CS211381B2 - Method of making the cis-4a-aryl-octahydro-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 to synthesize drugs (ie analgesics) capable of alleviating pain. The use of some common analgesics is limited by various unwanted side effects, which often accompany the continuous use of these analgesics. These side effects include addiction and allergies. To illustrate the novel analgesic drugs recently discovered, decahydro-hydroquinolines, in particular the 4α-aryl-trans-decahydrolsoquinolines, are disclosed 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 been synthesized so far. 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 (2j, 342-345 (1967), cf. A.A., Vol. 67, 6034 (1967)). Similarly, Procházka et al. prepared trans-octabydro-2-pyrindine containing a substituent at the position

4a [Coli. Czech. Chem. Commun., 31 (9), 3824-3828 (1966), cf. C.A., Vol. 65, 13651 (1966)].

The present invention provides a process for the preparation of novel starting materials useful for the preparation of cis-4a-phenyl- and unsubstituted phenyl-2,3,4,4a, 5,6,7,7a-ofetahydro-1H-2-pyrindines not previously known and intermediates used in the preparation of these compounds.

The invention relates to a process for the preparation of novel bicyclic compounds characterized as octahydro-1H-2-pyrindines, which may alternatively be named hexahydro-1H-cyclopentanediopyridines. In particular, the present invention provides a process for the preparation of cis-compounds of formula (II):

in which

R 1 represents a hydrogen atom, a C 1 -C 8 alkyl group or a radical of formula wherein n is 1 or 2, and

R 2 represents a hydrogen atom, a hydroxyl group or a C 1 -C 3 alkoxy group, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (III),

in which

R 1 'and R 2 are as defined above, reacted with a reducing agent, the resulting compound of formula II wherein R 1' is C 1 -C 8 alkyl or a radical of formula wherein n is as defined above, optionally cleaved to form compounds of formula II wherein R 1 'is hydrogen, and the resulting compounds of formula II wherein R 2 is C 1 -C 3 alkoxy are optionally deetherified to give compounds of formula II wherein R 2 is hydroxyl.

A preferred group of compounds of the invention are those compounds of formula (II) wherein R 1 is C 1 -C 8 alkyl. An even more preferred sub-group of compounds belonging to the aforementioned preferred group are those compounds of formula (II) wherein R 2 is a hydroxyl group or a methoxy group. A particularly preferred group of compounds of formula (II) wherein R 1 is hydrogen.

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 C 1 -C 8 alkyl groups 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-triinethylpentyl and related groups.

The symbol R 1 in formula II may also represent a radical of formula wherein n is 1 or 2.

A typical group in the meaning of the symbol R1 ‘is the henzyl group.

Pyrindine derivatives of the above formula (II) are prepared by first reacting an amine, in particular ammonia or a primary amine, with a cyclic anhydride, in particular 4α-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyran, in the sense of the following reaction. wherein R1 and R2 are as defined above:

The thus obtained cyclic imide - 1,3-dioxo-4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine - is then reduced to the oxo groups at the 1 and 3 positions, to form a pyrindine derivative of the Formula II. In practice, it is preferred to use 4α-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyranes of formula V wherein the substituent of the aryl radical represented by R2 in formula V is a hydrogen atom or a C1-C3 alkoxy group . 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. Similarly, amines such as ammonia, C1-C8-alkylamines, in particular methylamine, and arylamines, in particular benzylamine, are likewise preferred in the reaction of the amine with the cyclic anhydride described above. Indeed, the 2-methyl- and 2-benzylpyrindine derivatives thus formed are readily converted to the corresponding 2-unsubstituted pyrindines.

In the preparation of 1,3-dioxo-4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines of formula III by reaction according to the above reaction scheme, starting 4-aryl Tetrahydro-2,6-dioxocyclopenta [c] pyran and amine are usually contacted in equimolar amounts, although any of the reagents may be used in excess 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 reactions are generally 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 way that water is immediately removed from the reaction mixture. For this purpose, any of the techniques commonly used to keep the reaction mixture dry can be used, including the use of molecular sieves or alternatively azeotropic removal of water generated using a Dean-Stark trap and suitable solvents such as benzene and toluene. The reaction between the cyclic anhydride and the amine is normally practically complete in 24 to 72 hours, but further reaction times do not appear to be detrimental to the product formed and can therefore also be used if desired. The cyclic imide thus formed, namely 4α-aryl-2,3,4,4a, 5,6,7,7α-octahydro-1,3-dioxo-1H-2-pyrindine, is readily isolated by removal of the reaction solvent, for example by evaporation of vacuum, and can be further purified by standard procedures such as acid and base extraction, crystallization, and chromatography.

