CS211380B2 - Method of making the 4a-aryl-octyhydro-1h-2-pyrindines - Google Patents

Description

The present invention provides a process for the preparation of 4α-aryl-octahydro-1H-2-pyrindines.

Recently, many efforts have been made for the synthetic preparation of drugs (ie analgesics) capable of alleviating the symptoms of pain. Using some conventional analgesics is limited by various undesirable side reactions that often accompany the continuous use of ^one analgesic. These side effects include addiction and allergies. Illustrative of the novel analgesic drugs recently discovered include the decahydroisoquinolines, in particular the 4α-aryl-trans-decahydroisoquinolines described in Belgian patent specification 802,557.

The present invention relates to a process for the preparation of a group of cis-4a-aryl-2-subst.-octahydro-1H-2-pyrindines. These compounds are somewhat structurally related to the aforementioned isoquinoline derivatives, but the compounds of formula (I) below have not yet been synthesized. Only simple unsubstituted pyrindine analogs are known from the literature. For example, Volodina et al. have prepared certain octahydro-2-pyrindines, none of which are substituted at the 4a position [Doc. Akad. Nauk USSR 173 (2), 342-345 (1967), cf. C.A., Vol. 67, 6034 (1967)]. Similarly, Procházka et al. prepared trans-octahydro-2-pyrindine not containing a substituent in position 4a [Coll. Czech. Chem. Commun., 31 (9), 3824-3828 (1966), cf. C.A., Vol. 65, 13, 651 (1966)].

The present invention provides a process for the preparation of cis-4α-phenyl- and -substituted-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines which have not been prepared or known and intermediates used to prepare these substances.

The invention relates to a process for the preparation of novel bicyclic compounds characterized as octahydro-1H-2-pyrimidines, which may alternatively be named hexahydro-1H-cyclopenta [c] pyridines. In particular, the present invention provides a process for the preparation of cis-4a-aryl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindines of formula I,

in which it means

R 1 is C 1 -C 8 alkyl, the radical of formula CH 2 R 3 or wherein n is 1 or 2 and

R 5 represents a C 2 -C 4 alkenyl group, a C 3 -C 5 cycloalkyl group or a tetrahydrofuryl group, and

R2 is a hydrogen atom, a hydroxyl group or a (C1-C3) alkoxy group and their non-toxic, pharmaceutically acceptable acid addition salts, characterized in that the compound of formula (II):

in which

R2 is as defined above and

R * represents hydrogen, is reacted with an alkylating agent · to give a compound of the above: Formula I wherein R is alkyl having 1-8 carbon atoms or the radical CH2R3, wherein R is alkenyl having from 2 to _# 4, carbon or with an acylating agent followed by reduction to give a compound of formula (I) wherein R 1 is a radical of formula CH 2 R 3, wherein R 3 is a C 3 -C 5 cycloalkyl group or a tetrahydrofuryl group, or R 1 is a radical of formula or a radical of formula CH 2 R 3 wherein R 3 represents a C 2 -C 4 alkenyl group or a C 3 -C 5 cycloalkyl group. An even more preferred subgroup of compounds within the aforementioned preferred group are those compounds of formula (I) wherein R 2 is a hydroxyl group or a methoxy group.

In the specification and in the definition of the present invention, the term "C 1 -C 8 alkyl" refers to straight or branched chain alkyl groups containing 8 or fewer carbon atoms. Examples of typical alkyl groups having 1 to 8 carbon atoms include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, 3-methylpentyl, 1,2-dimethylpentyl, 2-methylbutyl, 3-ethylpentyl, n- octyl, 2-methylheptyl, isoheptyl,

3-ethylhexyl, 1,3,3-trimethylpentyl and related groups. ,

The term "radical of the formula CH 2 R 3 wherein R 3 represents a C 2 -C 4 alkenyl group" refers to both straight and branched alkenyl groups containing 5 or less carbon atoms, such as allyl, 3-pentenyl, 2-pentenyl, 3-pentenyl Or

2-ethyl-2-butenyl.

R1 in formula I is also a radical of the formula CH2R3 wherein R5 is C3 -C5 cycloalkyl. These include cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl groups. R @ 1 can furthermore be, for example, 2-tetrahydrofurylmethyl and 3-tetrahydro-furylmethyl.

R 1 in formula I may also represent a radical of formula wherein n is as defined above, and the product obtained in which R 2 represents a (C 1 -C 3) alkoxy group is optionally deetherified to form a compound of formula I wherein: R2 represents a hydroxyl group.

A preferred group of compounds of the invention are those compounds of formula (I) wherein R 1 is an alkyl group with 1 in which n is 1 or 2.

Pyrindine derivatives of the above formula (I) are prepared by first reacting an amine, in particular ammonia or a primary amine, with a cyclic anhydride, in particular 4α-aryl-tetrahydrofuran-2 ', beta-dioxocyclo-chloride [c] pyran, according to the following reaction scheme, wherein R1 and R2 are as defined above:

The cyclic imide thus formed, i.e., 1,3-dioxo-4α-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, is then reduced to the -oxo groups. in positions. 1 and 3, to form the pyrindine derivative of formula II. In practice, it is preferred to use the 4α-aryl-tetrahydro-2,6-dl-oxocyclopenta [c] pyranes of formula (V) wherein the substituent of the aryl radical represented by R 2 in formula (V) is a hydrogen atom or an alkoxy group having 1; up to 3 carbon atoms. Of these C 1 -C 3 alkoxy groups, methoxy is preferred because this group is readily demethylated in the subsequent reaction steps to form a hydroxyl group, as will be described in more detail below. text. . In the reaction of an amine with a cyclic anhydride as described above, amines such as ammonia, C1-C8-alkylamines, in particular methylamine, and also aryl-amines, in particular benzylamine, are also preferred. Indeed, the 2-methyl- and 2-benzylpyridine derivatives thus formed are readily converted to the corresponding 2-unsubstituted pyrindines which can be easily modified by alkylation or acylation to give other 2-substituted compounds of formula I. These modifications will be described below.

In the preparation of 1,3-dioxo-4a-ary-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines by reaction according to the above reaction scheme, the starting 4- aryl-tetrahydro-2,6-dioxocyclopentanediamine and amine are usually contacted in equimolar amounts, although any of the reagents in excess can be used if desired. The reaction may be carried out in any of a variety of commonly used non-reactive organic solvents, including aromatic solvents such as benzene, toluene, xylene, methoxybenzene. and nitrobenzene as well as non-aromatic solvents such as chloroform, dichloromethane, dimethylsulfoxide, nitromethane, acetone, -tetrahydrofuran, dimethylformamide and dioxane. The reaction is usually carried out at elevated temperature, for example at a temperature of about 50 to 200 ° C, preferably at a temperature of about 80 to 150 ° C. Since the reaction between the amine and the cyclic anhydride, resulting in the formation of the corresponding cyclic imide, is accompanied by the formation of water, it may be desirable to carry out the reaction in such a manner that water is immediately removed from the reaction mixture. For this purpose, any of the techniques commonly used to keep the reaction mixture in a dry state, including the use of molecular sieves or, alternatively, azeotropic removal of water produced using a Dean-Stark trap and suitable solvents such as benzene, may be used; toluene. The reaction between the cyclic anhydride and the amine is normally practically complete in 24 to 72 hours, but longer reaction times do not appear to be detrimental to the product formed and can therefore also be used if desired. Cyclic imide thus formed, namely the 4a-ai * y] ^ '2,3,4,4a, 5,6,' ^{^.,} 7 ^ - ^^ I ^ 1 ^^ octahydro-l, 3-dioxo-lH The 2-pyrindine is readily isolated by removing the reaction solvent, for example by evaporation under reduced pressure, and can be further purified by standard procedures such as acid extraction and base, crystallization and chromatography.

