.
nistactM).

The trans isomer exhibits narcotic analgesic activity and
Another narcotic antagonis
tactMty). The Piveridine Compounds of the present invention form pharmaceutically acceptable acid addition salts with a wide variety of inorganic and organic acids.

The acids used for salt formation need not be special, but the salts obtained must be substantially non-toxic to the animal body. Typical acids commonly used are sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, hydrobrodic acid, sulfamic acid, citric acid, acetic acid, maleic acid, malic acid, succinic acid,
These include tartaric acid, cinnamic acid, benzoic acid, and ascorbic acid. Piveridine compounds also form quaternary ammonium salts with a wide range of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. This kind of estel has
Methyl chloride, ethyl bromide, propyl iodide, butyl bromide, allyl iodide, isobutyl chloride, penzyl bromide, dimethyl sulfate, jetyl sulfate, methyl benzenesulfonate,
Contains ethyl toluenesulfonate, crotyl diodide, etc. According to the present invention, a 1,2,3-trisubstituted-3-arylpyrrolinium salt is obtained by alkylating the 1-position of a 2,3-disubstituted-3-arylpyrroline.

Reaction of this pyrrolinium salt with diazomethane gives a bicyclic compound, ie, a 1,2,3-trisubstituted 1,3-aryl-1,2-methylenepyrrolidinium salt. Heating the bimoat salt from about 1000 C to about 250 qo causes ring expansion to provide the corresponding 1,3,4-trisubstituted-4-aryl-1,4,5,6-tetrahydropyridinium salt. When this tetrahydropyridinium salt is neutralized and reduced, the 1,3,4-trisubstituted-4-arylpiveridine of the present invention is obtained. The piveridine compounds thus obtained are useful agents in their own right, but may be modified, if desired, to obtain other novel and effective compounds of the invention. For example, this modification includes removing the substituent at position 1 and realkylating with another substituent. The novel method described herein can be easily understood from the reaction scheme below. The first step of the above method is to treat 2,3-disubstituted-3-aryl-1-pyrroline with an alkylating agent to obtain 1,2,3
-trisubstituted-3-aryl-pyrrolinium salt.

Generally, the alkylating agent used to alkylate the pyrroline compound can be virtually any alkylating agent, although it will be appreciated that the alkyl group attached to the pyrroline should be stable throughout the process. For example, the alkyl group should be stable to relatively high temperatures, base treatment, and reduction, the specific reactions of which are discussed below. A typical alkylating agent used in this step is a compound represented by the formula R', Y (wherein Y is a non-nucleophilic anion and R' is as described above). As used herein, "non-nucleophilic anion" refers to an anion that does not attack the bicyclic pyrrolidinium system that is prepared in the next step by reacting the pyrrolinium salt with diazomethane.

Examples of non-nucleophilic anions include tetrafluoroborate, fluorosulfate, tetraphenylborate, perchlorate, and the like. Examples of such alkylating agents with non-nucleophilic anions include trimethyloxonium tetrafluoroborate, triethyloxonium tetraphenylborate, methyl fluorosulfate, ethyl perchlorate, penzyl perchlorate, etc. included. In practice, it is preferable to carry out the alkylation using a common low cost alkylating agent which introduces a more nucleophilic anion. Examples of strongly nucleophilic anions include halogen, alkyl, or arylsulfonate anions. However, if a nucleophilic anion is introduced into the pyrrolinium salt, it is necessary to replace it with a non-nucleophilic anion before reacting the pyrrolinium salt with diazomethane. Typical alkylating agents commonly used are sulfates, halides and aromatic sulfonate esters. Alkylating agents of this type include methyl chloride, ethyl bromide, isobutyl iodide, pentyl iodide, octyl bromide, isooctyl chloride, cyclopropylmethyl bromide, cyclobutylmethyl bromide, dimethyl sulfate, diisopropyl sulfate, Includes pendyl bromide, pendyl iodide, ethyl toluenesulfonate, methyl toluenesulfonate, etc. This nucleophilic anion is then replaced by a non-nucleophilic anion as described below. In a preferred embodiment of the present invention,
Pyrroline compounds are alkylated with easily removable groups such as methyl or pendyl. The 1-methyl or 1-benzyl pyrrolinium salt is converted to the corresponding piberidine compound according to the steps of the present method.

The resulting 1-methyl or 1-penzylpiveridine compound is then converted to a 1-unsubstituted piveridine compound, and this intermediate is alkylated again to lead to the desired target compound. Alkylation of pyrroline compounds is preferably carried out in a non-reactive organic solvent.

Suitable solvents include, for example, ketones (acetone, methyl ethyl ketone, diethyl ketone, etc.) and ethers (diethyl ether, dipropyl ether, dibutyl ether, etc.). More polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc. are also suitable solvents for alkylation. The particular solvent used is not critical to this reaction. The alkylation reaction is generally carried out at a temperature below about 180°C, usually from about 25°C to about 160°C.

The reaction is very conveniently carried out at the reflux temperature of the reaction solvent. The dosage of alkylating agent is generally approximately equivalent to the starting pyrroline, although an excess of alkylating agent may be used if desired.

If less than an equivalent amount of alkylating agent is used, a decrease in the yield of the 1-alkyl-1-pyrrolinium salt is usually observed.
Preferably, about a 1-15% molar excess of alkylating agent is used. Alkylation is substantially complete after about 1 hour to about 4 hours, and if necessary, excess alkylation is destroyed by adding an appropriate amount of a hydrogen source (eg, water or ethanol). For example, when an alkylating agent such as an alkyl sulfuric acid or an alkyl oxonium tetrafluoroborate is used, a proton source such as water is added to the reaction mixture. Decomposition of excess alkylating agent reduces the reaction mixture to approximately 2
If the lighting is performed at a temperature of 5°C to 150 pm, it will normally be completed in about 2 hours to about 1 hour. On the other hand, if an alkylating agent is used, such as methyl iodide, in which the excess reagent is removed by simple distillation, the removal of the excess reagent is carried out by evaporation. Alkylation products, 1, 2, 3-
Tri-substituted-3-aryl-1-pyrrolinium salts are generally isolated by removing water from the reaction mixture and recrystallizing the resulting salt.

If the salt thus obtained contains a non-nucleophilic anion (eg, tetrafluoroborate, perchlorate), it is isolated and used directly in the reaction with diazomethane. Furthermore, it is preferable that the pyrrolinium salt containing a nucleophilic anion (eg, chloride ion, methanesulfonate ion) is not isolated, but is reacted with a base in the reaction mixture to form 2-alkylidenepyrrolidine.

More specifically, the alkylation reaction mixture is made alkaline by adding an aqueous solution of an alkyl metal or alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide). If desired, ammonium hydroxides, organic bases, such as N-benzyltrimethylammonium hydroxide and triethylamine, and the like can also be used. The alkylated pyrrolinium salt in this basic aqueous solution is converted to 1,3-disubstituted-2-alkylidene-3-arylpyrrolidine as the free base. The pyrrolidine compound is generally insoluble in aqueous filtrates and is extracted with a suitable organic solvent (eg, diethyl ether, ethyl acetate, chloroform, benzene, etc.).
The solvent is removed from the extract, and the resulting pyrrolidine can be used without further purification, but if desired, it can be purified by conventional methods such as distillation, chromatography, and crystallization. This 2-alkylidene-113-di substitution-3
The -arylpyrrolidine is then treated with a suitable acid having a non-nucleophilic anion to convert it into a 1,2,3-trisubstituted-3-aryl-1-pyrrolinium salt.

Suitable acids include tetrafluoroboric acid, perchloric acid,
Examples include tetraphenylboric acid and fluorosulfuric acid. The reaction of the pyrrolidine compound with a suitable acid is carried out in a non-reactive organic solvent (
For example, diethyl ether, dipropyl ether, tetrahydrofuran, ethanol, methanol, benzene, chloroform, dichloromethane, etc.). The particular solvent used for this reaction is not critical. The reaction is carried out at a temperature below about 7yC, usually from about 0°C to about 5000C. Although the exact reaction temperature is not critical, it is preferably carried out at a temperature of about 15°C to about 35°C. in general,
An equivalent amount of acid is used relative to the starting pyrrolidine, although greater or lesser amounts may be used if desired. Preferably, the pH of the reaction mixture is about 3 to about 5.
Add enough acid to maintain The reaction is followed by testing the pH of the solution with a suitable acid indicator, such as Congo Red or Bromphenol Fluoride. The reaction is complete upon addition of the required amount of suitable acid, which usually takes from about 10 minutes to about 9 minutes.
It is 0 minutes. The resulting 1,2,3-trisubstituted-3-aryl-1-pyrrolinium salts (e.g. pyrrolinium perchlorate, pyrrolinium tetrafluoroborate) usually crystallize from the reaction mixture and can be collected by filtration of the reaction liquid. . This pyrrolinium salt can be used without further purification, but can be recrystallized from a suitable solvent if desired.
A 112.3-trisubstituted-3-free-1-pyrrolinium salt with a non-nucleophilic anion is treated with diasomethane to form a bicyclic pyrrolidinium salt.