As mentioned above, 4-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyran can be reacted with ammonia to give the corresponding 4α-aryl-2,3,4,4a, 5,6,7,7a- octahydro-1,3-dioxo-1H-2-pyrindine of formula III, which is not substituted in the 2-position, or alternatively, the pyran derivative can be reacted with a primary amine to give directly 4-aryl-2-subst.-2,3 4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine. It should further be emphasized that if it is desired to react the pyran derivative with a primary amine to form a 2-substituted or pyrindine derivative, the primary amine should preferably be methylamine or benzylamine. These primary amines are advantageous in that the reaction with 4-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyran affords 2-substituted 1,3-dioxopyrindine derivatives, from which 2-substituted pyrindine derivatives are substituted by reduction. However, it should be emphasized that although the preferred primary amines for the reaction with the aforementioned pyran derivative are methylamine and benzylamine, virtually all of the pyran derivative can be reacted with the pyran derivative. primary amines to obtain the corresponding 4a-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine. It should further be pointed out that, as the latter compound is a 1,3-dioxopyrindine derivative, it must undergo reduction at the oxo groups at the 1 and 3 positions to produce pharmacologically useful pyridines of formula II. It is therefore preferred that the group attached at the 2-position of these 4-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindines be a group practically resistant to the reduction procedures used to reduce the oxo groups at positions 1 and 3. Those groups which are so resistant to this reduction are preferably introduced by alkylation or acylation followed by reduction of the pyrindine derivatives unsubstituted at the 2-position.

Representative 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindines of formula (III), which are commonly prepared directly by reaction of an amine, are listed below. with a cyclic anhydride as described above, and which are then reduced as described below to pharmacologically useful pyrindine derivatives of formula II:

4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-ΙΗ-2-pyrindine,

4α-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine,

4α- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-ΙΗ-2-pyrindine,

4α-phenyl-2-phenylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine,

4- (3-Propoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo

-ΙΗ-2-pyrindine,

4a- (3-methoxyphenyl) -2-phenylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-ΙΗ-2-pyrindine,

4- [3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine.

As mentioned above, the aforementioned 4α-aryl-2,3,4,4a, 5,6,7,7α-octahydro-1,3-dioxo-1H-2-pyrindines of the formula III are converted to the 4α-aryl-4-arylamino. aryl-2,3,4,4a, 15,6,7,7a-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-dioxo-pyrindine derivative can 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 also be used. A preferred method for reducing the 4α-aryl-2,3,4,4a ₎ 5,6,7,7aoctahydro-1,3-dioxo-1H-2-pyrindine III is to use lithium aluminum hydride as a reducing agent. Typically, 4a-aryl-2,3,4,4a, 5,6,7,7a-o-ctahydro-1,3-dioxo-1H-2-pyrindine, such as 4a-phenyl-2, is used. methyl-2,3,4,4a, 5, e, 7,7a-octahylamine-1,3-dioxo-1H-2-pyrindine, is reacted with about twice the molar amount of lithium aluminum hydride in a non-reactive organic solvent. Non-reactive solvents commonly used in this reaction include tetrahydrofuran, diethyl ether, dioxane, diglyme, and related solvents. The reaction is normally carried out at a temperature of about 20 to 100 ° C, and is typically practically complete in about 4 to 20 hours at this temperature. 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 usually 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 were combined and concentrated by solvent evaporation to yield the reduced product, specifically therefore the 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro ^and OIK-lH-2-pyrindine of formula II . This product usually results 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.