As mentioned above, the 4-aryl-tetrahydrocarbonyl-2,6-dihydrocarbonyl-2,6-dihydro-pyrrolidin-2-ol may be subjected to [c] pyran. reaction with ammonia to give the corresponding 4α-aryl-2,3,4,4a, 5,6,7,7α-octahydro-1,3-dioxo-1H-2-pyrindine which is not substituted in the 2-position, or alternatively the pyran derivative may be reacted with the primary amine to give directly 4α-aryl-2-subst.-2,3,4,4a, 5,6,7,7α-octahydro-1,3-dioxo-1H- 2-pyrindine. It should further be appreciated that if it is desired to react the pyran derivative with a primary amine to form a 2-substituted pyrindine derivative, the primary amine should preferably be methylamine or benzylamine. These primary amines are advantageous in that, by reaction with -4-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyran, 2-substituted 1,3-dioxopyrindine derivatives are obtained, from which 2-substituted pyrindine derivatives are substituted, position 2 can be easily removed to give pyrindine derivatives unsubstituted at position 2. Pyrindine derivatives unsubstituted at position 2 are extremely important intermediates for the preparation of all other pyrindines of formula I, as will be described in more detail below. It should be noted, however, that although the preferred primary amines for reaction with the aforementioned pyran derivative are -methylamine and benzylamine, virtually all primary amines can be reacted with the pyran derivative to yield the corresponding 4a-aryl-2. -subst.-2,3,4,4.a, 5A7 _; 7α-octahydro-1,3-dioxo-ΙΗ-2-pyrindine. It should further be pointed out that, as the latter compound is a 1,3-dioxopyrindine derivative, it must undergo a reduction at the -oxo groups at the 1 and 3 positions to produce pharmacologically useful pyrindines of the general formula:

It is therefore preferred that the group be attached at the 2-position. 4a-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindines were practically resistant to the reduction procedures used to reduce the -oxo groups at positions 1 and -3. Those groups that are not as resistant to this reduction are preferred to introduce alkylation or acylation followed by reduction of the pyrindine derivatives unsubstituted at the 2-position.

As mentioned above, the aforementioned 4α-aryl-2,3,4,4a, 5,6,7,7α-octahydro-1,3'-dioxo-1 H-2-pyrindines of the general formula III are converted to 4α-α-. aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines of formula II by reduction of 1-oxo and 3-oxo. This reduction may be accomplished by any of a number of conventional reduction procedures known in the art. For example, the 1,3-di7 oxo-pyrindine derivative may be reacted with any of a number of alkali metal hydride reducing agents, including lithium aluminum hydride, sodium borohydride, lithium tri-tert-butoxyaluminium hydride and lithium trimethoxyaluminium hydride. If desired, other reducing agents such as zinc and acetic acid or catalytic hydrogenation may be used. A preferred method of reducing 4α-aryl-2,3,4,4α, 5,6,7,7α-octahydro-1,3-diclo-1 H-2-pyrindine of formula III is to use lithium aluminum hydride as a reducing agent. Typically, 4α-aryl-2,3,4,4a, 5,6,7,7α-octahydro-1,3-dioxo-1H-2-pyrindine, such as 4α-phenyl-2- methyl-2,3,4,4a, 5,6,7,7a-octahydrol, 3-dioxo-1H-2-pyrindine, is reacted with about twice the molar amount of lithium aluminum hydride in a non-reactive organic solvent. Non-reactive organic solvents commonly used in this reaction include tetrahydrofuran, diethyl ether, dioxane, diglyme, and related solvents. The reaction is normally conducted at a temperature from about 20 to 100 ^C and, at this temperature · it is usually substantially complete in about 4-20 hours. The product is normally isolated by first decomposing any unreacted reducing agent residues that may still be present in the reaction mixture. This decomposition is carried out, for example, when the reducing agent is lithium aluminum hydride by adding to the reaction mixture an ester readily reacting with the reducing agent. Ethyl acetate is usually used as the ester for this purpose. After addition of the ester, an aqueous solution of ammonium chloride is then added to the reaction mixture to precipitate any inorganic salts formed in the reaction, and the product is then extracted with a suitable organic solvent, such as ethyl acetate or tetrahydrofuran. The organic extracts are combined and concentrated by evaporation of the solvent to give a reduced product, namely 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in general of formula II. This product is usually obtained in the form of an oil and, if desired, is further purified, for example by distillation or chromatography, or alternatively it can be converted to an acid addition salt which can then be purified by crystallization.

Pyrindine derivatives unsubstituted at the 2-position, i.e. the compound of formula (II) in which:. R @ 1 represents a hydrogen atom, which can be easily alkylated or acylated at the 2-position to give the pharmacologically active octahydropyrindines of the formula I or, in the case of N-acylated derivatives, to give intermediates which can be easily converted into analgesically active compounds of the formula I. thus, it is often desirable to prepare 4a-aryl-2-subst.-2,3,4,4a, 5,6,7,77-octahydro-1H-2-pyrindines, the substituent at position 2 of which is readily cleavable to form the above-described process As mentioned above, the N-methyl and N-benzyl groups are readily cleavable to give the corresponding pyrindine derivative unsubstituted in the 2-position. The 2-methylpyrimidine derivatives prepared as described above are: can be reacted with a formic acid ester such as phenyl chloroformate or ethyl chloroformate to give pyrindi new derivatives containing the corresponding carbamate moiety at the 2-position. These carbamates can then be treated with an aqueous base such as sodium hydroxide to cleave the carbamate residue at the 2-position to give the corresponding pyrindine derivative unsubstituted at the 2-position. This method of cleavage of the N-methyl group has been described by Abel-Monone et al. J. Med. Chem., 15, 208 (1972).

Similarly, the aforementioned 4α-aryl-2-benzyl-2,3,4,4a, 5,6,7,7α-octahydro-1H-2-pyrindines are readily converted by simple debenzylation to the corresponding pyrindines unsubstituted at the 2-position. Debenzylation may be accomplished by catalytic hydrogenation using, for example, 5% palladium on carbon catalyst. Such debenzylation reactions are generally used to prepare secondary amines and are described in detail in Hartung and Simonoff, Org. Reactions, 7, 277 (1953) and Leonard and Fuji, J. Amer. Chem. Soc., 85, 3719 (1963).

The 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines unsubstituted at the 2-position as described above can be alkylated in the normal manner to produce pharmacologically active 2-substituted pyrindine. derivatives, or they can be acylated to give intermediates which are readily converted to analgesic active ingredients. For example, 4α-aryl-2,3,4,4a, 5,6,7,7α-tert-butyl-1H-2-pyrindine can be alkylated at the 2-position by reaction with virtually any reactive derivative of the alkyl group. Such alkylating agents are compounds of the general formula

R 1 -Z, wherein R 1 is as defined above and Z represents any of a series of groups commonly referred to as readily cleavable groups. The most common readily cleavable groups include halogen atoms, especially chlorine, bromine and iodine; It should be noted that the described alkylating agents of formula R 1 -Z may be modified in the alkyl moiety, for example by the presence of substituents containing multiple bonds, aryl substituents and cycloalkyl sub-211180 stituents. thus, for example, methyl chloride, ethyl bromide, 5-methylheptyltosylate, allyl bromide, cyclopropylmethyl chloride, cyclobutylmethyl iodide, 3-tetrahydrofurylmethyl bromide, 2-phenylethyl chloride and related compounds.