The stability of this bicyclic pyrrolidinium salt depends on the nucleophilicity of its anion. Preferred salts, such as perchlorate and tetrafluoroborate, especially tetrafluoroborate, are stable at temperatures below about 10,000 °C;
It decomposes at higher temperatures as described below. The reaction of the pyrrolinium salt with diazomethane is carried out in a non-reactive organic solvent, such as an ether (jethylenal, dipropyl ether, dibutyl ether, tetrahydrofuran, dimethoxychetane) or an aromatic solvent (benzene, tleso, xylene).

Halogenated hydrocarbons such as chloroform, dichloromethane and esters such as methyl acetate, ethyl acetate are also suitable solvents. The particular solvent used in this step is not critical. The reaction is generally carried out at a temperature of less than about 50 qC, preferably from about 10 qo to about 50 qC. More specifically, the temperature of the reaction mixture was set to about 1 OO
The diazomethane diethyl ether solvent is added to the pyrrolinium salt diethyl ether or dichloromethane suspension while maintaining the temperature between 0 and about 1500. After the addition of diazomethane is complete, the reaction concentrate is preferably warmed to about 20-3000 ℃. The amount of diazomethane is usually at least equivalent to the starting pyrrolinium salt. In practice, it is advantageous to use an excess of diazomethane in order to carry out the complete reaction. The amount of excess diazomethane is not critical and the reaction can be followed simply by observing the evolution of nitrogen gas. When gas evolution ceases, sufficient diazomethane should have been added. Alternatively, diasomethane may be added until the reaction solution turns yellow indicating the presence of excess diazomethane. The reaction is usually complete after about 1 hour to about 1 hour, but longer times may be used if necessary. Excess diazomethane is destroyed by adding a weak acid such as acetic acid or evaporated. The product is isolated by removing the reaction solvent, generally as a crystalline residue.
-213-trisubstituted-3-aryl-1,2-ethylenepyrrolidinium salt is obtained. Further purification is usually not necessary, but may be done if desired by recrystallization from a suitable solvent such as ethyl acetate, chloroform, benzene, ethanol, or the like. The 1,2,3-trisubstituted-3-aryl-1,2-methylenepyrrolidinium salt has approximately 100qC
Heating to a temperature of about 250° C. causes ring expansion of the bicyclic system, resulting in 1,3,4-trisubstituted-4-IJ-1.
A 4,5,6-tetrahydropyridinium salt is obtained.

Thermal decomposition of bicyclic systems may be carried out in a non-reactive solvent having a boiling point of about 100°C or higher. This type of solvent includes 1,3-dimethoxybenzene, 1,2-dimethylbenzene, 1,
2,3-trimethylbenzene, dimethyl sulfoxide;
Includes triethylphosphonate. Generally, in practice it is preferable to carry out the thermal decomposition reaction without the use of a solvent. In particular, about 150 qo of 1,2,3-trisubstituted-3-aryl-1,2-ethylenepyrrolidinium salt alone,
and heat to a temperature of about 225q0. This thermal decomposition reaction is
Substantially complete in about 15 minutes to about 90 minutes. The product is an acid addition salt of tetrahydropyrrolidine, such as the tetrafluoroborate or perchlorate. The salt can be isolated by crystallization and further purified by recrystallization if necessary, but it is preferably converted directly to the free tetrahydropyridine compound by adding a suitable base to the pyrolysis reaction mixture. More specifically, the reaction mixture is made alkaline by adding an aqueous solution of a base, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonium hydroxide, Triton B, or the like. The particular base used is not critical. Generally, an organic solvent is added to the reaction mixture to achieve complete dissolution of the reaction mixture. Typical solvents added to dissolve the tetrahydropyridine compound are alcohols such as ethanol, methanol, isopropanol, and ethers such as dioxane and tetrahydrofuran. The amount of solvent used is not critical, but is usually sufficient to dissolve the tetrahydropyridine compound. The tetrahydropyridine compound is extracted from the aqueous alkaline solution with a suitable immiscible organic solvent (eg, ethyl acetate, ethyl acetate, dichloromethane, benzene, etc.). When the solvent is evaporated from the extract, 1,3,4-trisubstituted-4-aryl-1,4,5
-Gives 6-tetrahydropyridine. This tetrahydropyridine compound can be used in the next step without further purification, but can be purified by conventional means such as distillation, chromatography, crystallization, etc., if necessary. This thermal decomposition reaction may give 3-alkylidene piveridine of the following formula in some cases.

Although the yield of this 3-alkylidene piveridine is generally very low, if necessary it can be isolated by a method such as chromatography, and upon reduction, the object compound of the present invention can be obtained. However, isolation and purification are generally not necessary due to low yields. The next step in the process of the invention is the reduction of the tetrahydropyridine compound to obtain the 1,3,4-trisubstituted-4-arylpiberidine. 1, 4, 5, 6
-Reduction of tetrahydropyridine can be carried out using any of a number of methods familiar to those skilled in the art.

More particularly, reduction may be carried out by reaction with a hydride reagent such as sodium borohydride, diborane, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and the like. This hydride reduction reaction is generally carried out in the presence of an ether (diethyl ether, dipropyl ether, tetrahydrofuran, diglyme, etc.) or alcohol (methanol, ethanol, isopropanol, etc.).
If desired, to make this reduction more efficient,
For example, a weak acid such as formic acid or acetic acid may be added to the reaction mixture. As an example of a preferable reduction method, 1, 4, 5, 6-
One method involves treating tetrahydropyridine with sodium borohydride in the presence of a suitable solvent such as tetrahydrofuran and an acid such as acetic acid. The amount of reducing agent used can vary within a wide range. Generally, an excess (usually 1 molar to about 10 molar excess) relative to the tetrahydropyridine is used, although more or less can be used if desired. The exact reaction temperature is not critical to the reaction, although the reaction is usually carried out at a temperature below about 180°C. Preferably, the reactants are mixed while maintaining the temperature from about 0°C to about 20°C, and then the temperature is raised to about 50°C to about 15°C.
Bring it to 0oo. Usually, the reduction time is about 1 hour to about 4 hours.
Complete in time. The product is recovered by making the reaction mixture alkaline with an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, or ammonium hydroxide, and extracting with a water-immiscible organic solvent such as diethyl ether, ethyl acetate, or dichloromethane. On the other hand, also a tetrahydride.

Reduction of PIIJdine can also be achieved by hydrogenation.
Hydrogenation is preferably carried out in a non-reactive solvent such as tetrahydrofuran, dioxane, ethanol, methanol, water, N·N-dimethylformamide. Although the particular solvent chosen is not critical, it is preferred that the chosen solvent dissolve at least a portion of the tetrahydropyridine. Hydrogenation is carried out in the presence of a catalyst such as Raney nickel, platinum oxide, platinum, palladium on a support such as carbon or barium sulfate. The specific reaction conditions for this hydrogenation are not critical, but generally at a temperature of about 25 qo to about 200 qo, about 2 qo. s. i
．． Or about 10 snakes. s. i. This is done at a hydrogen gas pressure of .
The type of catalyst used in the reaction will, to some extent, determine the type of isomer of piveridine that is formed. For example, when platinum oxide is chosen as the catalyst, the piveridine product is primarily the trans isomer. On the other hand, when hydrogenation is carried out in the presence of palladium-carbon, the piveridine product mainly becomes a trans isomer. cis- and trans-1 and 3
・The mixture of 4-trisubstituted-4-arylpiveridines is
If necessary, distillation, gas-liquid chromatography,
Separation can be performed by any conventional means such as solid-liquid chromatography or crystallization. 1・4・5・6-
It should be noted that care must be taken when reducing tetrahydropyridine when alkenyl substituents are present.