Compounds of formula II which are readily obtainable by reduction of the 1-oxo- and 3-oxo groups in the 4α-aryl-2,3,4,4a, 5,6,7,7a-octahydrol-3, 3-dioxo-1H The 2-pyrindine of formula III as described above includes, but is not limited to

4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine,

4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

4a- (3-ethoxyphenyl) -2-methyl-2,3,4 _l 4a, 5,6,7,7a-octahydro-lH-2-pyrindine,

4α-phenyl-2-ethyl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine,

4α- [3-iso-propoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

4a-phenyl-2-isobutyl-2,3,4,4a, 5,6,7,7a-octaihydro-1H-2-pyrindine; and

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

It is often desirable to prepare 4a-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines, the substituent at position 2 of which is readily cleavable to produce the above-described process. of the corresponding octahydropyrindine derivatives unsubstituted in the position

2. As mentioned above, the N-methyl and N-benzyl groups are readily cleavable to give the corresponding pyrindine derivative unsubstituted at the 2-position. The 2-m-ethylpyrindine derivatives prepared as described above may be reacted with an ester haloformates, such as phenyl chloroformate or ethyl chloroformate, to provide pyrindine derivatives containing the corresponding carbamate moiety at the 2-position. These carhamates 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 is described by Abel-Monen and Portoghese in 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. can be carried out 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 Hauptung and Simonoff, O-rg. Reactio ns, 7, 277 (1953) and Leonard and Fuji, J. Amer. Chem. Soc., 75, 3718 (1963).

It follows from the above that the following 2-unsubstituted a

2-substituted pyrindine derivatives of formula II:

4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine,

4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

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

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

4α-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

4a-phenyl-2-ethyl-2,3,4,4a, 5, e, 7,7a-octahydro-1H-2-pyrindine,

4a- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine; and

4α- (3-methoxyphenyl-2-isopropyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine).

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 II may be subjected to other modifications. For example, it may be advantageous to prepare 4a- (3-methoxyphenyl) -2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine and 3-methoxy in 4a- the aryl substituent of this compound to the hydroxyl group. This conversion is readily accomplished by reacting the 4- (3-methoxyphenyl) -pyrindine derivative with hydrobromic acid in acetic acid, which is generally used to convert a methoxyphenyl group to a hydroxyphenyl group.

As mentioned above, the 4α-aryl-2-substituted octahydro-1H-2-pyrindine derivatives of formula II can be reacted with organic or inorganic acids to form crystalline salts which can be purified by crystallization and can be converted back to the free pyrindine bases by treatment with a suitable base such as sodium hydroxide. Acid addition salts of the compounds of formula II 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 II. These non-toxic, pharmaceutically acceptable acid addition salts are prepared by reacting 4α-aryl-2-subst.-octahydro-1H-2-pyrindine of formula II with an organic or inorganic acid. Among the acids commonly used to prepare pharmaceutically acceptable acid addition salts of the compounds of formula (II) are hydrohalic acids such as hydrogen chloride, hydrogen bromide and hydrogen iodide as well as other acids such as sulfuric, phosphoric, nitric, perchloric, phosphite, nitrous and related acid. Organic acids commonly used to prepare pharmaceutically acceptable acid addition salts of the pyrindines of formula II 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 (II) may conveniently be prepared by dissolving 4α-aryl-2-subst.-octahydro-1H-2-pyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone or the like. % ethanol, and either an equivalent amount or an excess of the appropriate acid is added to the solution. The salt thus formed normally crystallizes out of 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 C1-4a-aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines are representative examples of the compounds of the invention:

4α-phenyl-2- (3-ethylpentyl) -2,3,4,4a, 5,0,7,7a-octahydro-1H-2-pyrindine,

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

It should be noted that the compounds of formula II contain two centers of asymmetry, namely positions 4a and 7a. The invention includes both the separate isomers and the racemic mixtures of these isomers, which are pharmacologically useful as agonists and antagonists of analgesics. However, the invention includes only the cis-isomers of the compounds of formula (II), 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 individual stereoisomers in a known manner. Even if all the useful pharmacological activity is concentrated in a single stereoisomer, the racemate (a mixture of d- and 1-isomers) is still useful since it contains a pharmacologically active isomer as its component.