Thus, 4α-aryl-2,3,4,4,4a, 5,6,7,7α-ootahydrol-1H-2-pyrindine can be reacted with an alkylating agent to give the corresponding 4α-aryl-2-subst.-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine with a suitable alkylating agent, preferably in a non-reactive organic solvent. Alkylating agent. It is usually used in excess, for example in an excess of about 0.5 to 2.0 mol, based on the pyrindine derivative. Non-reactive organic solvents commonly used in this reaction include ethers such as diethyl ether, dioxane and tetrahydrofuran, as well as solvents of other types, such as benzene, dichloromethane, dimethylformamide, dimethylsulfoxide, nitromethane and hexamethylphosphoric triamide. The alkylation reaction is preferably carried out in the presence of an acid acceptor base, since the reaction of the pyrindine derivative with an alkylation reaction. the agent is generally accompanied by the formation of an acid, such as hydrochloric acid or p-toluenesulfonic acid, which can bind the reacted 2-pyrindine derivative as a salt. Bases commonly used in such reactions as acid acceptors include sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine and pyridine. Typically, about 1 equivalent of base is used, although higher amounts can be used if desired. The alkylation reaction is normally carried out at an elevated temperature of about 50 to 200 ° C, and at this temperature the reaction is normally practically complete in about 1 to 10 hours. Longer reaction times are not a defect and can be used. The product is usually isolated by simply adding water to the reaction mixture and extracting with a water-immiscible organic solvent such as. benzene, ethyl acetate, dichloromethane, diphenyl ether, chloroform or a related solvent. Removal of the solvent from the extract, for example by evaporation under reduced pressure, yields the desired 4α-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octallydro-1H-2-pyridine which If desired, the product thus obtained may be further purified by standard procedures such as chromatography, crystallization or distillation, or alternatively, the obtained pyrindine may be converted by reaction with an inorganic acid into an acid addition salt. they usually are highly crystalline solids and readily give a highly pure solid salt by recrystallization, and if desired, they can be decomposed by treatment with a base such as sodium hydroxide or potassium carbonate to give purified 4α-aryl-2-carboxylic acid. 5,6,7,7a-octahydro-1H-2-pyrimidine free base.

As mentioned above, the pyrindine derivatives unsubstituted at the 2-position, namely 4α-aryl-octahydro-1 H, 2-pyrindines, can be converted to the 2-substituted pyrindine derivatives which either are themselves pharmacologically usable agents, or can be readily converted to pharmacologically useful agents. For example, reaction of 4α-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine with an alkylating agent such as 2-benzoylethyl iodide affords the corresponding 4α-aryl-2- ( 2-benzoylethyl) -2,3,4,4a, 5,6,7,77-octahydro-1H-2-pyridindine, which is analgesically active. If desired, this compound can be reduced to the carbonyl group of the benzoyl moiety, for example by treatment with a reducing agent such as lithium aluminum hydride to give the corresponding 4α-aryl-2- (3-hydroxy-3-phenyl) propyl-2, 3,4,4a, 5,6,7,77-o-Otahydro-1H-2-pyrimidine, which is also a useful analgesic agent and, in addition, the pyrindine derivatives unsubstituted at the 2-position can be acylated with any of a number of acylating agents to form N- an acylated pyrindine derivative represented by the general formula (I) in which R1 represents a —C — alk group,

II o

—C — Rs or

O -C- (CH _{z) n} riq / where Alk is an alkyl group having 1-7 carbon atoms and the remaining substituents are as defined above. From such N-acylated pyrindines, reduction of the carbonyl group yields analgesically active 2-substituted pyrindine derivatives of formula I. For example, 4a-aryl-3-alkyl-2,3,4,4a, 5,6,7,77-octahydro- 1H-2-pyrindine can be acylated with any of the conventional acylating agents, such as an acid halide or acid anhydride. Examples of commonly used acylating agents include acetyl chloride, pentanediyl, cyclobutylformyl bromide, 2- (tetrahydrofurylformyl chloride, benzoyl bromide, acetic anhydride and hexanoic anhydride.) Some of the reagents mentioned above are carried out by reacting roughly equimolar amounts of the pyrindine derivative and the acylating agent in a non-reactive organic solvent such as dichloromethane, ethanol or tetrahydrofuran. or propylene oxide serving as an acid acceptor The reaction is preferably carried out at a temperature of about -20 ° C to 30 ° C and is generally complete in 1 to 8 hours.

-acyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, is readily isolated by simple evaporation of the reaction solvent. The product thus obtained is usually not further purified, but is immediately reduced to the 4α-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine of formula (I). reduction of the carbonyl group of the N-acyl moiety can be accomplished by reacting the acylated pyrindine derivative with a reducing agent such as lithium aluminum hydride or catalytic hydrogenation.

It should further be appreciated that certain 4α-aryl-2-substituted-2,3,4,4a, 5,6,7,7α-octahydro-1H-2-pyrindines of formula I may be subjected to other modifications. For example, although the 4α-arylpyrindine derivative in which the aryl moiety is a 3-hydroxyphenyl group can be prepared using

2- (3-hydroxyphenyl) -2-ethoxycarbonylmethylcyclohexanone as a starting material, which compound is modified by various procedures described above, it may be advantageous to prepare 4a- (3-methoxyphenyl) -2-subst.-2,3,4,4a The 5,6,7,7a-octahydro-1H-2-pyrindine obecthoxy group in the 4a-aryl substituent of this compound is converted to a hydroxyl group. This conversion is readily accomplished by reacting the 4- (3-methoxyphenyl) pyrindine derivative with hydrobromic acid in acetic acid. This reaction is generally used to convert a methoxyphenyl group to a hydroxyphenyl group.

As mentioned above, the 4α-aryl-2-subst.-octahydro-1H-2-pyrindine derivatives of formula I can be reacted with organic or inorganic acids to form crystalline salts which can be purified by crystallization and can be recovered the free pyrindine bases by treatment with a suitable base such as sodium hydroxide. Acid addition salts of the compounds of formula I are within the scope of the invention. In particular, they are the non-toxic, pharmaceutically acceptable acid addition salts of the pyrindine bases of formula (I). These non-toxic, pharmaceutically acceptable acid addition salts are prepared by reacting 4α-aryl-2-subst.-octahydro-1H-2-pyrindine of formula I with an organic or inorganic acid. Acids commonly used to prepare pharmaceutically acceptable acid addition salts of the compounds of formula (I) include hydrohalic acids such as hydrochloric, hydrobromic and hydroiodic acids as well as other acids such as sulfuric, phosphoric, nitric, perchloric, phosphite, nitrous and related acids. Organic acids commonly used to prepare pharmaceutically useful acid addition salts of the pyrindines of Formula I include acetic, propionic, p-toluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic, benzoic and related acids. . The pharmaceutically acceptable acid addition salts of the compounds of formula (I) may conveniently be prepared by dissolving 4α-aryl-2-substituted-octahydro-1H-2-pyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone or ethanol. and either an equivalent amount or an excess of the appropriate acid is added to the solution. The salt thus formed normally crystallizes from the solution and can be isolated by filtration and either directly used as a pharmacological agent or further purified by recrystallization from conventional solvents such as acetone or methanol.

The following overview of cis-4a-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines contains representative examples of compounds of formula I:

4α-phenyl-2- (3-ethylpentyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

4a- [3-methoxyphenyl] -2- (n-octyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide,

4a- (3-hydroxyphenyl) -2- (2-propenyl) -2,3,4,4a ₎ 5,6,7,7a-octahydro-11-1-2-pyrindine,

4a- (3-hydroxyphenyl) -2-cyclopentylmethyl-2,3,4,4a, 5,6,7,7a-octahydro---2-pyrindinium oxalate,

4a- (3-ethoxyphenyl) -2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine.

