Method of producing cis-4a-phenylo-2-substituted-2,3,4,4a,5,6,7,7a-octahydro-1h-2-pyrindines

The subject of the invention is a process for the preparation of new cis-4a-phenyl-2-substituted-2,3,4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridines of the general formula, in which R 1 is an alkyl group having 1-8 carbon atoms or CH₂R₈where R._s represents an alkenyl group of 2-7 carbon atoms or a tetrahydrofuryl group, R₂is a hydrogen atom, a hydroxyl group or an alkoxy group of 1-3 carbon atoms as well as the non-toxic pharmacologically acceptable acid addition salts of these compounds.

In recent years, many studies have been carried out to synthesize new analgesics, since the use of a number of analgesics known to date is limited due to the side effects they induce, which often occur with continued administration of these drugs. Such side effects come down to getting the body used to the drug, i.e. addiction, as well as being allergic to the drug. An example of new, recently invented anesthetic drugs are the decane isoquinolines, especially the 4α-aryl-trans-decahydroisoquinoline described in Belgian Patent No. 802557.

The invention relates to a process for the preparation of the cis-4a-aryl-2-substituted-octane-1H-2-pyrinidine group. These compounds are structurally similar to the above-mentioned isoquinoline derivatives, however, the compounds of the above-mentioned formula have not been prepared by synthesis so far, and only simple, unsubstituted analogs have been reported from the literature. At the docks. Akad. Of Sciences of the USSR 173 (12), 342-5 (1967); CA Vol 67, 6034 (1967) Volo₅ dina et al. describe the preparation of certain octane-2-pyridines, none of which, however, is substituted in the 4a-position. Prochaska et al. Described the preparation of trans-octahydro-2-pyridines, but without a substituent in the 4a position,₁₀ see Coli. Czech. Chem. Commun. 31 (9), 3824-8 (1966), CF Vol. 65, 13651 (1966).

The cis-4-phenyl and phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-pyridines produced by the method according to the invention are₁₅ can be distinguished by the hitherto not described ones, as is the method of their preparation from the new starting compounds of the formula II.

The compounds of formula I are unlike the completely inactive analgesic starting compounds_M. They have valuable anesthetic properties and, unlike compounds known to date, their administration does not induce a drug dependence syndrome, some of which are useful in combating₂₅ drugs caused by opium drugs such as morphine.

As previously stated, the invention relates to a process for the preparation of novel dicyclic compounds which are octahydro-1H-2-pyridines, optionally derived from hexahydro-1H-2-pyridines.

109 690

-1H-cyclopentaIc] -pyridines, especially for the preparation of cis-4a-phenyl-2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridines of general formula 1. Compounds those of the invention are prepared by reacting a compound of general formula 2, wherein R₂ is as defined above, and R'i is hydrogen, with an alkylating agent of formula RiZ as defined above, and Z is a group departing from the normal range found in alkylating agents and optional de-etherification of the resulting compound when Rj is an alkoxy group of 1-3 carbon atoms to give a compound of formula 1, wherein R₂ represents a hydroxyl group.

A preferred group of compounds according to the invention are those compounds of formula I in which R 1 represents an alkyl group of 1-8 carbon atoms or a CH group₂R₂where r₂ represents an alkenyl group with 2 · to 7 carbon atoms. A more preferred group of compounds of the latter mentioned are compounds of formula I in which R₂is hydroxy or methoxy.

The term "1-8 carbon alkyl" as used in the specification and claims denotes a straight or branched carbon chain alkyl group. Typical examples of such alkyl groups with 1 to 8 carbon atoms are especially methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, 3-methylpentyl, 1,2-dimethylpentyl, 2-methylbutyl, 3-ethylpentyl, octyl, 2-methylheptyl, isoheptyl, 3-ethylhexyl, 1,3,3-trimethylpentyl.

The term "CH group₂R₂in which R.₂ denotes a 2-7 carbon alkenyl group "includes straight and branched carbon chain alkenyl groups including allyl, 3-butenyl, 2-pentyl, 3-pentenyl, 2-methyl-2-butenyl, 3-methyl-3-pentenyl, 3-isohexenyl, 2-ethyl-3-butenyl, 4-hexenyl, 3-methyl-2-pentenyl, 3-octenyl, 2-isooctenyl, 2-isopropyl-3-butenyl,

2.3-dimethyl-2-butenyl, 5-heptene Iowa, 6-octenyl, 2-methyl-3-heptenyl and their related alkenyl groups.