Generally, reducing agents are selected for such reductions that do not normally reduce isolated carbon-carbon double bonds. For example, sodium borohydride and lithium aluminum hydride are generally preferred. The 1,3,4-trisubstituted-4-arylpiveridines produced by the above method are valuable pharmaceuticals. Some of these piveridines are useful as intermediates in the synthesis of other 1,3,4-trisubstituted-4-aryl piveridines. More specifically, some of these piverdine compounds are converted to 3,4-disubstituted-4-arylpiveridines, the latter being valuable intermediates for the preparation of the compounds of the present invention. . For example, 1-methyl-3,4-disubstituted-4-arylpiveridine is demethylated to lead to the corresponding secondary amine. In particular, when 1-methyl-3,4-disubstituted-4-arylpiveridine is reacted with a halogen formate, a carbamate is produced, and when a base is reacted with this, a secondary amine is obtained. This type of reaction is described in more detail by Awel-Monen and Porogese.
hese, J. Med. Chem. 15, 208 (19
72)). In particular, carbamates are obtained when halogenoformates such as phenyl chloroformate, ethyl furoformate, pendyl chloroformate are reacted with a tertiary amine, in this case a 1-methylpiveridine derivative. This reaction is generally carried out in a non-reactive solvent such as dichloromethane, chloroform, acetone, ethyl acetate. The reaction temperature is generally below about 20,000 ℃ and the reaction is substantially complete in about 1 hour to about 5 hours. The carbamate grade product can be isolated simply by distilling off the reaction solvent,
Generally no further purification is required. This carbamate can be prepared by reacting with a base such as an aqueous sodium hydroxide solution or an aqueous potassium carbonate solution.
- Converted to arylpiveridine. A suitable organic solvent is usually added to the reaction solution to dissolve the carbamate. Suitable solvents include alcohols such as ethanol and methanol, ethers such as dioxane and tetrahydrofuran, and the like. The hydrolysis reaction reduces this to approximately 500
When carried out at temperatures from 0 to about 150 oo, generally about 1
It can be completed in 1 hour or about 3 anchor hours. The product is isolated by extracting the aqueous reaction mixture with a solvent such as diethyl ether or ethyl acetate. This 3・
The 4-disubstituted-4-arylpiveridine is further purified by methods such as chromatography, crystallization, and distillation. By alkylating this 3,4-disubstituted-4-arylpiveridine at its 1-position, any of the compounds targeted by the present invention can be produced. For example, the Piveridine Compound can be alkylated with an alkyl halide, an alkenyl halide, a substituted alkyl halide, and the like. Representative examples of alkylating agents include isooctyl bromide, 3-hexenyl bromide, cyclopropylmethyl chloride, penzoyl ethyl bromide, 3-hydroxy-3-phenylpropyl bromide, 4-nitrobenzyl bromide, 3-phenyl-3-probenyl compound, 3-probenyl compound
1-(4-ethoxyphenyl)bropyl, and the like. The desired 1,3,4-trisubstituted-4-arylpiveridine is prepared by reacting the appropriate 3,4-disubstituted-4-arylpiveridine with an alkylating agent.

Generally, both reactants are mixed in approximately equimolar amounts, preferably in an organic solvent. Commonly used typical solvents include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, aromatics such as benzene and toluene, and ketones such as acetone. Generally, a base is added to the reaction mixture to act as an acid binder. Typical bases include sodium bicarbonate, potassium carbonate, magnesium hydroxide, and triethylamine. This alkylation is generally complete after about 1 hour to about 1 hour when carried out at a temperature of about 2000 to 120°C. The product is isolated in conventional manner and further purified if desired. The substituent at position 1 can be further modified if necessary.

For example, the oxo group present on the substituent at the 1-position can be reduced to a hydroxy group by a conventional method, and if necessary, this hydroxy group can be removed by dehydration. As mentioned above, a piveridine with a 3-methoxyphenyl substituent can be converted to the corresponding 3-hydroxyphenyl substituted piveridine.

For example, a methoxy group can be converted to a hydroxy group by the action of hydrobromic acid-acetic acid, boron tribromide, and the like. Such ether cleavage methods are well known to those skilled in the art and reference may be made, for example, to US Pat. No. 3,324,13y. The corresponding 3-hydroxyphenyl-substituted piverizines are useful as analgesics and as intermediates for the preparation of other piveridine compounds. Salts of Pibe IJ gin compounds are prepared by conventional methods used for the preparation of amine salts.

In particular, the acid addition salt of the piverizine compound has a pKa value of about 4.
They are prepared by reacting a smaller suitable acid with a piverizine compound, generally in a non-reactive organic solvent.
Suitable acids include mineral acids such as hydrochloric, hydrobromic, hydrobrodic, sulfuric, phosphoric, and the like. Organic acids can also be used, such as acetic acid, p-toluenesulfonic acid, chloroacetic acid, and the like. Solvents commonly used for this reaction include acetone, tetrahydrofuran, diethylenal, and ethyl acetate. Quaternary salts are generally prepared in a similar manner by reacting a piverdine compound with an alkyl sulfate or alkyl halide (eg, methyl sulfate, methyl iodide, ethyl bromide, propyl iodide, etc.). When the novel piberidines are mentioned herein, it should be understood that their salts are also included.

For example, when 1,3,4-trialkyl-4-arylpiveridine is described, its cis form, trans form,
Cis-trans mixtures and their salts are included. In general, the novel piveridines of the present invention are valuable compounds for use in humans.

In recent years, there has been a strong demand for powerful narcotic blockers for the treatment of drug addiction. The trans-1,3,4-trisubstituted-4-arylpiveridines of the present invention are strong anti-narcotic agents and also have analgesic effects. Also, cis-1・
3,4-Trisubstituted-4-arylpiverizines are particularly useful as narcotic analgesics and exhibit little addictive properties. These compounds can be administered orally or parenterally. For oral administration, they are formulated in the form of tablets or solutions dissolved or suspended in a suitable carrier such as water. Generally, the dosage will be determined according to body weight or individual needs. When the active ingredient is put into tablet form, for example, the tablets may be scored if they are to be used in lower or divided doses. Subcutaneous injection administration can be carried out as a suspension of the active substance, for example in acetone, in water. The physiological activity of representative compounds of the present invention was evaluated in a mouse writhing test (Mi
thimgtests) and tail in rats.
It was tested using a heat test (sts on tailheat).

1. Writhing test (Table 1) Using mice weighing 20-22 mm, acetic acid was intraperitoneally injected to induce writhing (mithe) characterized by contraction of the abdominal muscles, extension of the hind limbs, and reversal of body movements. .

The frequency of writhing in a group of five mice treated with a saponified compound was compared with that in an untreated control group of five mice. A reduction of 40% or more in the number of times of distress is considered effective. Oral administration of aspirin at 50 females/k9 reduces the frequency of writhing. The “time” shown in Table 1 refers to the time when the test compound was administered orally (O
R) or the time from subcutaneous (SC) administration to intraperitoneal administration of acetic acid. 2 Tail heat test (Table U
) A rat weighing 70 to 80 mm was used, and its tail was placed on two metal tubes through which a nichrome wire was passed.

This resistance wire was energized to generate heat, and the time from the start of energization to the tail-raising reflex was measured. The reflex times of the saponified compound-administered group (5 animals per group) were compared with 5 animals.

The efficacy was confirmed by comparing it with that of the control group and performing statistical analysis (95%) using the Student's "t" method.

When propoxyphene is administered subcutaneously, 9/2.0
Shows activity at k9. Table 1 Comparison of compound numbers and compound names using Mathus-Rising method 1 trans-1,3,4-trimethyl-4-phenylpiveridine 2 cis-1,3-dimethyl-4-ethyl-4
-Phenylpiveridine hydrochloride 3 trans-1,3-dimethyl-4-propyl-4-(3-methoxyphenyl)
Piveridine hydrobromide 4 Cis-1-cyclopropylmethyl-3-methyl-4-ethyl-4-phenylpiveridine hydrobromide 5 Cis-1-(2-phenylethyl)-3-methyl-4-ethyl -4-phenylpiveridine hydrobromide 6 cis-1-(2-phenylethyl)-3-methyl-4-propyl-4-phenylpiveridine hydrobromide 7 cis-1-cyclopropylmethyl-3-
Methyl-4-propyl-4-phenylpiveridine hydrobromide 8 trans-1-aryl-3-methyl-4-ph.

Ropyru 4-(3-methoxyphenyl)piverizine hydrobromide 9 trans-1-cyclopropylmethyl-3
-Methyl-4-propyl-4-(3-methoxyphenyl)piveridine hydrobromide 10 cis-1,3-dimethyl-4-propyl-4-(3-methoxyphenyl)piveridine hydrobromide 11 trans-1-3-methyl-4-propyl-4- (3-Hydroxyphenyl)piveridine 12 trans-11-(2-phenylethyl)-3-methyl-4-propyl-4-(3-hydroxyphenyl)piveridine hydrobromide 13 cis-1,3-dimethyl-
4-propyl-4-(3-hydroxyphenyl)piveridine hydrobromide 14 cis-1,3,4-trimethyl-4-phenylpiveridine hydrobromide 15 cis-1
-Aryru-3,4-dimethyl-4-phenylpiveridine hydrobromide 16 cis-
1-Allyl-3-methyl-4-propyl-4-(3-methoxyphenyl)piveridine hydrobromide 18 cis-
1-Cyclopropylmethyl-3-methyl-4-propyl-4-(3-methoxyphenyl)piveridine hydrobromide 19 Cis-1-(2-phenylethyl)-3-methyl-4-propyl-4-(3 -methoxyphenyl)piveridine hydrobromide 20 cis-1-(2-phenylethyl)-3-methyl-4-propyl-4-(3-hydroxyphenyl)piveridine 21 cis-1-ethyl-3
・4-dimethyl-4-phenylpiveridine hydrobromide 22 trans-1-propyl-3,4-dimethyl-4
-Phenylpiveridine hydrobromide 23 trans-1
-Ethyl-3,4-dimethyl-4-phenylpiveridine hydrobromide 24 cis(2-penzoylethyl)-
3,4-dimethyl-4-phenylpiveridine hydrobromide 25 cis-1-cyclof.