It should be noted that the compounds of formula I contain two centers of asymmetry, namely positions 4a and 7a. The invention encompasses both separate isomers and racemic mixtures of these isomers, which are pharmacologically useful as analgesic agonists and antagonists. However, the invention includes only the cis-isomers of the compounds of formula (I), i.e., those in which the 4α-aryl group is on the same side of the plane of the molecule as the hydrogen atom at the 7a position. Accordingly, the invention includes pharmacologically active individual optically active cis-isomers and a racemic mixture of these cis-isomers. This racemic pair of cis-octahydropyrindines can be resolved into the individual stereoisomers in a known manner. Even if all of the useful pharmacological activity is concentrated in only one stereoisomer, the racemate (mixture of d- and 1-isomers) is still useful since it contains a pharmacologically active isomer as its component.

The preparation of the 4α-aryl-octahydropyrindines of formula I requires the use of starting materials, many of which have not been known and available. 4a-Aryl-tetrahydro-2,6-dioxocyclopenta [c] pyranes are used as starting materials in the preparation of the pyrindines of formula (I). These starting materials are prepared from 2-arylcyclohexanones, such as 2-phenylcyclohexanone and 2- (3-methoxyphenyl) cyclohexanone. To prepare dioxocyclopentapyran derivatives, the 2-arylcyclohexanone is alkylated at the 2-position by reaction with an alkyl haloacetate such as ethyl chloroacetate in the presence of a base such as sodium hydride to give the corresponding 2-alkyl-2-alkoxycarbonylmethylcyclohexanone. Similarly, in the preparation of 2-aryl-2-alkenyl-4-aminomethylcyclopentanes, the 2-arylcyclohexanone at the 2-position is first alkylated by reaction with an alkenyl halide such as allyl iodide or 2-butenyl bromide in the presence of a base such as sodium hydride to give the corresponding 2-aryl-2- alkenylcyclohexanone. Both the 2-aryl-2-alkoxycarbonylmethylcyclohexanones and the 2-aryl-2-alkenylcyclohexanones are then formulated at the 6-position by reaction with an alkyl formate such as ethyl formate in the presence of sodium metal or potassium. The formylcyclohexanone derivatives are then reacted with p-toluenesulfonylazide to replace the 6-formyl radical with a diazo group to form 2-aryl-2-alkoxycarbonylmethyl-6-diazocyclohexanes, respectively. 2-aryl-2-alkenyl-6-diazocyclohexanes. These diazocyclohexane derivatives are then photolyzed with light of about 300 nm in an alcoholic solvent such as methanol to narrow the ring with the release of nitrogen gas and to form 2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl. (^: ^^^ l ^ C ^ &apos; b (n ^ ⁱ ^, L <^ (^ T ^^ l-ethyl-methoxykarbonylcyklopentanů, respectively. 2-aryl-2-alkenyl-l-methoxykarbonylcyklopentanů. These compounds in particular by hydrolyzing 2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentane to give the corresponding 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane and similarly by hydrolysis

2-Aryl-2-alkenyl-1-methoxycarbonylcyclopentane gives the corresponding 2-aryl-2-alkenyl-1-hydroxycarbonylcyclopentane. The acid, 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane, is further cyclized by reaction with an acid halide such as acetyl chloride to give the corresponding anhydride, namely 4α-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyran. Such pyranes are used as starting materials for the preparation of the pyrindines of formula I.

Certain 4α-aryl-2-subst.-octahydro-1H-2-pyrindines of formula I have been found to be useful in the treatment of pain conditions and accordingly can be used as analgesics in patients suffering from pain and in need of treatment. In addition, it has been found that the pyrimidine derivatives of formula (I) exhibit both agonist and antagonist properties of analgesics and are therefore capable of inducing analgesia in mammals while at the same time having a significantly reduced susceptibility to analgesics. addiction (due to its effectiveness as an analgesic antagonist). Thus, the disclosed ability of the compounds to act as both agonists and antagonists of analgesics results in a decrease in the ability of the drug in question to exert physical dependence (addiction) due to its opioid analgesic effect. Thus, the compounds of the invention are particularly valuable because they induce analgesia with only minimal ability to induce physical dependence. Some of these compounds are further useful in eliminating opiate-induced adverse events such as morphine.

The analgesic activity of the compounds of formula I was investigated by standard animal tests commonly used to determine analgesic activity. These tests include a mouse test in painful convulsions and a rat test in which the rats twitch their tails away from the site of the pain stimulus.

As mentioned above, the analgesic activity of the compounds of formula I was investigated in mice in painful convulsions. In this test, mice induce painful convulsions (writhing) by intraperitoneal injection of acetic acid. The amount of analgesic efficacy of the respective drug is then determined by observing inhibition of these painful convulsions when the test compound is administered prior to acetic acid administration. When administered 4α- (3-t] ethoxyphenyl) -2-methyl-2,3,4,4a, 5,6,11-, 4'- (4'-) - (4'-hydroxy) -1'-2H-2-ol -pyrindinium chloride at a dose of 20 mg / kg body weight (subcutaneously) to mice experiencing painful writhing, 100% inhibition of these painful convulsions was observed. A subcutaneous dose of 10 mg / kg inhibits painful spasms by 96%. Similarly, oral administration of a 20 mg / kg dose of the compound described above results in 100% inhibition of painful convulsions and an oral administration of 10 mg / kg at 98% inhibition. In addition, naloxone, administered subcutaneously at a dose of 5 mg / kg, was found to completely inhibit the inhibitory effect of the test compound, suggesting that the compound is an opioid-type analgesic. When tested in rats to remove tails from painful stimuli, the above compound, when administered subcutaneously or orally at 80 mg / kg, exhibited a significant increase in reaction time and showed the same effect when administered orally at 20 mg / kg (all measurements). was performed at 0.5 and 2 hours after administration).

Similarly, 4α- (3-hydroxyphenyl-4-methyl-4-α-α-γ-α-octahydro-1H-β-pyrinidine) was tested and administered at a subcutaneous dose of 0.5 mg / kg 75% inhibition of pain At oral administration of 10 mg / kg of this compound, 93% inhibition of painful seizures was observed 0.5 hours after administration Naloxone administered subcutaneously at 0.5 mg / kg completely prevents this inhibitory effect of the test compound. In the rat test described above, the above compound results in a marked increase in reaction time by subcutaneous and oral administration at a dose of 20 mg / kg.

4a-Phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydric-1H-2-pyridine bromide, which is another

The β-β compound of the invention causes a 70% inhibition of painful convulsions in a group of experimental animals at 0.5 hour after administration at a dose of 100 mg / kg. Oral / m administration at 20 mg / kg causes 58% inhibition 1.5 hours after dosing, which is completely prevented by the presence of naloxone. From the rat test described above, the above compound administered at 80 mg / kg produced only an average increase in reaction time.

In the test in mice writhing in painful cramps and in the test in rats to remove the tail from the pain stimulus, ED50 values (dose reducing the above-mentioned pain manifestations by 50% compared to the control group of animals) were found for the individual compounds of formula I and their salts. ) listed in the following table:

TABLE Example compound no.

salt test in mice (ED50) test in rats (ED50)

7 hydrochloride 5 «80 8 - 0.4 0.2 9 hydrobrcmid 1.0 1.0 10 hydrochloride > 20 > 80 11 hydrobrcmid 1.0 0.5 12 - 20 May > 80 13 hydrobromide 50 > 80 14 hydrobromide 20 May - 15 Dec hydrobromide 20 May > 80 16 hydrobromide 1.0 «80

4a-Aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines of formula I and their salts are therefore useful for inducing analgesia in animals, such as humans . These compounds can be administered to mammals either orally or parenterally. For oral administration, a pharmaceutically acceptable salt of the pyrindine derivative with an acid is generally generally used, since the salt is readily formulated into dosage forms suitable for oral administration. For example, one or more pharmacologically active compounds of formula I, either in the form of aqueous bases or in the form of pharmaceutically acceptable acid addition salts, may be formulated for oral administration by mixing with any of a variety of commonly used diluents, excipients and carrier substances. Examples of such excipients commonly used in the preparation of dosage forms include powdered starch, sucrose, cellulose, magnesium stearate, lactose, calcium sulfate, sodium benzoate and similar diluents. The mixtures obtained can either be compressed into tablets or filled with push-fit gelatin capsules. If desired, the active compounds of the invention may be further combined with one or more other agents known to act as analgesics, such as caffeine, acetaminophen and propoxyphene.