The preparation of the 4α-aryloctahydropyrindines of formula II requires the use of starting materials, many of which have not been known and available to date. They are used as starting materials in the preparation of the pyrindines of formula II

4-aryl-tetrahydro-2,6-dioxocyclopenta [c] pyranes. 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-1-aminomethylcyclopentanes, the 2-arylcyclohexanone at the 2-position is first alkylated by reaction with an alkenyl halide such as allyl iodide or 2-butenylbromide in the presence of a base such as sodium hydride to give the corresponding 2 -aryl-2-alkenylcyclohexanone. Both 2-aryl-2-alkoxycarbonylmethylcyclohexanones and 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-diazocyclohexanones, respectively. 2-aryl-2-alkenyl-6-diazocyclohexanones. The diazocyclohexanone derivatives are then photolyzed with light at about 300 nm in an alcoholic solvent such as methanol to constrict the ring with the release of nitrogen gas to form 2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentanes, respectively. 2-aryl-2-alkenyl-1-methoxycarbonylcyclopentanes. These compounds are then de-esterified (i.e., hydrolyzed) by treatment with an aqueous base solution to give the corresponding diacid and monoacid. In particular, hydrolysis of 2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentane gives the corresponding 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane and similarly hydrolysis of 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 II.

Certain 4α-aryl-2-subst.-octahydro-1H-2-pyrindines of formula II have been found to be useful in the treatment of pain conditions and accordingly may be used as analgesics in patients suffering from pain and in need of treatment. In addition, it has been found that the pyrindine derivatives of formula (II) possess both analgesic agonist and antagonist properties and are therefore capable of inducing analgesia in mammals at the same time with a significantly reduced incidence of addiction (due to their potency as analgesic antagonists). 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 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 (II) was investigated by standard animal tests commonly used to determine analgesic activity. These tests include a test in mice in painful cramps and a test in rats in which rats twitch their tails away from the site of a painful stimulus.

As noted above, the analgesic activity of the compounds of Formula II was investigated in mice in painful spasms. 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 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium chloride is administered at a dose of 20 mg / kg body weight (subcutaneously) 100% inhibition of these painful convulsions was observed in mice experiencing pain writhing. 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 dose of 10 mg / kg 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, indicating that the compound is an opioid-type analgesic. In the tail-jaw rat test, the above compound, when administered subcutaneously or orally at 80 mg / kg, results in a significant increase in reaction time and the same effect when administered orally at a dose of 20 mg / kg (all measurements taken after 0.5 and hours after administration).

Similarly, 4a- (3-hydroxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine was also tested. At a subcutaneous dose of 0.5 mg / kg, this compound inhibits 75% of painful convulsions in experimental animals. At an oral dose of 10 mg / kg of this compound, 98o / o inhibition of painful seizures was observed 0.5 hours after administration. Naloxone administered subcutaneously at a dose of 0.5 mg / / kg completely prevents this inhibitory effect of the test compound. In the rat test described above, the above compound causes a significant increase in reaction time when administered subcutaneously and orally at a dose of 20 mg / kg.

4α-Phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide, another compound of the invention, causes 0.5 hours after administration at a dose of 100 mg / kg 70% inhibition of painful convulsions in a group of experimental animals. When administered orally at a dose of 20 mg / kg, the compound causes 58% inhibition 1.5 hours after administration, 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 site of the pain stimulus, ED 50 values (dose reducing the above-mentioned pain manifestations by 50% compared to the above) were found for the individual compounds of formula II and their salts. control group of animals) listed in the following table.

TABLE compound salt of example no.

hydrochloride -

hydrobromide hydrobromide

4a-Aryl-2-subst.-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines of formula II and their salts are therefore useful for inducing analgesia in animals, such as people. The compounds may be administered to mammals either orally or parenterally. For oral administration, a pharmaceutically acceptable acid addition salt of the pyrindine derivative is generally preferred, since the salt is readily formulated into dosage forms suitable for oral administration. For example, one or more of the pharmacologically active compounds of formula II, either in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts, may be formulated for oral administration by mixing with any of a number 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 the like. 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 generally 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 II or salts thereof, administered to mammals as a human mouse mouse test (ED 50). (ED50) <80

0.4 0.2> 80

1.0 <80 kc, may vary within a relatively wide range, and it is necessary that the pharmaceutical preparation contain the amount of one or more active ingredients of the invention required to achieve a suitable dosage. This appropriate dose will depend upon the desired therapeutic effect, the route of administration utilized, the duration of action as well as the condition being treated. In general, the dosage of the active compounds according to the invention ranges from about 1.0 to 25 mg / kg of body weight per day. This total daily dose may be administered in divided doses one to four times daily. The preferred dosage for oral administration is from about 2 to about 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 ether extracts were combined, washed with water, and after drying the solvent was evaporated under reduced pressure. 98 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone are obtained in the form of an oil having a boiling point of 158 DEG-175 DEG C./0 mm Hg.