Lopylmethyl-3. 4-dimethyl-4-phenylpiveridine hydrobromide 26 trans-1-1-cyclopropylmethyl-3,4-dimethyl-4-phenylpiveridine hydrobromide 27 trans-111[21(4-nitrophenyl ) Ethyl]-314-dimethyl-4-phenylpiveridine hydrochloride 28 trans-1-(3-phenyl-3-hydroxypropyl)-3,4-dimethyl-4-
Phenylpiveridine Hydrochloride 29 Cis-1-(3-phenyl-3-hydroxyp.

Pill)-314-dimethyl-4-phenylpiveridine hydrochloride 30 trans-1-[2-(4-aminophenyl)ethyl]-3,4-dimethyl-4-phenylpiveridine hydrochloride 31 trans-1-[ 2-(4-Hydroxyphenyl)ethyl]-3,4-dimethyl-4-phenylpiveridine hydrobromide 32 cis-113-dimethyl-
4-ethyl-4-(3-methoxyphenyl)piveridine hydrobromide 33 trans-1-cyclopropylmethyl-3,4-dimethyl-4-(3-methoxyphenyl)
Piveridine 34 Cis-1,3-dimethyl-4-propyl-4-phenylpiveridine 35 Trans-1-cyclopropylmethyl-3,4-dimethyl-4-phenylpiveridine hydrobromide 36 Trans-1. 3-dimethyl-4-ethyl-4-phenylpiveridine hydrobromide 37 trans-1-cyclopropylmethyl-3-methyl-4-ethyl-4-phenylpiveridine hydrobromide 38 trans -1,3-dimethyl-4-propyl-4
-Phenylpiveridine hydrobromide 39 trans-3
-Methyl-4-propyl-4-phenylpiveridine 40
trans-1-aryl-3-methyl-4-propylpiveridine hydrobromide 41 trans-1-cyclopropylmethyl-3-methyl-4-propyl-4-phenylpiveridine hydrobromide 42 trans-1- (2-phenylethyl)-3-methyl-4-propyl-4-phenylpiveridine hydrobromide 43 cis-1,3-dimethyl-4-propyl-4-(3-hydroxyphenyl)
Piveridine Hydrochloride 44 Cis-1,3-dimethyl-4-
Propyl-4-phenylpiveridine The following examples are presented in order to more fully illustrate the invention.

The examples are intended to be illustrative only and are not intended to limit the scope of the invention. In the examples, boiling points or melting points and elemental analysis values are shown as identification data.
Example 1 Trans-1,3,4-trimethyl-4-phenylpiberidine A 2,3-dimethyl-3-phenyl-1-pyrroline 150 and methyl ethyl ketone 325C
Add 0.0% to the solution dissolved in c. 94.87 g of dimethyl sulfate was added dropwise over a period of time.

The reaction mixture was heated to reflux for 2 hours. Approximately 25 oo of reactive tear fluid
After cooling to 0. 575 cc of water was added dropwise over a period of time, and the aqueous reaction mixture was heated under reflux for 3 hours. The reaction mixture was cooled to about 2,500 ml and left at room temperature for several hours. The product was subjected to step B in salt form without being isolated. B
A 50% aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, and the pH was adjusted to about 11.

The alkaline aqueous solution was extracted with diethyl ether, and the ether extract was washed with water and dried. The solvent was distilled off under reduced pressure to obtain 160.5 g of 2-exomethylene-1,3-dimethyl-3-phenylpyrrolidine. Bp66-7400 (
0.05% Hg) C 50% tetrafluoroboric acid was added to a solution of 190 ml of 2-exomethylene-1,3-dimethyl-3-phenylpyrrolidine dissolved in 4000 cc of diethyl ether until it showed acidity with Congo red test paper.
Added ethanol solution. The precipitated 1,2,3-trimethyl-3-phenyl-1-pyrrolinium tetrafluoroborate was collected in a furnace and dried. Mp143-14400 Analysis value C, 3 days, 8NBF4 Calculated value C56.75: Day 6.60: N5.09 Experimental value C57.79: Day 6.80; N5.79D Tetrafluoroboric acid 112,3-trimethyl-3-phenyl A solution of 1-pyrrolinium 17 dissolved in 400 cc of dichloromethane was cooled to 0°C in an ice-water bath.

2. A solution of diazomethane in diethyl ether was added dropwise over a period of time, and the reaction mixture was warmed to 25°C and stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain 1,2,3-trimethyl-3-phenyl-1,2-methylenepyrrolidinium tetrafluoroborate as a solid. Mp151
-155qo Analysis value C, 4 days 2buBF4 Calculated value C58.15: Day 6.97; N4.84 Actual value C58.02; Day 7.12: N5.01 Above A, B
, C, and D, the following 1,2,3-trisubstituted 1,2,3-aryl-1,2-methylpyrrolidinium tetrafluoroborate was obtained.

1,2-dimethyl-3-ethyl tetrafluoroborate
3-Phenyl-1,2-methylenepyrrolidinium Analysis value C, 5 days 22NBF4 Calculated value C59.42; Day 7.32: N4.62 Experimental value C59.23; Day 7.48; N4.37 Tetrafluoroboric acid 1,2,3-trimethyl-3(3-methoxyphenyl)-1,2-methylenepyrrolidinium Mp98
-101℃ Analysis value C, 5 days 22NOBF4 Calculated value C56.45; Day 6.95: N4.39 Experimental value C56.17; Day 7.14; N4.39 1,2-dimethyl-n-propyl-tetrafluoroborate 3-(3-
Methoxyphenyl)-1,2-ethylenepyrrolidinium Mp121-124o○ Analysis value C, 7 days 26 NOB
F4 calculated value C58.80; day 7.55; N4.03 experimental value C58.77; day 7.69; N4.21E Tetrafluoroboric acid 1,2,3-trimethyl-3-phenyl-1,2-methylenepyrrolidi Nium, Yu Yuchu, 18
Heated for 45 minutes at 0qo.

The crystalline residue was 1,314-trimethyl-4-phenyl-114,506-tetrahydropyridinium tetrafluoroborate. F The above crystalline residue was dissolved in ethanol, and a 20% aqueous sodium hydroxide solution was added until the mixture became alkaline.

This mixture was extracted with diethyl ether, and the ether extract was washed with water and dried. The solvent was removed under reduced pressure to obtain 1,3,4-trimethyl-4-phenyl-1 as an oil.
04.516-tetrahydropyridine was obtained. Bp76
-8000 (Hg on 0.5 side) Analysis value C, 4 days, Calculated value C83.53; Day 9.51; N6.96 Experimental value C83.47; Day 9.42; N6.74 By the above method, Furthermore, the following 1,314-trisubstituted-4-aryl-1,4,5,6-tetrahydropyridine was obtained.

1,3-dimethyl-4-n-propyl-4-phenyl-1,4,5,6-tetrahydropyridine Bp90-95
Noon 0 (0.15 skin Hg) Analysis value C, 6th day 23N Calculated value C83.79: HIO. 11: N6.11 experimental value C83.86: day 9.86: N5・931・3-dimethyl-4-ethyl-4-(3-methoxyphenyl)-
1,4,516-tetrahydropyridine Bpl18-
12500 (0.1 Yanagi Hg) Analysis value C, 6th 23NO
Calculated value C78.32; Sun 9.45: N5.71 Experimental value C78.10; Sun 9.24: N5.721.3-dimethyl-4-n-propyl-4-(3-methoxyphenyl)-1.4. 5.6-tetrahydropyridine Bp12
4-135q0 (0.1 Hg) analysis value C, 7th day 25
NO calculation value C78.72; Sun 9.71: N5.40 Experimental value C78.48: Sun 9.80: N5.43 G113
・Add 50 parts of 4-trimethyl-4-phenyl-1,4,5,6-tetrahydropyridine to 2,600 cc of tetrahydrofuran containing 38 parts of sodium borohydride,
Cooled to 5°C in an ice-water bath.

To this solution was added 578 cc of glacial acetic acid at a rate that maintained the temperature of the mixture between 500 and 1020 °C. The reaction mixture was then concentrated at 1oooO for 0.5 hour, and further heated under reflux for 1 hour. The reaction mixture was cooled to about 260 and the pH was adjusted to 11.5 by adding 25% sodium hydroxide solution. This alkaline liquid was extracted with diethyl ether. E7
The extract was washed with water and dried over sodium sulfate. The drying agent was removed in the oven, and the solvent was distilled off under reduced pressure to obtain substantially pure trans-1.304-trimethyl-4-phenylpiberidine. Bp90-9 or 0 (0.15 ribs H
g) Analytical value C, 4 days 2, N Calculated value C82.70; HIO. 41: N6.89 experimental value C82.47: HIO. 11; N7.03 Example
2-trans-1,3,4-trimethyl-4-phenylpiveridine hydrobromide 1,304-trimethyl-4-phenyl-1,4,5,6-tetrahydropyridine 42% was dissolved in 450 cc of ethanol, Add 4.0% platinum oxide and heat at room temperature. s. i. 16 in a hydrogen gas atmosphere of
I worshiped the time light.