Further, the active compounds according to the invention can be formulated into sterile aqueous or non-aqueous solutions, suspensions and emulsions suitable for parenteral administration. Non-aqueous vehicles commonly used to prepare these dosage forms include propylene glycol, vegetable oils such as olive oil, and various organic esters such as ethyl oleate.

A suitable aqueous solution for oral and parenteral administration is an isotonic sodium chloride solution.

The exact dose of the active ingredient, i.e. the amount of one or more of the 4α-aryl-2-subst.-octahydro-1H-2-pyrindines of formula I or salts thereof, administered to mammals, such as humans, can be varied within a relatively wide range. it is necessary that the pharmaceutical preparation contain the amount of one or more active ingredients according to the invention required to achieve a suitable dosage. This suitable dose will depend upon the desired therapeutic effect, the route of administration utilized, the duration of action as well as the condition being treated. Usually, the dosage of the active compounds of the invention ranges from about 1.0 to 25 mg / kg of body weight per day. This total daily dose is possible; administered in divided doses one to four times daily. The preferred dosage for oral administration is from about 2 to 50 mg / kg.

The preparation of the starting materials and compounds of the invention is illustrated by the following non-limiting examples.

Preparation of starting materials

Example A

A solution of 130 g of 2-phenyl-2-ethoxycarbonylmethylcyclohexanone in 2000 ml of diethyl ether containing 56 g of ethyl formate and 11.5 g of sodium metal was stirred at 25 ° C for 48 hours. The reaction mixture is poured into 1000 ml of ice-water, the ether layer is separated, the aqueous layer is acidified to pH 6.5 by addition of 1N hydrochloric acid and extracted with fresh diethyl ether. The ethereal extracts were combined, washed with water and dried to remove the solvent under reduced pressure. 98 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone are obtained in the form of an oil, b.p. 158 DEG-175 DEG C./0 mm Hg.

For C17H20O4: calculated: 70.81% C · 6.99% Ht;

Found: 70.85% C · 6.77% H.

Example B

Following the procedure described in Example A above, the reaction of 2- (3-methoxyphenyl) -2-ethoxycarbonylmethylcyclohexanone with ethyl formate in the presence of sodium metal gives

2- (3-methoxyphenyl) -4-ethoxycarbonylmethyl-β-formylcyclohexanone.

Example C

A solution of 87.0 g of 2-phenylcyclohexanone in 100 ml of benzene is added dropwise over 1 hour to a solution of 28.0 g of sodium amide in 400 ml of benzene, while stirring and refluxing. The reaction mixture was heated at reflux for a further 2.5 hours, then cooled to 0 ° C in ice and treated with a solution of 83.5 g allyl iodide in 100 ml benzene in one portion. The resulting mixture was heated at reflux for 0.5 h, then cooled to 25 ° C and poured onto 400 g of ice. The benzene layer is separated and dried after washing. Evaporation of the solvent gave 50 g of 2-phenyl-2- (2-propenyl) cyclrhexanone having a boiling point of 114-120 [deg.] C / 13 Pa as a residue.

Example D

A solution of 30 g of 2-phenyl-2- (2-propenyl) -cyclohexanone in -00 ml of diethyl ether containing 3.4 g of sodium metal and 11.8 g of ethyl formate was stirred at 25 ° C for 48 hours. The organic layer was acidified to pH 2.5 by addition of aqueous hydrochloric acid and extracted with fresh diethyl ether. The ether extracts were combined, washed with water and dried to evaporate the solvent. The oil residue was distilled to give 14.6 g

2-phenyl-2- (2-propenyl j -6-formylcyclohexanone of boiling point 125 to 13O ^Q C / 13 mbar.

Example E

To a solution of 50.0 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone in 500 ml of diethyl ether was stirred at 25 ° while stirring.

A solution of 24.8 g diethylamine in 100 ml diethyl ether is added dropwise over 30 minutes. The reaction mixture was stirred at 25 ° C still

1: ^ ос111 ^ 1, then cool to 50 ^° C and during. A solution of 33.5 g of p-toluenesulfonyl azide in 50 ml of diethyl ether was added dropwise over 15 minutes. The resulting mixture was allowed to warm to room temperature, stirred for an additional 5 hours, then washed with water and dried. · Evaporation of the solvent under reduced pressure gave 43.0 g of Z-phenyl-Z-S-ethoKykarbonylmethyl diazocyklohexanonu as an oil, having an IR spectrum measured in a substance, comprising a band at 2080 cm ^_1 for diazo.

Examples F - G

Following the procedure described in Example E above

2- (3--1 ^ 11-7-71) -2-ethoxycarbonylmethyl-6-formylcyclohexanone is converted to 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-Si-4-azocycle-hexanone and 2-phenyl- 2- (2-Propenyl) -6-formylcyclohexanone was converted to 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone.

Example 1 H d

A solution of 57 g of 2-phenyl-2-ethoxycarbonylmethyl-6-diazocyclohexanone in 500 ml of anhydrous methanol is photo-lysed using a quartz lamp (wavelength 300 nm) with stirring at 25 ° C under a stream of nitrogen for 40 hours. The solvent was evaporated under reduced pressure, and the crude oily product was dissolved in 500 ml of diethyl ether, and the ethereal solution was washed with aqueous sodium bicarbonate solution and water and dried, and the solvent was evaporated under reduced pressure to give 27.4 g of 2-phenyl-2- ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane in the form of an oil, which is further purified by distillation, the product boiling at 160 to 190 ° C / 2.7 Pa,

Analysis: for C 17 H 22 O 1 calculated: 70.32% C · 7.64% H;

Found: C, 70.30; H, 7.3-6.

Examples I-J

Following the procedure described in Example H, 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6-diazocyclohexanone was photolyzed at 300 nm light to give 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane at a temperature of bp 190-210 ° C.

For C18H24O5: calculated: 67.48% C, 7.55% H;

Found: 67.1 ·% C, 7.77% · H.

Similarly, 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone yields 2-phenyl-2- (2-propenyl) -1-methoxycarbonylcyclopentanone at boiling point after irradiation with 300 nm UV light from a quartz lamp in the presence of methanol. 113-115 ° C // 13 Pa.

For C16H20O2 calculated: 78.65 ¹⁰ / C, 8.25% H;

Found: C 78.80; H 7.99.

ί13 Я О

Analysis: for С19Ы25О5 calculated: found:

% C, 68.24;% H, 7.84;

68.15 ^<o / o C, 7.57% H.

P г í к 1 a d O

Following the procedure described in Example N, 2- (3-methoxyphenyl) -2-hydroxycarbonyl-1-hydroxycarbonylcyclopentane is dehydrated and cyclized by treatment with acetyl chloride to give tetrahydrofuran-4 (3-methoxyphenyl) -2,6-dioxocyclopentaphthyl] pyran o. boiling point 200-220 ^° C.

Example К

Example P

A solution of 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane in 650 mL of 1,4-dioxane containing 500 mL of 5% aqueous potassium hydroxide was heated under reflux for 12 hours. After cooling to room temperature, 500 ml of water are added to the reaction mixture, the resulting mixture is acidified by the addition of 2N hydrochloric acid and extracted several times with equal volumes of diethyl ether. The ether extracts were combined and dried after washing with water. Evaporation of the solvent under reduced pressure gave 38 g of 2- (3-methoxyphenyl) -2-hydroxycarbonylmethyl-1-hydroxycarboinylcyclopentane as a crystalline solid, m.p. 175-180 ° C.