In addition, groups of formula CH are included in the groups represented by Ri in formula 1₂R₂where R.₂ is a radical such as 2-tetrahydrofuryl, hydrofurylmethyl and 3-furylmethyl.

The previously discussed pyridine derivatives of formula 1 are prepared by reacting a cyclic anhydride of formula 3 in which R₂ is as defined above, i.e. 4α-aryl-tetrahydro-2,6-two-cyclopenta (c) -pyran, with an amine, in particular with ammonia or with a primary amine according to the commercially provided scheme, where in Formula 4 the symbol Ri is as defined above importance. The cyclic imide produced in this way, i.e.

1.3-di-eo-4-a-aryl-2, 3, 4, 4a, 5, 6, 7, 7a, - octahydro-1H-12-pyridine is then reduced at the 1-position and at the 3-keto group to form a pyridine derivative with Such reduction can be performed by one of the numerous known reduction methods according to methods appropriate for this type of compound. For example, the 1,3-diceopyridine derivative may be reacted with one of a number of reducing agents such as hydride and alkali metal, e.g. with lithium aluminum hydride, sodium borohydride, lithium III-butoxy aluminum hydride and lithium triethoxy aluminum hydride. Reducing agents such as zinc and acetic acid, and catalytic hydrogenation can also be used as desired.

The reduction with lithium aluminum hydride is carried out in a non-reactive organic solvent, especially tetrahydrofuran, diethyl ether, dioxane, diglyme and others. The product obtained is normally isolated after decomposing the remaining unreacted reducing agent contained in the reaction mixture. Such decomposition of the reducing agent, e.g. when lithium aluminum hydride is used, an ester is added to the reaction mixture which readily reacts with an excess of a reducing agent, usually such as ethyl acetate. After the ester is added, an aqueous ammonium chloride solution is usually added to the reaction mixture to facilitate coagulation of the inorganic salts formed during the reaction and subsequent extraction of the product with a suitable organic solvent such as ethyl acetate or tetrahydrofuran. The solvent was evaporated from the combined extracts and the reduced product was obtained as a residue, i.e. 4a-aryl-2,3,4, 4a, 5, 6, 7, 7a-octahydro-1H-'2-pyridine of formula 2. This product is usually obtained in the form of an oil which, if desired, is purified in a known manner, e.g. by distillation and chromatography or by conversion into an acid addition salt, which salt is then purified by crystallization.

Preference is given to using the compounds obtained by reducing the 1-keto and 3-keto groups to 4-aryl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1,3-diceto-1H-2 as starting products. -pyridines such as: 4a-phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine, 4a-(3-methoxyphenyl) -2, 3, 4, 4a, 5 , 6, 7, 7a-octahydro-1H-^l2-pyridine,

4a- (3-ethoxyphenyl / H2-methyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine,

4a-phenyl-2-ethyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine,

4a- (3-isopropoxyphenyl) -2-benzyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine, 4a-phenyl-2-isobutyl-2, 3, 4, 4a, 5, 6, 7a-octahydro-1H-2-pyridine,

4a- (3-methoxyphenyl) -2-i (4-ethylhexyl) H2, 3, 4, 4a,

5, 6, 7, 7a-octahydro-1H-pyrindine,

4a- (3-ethoxyphenyl) -2- (3-chlorobenzyl) -2, 3, 4, 4a, 5,

6, 7, 7a-octahydro-1H-β-pyrindine.

As previously mentioned, very important starting compounds are the 2-unsubstituted pyridine derivatives of the formula II in which R 1 is hydrogen. Such compounds can be easily alkylated at the 2-position to form the pharmacologically active octahydroparidines of formula 1. For this reason, it is also often desirable to prepare 2, 3, 4, 4a, 5, 6, 7-substituted 4α-aryl-2 2 by the methods described above. 7a-octahydro-»lHJ2-pyrinidine,

109 690 in which the 2-position substituent is readily removable to give 2-unsubstituted pyridines of formula 2. The 2-position N-methyl and N-benzyl groups are very easily cleaved off to give 2-unsubstituted pyridines. The 2-methylpyridine derivative prepared above can be reacted with an ester of a haloformic acid such as a chloroformateⁿ phenyl or ethyl to form the corresponding carbamate bound at the 2-position of the ptrindine. This carbamate is then reacted with an aqueous solution of a base such as sodium hydroxide to cleave the 2-position carbamindane molecule to produce the corresponding unsubstituted X-pyridine derivative. Cleavage of the N-methyl group is carried out by the Abel-Monen and Portoghese method. and in J. Med. Chem. 15, 208 <1972).