The reaction mixture was filtered through a furnace, and the furnace liquid was evaporated under reduced pressure. The remaining oily residue was dissolved in diethyl ether and hydrogen bromide gas was introduced. The crystalline salt was collected in an oven and recrystallized from 100 cc of isopropyl ether, 300 cc of isopropanol and 350 cc of ethanol. The product was collected in an oven and dried to obtain 31.3 g of trans-1,3,4-trimethyl-4-phenylpiveridine hydrobromide with a purity of 80%. Mp242-245℃ Analysis value C, 4 days 22NBr Calculated value C59.16: Day 7.80; N4.93 Experimental value C59.29: Day 8.06; N5.09 Example 3-
7 The following 1,3,4-trisubstituted-4-arylpiveridines were prepared from the corresponding 103,4-trisubstituted-4-aryl-1,4,516-tetrahydropyridines by the method described in Example 2, and Reaction with hydrogen bromide gave the corresponding hydrobromide salt.

Trans-1,4-dimethyl-3-ethyl-4-phenylpiveridine hydrobromide Mp230qC or higher (decomposition) Analysis value C, 5 days 24NBr Calculated value C60.40; Day 8.11; N4. 70 Experimental value C60.34; Sun 8.12; N4.47 Trans-1
・4-dimethyl-3-n-propyl-4-phenylpiveridine hydrobromide Mp256℃ (decomposition) Analytical value C, 6 days 26NBr Calculated value C61.54: Day 8.39: N4.49 Experimental value C61 .74: Sun 8.47: N4.44 Trans-1
-Phenethyl-3-n-propyl-4-methyl-4-phenylpiveridine hydrobromide Mp228-230q
o Analysis value C22 day 32NBr Calculated value C67. Group: Sun 8.24: N3.59 experimental value
C67.96; Sun 8.04: N3.77 Trans-1-
Cyclopropylmethyl-3-n-propyl-4-methylphenylpiveridine hydrobromide Mp165.5-167.5C Analysis value C, Niji 3F Br calculation value C64
．． 77; Sun 8.58; N3. Iso experimental value C64.50:
Sun 8.82: N3.86 Trans 11-Ariru 31n
-Propyl-4-methyl-phenylpiveridine hydrobromide Mp169-17 is ○Analytical value C, 8 days 28NBr Calculated value C63.90; Day 8.34: N4.14 Experimental value C63.61: Day 8. 12:N4.38 Example 8 900cc of glacial acetic acid containing 5% cis-1,3,4-trimethyl-4-phenylpiveridine and 3.6% palladium-carbon
1,3,4-trimethyl-4-phenyl-1,4,5
・Dissolve 56.0% of 6-tetrahydropyridine and stir at room temperature. s. i. The mixture was concentrated in a hydrogen atmosphere for 4 hours.

The reaction mixture was diluted with 400 cc of water, concentrated under reduced pressure, and made alkaline by adding an aqueous sodium hydroxide solution. The alkaline aqueous solution was extracted with diethyl ether, and the ether extract was washed with water and dried. Removal of the solvent under reduced pressure gave cis-1,3,4-trimethyl-4-phenylpiveridine, which was converted into the hydrobromide salt by reaction with hydrogen bromide. Mp230-23 is 0 analysis value C. 4th 22nd
NBr Calculated value C59.16: Sun 7.80: N4 93 Experimental value C59.34: Sun 7.59: N 5.09 Example 9-14 By the method described in Example 8, the following 1, 3, 4- Tri-substituted-4-arylpiveridine corresponding to 1,3,4
-Trisubstituted-4-aryl was prepared from 1,4,5,6-tetrahydropyridine, and each hydrobromide salt was further prepared.

Cis-1,4-dimethyl-3-ethyl-4-phenylpiveridine hydrobromide Mpl96-199℃ analysis value
C, 5th day 24NBr calculated value C60.40: day 8.11
:N4.70 experimental value C60.17: day 7.90: N4
．． 70cis-1,4-dimethyl-3-n-propyl-4
-Phenylpiveridine hydrobromide Mp208-21
100 Analysis value C, 6 days 26NBr Calculated value C61.54: Day 8.39; N4.49 Experimental value C61.53: Day 8.10: N4.46 cis-1-benzene-3-n-propyl-4-methyl-4-ph Enylpiveridine hydrobromide Mp162-164q0 Analysis value C2 Rainbow 34NBr Calculated value C65.21; Day 9.30; N3.80 Experimental value C65.28: Day 9.17: N3.92 cis-1-allyl- 3-n-propyl-4-methyl-4-phenylpiveridine hydrobromide Mp240-2420 analysis value C
．． 8 days 28NBr Calculated value C63.90: Day 8.34: N4.14 Experimental value C64.27: Day 8.40: N4.24 Cis-1-phenethyl-3-n-propyl-4-methyl-4-phenylpiberidine bromide Hydrogen salt Mpl92-19400 analytical value C23 day 32NBr calculated value C68.65; day 8.02: N3.48 experimental value C68.41: day 7.93: N3.67 cis-1-cyclopropylmethyl-31n -Propyl-4-methyl-
4-phenylpiveridine hydrobromide Mp249.5
-251.5q0 analysis value C, 9 days 3bu Br calculation value C
64.77: Sun 8.58; N3.98 experimental value C64.
98: Sun 8.64; N3.92 Example 15 Sis 1・
3-dimethyl-4-n-propyl-4-(3-methoxyphenyl)piveridine By the method described in Example 1, 1.
3-dimethyl-4-2-propyl-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyridine from the corresponding 2-methyl-3-n-propyl-3-(3-methoxyphenyl)-1-pyrroline Manufactured.

5% palladium-carbon 8.0 liters in ethanol 650cc
In addition to 1,3-dimethyl-41 n-probyl-41 (
3-Methoxyphenyl)-1,4,5,6-Tetrahydropyridine (81%) was dissolved at room temperature. s. i. Iso worshiped for 16 hours in a hydrogen atmosphere.

The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to obtain an oily product. Producing hydrobromide by the method of Example 2,
cis-1,3-dimethyl-4-n-propyl-4-(3
-methoxyphenyl)piverizine hydrobromide was obtained. Mp167-169. yo analysis value C, 7 days 28
NOBr calculation value C59.65; day 8.24; N4.0
9 Experimental value C59.88: Day 8.46; N4.00 Example 16 Trans-1,3,4-dimethyl-4-phenylpiveridine Trans-1,3,4-trimethyl-4-phenylpiveridine 32. 3 evenings of dichloromethane 300cc
Dissolve phenyl chloroformate in dichloromethane 75c
After adding the solution dissolved in c and feeding for one hour at room temperature,
The mixture was heated under reflux for 2 hours.

The reaction mixture was evaporated to dryness under reduced pressure, and 360 cc of a 50% aqueous potassium hydroxide solution and 2000 cc of ethanol were added to the residue, which was further diluted with 1450 cc of water. This alkaline mixture was heated to reflux for 2 hours. The reaction mixture was extracted with diethyl ether, and the combined extracts were washed with water and dried. The solvent was distilled off under reduced pressure to obtain 23 trans-3,4-dimethyl-4-phenylpiveridine. Bp78-84qo
(1.5 side Hg) Analysis value C, 3 days, calculated value C82.48: HIO. 12: N7.40 experimental value C82.60; HIO. 34:N7.59 Example
17-22 The following 3,4-disubstituted-4-arylpiveridines were prepared from the corresponding 1,314-trisubstituted-4-arylpiveridines by the method of Example 16.

Cis-3-methyl-4-ethyl-4-phenylpiveridine Analysis value C, 4 days 2,N Calculated value C82.70: HIO. 41; N6.89 experimental value C82.88; HIO. 11:N6.81 Sis 3
-Methyl-4-n-ph.