Examples L-M: 2-Phenyl-2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane. is hydrolyzed as described in Example K to form

2-fluoro-phenyl ^and 2-hydroxycarbonylmethyl-l-on hydroxykarbonylcyklopentanu> mp 205-208 ° C.

For C14H16G4: calculated: 67.73 ° C, 6.50% H;

Found: C, 67.70; H, 6.32.

2-Phenyl-1- (2-propenyl) -1-methoxycarbonylcyclopentane is hydrolyzed by treatment with aqueous potassium hydroxide to give 2-phenyl-2- (2-propenyl) -1-oxycarbonylcyclopentane.

Example N

A solution of 25 g of 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane in 150 ml of ethyl chloride was added. Heat to reflux with stirring for 4 hours; After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure to give 26 g of oily tetrahydro-4-phenyl-2,6-dioxocyclopenta [c] pyran which was further purified by distillation. The product boils at 205 to 207 ° C / 33 Pa.

Analysis: for C 14 H 15 O 5 calculated: 73.03% C, 6.13% H;

Found: C, 73.30; H, 6.37.

To a solution of 6.2 g of 2-phenyl-2- (2-propenyl) -1-hydroxycarbonylcyclopentane in 100 ml of chloroform, 30 g of thionyl chloride are added dropwise over 30 minutes, the reaction mixture is heated under reflux for 15 hours with stirring. After cooling, the solvent was evaporated under reduced pressure. 7.4 g of 2-phenyl-2- (2-propenyl) -1-chlorocarbonylcyclopentane are obtained.

Example Q

To a solution of 10.7 g of benzylamine in 100 ml of toluene was added dropwise a solution of tetrahydro-4- (3-methoxyphenyl) -2,6-desulfonic acid [c] pyran in 300 ml of toluene over 1 hour with stirring at 25 ° C. After completion of the dropwise addition of the pyran derivative, the reaction mixture was refluxed for 3 days equipped with a Dean-Stark well to remove water. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The crude oil was dissolved in 400 ml of 1 N sodium hydroxide solution and the basic reaction mixture was heated at 50 ° C for 15 minutes. The basic aqueous mixture was then extracted with diethyl ether, the ether extracts were combined, washed with water and, after drying, the solvents were evaporated under reduced pressure. The solid residue yielded 4α- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine from recrystallization from di-ethyl ether. mp 75-77 ° C.

Calcd for C22H23NO3:

% H, 6.63;% N, 4.01; ηο1ρ7ΡΠβ ·

H, 6.58; N, 3.78.

Example R

Using the procedure described in Example Q, reaction of tetrahydro-4-phenyl-2,6-dioxocyclopenta [c] pyran with benzylamine affords 4α-phenyl-2-benzyl-2,3 ₎ 4,4a, 5,6,7, 7α-octahydro-1,3-diOxo-1H-2-pyrindine, m.p. 77-79 ° C.

Calcd for C21H21NO2:

78.97 _0/0 C, 6.63% H, 4.39% N;

found:

78.73% C, ^6.65 liters Η%, 4.26% N.

Preparation of final products

Example 1

To a solution of 2 g of 4α-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 30 ml of N, N-dimethylformamide containing 1.23 g of sodium hydrogen carbonate, 1.23 g of 2-propenyl bromide are added in a single portion under stirring at 25 ° C. The reaction mixture was heated under reflux for 4 hours, then cooled to room temperature, filtered and concentrated under reduced pressure. pressure. The oily residue is dissolved in 300 ml of diethyl ether, the ethereal solution is washed with water, dried and the solvent is evaporated off under reduced pressure to give oily 4α-phenyl-2- (2-propenyl) -2,3,4 4a, 5,6,7,7a-octahydro-1H-2-pyrindine. The oil thus obtained is dissolved in 150 ml of fresh diethyl ether and ethereal. hydrogen bromide gas is introduced into the solution. The precipitated salt is filtered off and recrystallized from diisopropyl ether and isopropanol. 1.3 g of 4α-phenyl-2- (2-propenyl) -2,3,4,4a, 5,6,7,77-ocahydro-1H-2-pyrindinium bromide are obtained, m.p. 185-187 °. Celsius.

Analysis calculated for: CinHzBrN:

% C, 63.36;% H, 7.51;% N, 3.35.

H, 7.24; N, 4.24.

Examples 2a 3

Analogously · · procedure as in Example No. 1, on reaction of 4a-phenyl-2,3,4,4a, 5,6,7,7a-ok ^tahyidro-1 H-2-pyrin.dinu · · with appropriate alkylating agents gives the following 1-alkylpyrindines:

. 4a-phenyl-2-n-propyl-2,3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindinium bromide, m.p. 245-247 ° C.

. Analysis calculated for: C 17 H 26 BrN:

% C, 62.96;% H, 8.08;% N, 4.32.

% C, 62.74;% H, 8.22;

4a-Phenyl-2-n-pentyl-2,3,4,4a, 5,6,7,7aoctahydro-4- (1H-pyrimidinium-bimide), m.p. 240-243 ° C.

Calcd for C19H30BrN:

% C, 64.77;% H, 8.58;% N, 3.98.

65.04 O / ₀ C, 8.70% H 3.87% N

Example 4

To a solution of 3.0 g of 4α-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 10 mL of 88% formic acid is added dropwise at 20 ° C under stirring. over 15 minutes with 10 ml of 38% formaldehyde. The reaction mixture was heated at 95 ° C for 8 hours then. cools. to 25 ° C and 100 ml of 4N is added dropwise over 30 minutes. hydrochloric acid. The acidic aqueous reaction mixture was concentrated under reduced pressure to an oily residue which was dissolved in 100 ml of water and the aqueous solution was basified by addition of 50% aqueous hydroxide solution. sodium. The product precipitated from the alkaline aqueous solution was extracted with diethyl ether, the ether extracts combined, washed. water and po. drying, evaporating the solvent under reduced pressure. Gets. se. oily 4α-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine, which is dissolved in 150 mL of diethyl ether. 10 ml of 48% hydrobromic acid in 10 ml of ethanol are added dropwise to the ether solution with stirring at 2-5 ° C over 10 minutes. The product which precipitates from the solution is filtered off and recrystallized from diisopropyl ether and isopropanol. 2.7 g of 4α-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide, m.p. 209 DEG-210 DEG C., are obtained.

Analysis calculated for C 18 H 21 BrN:

60.81 θ / ο C,. 7.49. θ / o H, 4.73 θ / ο. N, found: · ./. ·?.; ·

60.55. θ / ο C,. 7.49% H, 4.57 N / N.

Example 5

To a cold solution (0 to 5 Τ) of 3.0 g of 4α-phenyl-2,3,4,4a, 5,6,7,7 α-ocahydro-1H-2-pyrindine in 47 ml of methanol containing 14 ml of water and 2.6 g of potassium carbonate, 2.6 g of phenylacetyl chloride are added in a single portion. The reaction mixture was stirred at 0-5 ° C for 30 minutes, then warmed to 25 ° C and stirred at this temperature for an additional hour. The reaction mixture was concentrated under reduced pressure, the oily residue was dissolved in 500 ml of diethyl ether, and the solution was concentrated. Wash with dilute aqueous sodium bicarbonate and water. After drying out. from ether solution evaporated under reduced pressure. The solvent was evaporated under reduced pressure to give 4α-phenyl-2-phenylacetyl-2,3,4,43,5,67,77-octahydro-1H-2-pyrimidine, as a result of the above acylation reaction as an oil.