For C17H20O1: calculated: 70.81% C, 6.99% H;

Found: C, 70.85; H, 6.77.

Example Β

Following the procedure described in Example A above, 2- (3-methoxyphenyl) -2-ethoxycarbonylmethylcyclohexanone with ethyl formate in the presence of sodium metal provides 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6-formylcyclohexanone.

Example C

A solution of 77.0 g of 2-phenylcyclohexanone in 100 ml of benzene is added dropwise to the solution of 28.0 g of sodium amide in 400 ml of benzene, with stirring and refluxing, over 1 hour. The reaction mixture was heated under reflux for a further 2.5 hours, then cooled to 0 ° C in ice and treated with a solution of 83.5 g of allyl iodide in 100 ml of 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 was separated and dried after washing with water. Evaporation of the solvent gave 50 g of 2-phenyl-2- (2-propenyl) cyclohexanone, b.p.

Example D

A solution of 30 g of 2-phenyl-2- (2-propenyl) -cyclohexanone in 600 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 reaction mixture was poured into water, the organic layer was separated and discarded. The aqueous 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 remove the solvent under reduced pressure. The oily residue was distilled to give 14.6 g of 2-phenyl-2- (2-propenyl) -6-methylcyclohexanone, b.p. 125-130 ° C / 13 Pa. Example E

To a solution of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone (50.0 g) in diethyl ether (500 mL) was added dropwise a solution of diethylamine (24.8 g) in diethyl ether (100 mL) with stirring at 25 ° C. The reaction mixture was stirred at 25 ° C for 2 hours, then cooled to 5 ° C, and 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 2-phenyl-2-ethoxycarbonylmethyl-6-diazocyclohexanone as an oil whose IR spectrum, measured in the substance, contained a band at 2080 cm ^-1 for the diazo group.

Examples F - G

Following the procedure described in Example E above, 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6-formylcyclohexanone was converted to 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6-diazocyclohexanone and 2-phenyl-2- (2-Propenyl) -6-formylcyclohexanone was converted to 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone.

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

For C17H22O4: calculated: 70.32% C, 7.64% H;

Found: C, 70.30; H, 7.36.

Examples I-J

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

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

Found: C, 67.61; H, 7.37.

Similarly, 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone gives 300 nm, after irradiation with ultraviolet radiation: from a quartz lamp in the presence of methanol, 2-phenyl-2- (2-propenyl) -1- methoxycarbonylcyclopentanone, boiling point 113 DEG-115 DEG C./0.1 mbar.

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

Found: C 78.80; H 7.99.

Analysis: Calculated for C19H25O5: 68.24 ^t0 / o C, 7.84% H;

Found: C, 68.15; H, 7.57.

Example K

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 refluxed for 12 hours with stirring. 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-hydroxycarbonylcyclopentane as a crystalline solid, m.p. 175-180 ° C. Examples L-M

2-Phenyl-2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane was hydrolyzed as described in Example K to give 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane, m.p. 205-208 ° C.

For C14H16O1: calculated: 67.73% C, 6.50% H;

Found: C, 67.70; H, 6.32.

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

Example N

A solution of 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane (25 g) in acetyl chloride (150 ml) was heated at reflux for 4 hours with stirring. 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.

Analýba: calculated for C14H15O3: 73.03% C, 6.13 ^Ό / ο H;

Found: C, 73.30; H, 6.37.

Example O

Following the procedure described in Example N, Z- (3-methoxyphenyl) -2-hydroxycarbonyl-1-hydroxycarbonylcyclopentane is dehydrated and cyclized by treatment with acetyl chloride to give tetrahydro-4- (3-methoxyphenyl) -2,6-dioxocyclopenta [c] pyran Boiling point 200-220 ^° C.