Lopyl-4-phenylpiveridine analysis value C, 5th day 23
N Calculated value C82.89; HIO. 67; N6.44 experimental value C82.84: HIO. 42:N6.24 trans-3-methyl-4-ethyl-4-phenylpiveridine
Bplo0-10500 (4th side Hg) analysis value C, 4 days 2, N calculated value C82.70; HIO. 41; N6.8
9 Experimental value C82.48; HIO. 23; N7.15 trans-3-methyl-4-propyl-4-phenylpiveridine Bp133-140qC (5-side Hg) analysis value C, 5 days 23N calculated value C82.89; HIO. 67; N6.44 experimental value C82.91; HIO. 61: N6.15 trans-3,4-dimethyl-4-(3-methoxyphenyl)piveridine Bp150-155q○ (3 skin Hg) Analysis value C, 4 days 2, NO Calculated value C76.67: Day 9.65 ; N6.39 experimental value C76.92; day 9.91; N6.61 trans-3
-Methyl-4-ethyl-4-(3-methoxyphenyl)
Piveridine Bp145-150℃ (5 legs Hg) Analysis value C, 5 days 2bu○ Calculated value C77.21; Day 9.94: N6.00 Experimental value C77.26: Day 9.71: N5.75 Example 23
Add 0.96 ml of cis-1-ethyl-3,4-dimethyl-4-phenylpiveridine sodium bicarbonate to 24 cc of dimethylformamide, and add cis-304-dimethyl-4-dimethyl-4.
- 1.5 hours of phenylpiberidine was dissolved, and 1.14 hours of ethyl iodide was added thereto.

The reaction slurry was heated to reflux for 1 hour. Approximately 2,500 liters of reaction hawk solution
250 cc of water was added, and the mixture was extracted with diethyl ether. The ether extract was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain 1.62 ml of oily 1-ethyl-3,4-dimethyl-4-phenylpiberidine. This was dissolved in diethyl ether and hydrogen bromide was added to this solution. The precipitated crystals were collected in a furnace and recrystallized from 100 cc of isopropanol and 30 cc of isopropyl ether to obtain 1.61 g of cis-1-ethyl-314-dimethyl-4-phenylpiberidine hydrobromide. Ta. Mp224-22600 Analysis value C, 5th 24NBr Calculated value C60.40; Day 8.11: N4.70 Experimental value C60.64; Day 7.83: N4.97 Example 24
-32 Compound 3 corresponding to the following compound by the method of Example 23
- Prepared by reacting 4-di-substituted-4-arylpiveridine with a suitable alkylating agent.

trans-1-n-propyl-3,4-dimethyl-4-phenylpiveridine hydrobromide Mp214.5-21
70 Analytical value C, 6th day 26NBr Calculated value C61.54; day 8.39; N4.49 experimental value C61.57; day 8.56: N4.54 trans-1
-(2-probenyl) -3,4-dimethyl-4-phenylpiveridine hydrobromide Mpl94-195qC Analysis value C, Phantom 24NBr Calculated value C61.94; Day 7.80: N4.51 Experimental value C62.20; Sun 8.05: N4.63 Trans-1
-Cyclopropylmethyl-3,4-dimethyl-4-phenylpiveridine hydrobromide Mpl97-19900
Analysis value C, 7 days 26NBr calculated value C62.96: day 8.08; N4.32 experimental value C62.83: day 8.3
0:N4.47 trans-1-[2-(4nitrophenyl)ethyl]-13,4-dimethyl-4-phenylpiveridine hydrochloride Mp225-22800 Analysis value C2,
Sun 27N202CI Calculated value C67.28; Sun 7.26: N7.47 Experimental value C67.07: Sun 7.38: N7.75 Trans-1
1[2-(4-Hydroxyfer)ethyl]3,4-dimethyl-4-phenylpiveridine hydrobromide Mp2
53-255q○ Analysis value C2, Sun 28 NOBr calculated value C64.61; Sun 7.23: N3.59 Experimental value C6
4.36: Sun 7.29; N3.46 Trans-1 (2
-probenyl)-3,4-dimethyl-4-(3-methoxyphenyl)piveridine hydrobromide Mp145-1
47o0 analysis value C, 7 days 26NOBr calculation value C60
．． 00: Sun 7.78: N4.12 Experimental value C59.81
: Day 7.96: N4.08 trans-1-cyclopropylmethyl-3,4-dimethyl-4-(3-methoxyphenyl)piveridine hydrochloride Mp186-18800 Analysis value C. 8 days 28NOCI Calculated value C69.77; Day 9.11; N4.52 Experimental value C69.54: Day 8.95; N4.75 cis-1-(
2-probenyl)-3,4-dimethyl-4-phenylpiveridine hydrobromide Mpl95-1970 analysis value C
, 6 days 24NBr Calculated value C61.94; Day 7.80; N4.51 Experimental value C61.66; Day 7.53: N4.76 Cis-1-cyclobutylmethyl-3,4-dimethyl-4-phenylpi Veridine hydrobromide Mp250-25○ Analysis value C
, 8 days 28NBr Calculated value C63.90: Day 8.34: N4.14 Experimental value C64.09: Day 8.38: N4.34 Example 33
trans-1-phenacetyl-3,4-dimethyl-4-phenylpiveridine potassium carbonate 4.2 hours and water 22 cc
Dissolve 4.0 ml of trans-13,4-dimethyl-4-phenylpiberidine in 75 cc of methanol containing 100 ml of phenacetyl chloride, cool it, and add 4.2 ml of phenacetyl chloride to a reaction temperature of about 5-10°C. It was dropped at a constant speed.

After completion of the dropwise addition, the reaction mixture was adjusted to 0.5-1oo○. I worshiped the hawk for insect time, and then worshiped for another 15 hours at about 24 qo. The reaction mixture was concentrated under reduced pressure, and the residual light was dissolved in diethyl ether.
The ether solution was washed successively with dilute aqueous sodium bicarbonate solution, dilute hydrochloric acid and water. After drying with potassium carbonate, the desiccant was removed from the oven, and the solvent was distilled off under reduced pressure to obtain 4.3 g of trans-1-phenacetyl-3,4-dimethyl-4-phenylpiberidine. Example 34 Trans-1-(2-phenylethyl)-3,4-dimethyl-4-phenylpiveridine Trans-1-1-phenacetyl-3,4-dimethyl-4-phenylpiveridine4.
In a solution of 300g dissolved in 25cc of tetrahydrofuran,
A solution of 3.2 liters of lithium aluminum hydride dissolved in 150 cc of tetrahydrofuran was added dropwise.

The reaction mixture was heated under reflux for 4 hours, and after cooling, it was added to 30 cc of water containing 6 cc of a 20% aqueous sodium hydroxide solution.
The alkaline aqueous solution was extracted with diethyl ether, and the extract was washed with water and dried. The solvent was evaporated under reduced pressure to produce an oily product 4. I got the evening. This oil was dissolved in diethyl ether and hydrogen bromide gas was added to give 2.8 g of trans-1-(2-phenylethyl)-13,4-dimethyl-4-phenylpiveridine hydrobromide. Mp256-258
00 Analysis value C2, day 28NBr Calculated value C67.38: day 7.54: N3.74 Experimental value C67.68: day 7.81: N3.81 Example 35
-37 The following compound was obtained by the method of Example 34 from the corresponding substituted piberidine.

Trans-1-[2-(4-methoxyphenyl)ethyl]-3,4-dimethyl-4-phenylpiveridine hydrobromide Mp265o0 (dec.) Analysis value C22, 3 states OBr calculated value C65.34 : Sun 7.48: N3.
46 Experimental value C65.57; Sun 7.38: N3.57 trans-11-[21-(4-hydroxyphenyl)ethyl]-3,4-dimethyl-4-phenylpiveridine hydrobromide Mp253 -255qo analysis value C2, day 28
NOBr calculation value C64.61; Sun 7.23; N3.5
9 Experimental value C64.36: Day 7.29: N3.46 trans-1-(2-phenylethyl)-13,4-dimethyl-4-(3-methoxyphenyl)piveridine hydrobromide Mp229-231°C Analysis value C22 days 3bu OBr
Calculated value C65.34; Day 7.48; N3.46 Experimental value C65.29; Day 7.32; N3.44 Example 38
Trans-1-(2-benzoylethyl)-3,4-dimethyl-4-phenylpiveridine sodium carbonate 3.2
3.0 cc of trans-13,4-dimethyl-4-phenylpiberidine was dissolved in 25 cc of dimethylformamide to which 6 cc of dimethylformamide had been added, and 5.42 cc of (2-penzoylethyl)-trimethylammonium diodide was added thereto.

The reaction mixture was incubated at 25° C. for 5 hours in a nitrogen atmosphere. The mixture was diluted with 200 cc of water and extracted with diethyl ether. The ether extracts were combined, washed with water, and dried over potassium carbonate.
The drying agent was removed from the oven, and the oven solution was evaporated to dryness under reduced pressure to obtain an oily product of 5.0%. This oil was dissolved in diethyl ether and hydrogen bromide gas was added. The precipitate was collected in a furnace and recrystallized from 100 cc of isopropanol to obtain trans-1-
5.05 g of (2-penzoylethyl)-3,4-dimethyl-4-phenylpiveridine hydrobromide was obtained. Mp
200-20y0 Analysis value C22nd 28NOBr calculated value C65.67: Day 7.01: N3.48 Experimental value C6
5.60: Sun 7.03: N3.46 Example 39 The following compound was prepared by the method of Example 38.