Likewise, the above-mentioned 4α-aryl-2-benzyl 2,3,4,4a, 5,6, 7,7a-octahydro-1H-2-pyridines can be easily converted into 2-unsubstituted pyridines by simple depenzylation. Such debenzylation can be accomplished by catalytic hydrogenation using, for example, a catalyst such as 5 · / · palladium on carbon.

Such debenzylation reactions are generally used in the preparation of secondary amines and are described in detail by Hartung and Simonoff a Org. Reactions 7, 277 (1953) and by Leonard and Fuji! in J. Amer. Chem. Soc. 85, 3719 (1963).

As can be seen from the above discussion, the following^? typical 2-unsubstituted pyridines of formula 3, wherein R'j is hydrogen, are also important intermediates for the preparation of pyridines of formula T, such as, for example:

4a- (phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine, 4a- (3-methOxyphenyl) 42, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H- <2-pyridine, '

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

4a- (3-isopropoxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-a-pyridine.

The 4a-aryl-2-unsubstituted-2,3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridines thus produced are alkylated according to the invention to the pharmacologically active N -substituted pyridine derivatives. For example, 4a-aryl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridines can be alkylated at the 2-position by reacting them with substantially any reactive derivative of an alkyl group. Such alkylating agents are compounds of formula R_vol-IZ, in which Ri is as defined above and Z is one of the easily exchangeable groups, such as halogen, especially chlorine, bromine and iodine, p-toluenesulfonyl (tosyl), fehyflosulfonyl, methanesulfonyl (mesyl), p-bromophenylsulfonyl (brosyl) and an azido group. It should be noted that the RiZ alkylating agent may be derived, for example, from from unsaturated aryl and cycloalkyl substituents, so the term "alkylating agent" includes compounds such as methyl chloride, ethyl bromide, 5-methylhepitylsylate, allyl bromide, 4-hexa6yl iodide, 3-ethyl-4-pentyl brosylate, cyclopropylmethylchloride, cyclopropylmethylmethyl chloride , cyclohexylmethyl mesylate, 3-tetrahydrofurylmethyl bromide, 2-phenylethyl chloride, 3-benzoylpropyl bromide, 2- (3-chlorophenylthio) ethyl azide, phenoxymethyl bromide, 3-isopropylphenylthiomethyl bromide and other similar compounds.

Thus, 4a-aryl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine can be reacted with an alkylating agent to produce the corresponding 4a-aryl-2-substituted 2, 3 , 4, 4a, 5, 6, 7, 7a-octahydro-1H-pyridine. This reaction is generally known and can be accomplished by treating the appropriate 4α-aryl-octahydro-1H-pyrindine with a suitable alkylating agent, preferably in a non-reactive organic solvent. Such alkylating agents are typically used in an excess of from about 0.5 to about 2.0 moles with respect to the pyridine derivative.

Non-reactive organic solvents commonly used in this reaction are ethers such as diethyl ether, dioxane, tetrahydrofuran, as well as solvents such as benzene, dichloromethane, diethylformamide, dimethylsulfoxide, nitromethane, and hexamethylphosphoric triamide. The base used in the alkylation reaction acts as an acid binder because the alkylation reaction produces a free acid that can bind unreacted 2-pyridine as a salt. Bases generally used as an acid binder in such reactions are sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, and pyridine. Usually it is preferable to use about an equimolar amount of base, however an excess of base can also be used if desired. The alkylation reaction is normally carried out at an elevated temperature in the range of about 50-200 ° C, and under these conditions the alkylation reaction is complete in 1-10 hours, however, the reaction time is not limited to the above range and may be extended as appropriate if desired. .

The reaction product is generally easily isolated by adding water to the reaction mixture and subsequent extraction with a water-immiscible organic solvent, especially benzene, ethyl acetate, dichloromethane, diethyl ether, chloroform. After removing the solvent from the extract by evaporation under reduced pressure, the product is obtained, i.e. 4a-aryl-? 2H-substituted-i2, 3, 4, 4a, 5, 6, 7, 7a-octahydropyridine in the form of an oil or a solid compound at room temperature. The product, if desired, can be purified by known methods, such as, for example, by chromatography, crystallization, distillation or by converting the pyridine derivative into an addition salt with an inorganic or organic acid. Such salts are usually perfectly crystallizing compounds and, after crystallization, give salts of a high degree of purity. If desired, the salt can be broken down into the free compound by treatment with a base such as hydrogen chloride. sodium oxide or potassium carbonate to obtain purified 4a-aryl-2'-substituted-2,3,4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine in free form. orchards.