Example P

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, and 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 1 Q d

A solution of tetrahydro-4- (3-methoxyphenyl) -2,6-dioxocyclopenta [c] pyran in 300 ml of toluene was added dropwise over 1 hour to a solution of 10.7 g of benzylamine in 100 ml of toluene with stirring at 25 ° C. After completion of the dropwise addition of the pyran derivative, the reaction mixture was heated to reflux 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 oily product 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 dried to evaporate the solvent under reduced pressure. The solid residue, after recrystallization from diethyl ether, gave 4a- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine. mp 75-77 ° C.

Calcd for C22H23NO3:

75.62% C, 6.63 ^! % H, 4.01% N; found:

75.40% C, 6.58 o / _o o / _o h, 3.78 θ / ο N.

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, 5,6,7,7a -octahydro-1,3-dioxo-1H-2-pyrindine, m.p. 77-79 ° C.

Calcd for C21H21NO2:

% C, 78.97;% H, 6.63;% N, 4.39;

found:

78.73 _0/0 C, 6.6 · 5% H 4.26% N

Preparation of final products

He did

To a suspension of 5.8 g of lithium aluminum hydride in 150 ml of tetrahydrofuran, a solution of 18 g of 4α-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3 is added dropwise with stirring over 90 minutes. -dioxo-1H-2-pyridine in 200 ml tetrahydrofuran. After the addition was complete, the reaction mixture was refluxed for 10 hours, then 50 mL of ethyl acetate was added dropwise over 15 minutes while maintaining the temperature below 50 ° C, followed by the addition of 100 mL of aqueous ammonium chloride solution. Additional tetrahydrofuran was added to the aqueous reaction mixture to separate the organic layer from the aqueous layer, the organic layer was decanted off and concentrated under reduced pressure. The oily residue is dissolved in 500 ml of diethyl ether, the ether solution is washed with water and, after drying, the solvent is evaporated off under reduced pressure. 15 g of 4α-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine are obtained. M ⁺ / e 291 (molecular signal), 213 (7777, phenyl) and 200 (9191, benzyl).

Example 2

Using the procedure described in Example 1, reduction of 4a- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine treatment with Uthium aluminum hydride affords 4- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. The yield of product was 97 ^l%.

Example 3

To a solution of 21 g of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 172 ml of ethanol, 7 g of 5% is added under stirring in a single portion. palladium on coal. The reaction mixture was stirred under heating at 60 ° C under 50 psi of hydrogen for 3 hours, then cooled to room temperature, filtered and the solvent was evaporated under reduced pressure. 13.3 g of an oily product are obtained, which is distilled to give 4α-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine.

Example 4

Analogously to Example 3, 4- [alpha] - (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is hydrogenated in the presence of palladium on carbon. There was obtained 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, bp 145-160 ° C / 7 Pa. Yield 66%.

Example 5

A solution of 8.4 g of 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 60 ml of glacial acetic acid and 60 ml of 48% aq. of hydrogen bromide is heated to reflux for 15 hours with stirring. After cooling to room temperature, 100 g of ice was added to the reaction mixture, and the pH of the resulting aqueous solution was adjusted to pH 10.2 by addition of concentrated aqueous sodium hydroxide solution. The basic reaction mixture was extracted with 400 ml of a mixture of 3 parts of n-butanol and 1 part of benzene, the extract was separated, washed several times with water, dried and the solvent was evaporated under reduced pressure. The crude solid was crystallized from ethyl acetate 4.2 g of 4a- (3-hydroxyphenyl) _{-2,3,4,4a-5),} 6,7,7a-octahydro-2-pyrindine, m.p. 180-181 ° C.

Calcd for C14H19NO:

77.38 a / _o C, 8.81 '% H, 6.45% N; found:

% C, 77.56;% H, 8.84;% 6.24.

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 0c and a solution of 10.4 g of tetrahydro-4- (added dropwise) was added dropwise over 30 minutes. 3-methoxyphenyl) -2,6-dioxoeyclopenta [c] pyran 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 under reduced pressure. The oily residue is dissolved at room temperature and concentrated under sníže152 ml of IN sodium hydroxide solution and stirring for 15 minutes heated to ^{50, or} C. The product of the alkaline aqueous reaction mixture with diethyl ether, and the ethereal extracts were combined, washed with water and dried the solvent was evaporated under reduced pressure ... to give 8.3 g of 4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo. -1H-2-pyrindine.