Cis-1-(2-benzoylethyl)-3,4-dimethyl-4-phenylpiveridine hydrobromide Mp204
-20600 Analysis value C22nd 28NOBr Calculated value C65.67; Day 7.01; N3.48 Experimental value C65.45: Day 6.80: N3.59 Example 40
trans-1-(2-phenylethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine 48
9.29 of trans-1-(2-phenylethyl)-13,4-dimethyl-4-(3-methoxyphenyl)piveridine was dissolved in a mixture of 100 cc of % hydrobromic acid and 100 cc of acetic acid and heated under reflux for 4 hours.

The reaction mixture was cooled to about 25:00, 200 cc of water was added, and the mixture was made basic with ammonium hydroxide. The basic mixture was extracted with ethyl acetate, and the organic extracts were combined, washed with water, and then dried. The oily product obtained by distilling off the solvent is dissolved in diethyl ether, hydrogen chloride gas is added, and the precipitated white crystals are collected in an oven and dried to give trans-1-(2-phenylethyl).
-3,4-dimethyl-4-(3-hydroxyphenyl)
Piveridine hydrochloride was obtained. Mp166-170qC Analysis value C2, Day 28 NOCI Calculated value C72.92: Day 8.16: N4.05 Experimental value C? 3.07; Sun 8.25; N4.02 Example 41
-44 The following compound was prepared by the method of Example 40 from the corresponding 1,3,4-trisubstituted-4-(3-methoxyphenyl)piveridine.

Cis-113-dimethyl-4-ethyl-4-(3-hydroxyphenyl)piveridine hydrobromide Mp228
-23zo○ Analytical value C, 5 days 24 NOBr Calculated value C57.33; Day 7.70; N4.46 Experimental value C57.54: Day 7.53: N4.24 Trans-1
-cyclopropylmethyl-3,4-dimethyl-4-(3
-Hydroxyphenyl)piveridine hydrochloride Mp179
-181℃ Analysis value C, 7 days 26 NOCI Calculated value C69.02; Day 8.86: N4.73 Experimental value C Iso. 80; Sun 9.07: N4.99 transformer 1.
13,4-trimethyl-4-(3-hydroxyphenyl)viveridine hydrochloride Mp185-1870 Analytical value C, 4 days 22NOCI Calculated value C65.74: Day 8.67: N5.48 Experimental value C65.73; Day 8. 69:N5.35 transformer-3
・4-dimethyl-4-(3-hydroxyphenyl)piverizine Mp159-164℃ Analysis value C, 3 days, ○
Calculated value C76.06: Sun 9.33: N6.82 Experimental value C75.87: Sun 9.23: N6.86 Example 45
Cis-1-(3-phenyl-3-hydroxypropyl)
-3,4-dimethyl-4-phenylpiveridine cis-1
-(2-benzoylethyl)-3.4-dimethyl-4-phenylpiveridine dissolved in 20 cc of anhydrous benzene was dissolved in hydrogenated bis(2-methoxyethoxy).
It was added dropwise to a 70% solution of lithium aluminum at a rate that maintained the temperature between 25°C and about 45°C with candlelight.

After the dropwise addition was completed, the reaction mixture was heated under reflux for 2 hours, further cooled to about 25 qo, and continued to reflux for 1 hour. I to reaction deer liquid
Add 50 cc of N sodium hydroxide to make it alkaline.
The alkaline mixture was extracted with diethyl ether. The ether extract was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain cis-1-(3-phenyl-3-hydroxypropyl)-3.
- 4-dimethyl-4-phenylpiveridine was obtained. The hydrochloride was produced by a conventional method. Mp144-149qO analysis value C22nd 3bu OCI calculated value C73.41; day 8.
40: N3.89 experimental value C73.64: day 8.55;
N3.95 Examples 46-60 The following compounds were prepared by the method of Examples 1, 102334 and 41.

trans-1-(2-propanyl)-3-methyl-4-
Ethyl-4-phenylpiveridine hydrobromide Mp2
00-203℃ Analysis value C, 7 days 28NBr Calculated value C62.96: Day 8.08; N4.32 Experimental value C62.90; Day 7.99: N4.17 Trans-1
-Cyclopropylmethyl-3-methyl-4-ethyl-4
-Phenylpiveridine hydrobromide Mp228-23
000 Analysis value C, 8 days 28NBr Calculated value C63.90: Day 8.34: N4.14 Experimental value C63.65: Day 8.50: N4.35 Trans-1
1(2-phenylethyl)-3-methyl-4-ethyl-4-phenylpiveridine hydrobromide Mp275oo
(dec.) Analytical value C22 days 3bu Br Calculated value C68.03: day 7.79: N3.61 experimental value C68.01; day 8.01; N3.32 cis-1-cyclopropylmethyl-3-methyl -4-Ethyl-4-phenylpiveridine hydrobromide Mpl93-1950
0 Analysis value C, 8 days 28NBr Calculated value C63.90: Day 8.34: N4.14 Experimental value C64.17: Day 8.43: N4.13 Sis 1.3
-dimethyl-4-ethyl-4-(3-methoxyphenyl)piveridine picrate Mp130-13500 Analysis value C22 day 28N408 Calculated value C55.46; day 5.92: NIl. 76 Experimental Value C55.26: Day 6.14; NIl. 67 trans-1,3-dimethyl-41n-propyl-4-phenylpiberidine hydrobromide Mp254-257 pm 0 Analysis value C, 6 days 26NBr Calculated value C61.54: Day 8.39: N4.49 Experiment Value C61.61; Sun 8.16: N4.38 Trans-1
-(2-probenyl)-3-methyl-4-n-propyl-4-phenylpiveridine hydrobromide Mp179-
18ro analysis value C, 8 days 28NBr calculated value C63.90: day 8.34; N4.14 experimental value C63.81: day 8.51: N4.30 trans-1
・3-dimethyl-4-n-propyl-4-(3-methoxyphenyl)piveridine hydrobromide Mp222-2
29°C analytical value C, 7 days 28NOBr Calculated value C59.65: Day 8.24: N4.09 Experimental value C59.82; Day 7.94: N4.29 Trans-1
・3-Dimethyl-4-n-propyl-4-(3-hydroxyphenyl)piverizine hydrobromide Mp261-26〆○ Analysis value C, 6 days 26 NOBr Calculated value C58.54: Day 7.98: N4.27 Experimental value C58.28: day 7.71; N4.04 transformer-1
-(2-phenylethyl)-3-methyl-4-n-propyl-4-(3-hydroxyphenyl)piverizine hydrobromide Mp124-12800 Analysis value C23 day 3
2NOBr Calculated value C66.02; Day 7.71: N3.35 Experimental value C66.24: Day 7.70: N3.06 cis-1-cyclopropylmethyl-3-methyl-4-n-propyl-
4-phenylpiveridine hydrobromide Mp217-2
21°C analysis value C, Pan-3Br Calculated value C64.77: day 8.58; N3.98 experimental value C64.48: day 845: N3.84 cis-1,3-dimethyl-4-n-propyl-4- (3-methoxyphenyl)piverizine hydrobromide Mp167-169.
5qo analytical value C, 7 days 28NOBr calculated value C59.65; day 8.24: N4.09 experimental value C59.88: day 8.46; N4.00 cis-1-(
2-probenyl)-3-methyl-4-n-propyl-4
-(3-methoxyphenyl)piverizine hydrobromide
Mp184-186q○ Analysis value C, General 3bu OBr calculated value C61.95; Sun 8.21: N3.80 Experimental value C
61.92: Sun 7.96: N3.61 cis-1,3-dimethyl-4-n-propyl-4-(3-hydroxyphenyl)piveridine hydrobromide Mp222-224q
o Analytical value C, 6 days 26NOBr Calculated value C58.54: Day 7.98: N4.20 Experimental value C58.83: Day 8.09: N4.02
2-phenylethyl)-3-methyl-4-n-propyl-4-(3.-hydroxyphenyl)piveridine Mp
182-18400 analysis value C23rd 3, NO calculated value
C81.85: Sun 9.26: N4.15 Experimental value C82
．． 12: Sun 9.32: N4.04 Example 61 Iodination (
2-Penzoylethyl)-trimethylammonium was dissolved in dimethylformamide and reacted with trans-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine in the presence of sodium carbonate to form trans-1-(
2-Besozylethyl)-3,4-dimethyl-4-(3
-hydroxyphenyl)piveridine was prepared and further reaction with maleic acid gave the corresponding maleate salt.

Mp73-7400 analysis value C26th 3, N06 calculated value C68.86; day 6.89: N3.09 experimental value C68.64: day 7.08: N2.85 Example 62
Allyl bromide was dissolved in dimethylformamide and reacted with trans-1-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine to form trans-1-allyl-3.
4-dimethyl-4-(3-hydroxyphenyl)piveridine was prepared and further reacted with hydrogen chloride to obtain the corresponding hydrochloride.