It should be noted that the obtained 3-alkoxy derivative of the compound of formula 1 can, according to the invention, be subjected to de-etherization and the 3-hydroxy derivative of the compound of formula 1 can be obtained. Such a conversion is easily carried out by reacting n and p. 4a (3-methoxyphenyl) -pyridine derivative with hydrobromic acid in acetic acid. These reactions are generally used to convert methoxyphenyl groups into hydroxyphenyl groups.

As previously reported, the 4α-aryl-2-substituted-octane-1H-β-pyridine derivatives of formula 1 can be reacted with an organic or inorganic acid and the salts thus obtained are purified by crystallization and then decomposed into the free base by treating this salt. with a suitable base, such as sodium hydroxide. Some of the acid addition salts of the compound of formula I fall within the scope of the present invention, especially the non-toxic, pharmacologically acceptable addition salts of the above-described pyridine bases. These non-toxic pharmacologically acceptable addition salts are prepared by reacting a 4α-aryl-2-substituted-octahydro-1H-2-pyridine of the formula I with an organic or inorganic acid. Acids customarily used to prepare pharmacologically acceptable addition salts of the compounds of formula I are especially the hydrohalides such as hydrogen chloride, hydrogen bromide and hydrogen iodide, as well as sulfuric, phosphoric, nitric, perchloric, phosphorous and nitrous acids. Among the organic acids used in the preparation of the pharmacologically acceptable pyridine addition salts of the formula I, especially acids such as acetic, propionic, p-toluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic and benzoic are mentioned.

The pharmaceutically acceptable addition salts of the compounds of formula I are conveniently prepared by simply dissolving 4α-aryl-2-substituted-octahydro-1H-pyrinidine in a suitable solvent such as diethyl ether, ethyl acetate, acetone or ethanol and adding the appropriate acid to the solution. in equimolar amount or in excess. The salt thus produced crystallizes out of solution and can be isolated by filtration and is usually already suitable for use as a pharmacological agent or can be purified by recrystallization from common solvents such as acetone and methanol.

A series of cis-4a-aryl-2-substituted-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-pyrinidines are listed below, typical compounds represented by Formula 1.

4a-phenyl-2- (3-ethylpentyl) - "2, 3, 4, 4a, 5, 6, 7, 7a-eight hydro-ΙΗ-β-pyridine, 4a-bromide (3-methoxyphenyl) -2- / n-octyl / -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H- »2-pyridine,

4a- (3-hydroxyphenyl) -2- (2-propylene) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine, 4a- (3-propoxyphenyl) -2- (2,3-dimethyl-4-hexenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-, 2-pyridine, 4a-phenyl-i2- (5-heptenyl) acetate) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine, 4a- / 3-etho^lxyphenyl) - 2- (2-tetrahydrofurylmethyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrine.

It should be noted that the compounds of formula I contain two asymmetric centers, namely at position 4a and position 7a. The method of the invention comprises the preparation of both individual isomers as well as a racelmic mixture of these isomers which are pharmacologically acceptable as analgesics or antagonists.

However, only the cis-isomer of the compound of formula I is mentioned, namely one in which the aryl group at position 4a is in the same plane and direction as the molecule located at the atom located at position 7a. The invention thus includes pharmacologically active, individual optically active cis-isomers, including a racemic mixture of cis-isomers. Such racemic pairs of cis-octahydropyridines can be separated into the individual stereoisomers by known methods.

Where there are pharmacologically active molecules in one stereoisomer, the dl racemate is a more useful substance because it contains one of the pharmacologically more active isomers.