The oily product prepared above was dissolved in 25 ml of tetrahydrofuran and the solution was stirred for 30 minutes. stirring dropwise. to a suspension of 3.0 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. After the addition was complete, the reaction mixture was refluxed for 4 hours with stirring, then cooled to 30 ° C and 60 ml of ethyl acetate were added first, followed by 100 ml of saturated aqueous ammonium tartrate solution. The organic layer was decanted off and the aqueous layer was extracted with diethyl ether. The organic phases were combined and concentrated under reduced pressure. The crude oil was dissolved in 400 ml of diethyl ether, washed with water and dried. Evaporation of the solvent under reduced pressure gave oily 4α-phenyl-2- (2-phenylethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. The oily product was dissolved in 150 ml of diethyl ether and added to a solution of 10 ml of 48% hydrobromic acid in 10 ml of ethanol. The hydrobromide of the above pyrindine derivative, which precipitates from solution, is recrystallized from diisopropyl ether and isopropanol. 2.4 g of 4α-phenyl-2- [2-phenylethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide, m.p. 269 DEG-270 DEG C., are obtained. .

Analysis calculated for C CžHžeBBrN:

% C, 68.39;% H, 7.30;% N, 3.63.

Я Я 1Ρ7 · 0 ι *

68.61% C, 7.57% H, 3.69% N.

Example 6

Using the procedure described in Example 5, 4α-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is acylated with cyclopropanecarboxylic acid chloride to give 4α-phenyl-2-cyclopropanecarbonyl-2 , 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. Reduction of the acylated intermediate pyrindine derivative with lithium aluminum hydride affords the corresponding 2-alkylpyrindine, which then reacts with hydrobromic acid to provide 4α-phenyl-2-cyclopropylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2- pyrindinium bromide, m.p. 240 DEG-241 DEG. Yield 63%.

Analysis calculated for C 18 H 26 BrN:

64.28% c, 7.79% H, 4.16% N,

ΤΊλΙρΤΡΤΊιΠ ·

% H, 7.51;% N, 4.13.

Example 7

A solution of 1.76 mL of liquid methylamine in 75 mL of toluene was cooled to -70 ° C in a solid carbon dioxide cooling bath in acetone and a solution of 10.4 g of tetrahydro-4- (3-methoxyphenyl) was added dropwise over 30 minutes with stirring. enyl) -2,6-dioxocyclopentanedpyran in 125 ml toluene. The reaction mixture was warmed to room temperature and then heated under reflux for 22 hours. The reaction mixture was recooled to room temperature and concentrated under reduced pressure. The oily residue was dissolved in 152 ml of 1N sodium hydroxide solution and heated to 50 ° C with stirring for 15 minutes. The product was extracted from the alkaline aqueous reaction mixture with diethyl ether, the ether extracts were combined, washed with water and, after drying, the solvent was evaporated under reduced pressure. 8.3 g of 4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine are obtained.

To a suspension of 2.5 g of lithium aluminum hydride in 75 ml of tetrahydrofuran, a solution of the above 4α- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a is added dropwise with stirring over 90 minutes. -octahydro-1,3-dioxo-1H-2-pyrindine in 100 mL of tetrahydrofuran. After the addition was complete, the reaction mixture was refluxed for 10 hours and 25 ml of ethyl acetate were added dropwise thereto over 15 minutes while maintaining the temperature below 50 ° C, followed by the addition of 50 ml of aqueous ammonium chloride solution. To separate the organic layer from the aqueous layer, additional tetrahydrofuran was added to the aqueous reaction mixture, the organic layer was decanted off and concentrated under reduced pressure. The oily residue is dissolved in 250 ml of diethyl ether, the ether solution is washed with water and, after drying, the solvent is evaporated off under reduced pressure. To give 4.6 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-lH-2-pyrindine of boiling point 133 to 138 ^and C / 33 Pa.

Analysis calculated for C16H23NO:

78.32% C, 9.45 o / _o H, 5.71% N, found:

% C, 78.13;% H, 9.30;% N, 5.68.

To a solution of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 100 mL diethyl ether was added hydrogen chloride gas with stirring. The reaction mixture was stirred for 30 minutes and then filtered. After recrystallization from diisopropyl ether and isopropanol, the solid product yields 4α- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindinium chloride, m.p. 175-177. Deň: 32 ° C.

Calcd for C16H24NOCl:

68.19% C, 8.58% H, 4.97% N, found:

% H, 8.22;% N, 4.68.

Example 8

A solution of 1.6 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 12 ml of acetic acid containing

211388 mL of 48% aqueous hydrobromic acid was heated to reflux with stirring for 15 hours. The acidic reaction mixture was cooled to about 10 ° C and adjusted to pH 10.2 by addition of 50% aqueous sodium hydroxide solution. The desired product is insoluble in a basic aqueous solution and extracted with a solution of 90 ml of n-butanol and 30 ml of benzene. The organic solution is separated, washed with water and dried. Evaporation of the solvent under reduced pressure gave the demethylated product as an oil which, after crystallization from diethyl ether and ethyl acetate, gave 4a- (3-hydroxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro 151-153 ° C. Yield 54%.

Calcd for C15H21NO:

% C, 77.88;% H, 9.15;% N, 6.05.

77.60 O / o C, 8.88% H, 5.76% N.

Example 1 a d 9

To a solution of 2.17 g of 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, prepared as described in Example 5, in 50 ml of Ν, Ν Dimethylformamide containing 3.95 g of triethylamine was added dropwise with stirring at room temperature over 15 minutes to 3.87 g of phenylacetyl chloride. After the addition was complete, the reaction mixture was heated at 70 ° C for 2 hours and then poured into 200 ml of water. The aqueous mixture was extracted several times with diethyl ether, the ether extracts were combined, washed with a saturated aqueous solution of sodium chloride and water, and dried. Evaporation of the solvent under reduced pressure gave 4α -, (3-hydroxyphenyl) -2- (2-phenylacetyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine.

This product was dissolved in 50 ml of tetrahydrofuran and a solution of 4.0 g of lithium aluminum hydride in 150 ml of tetrahydrofuran was added dropwise over 30 minutes with stirring. The reaction mixture was heated under reflux for 4 hours, then cooled to about 25 ° C and 25 ml of ethyl acetate were added thereto with stirring, followed by a saturated aqueous solution of ammonium tartrate. The resulting mixture was filtered and the solvent was evaporated under reduced pressure. The product thus obtained was dissolved in diethyl ether, washed with water and dried. Evaporation of the solvent gave oily 4α - (3-hydroxyphenyl) -2- (2-phenylethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine.

The oily product is dissolved in 150 ml of diethyl ether and a 50% solution of 48% hydrobromic acid in ethanol is added with stirring. The crystallized hydrobromide of the above compound is filtered off and recrystallized from ethyl acetate. 1.3 g of 4a (3-hydroxyphenyl) -2- (2-phenylethyl) -2,3,4,4a5,6,7,7a-octahydro-1H-2-pyrindinium bromide are obtained, m.p. 135-137 ° C. .

Calcd for C22H23NBrO:

65.67% C, 7.01% H, 3.47 _0/0 N,

Я Р1 Р7РПЛ ’

65.41% C, 7.12% T-3.66 _0/0 N.

Example 10

Using the procedure described in Example 9, 4a-

- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrrolidine is reacted with cyclopropanecarboxylic acid chloride in the presence of potassium carbonate, to form 4α-

- (3-hydroxyphenyl) -2-cyclopropylcarbonyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. The latter compound is reduced by treatment with lithium aluminum hydride to give 4a- (3-hydroxyphenyl) -2-cyclopropylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine which is reacted with with hydrogen chloride gas in ether is converted to the hydrochloride. The resulting product melts at 256-258 ^° C. The yield is 66%.