Mp200.5-203oo analysis value C. 6th 24NO
CI Calculated value C68.19; Day 8.58; N4.97 Experimental value C67.94: Day 8.70: N5.05 Example 63
By the method described in Example 61, trans-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine was alkylated to give trans-1-(2-benzoylethyl)-3,4-dimethyl-4-(3 -hydroxyphenyl)piveridine was prepared and further reaction with hydrogen bromide gave the corresponding hydrobromide salt.

Mp200-20300 Analysis value C22nd 28NOBr Calculated value C65.67: Day 7.01: N3.48 Experimental value C65.60; Day 7.03: N3.46 Example 64
3-Phenyl-2-propanyl bromide was dissolved in dimethylformamide and trans-3,4-dimethyl-4-(3
-Methoxyphenyl)piveridine to produce trans-1-(3-phenyl-2-probenyl)-13,4-dimethyl-4-(3-methoxyphenyl)piveridine, and further reaction with hydrogen chloride to produce the corresponding hydrochloric acid. Got salt.

Mp187-189q○ Analysis value C23 Day 3bu OCI Calculated value C74.27; Day 8.13; N3.77 Experimental value C74.14; Day 7.91: N3.81 Example 65
Trans-1-3,4-dimethyl-41-(3-methoxyphenyl)piveridine was alkylated to form trans-1-1-(2-benzoyl)-3, by the method described in Example 61.
4-dimethyl-4-(3-methoxyphenyl)piveridine was prepared and further reacted with hydrogen chloride to obtain the corresponding hydrochloride.

Mp21000 or more (decomposition) analysis value C2, day 28NO
CI Calculated value C71.21: Day 7.79; N3.61 Experimental value C70.74; Day 7.89; N3.84 Example 66
Trans-1-(3-phenylpropyl)-3,4-dimethyl-4-(3-methoxyphenyl)piveridine is
Trans-11-(3-phenyl-2-probenyl)-3
・Produced by reducing 4-dimethyl-4-(3-methoxyphenyl)piveridine with palladium-carbon,
Furthermore, the corresponding hydrochloride was obtained by reaction with hydrogen chloride.

Mp178.5-180.500 Analysis value C23rd 32
NOCI Calculated value C73.87: Sun 8.63: N3.75 Experimental value C73.68: Sun 8.37: N3.78 Example 67
Trans-1-[(3-hydroxy-3-phenyl)propyl]-3,4-dimethyl-4-1(3-hydroxyphenyl)piveridine is trans-11-(2-penzoylethyl)-3,4-dimethyl-4-(3 -hydroxyphenyl)piveridine was prepared by reduction with palladium-carbon, and further reaction with hydrogen chloride gave the corresponding hydrochloric acid.

Mp86-89q0 analysis value C22 day 3pu02CI calculated value C70.29; day 8.04; N3.73 experimental value C70.12: day 8.02; N3.57 Example 68
Alkylating cis-3,4 dimethyl-4-(3-hydroxyphenyl)piveridine to give cis-1-(2-penzoylethyl)-3,4 by the method described in Example 61.
-dimethyl-4-(3-hydroxyphenyl)piveridine was prepared, and the corresponding hydrochloride was further obtained by reaction with hydrogen chloride.

Mp147-149.5)○ Analysis value C22nd 28NO
CI Calculated value C70.67; Sun 7.55: N3.75 Experimental value C70.86: Sun 7.84: N3.54 Example 69
By the method described in Examples 33 and 34, cis-3.
4-Dimethyl-4-(3-hydroxyphenyl)piveridine is acylated and further reduced to produce cis-1-cyclopropylmethyl-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine, which is then further reduced with hydrogen chloride. The corresponding hydrochloride was obtained by the reaction.

Mp207-21000 analytical value CnH26NOCI calculated value C69.02: day 8.86; N4.73 experimental value
C68.89; Sun 8.72; N4.75 Example 70 By the method described in Examples 33 and 34, cis-3.4
-dimethyl-4-(3-methoxyphenyl)piveridine is acylated, further reduced to produce cis-1-cyclopropylmethyl-3,4-dimethyl-4-(3-methoxyphenyl)piveridine, and further combined with hydrogen chloride. The corresponding hydrochloride was obtained by the reaction.

Mpl97-19900 (decomposition) analysis value C, 8th 28
NOCI calculation value C69.77; Sun 9.11; N4.5
2 Experimental value C69.55; day 8.81; N4.47 Example 71 By the method described in Example 23, cis-3.4
-Alkylation of dimethyl-4-(3-methoxyphenyl)piveritadine to produce cis-1-allyl-3,4-dimethyl-4-(3-methoxyphenyl)piveritadine, and further reaction with hydrogen chloride to produce the corresponding hydrochloride. Obtained.

Mp186-18800 analysis value C, 7 days 26 NOCI
O Calculated value C69.02; Day 8.863 N4.73 Experimental value C68.84; Day 8.87: N4.96 Example
72 By the method described in Examples 33 and 34, cis-
3,4-Dimethyl-4-(3-methoxyphenyl)piveridine is acylated and further reduced to yield cis-1-phenethyl-3,4-dimethyl-4-(3-methoxyphenyl)
Piveridine was prepared and further reaction with hydrogen chloride gave the corresponding hydrochloride.

Mp238-24000 Analysis value C22nd 3bu OCI Calculated value C73.41; Day 8.40; N3.89 Experimental value C73.47: Day 8.41: N3.99 Example 73
By the method described in Example 23, cis-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine was alkylated to give cis-1-aryl-3,4-dimethyl-4-
(3-Hydroxyphenyl)piveridine was prepared and further reacted with hydrogen chloride to obtain the corresponding hydrochloride.

Mp209-211℃ analytical value C, 6 days 24 NOCI calculated value C68.19; day 8.58; N4.97 experimental value
C68.24; Sun 8.31; N4.80 Example 74 Cis-1,3,4-trimethyl-4-(3-methoxyphenyl)piveridine is demethylated to give cis-1,3,4-
Trimethyl-4-(3-hydroxyphenyl)piveridine was prepared and further reacted with hydrogen bromide to obtain the corresponding hydrobromide salt.

Mp200-203qo Analysis value C, 4 days 22NOBr Calculated value C55.01: Day 7.39: N4.67 Experimental value C56.22; Day 7.21; N4.59 Example 75
Cis-1-phenethyl-3,4-dimethyl-4-(3-methoxyphenyl)piveridine is demethylated and cis-
1-Phenethyl-3,4-dimethyl-4-(3-hydroxyphenyl)piveridine was prepared and further reacted with hydrogen chloride to obtain the corresponding hydrochloride.

Mp228-2320 (decomposition) analysis value C2, day 28N
OCI calculation value C72.92: Sun 8.16: N4.05
Experimental value C71.95: Day 7.87; N4.15 Example 761.3.4-Trimethyl-4-(3-methoxyphenyl)piveridine was reduced with palladium-carbon to give cis-1.3.4-trimethyl-4- (3-Methoxyphenyl)piveridine was prepared and further reacted with hydrogen bromide to give the corresponding hydrobromide salt.

Mp148.5-150. y○ Analysis value C. 5 days 24N
OBr

Claims (1)

[Claims] 1. A compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or a salt thereof. However, in the formula, the dotted line represents the presence or absence of a double bond; R_1 is hydrogen, alkyl having 1 to 8 carbon atoms, alkenyl having 3 to 8 carbon atoms, (cycloalkyl)alkyl having 4 to 8 carbon atoms, or Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, n is 1, 2 or 3; m is 0 or 1 (however, when n is 3, m is 0); X is CO, CH
OH or CH=CH; R_5 is hydrogen, C1-C3 alkoxy, nitro, amino or hydroxy. ); R_2 is hydrogen or has 1 to 4 carbon atoms
alkyl; R_3 is alkyl having 1 to 4 carbon atoms; R
_4 represents hydrogen, hydroxy, or alkoxy having 1 to 3 carbon atoms, respectively. 2. The compound according to claim 1, which is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or a salt thereof. However, in the formula, R'_1 is alkyl having 1 to 8 carbon atoms;
R_2 is hydrogen; R_3 is alkyl having 1 to 4 carbon atoms; R'
_4 represents hydrogen or alkoxy having 1 to 3 carbon atoms, respectively. 3. The compound according to claim 1, which is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or a salt thereof. However, in the formula, R_1, R_2, R_3 and R_4
have the same meanings as above. 4. The method according to claim 3, which is a cis isomer. 5. The method according to claim 3, which is a trans isomer. 6 R_1 is alkyl having 1 to 8 carbon atoms, (cycloalkyl)alkyl having 4 to 8 carbon atoms, or benzyl, and R
4. The compound according to claim 3, wherein _4 is hydrogen, hydroxy, or alkoxy having 1 to 3 carbon atoms. 7. The compound according to claim 6, wherein R_1 is methyl.