The preparation of the 4a-aryl-octahydropyridine 55 of the formula I requires the use of starting materials which are mostly new, hitherto unknown and not readily available. The food product used to prepare the compounds of formula 1 is 4α-aryl-tetrahydro -2,6-dice-cyclopenta (c) -pyran. These starting materials are prepared from 2-arylcyclohephosanones such as 2-phenylcyclohexanone and 2- (3-methoxyphenyl) -cyclohexanone. To prepare dicetocyclopentapyrane derivatives, 2-arylcyclohexanone is alkylated in position 2 by reaction with an alkylhaloacetate such as ethyl chloroacetate in the presence of a base such as sodium hydride to form the corresponding 2-aryl-2-alkoxycarbonylmethylcyclohexanone. Similarly, to prepare 2-aryl-2-alkenyl-1-aminomethylcyclopentane, the 2-arylcyclohexanone is first alkylated at the 2-position 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 prepare the corresponding 2-aryl-2-alkenylcyclohexanone as well as the 2-aryl-'2-alkenylcyclohexanone are then formylated at the 6-position by reaction with an alkyl formate such as ethyl formate. in the presence of metallic sodium or potassium. The formyl cyclohexanone derivatives are then reacted with p-toluenesulfonyl azide and the reaction of the formyl molecule at the 6-position with the azo group yields 2-aryl2-alkoxycarboonylmethyl-6-diazocyclohexanone and 2-arylalke109 690 nyl, respectively. 6-diazocyclohexanone. These diazocyclohexanone derivatives are then photolyzed with light at a wavelength of about 3000 Angstroms in an alkanol solvent such as methanol to form a ring with nitrogen gas evolution to give 2-aryl-2-alkoxy respectively.^,dwarf onylmethyl-1-methoxycarbonylcyclopentane and 2-aryl-2-alenyl-1-methoxycarbonylcyclopentane. These compounds are then subjected to deesterification, i.e. hydrolysis, with an aqueous alkali to generate the corresponding diacid and monoacid.

More specifically, hydrolysis of 2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentane yields the corresponding 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane. Similarly, hydrolysis of 2-aryl-2-alkenyl-1-methoxycarbonylcyclopenyltane produces the corresponding 2-aryl-2-alkenyl-1-hydroxycarbonylcyclopentane. Diazic acids, namely 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclppentane are then cyclized by reaction with an acid halide such as acetyl chloride to form the corresponding 4α-aryl-tetrahydro-2,6-dicetocyclopene anhydride c / ^ pyran. Such pyranes are the starting materials for the pyridines of formula 1.

The 4α-aryl-2-substituted octane-1H-2-pyridines have been found to be suitable for the control of pain, and therefore these compounds can be used as analgesics. In addition, it has been found that the pyridine derivatives of formula I, unlike the starting compounds of formula II, have both pain agonist and antagonistic properties, and since they simultaneously induce anesthesia in mammals, the compounds can be administered to mammals as analgesics. This action is associated with a greatly diminished risk of developing drug addiction which could result from their opium-type action.

The analgesic activity of the compounds of formula I was determined in animal studies according to generally accepted methods for the determination of analgesic activity. Such tests include the mobility test, i.e. the curl of the mouse, and the method of determining the vibrations of the rat's tail.

As previously noted, the compounds of formula I exhibit analgesic activity as determined by the mouse curl test. According to this test, mice "wriggle" is caused by an intraperitoneal injection of acetic acid. The degree of analgesic activity of the drug is determined by observing mice writhing when injected with acetic acid after administration of the drug. If 4a (3-methoxyphenyl) -2-methyl-2,3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine hydrochloride is administered subcutaneously in the amount of 20 mg / kg of weight in the body, the mice that induced the flagella showed a 10% reduction in the flagella. A subcutaneous dose of 10 mg / kg causes 98 · / · inhibition of flagella. Similarly, an oral dose of the above specified compound of 20 mg / kg produced 100 percent inhibition of convolution, and a dose of 10 mg / kg resulted in 98 percent inhibition. Moreover, it has been found that a subcutaneous dose of 5 mg / kg naloxone causes complete inhibition of the activity of the compound of the invention, which means that the compound of the invention induces opium-type anesthesia. The above-mentioned rat tail jerk test compound causes a significant prolongation of the reaction time at doses of the order of 80 mg / kg, given both subcutaneously and orally, giving the same effect also at a dose as low as 20 mg / kg. All measurements were taken at 0.5 and 2 hours after drug administration.

4- (3-hydroxyphenyl-2-methyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine was tested similarly). At a subcutaneous dose of 0.5 µg / kg, this compound caused a 75% inhibition of wrinkling in animals, and at an oral dose of 10 mg / kg, there was 98% inhibition of wrinkling at the 0.5 hour dose. Naloxone completely inhibited the activity of the test compound at a subcutaneous dose of 0.5 mg / kg. The rat tail vibration test revealed that the test compound causes a significant increase in reaction time at subcutaneous and oral doses of 20 mg / kg.

Another compound of formula 1, namely 4a-phenyl-2-methyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pi <RTI ID = 0.0> bromide at a dose of 100 mg / g / g administered after 0.5 hour it causes a 70% inhibition of flagella in the group of mice tested. An oral dose of 20 mg / kg of this compound, given after 1.5 hours, produced 58% inhibition which was completely eliminated with naloxone. The rat tail test showed that this compound caused a moderate increase in reaction time at the dose of 80 mg / kg.