Analysis calculated for C18H18NOC1:

70.22% C 8.51 a / _o H, 4.55% N, 11.52% Cl found:

69.93% C, 8.25% H, 4.72% N, 11.52 _0/0 Cl.

Example 11

A solution of 1.5 g of 4a- (3-hydroxyphenyl) -2,3,4,4a5,6,7,7a-octahydro-1H-2-pyrindine in 15 ml of N, N-dimethylformamide, containing 1, Sodium bicarbonate (0 g) and 2-tetrahydrofurylmethyl bromide (0.95 g) were heated under reflux for 4 hours. After cooling to about 25 ° C, the reaction mixture is extracted several times with diethyl ether, the ether extracts are combined, washed with water and dried. Evaporation of the solvent under reduced pressure gave oily 4a- [3-hydroxyphenyl) -2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. This oily product was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The product which crystallizes from the solution is filtered off. 1.0 g of 4- (3-hydroxyphenyl) -2- (2-tetrahydrofurylmethyl) -2,3,4,4a5,6,7,7a-octahydro-1H-2-pyrindinium bromide is obtained, m.p. 190-192. Deň: 32 ° C.

Analysis: calculated for C19H28NO2B1:

% C, 59.69;% H, 7.38;% N, 3.66.

% C, 59.89;% H, 7.40;

Examples 12-14

Using the procedure described in Example 11, 4α- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7 α-octahydro-1H-2-pyrindine is reacted with allyl iodide in the presence of sodium bicarbonate, to give 4a- (3-hydroxyphenyl) -2- (2-propenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, m.p. 106-108 ° C.

Calcd for C17H23NO:

79.33% C, 9.01% H, 5.44% N,

ΡΎΡ A 1ΡΎΡ ΓΊ Ω /

79.29 ° C, 8.92 ° H, 5.44 ° N

Similarly, 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is reacted with 1-iodopropane in the presence of sodium bicarbonate to give 4a- (3-methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, which is then converted to the hydrobromide by treatment with hydrogen bromide gas in diethyl ether. The resulting product melts at 197-199 ° C.

For C18H18NOBr:

61.02% C, 7.97 0/0 H, 3.95 θ / ο N,

n.3. lezeno *

% H, 7.52;% N, 4.07.

Similarly, 4a- (3-methoxyphenyl) -2,3,4a, 4a5,6,7,7a-octahydro-1H-2-pyrindine is reacted with 1-bromopentane in the presence of sodium bicarbonate to give 4a (3-methoxyphenyl) ) -2-n-Pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. This compound, by treatment with hydrogen bromide gas in diethyl ether, provides 4α- (3-methoxyphenyl-2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide) as a crystalline solid mp 179-181 ° C.

Analysis calculated for C20toNOBr:

62.82% C, 8.44% H, 4.18% N, found ·

62.87% c, 7.98 θ / ο H, 4.02% N.

Example 15

A solution of 2.0 g of 4- (3-methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, prepared as described in Example 13, in 20 ml of glacial acetic acid and 20 ml of 48% aqueous hydrobromic acid were stirred and refluxed for 12 hours. The reaction mixture was cooled, poured onto 100 g of ice and the resulting aqueous solution was basified by addition of aqueous; sodium hydroxide solution to pH 10.2. The basic aqueous mixture was extracted with 200 mL of a mixture of 3 parts n-butanol and 1 part benzene. The extracts were combined, washed with water and dried. Evaporation of the solvent under reduced pressure yielded 1.3 g of 4a- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine as oils. The oily product is dissolved in diethyl ether and added to a solution of hydrogen bromide in diethyl ether, whereupon the hydrobromide of the above compound crystallizes and is filtered off. 1.1 g of 4a- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide are obtained, m.p. 235 DEG-236 DEG. C.

Analysis calculated for C 18 H 18 NOBr:

H, 7.70; N, 4.12.

1 A 1P 7 ΡΠ · Π · ’

59.97% C, 7.50% H, 3.98% N.

Example 1 a d 16

Using the procedure described in Example 15, 4a- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was reacted with aqueous acid hydrobromic acid in glacial acetic acid. There was obtained 4a- (3-hydroxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7 α-octahydro-1H-2-pyrindine which was then converted to the corresponding hydrobromide with mp 171-173 ° C. The yield was 42%.

For C20H10NOBr, calculated:

61,95 θ / ο C, 8,21 θ / ο H, 3,80 θ / ο N

61.65 θ / ο С, 7.93% Η, 3.54% Ν.

Claims (9)

SUBJECT OF THE INVENTION A process for the preparation of 4α-aryl-octahydro-1H-2-pyrindines of general formula I, (I) in which: R 1 is C 1 -C 8 alkyl, the radical of formula CH 2 R 3 or wherein n is 1 or 2 a R 3 represents C 2 -C 4 alkenyl, C 3 -C 5 cycloalkyl or tetrahydrofuryl, and R 2 is hydrogen, hydroxyl or C 1 -C 3 alkoxy, and non-toxic, pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (II) in which: R2 is as defined above, and R? is hydrogen, reacted with an alkylating agent of formula Ri — Z in which R 1 is as defined above, and Z represents a leaving group such as a halogen atom, tosyl, mesyl, brosyl, phenylsulfonyl or azidoscine, in the presence of a non-reactive group; an organic solvent, and optionally in the presence of a base, at a temperature of 50 to 200 ^° C, to form a compound of the above formula I wherein R 1 is an alkyl group having C 1 -C 8 or a radical of the formula CH 2 R 3 wherein R 3 is C 2 -C 4 alkenyl or an acylating agent such as the corresponding acid halide or anhydride in a non-reactive organic solvent in the presence of a base at a temperature of from -20 to 4-30 ° C, followed by reduction, to give the compound of formula (I) above, wherein R 1 is a radical of formula CH 2 R 3, wherein R 3 is a C 3 -C 5 cycloalkyl or tetrahydrofuryl group, or wherein R 1 is a radical of formula n is as defined above, and the product of formula (I) in which R a is C 1 -C 3 alkoxy is optionally deetherified with hydrogen bromide in acetic acid to give a compound of formula (I) in which R 2 is hydroxyl. 2. The process of item 1 for producing 4α- (3-hydroxyphenyl) -2- (2-phenylethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized by: The process of claim 1, wherein 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is acylated with phenylacetyl chloride followed by reduction with lithium aluminum hydride. 3. A process according to claim 1 for the preparation of 4a- (3-hydroxyphenyl) -2-cyclopropylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized in that: with 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is acylated with cyclopropanecarboxylic acid followed by reduction with lithium aluminum hydride. 4. The process of item 1 for producing 4α- (3-hydroxyphenyl) -2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5,6,7,7.a-octahydro-1H- 2-pyrindine, characterized in that 4α- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine is alkylated with 2-tetrahydroifurylmethyl bromide. 5. The process of clause 1 for producing 4a- (3-hydroxyphenyl) -2- (2-propenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2- pyrindine, characterized in that 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is alkylated with allyl iodide. 6. The process of item 1 for producing 4a- (3-methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, The process of claim 4 wherein the 4α- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is alkylated with 1-iodopropane. 7. A process according to claim 1 for the preparation of 4- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized by: 211 by alkylating 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine with 1-bromopentane. 8. A process according to claim 6 for the preparation of 4a -, (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized by: by 4- (3-methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine de- It is etherified with aqueous hydrobromic acid in glacial acetic acid. 9. The method of item 7 for the preparation of 4α- (3-hydroxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized in that 4. A method according to claim 1, wherein 4a- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine deether is treated with aqueous hydrobromic acid in glacial acetic acid.