By reducing 8.2 g of 4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-ΙΗ-2-pyrindine by reaction with lithium aluminum hydride to give Using the procedure described in Example 1, 4.6 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-2-2-pyrindine are obtained at boiling point. 133 to 138 ^° C / 33 Pa.

Analysis calculated for C18 H23 NO:

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

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

To a solution of 4a- (3-methoxyphienyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrrolidine in 100 mL diethyl ether was added with stirring gaseous hydrogen chloride. The reaction mixture was stirred for 30 minutes and then filtered. The solid product was recrystallized from diisopropyl ether and isopropanol to give 4α- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2211381

-pyrindinium chloride, m.p. 175-177 ° C.

Calcd for C18H21NOC1:

H, 8.58;% N, 4.97; found:

H, 8.22; N, 4.68. Example 7

A solution of 1.6 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydr-o-1H-2-pyrindine in 12 ml of acetic acid containing 12 ml of 48% aqueous hydrobromic acid was stirred and refluxed 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 was 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, afforded 4α- (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; found:

77.60 O / o C, 8.88% H, 5.76% N. Example 8

A solution of 2.0 g of 4a- (3-methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 20 ml of glacial acetic acid and ml 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 and the basic aqueous mixture was extracted with 200 ml. a mixture of 3 parts of n-butanol and 1 part of benzene, the extracts were combined, washed with water and dried by evaporation: the solvent under reduced pressure gave 1.3 g of 4- (3-hydroxyphenyl) -2-n-propyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine as an oil The oil-yellow product is dissolved in diethyl ether and added to a solution of hydrogen bromide in diethyl ether to crystallize the hydrobromide of the above compound which Filtration gave 1.1 g of 4- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide, m.p. 236 Deň: 32 ° C.

Analysis calculated for C 18 H 26 NOBr:

% C, 60.00;% H, 7.70;% N, 4.12; found:

59.98 o / o C, 7.50% h, 3.98% N. Example 9

Using the procedure described in Example 8, 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, 5,6,7,7a-octahydro-1H-2-pyrindine which was then converted to the corresponding hydrobromide at a temperature of mp 171-173 ° C. Yield 42 ^l%. For C 20 H 30 NOBr calculated:

% H, 8.21;% N, 3.80. found:

61.65 a / _o C, 7.93% H, 3.54% N.

Claims (7)

A process for the preparation of cis -4a-aryl-octahydro---2-pyridines of the general formula II, R 1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a radical of formula wherein n is 1 or 2, and R 2 represents a hydrogen atom, a hydroxyl group or a C 1 -C 3 alkoxy group, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (III): R 1 and R 2 are as defined above, reacted with a reducing agent such as an alkali metal hydride or zinc and acetic acid, or subjected to catalytic hydrogenation, in a non-reactive organic solvent at a temperature of 20 to 100 ° C to obtain the compound of formula II optionally cleaved, when R 1 'is C 1 -C 8 -alkyl, with a formic halide ester and an aqueous base, and when R 1' is a radical of formula wherein n is as defined above, catalytic hydrogenation to form a compound of formula II wherein R 1 is hydrogen and the resulting compounds of formula II wherein R 2 is C 1 -C 3 alkoxy are optionally deetherified by treatment with hydrogen bromide and acetic acid to form compounds of the general formula of formula II wherein R 2 represents a hydroxyl group. 2. A process according to claim 1 for the preparation of 4- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized in that: 4 - (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine is reduced with lithium aluminum hydride. 3. The process according to claim 1 for the preparation of 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized in that 4a-phenyl-2-benzyl- 2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-ΙΗ-2-pyrindine is reduced with lithium aluminum hydride followed by digestion with palladium on carbon. 4. The process of claim 1 for the preparation of 4α- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octah-1 H-2-pyrindine, characterized in that (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine was reduced with lithium aluminum hydride followed by palladium on carbon cleavage. 5. A process according to item 4 for the preparation of 4- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine, characterized in that 4- (3) -methoxyphenyl] -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine deetherified with aqueous hydrogen bromide in glacial acetic acid. 6. A process according to claim 1 for the preparation of 4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized in that: 4a- (3-Methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyridine is reduced with lithium aluminum hydride. 7. A process according to claim 6 for the preparation of 4- (3-hydroxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, characterized in that: 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine deetherifies with aqueous hydrobromic acid in acetic acid.