The amount of the ED50 dose, i.e. the dose which in the tested mice and rats reduces the number of "folds" by 5O * / s compared to the control animals, determined for the compound of formula 1, in individual studies is illustrated in the following table:

Ta b 1 ica

<td>Example no</td><td>salt</td><td>ED mice flagella test_M.</td><td>_vol Total test in the ED50 rat</td>

<td>V</td><td> _</td><td> 0,4</td><td> 0,2</td>

<td>VI</td><td>HBr</td><td> 1,0</td><td> 0,5</td>

<td>VII</td><td> —</td><td> 20</td><td> 80</td>

<td>VIII</td><td>HBr</td><td> 50</td><td> 80</td>

<td>IX</td><td>HBr</td><td> 20</td><td> —</td>

<td>X</td><td>HBr</td><td> 20</td><td> 80</td>

<td>XI</td><td>HBr</td><td> 1,0 .</td><td> 80</td>

The 4a-aryl-2-substituted-2j 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridines of formula 1 are therefore useful for inducing anesthesia in mammals such as man. These compounds can be administered orally or parenterally to mammals. In general, it is preferred to use pharmaceutically acceptable acid addition salts of these compounds when administered by the oral route, as such salts are readily converted into known oral formulations. For example, one or more pharmacologically active compounds of formula I in free base form or in pharmaceutically acceptable acid addition salt form can be made into a suitable formulation by reducing the compounds with one of the numerous diluents, excipients or carriers known and used for this purpose. Examples of such diluents and excipients are those conventionally used in the preparation of pharmaceutical formulations, especially scrap powders, sucrose, cellulose, magnesium stearate, lactose, calcium sulfate and sodium benzoate. Such mixtures can be melted and made into tablets or filled into telescopic, sealed gelatin capsules suitable for administration. If desired, the active compounds of the formula I can additionally be mixed with other known substances to increase the anesthetic effect, such as caffeine,? -Cetoaminophenone and propoxyphenone.

The active compounds of the formula I can be used in addition to sterile aqueous and non-aqueous solutions, as well as suspensions and emulsions suitable for parenteral administration.

Suitable diluent carriers for the preparation of non-aqueous solutions are those which are generally used in the preparation of preparations such as propylene glycol, vegetable oils such as olive oil, as well as various organic esters such as ethyl oleate. Aqueous solutions for peros and parenteral use may include isotonic saline solutions.

The dose of a preparation containing one or more of the active 4a-aryl-2-substituted-octahydro-! H ^ 2-pyridines of formula 1 for mammals, such as humans, may vary within very wide limits and its amount depends both on the intended therapeutic effect , the method and route of administration, and the complaints and duration of the "treatment". A typical, suitable dose is 1.0 to about 25 mg / kg body weight in 1 day, the dose optionally being divided and given in 2 to 4 portions over the course of the day. A preferred oral dose is 2 to about 50 mg / kg.

Example I. For a solution of 2 g of 4a-phenyl-2, 3,

4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine in 30 ml of N, N-dimethylformamide, containing 1.23 g of sodium bicarbonate, passing at 25 ° C, is added in one portion, 1 23 g of 2-propenyl bromide and the reaction mixture is refluxed with stirring for 4 hours. After the reaction mixture has cooled to room temperature, it is filtered and evaporated under reduced pressure to obtain an oily residue. The oil obtained is dissolved in 300 ml of diethyl ether and the solution is washed with water, dried and then the solvent is removed by distillation under reduced pressure. 4 [alpha] -phenyl-2- (2-propenyl) -2, 3, 4, 4 [alpha], 5, 6, 7, 7 [alpha] -phenyl-1-H ^ 2-pyridine is obtained as an oil. The oil was dissolved in 150 ml of fresh diethyl ether and a stream of hydrogen bromide gas was passed through the resulting 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, 4α, 5, 6, 7, 7a-octahydro-1H-pyridinium bromide, m.p. 185-87 ° C, of ​​formula Is the group -CH₂CH = CH₂and R.₂= H:

Analysis for C.₁₇H.₂₄BrN.

Calculated:% C 63.36,% H 7.51,% N 4.35

Found:% C 63.63,% H 7.24,% N 4.24. Example II and III. The procedure described in Example 1 was repeated to prepare the following 1-alkylpyridine derivatives by reacting 4a-phenyl-2,3, 4, 4a, 5, 6, 7, 7a-octane-1H-2-pyridine with the appropriate alkylating agents.

4a-phenyl-2-n-propyl-2,3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridinium bromide, m.p. 245-247 ° C as defined by formula 1, where R / CHa / dGHj, and R₂= H.

Analysis for C ^ BrN.

Calculated:% C 62.96, ° H H 8.08,% N 4.32. Found:% C 62.74,% H 8.22,% N 4 E 3.

4-phenyl-2-n-pentyl-2,3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridinium bromide, mp 240-243 ° C, defined by formula 1, where R ^ / CH ^ CH, and R₂= H.

Analysis for C.₁₉H._inBrN.

Calculated:% C 64.77,% H 8.58,% N 3.98. Found:% C 65.04,% H 8.70,% N 3.87.

Example IV. To a solution of 3.Q g 4a-phenyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine in 10 ml of 88% formic acid, while stirring at 200 ° C, is added, 10 ml of 38% formaldehyde dropwise over 15 minutes, then the reaction mixture is kept at 95 ° C for 8 hours. The reaction mixture is then cooled to 25 ° C, and 100 ml of a 4N hydrochloric acid solution are added dropwise thereto over 30 minutes. The acidic reaction mixture was concentrated under reduced pressure to obtain an oily product which was dissolved in 100 ml of water. The aqueous solution is made alkaline by adding 50% aqueous sodium hydroxide solution. The product which precipitates from the alkaline solution is extracted with diethyl ether. The ether extract is washed with water, dried and the solvent is evaporated under reduced pressure to give 4a-phenyl-2-methyl-2,3,4,4a,

5, 6, 7, 7a-octahydro-1H-'2-pyrinidine in the form of an oil. The phen oil is dissolved in 150 ml of diethyl ether and, while stirring, to the ethereal solution at 25 ° C, 10 ml of 48% hydrobromic acid in 10 ml of ethanol are added dropwise over 10 minutes. The product that precipitated out of solution was isolated by filtration. After recrystallization from diisopropyl ether, 2.7 g of 4α-phenyl-2-methyl-2, 3, 4, 4a, 5, 6 bromide are obtained.

7, 7a-octahydro-1H-2-pyrindinium, mp 209-210 ° C, defined by formula 1, where R, CHj, and R₂= H.

Analysis for CuIfeBrN.

Calculated:% C 60.81,% H 7.49,% N 4.73. Found:% C 60.55,% H 7.49,% N 4.57.

Example 5 Solution 1.6 g of 4a- (3-methoxyphenyl) -2-methyl-2,3, 4, 4a, 5, 6, 7, 7a-octahydro 109 690

-ΙΗ-2-pyridine in 12 ml of acetic acid containing 12 ml of 48% aqueous hydrobromic acid solution is stirred and refluxed for 15 hours. The acidic reaction mixture is cooled to about 10 ° C and the pH of the solution is adjusted to about 19.2 by adding 50% aqueous sodium hydroxide solution. The product obtained is soluble in an alkaline aqueous solution and this product is extracted with a solution of 90 ml of n-butanol with 30 ml of benzene. The organic layer is separated, washed with water and dried. The excess solvent is evaporated off under reduced pressure to give the demethylated oil product which, after crystallization from diethyl ether and ethyl acetate, forms 4- (3-hydroxyphenyl) -2-methylO'i-2, 3, 4, 4a, 5, 6 , 7, 7a-octahydro-1H-2-pyridine, mp 151-153 ° C as defined by Formula I, where 'Ri = CH | and R_vol“OH.

Analysis for C ^H ^NO. _#

Calculated:% C 77.83, '/' H 9 * 15, VoN 6.06 Found:% C 77.60,% H 8.88. ^e/ iN 5.76.

Example VI. Solution, 1.5 g of 4- (3-hydroxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine in 15 ml of Ν, Ν-dimethylformamide, containing 1.0 g of sodium bicarbonate and 0.95 g of 2-tetrahydrofuryl bromide are refluxed for 4 hours, the reaction mixture is cooled to about 25 ° C and the mixture is extracted several times with diethyl ether. The combined extracts are washed with water and dried. The solvent is removed under reduced pressure to give 4a- (3-hydroxyphenyl) -2- (2-tetrahydrofurylmethyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1'H-2-pyridine as oil. The oil obtained is dissolved in diethyl ether and a solution of gaseous hydrogen bromide in diethyl ether is introduced into the solution. After crystallization, the product is filtered off to obtain 1.0 g of 4- (3-hydroxyphenyl) -2- (2-tetrahydrofuryl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridinium bromide. mp 190-192 ° C as defined by Formula I, where R 1 is tetrahydrofurylmethyl and R 1⁼= OH.

Analysis for 0₁₉Η_μΝ₂ΟΒγ.

Calculated:% C 59.69,% H 7.38,% N 3.66 Found:% C 59.89,% H 7.40,% N 3.78.

Examples VII-IX. The procedure described in Example 6 is followed by reacting with an alkyl iodide in the presence of sodium bicarbonate 4- (3-hydrosyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyrinidines to obtaining 4a- (3-hydroxyphenyl) -2- (2-propenyl) -2, 3, 4, 4a, 5, 6, 7, 7a, octane-1H-2-pyridine with a melting point of 0Θ -108 ° C, determined by formula 1, where

R₁-CH /: H = CH₂and R ^ = OH.

Calculated:% C 79.33,% H 9.01,% N 5.44 Found: ° C 79.29, EH 8.92,% N 5.44.

In a similar manner, 4a- (3-methoxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2H-pyridine obtained according to Example 6 is reacted with 1-iodopropane in the presence of sodium bicarbonate to obtain 4a- (3-methoxyphenyl) -2-n-propyl-2,

3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine, which is converted into a salt with hydrogen bromide by reaction with gaseous hydrogen bromide in diethyl ether, melting at 197 ° -199 * ° C , represented by formula 1, wherein Rj is (CHj) 2CHe and Rt = O 4H&gt;.

Analysis for CjgH ^ NOBr.

Calculated: ° / ° C 61.0 * 2, '/ · Η 7.97,% N 3.95. Found:% 60.65,% H 7.7, '52,% N 4.07.

In a similar manner, 4a- (3-methoxyphenyl) -2, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine was 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, 7 ao hydrogen o-1H-2-pyridine, which was converted into crystalline bromide 4a with a solution of gaseous hydrogen bromide in diethyl ether - (3-methoxyphenyl) -2-n-pentyl-2,3,4, 4a, 5, 6, 7, 7a-octahydro-ΙΗ-2-pyridinium, m.p. 179-181 ° C, is defined by formula 1, wherein Ri is / CH2 and CHj and R &amp; lt;⁼OH

Analysis for Ό_μΗ * ΝΟΒγ.

Calculated:% C 62.82,% H 8.44,% N 4.18. Found:% C 62.87,% H 7.98,% N 4.02.

Example X. A solution of 2.0 g of 4a- (3-methoxyphenyl) -2-n-propyl-2,3,4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine prepared according to example 8 in 20 ml of glacial acetic acid and 29 ml of 48% aqueous hydrobromic acid solution and stirred and refluxed for 12 hours. The mixture is then cooled and poured onto 108 g of ice, the resulting mixture is basified with an aqueous sodium hydroxide solution to pH 10.2 and extracted with 200 ml of a mixture of 3 parts of n-butanol and 1 part of benzene. The combined extracts are washed by evaporation under reduced pressure to give 1.3 g of 4a-(3-hydroxyphenide) -2-n-propyl-2,3,4,4a, 5, 6, 7, 7a-octahydro-1H ^ 2 -pyridine in the form of an oil. The oil was dissolved in diethyl ether and the resulting solution was added to a solution of gaseous hydrogen bromide in diethyl ether. The obtained 861 hydrobromic acid of the above compound was isolated by filtration to obtain 1.1 g of 4- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5, 6, 7, 7a-octahydro-1H-2. -pyridinium, mp 235-236 ° C, defined by formula I, in which R 1 is a group of formula / CHj / jCH6 and R ± = = OH.

Analysis for C ^ H ^ NOBr.

Calculated:% C 60.00,% H 7.70,% N 4.12. Found:% C 59.98,% H 7.50,% N 3.98.

Example XI. The procedure described in Example 10 is followed by reacting 4a-Z3-methoxyphenyl (-2-n-pentyl-2, 3, 4, 4a, 5, 6, 7, 7a-octahydro) with an aqueous solution of hydrobromic acid in glacial acetic acid. 4H-2-pyrindine. The obtained 2-n-pentyl-2,3, 4, 4a, 5, 6, 7, 7a-octahydro-1H-2-pyridine is converted into the corresponding hydrobromic acid salt, melting at 171-173 ° C, defined by the formula 3. The compound of claim 1, wherein Ri is / CH / 4GH4 and R1 = OH.

109 690

Analysis for C ^ H ^ NOBr.

Calculated:% C 61.95,% H 8.21,% N 3.80. Found: ° C 51.55,% H 7.9 (3.% N 3.54.