DE2748466A1 - 4A-ARYLOCTAHYDRO-1H-2-PYRINDINE - Google Patents

Description

Χ-4466

Eli Lilly and Company , Indianapolis, Indiana, V. St. A.

4a-Aryloctahydro-iH-2-pyrindine

8Q9818 / 0932

Recently, strong efforts have been made in the field of synthesis of analgesics, i.e. drugs, that can eliminate the sensation of pain. Some of the currently available analgesics are in their use limited as a result of various undesirable side effects that often occur with continuous use. Such side effects are for example addiction and allergy. Examples of new analgesics that have been discovered lately are the decahydroisoquinolines, especially the 4a-aryl-trans-decahydroisoquinolines, which are known from BE-PS 802.

The present invention relates to a group of in the 2-position substituted cis-4a-aryl-octahydro-1H-2-pyrindines. These compounds are structurally related to the above isoquinoline derivatives something related; however, the compounds of the formula I given below have hitherto not been synthetically producible. Only simple, unsubstituted pyrindine analogs are known in the literature. For example, from Dokl. Acad. Nauk USSR 173 (2): 342-5 (1967); cf. Chem. Abstr. 67, 6034 (1967) certain octahydro-2-pyrindines known, of which however, none is substituted in the 4a-position. Similar is from Coll. Czech. Chem. Commun., 31 (9), 3824-8 (1966); cf. Chem. Abstr. 65, 13651 (1966) a trans-octahydro-2-pyrindine which is not substituted in the 4a-position is known.

There were now new 2,3,4,4a, 5,6,7-7a-octahydro-1H-2-pyrindines substituted in the cis-4a position with a phenyl radical or substituted phenyl radical as well as intermediates that are suitable for their production, found. These are to new bicyclic compounds, also called hexahydro-1H-cyclopenta- / c / -pyridines are designated.

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The invention relates to those substituted in the 2-position cis -4a-Aryl-2,3, 4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine der general formula

U)

Hydrogen, an alkyl radical with 1 to 8 carbon atoms, the group CH ₉ R- or the group

^R 6

means in which

R _{3 represents} an alkenyl group having 2 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a furyl or tetrahydrofuryl group;

R- and R- independently of one another hydrogen, one Represent an alkyl group having 1 to 3 carbon atoms or a halogen atom;

η is 0, 1, 2 or 3;

m is 0 or 1 except that when m

is, η does not have the value 0;

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· * ■■■

2748A66

X is one of the groups CO, CHOH, CH =CH, S or

Is 0 with the exception that when η is 0, X is neither sulfur nor oxygen means; and

R “hydrogen, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or an alkanoyloxy group having 1 to 3 carbon atoms;

as well as the non-toxic pharmaceutically acceptable acid addition salts of that.

Some of the compounds of the formula I in which the substituent in the 2-position is restricted to certain radicals are according to manufactured using the method described in more detail below.

The invention furthermore relates to a process for the preparation of a cis compound of the general formula

ν V

'an alkyl group having 1 to 8 carbon atoms or a remainder of the formula

R.

CH ₂ R ₃ or.

is where

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R s

R_ is an alkenyl group with 2 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a furyl or tetrahydrofuryl group;

R. and R ₁ . are independently hydrogen, an alkyl group having 1 to 3 carbon atoms or a halogen radical;

η is 0, 1, 2 or 3;

m is 0 or 1 except that when m is 0, η is not 0;

X is a group of the formula CO, CHOH, CH = CH,

Is S or 0, except that when η is O, X is neither S nor 0, and

R_ hydrogen, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or an alkanoyloxy group having 1 to 3 carbon atoms;

as well as the non-toxic, pharmaceutically acceptable acid addition salts thereof, which is characterized in that a compound of the general formula

(HD,

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where R _? has the meaning given above and R ₁ ″ denotes hydrogen, with an alkylating agent to form a compound of the formula II in which R 'denotes an alkyl group having 1 to 8 carbon atoms or a group of the formula CH ₃ R ₃ in which R ^ is an alkenyl group 2 to 7 carbon atoms, or with an acylating agent with subsequent reduction to a compound of the formula II in which R ₁ ^{1 is} a group CH ₂ R, in which R ^. a cycloalkyl group with 3 to 6 carbon atoms, a furyl or tetrahydrofuryl group or a group of the general formula

denotes, in which n, m, R. and R ^ have the meanings given above, optionally carries out an ether cleavage if R ₂ denotes an alkoxy group having 1 to 3 carbons, a compound of the formula II being obtained in which R ₂ is a hydroxyl group, and optionally acylated a compound of the formula II in which R "denotes a hydroxyl group to give a compound of the formula II in which R" denotes an alkanoyloxy group having 1 to 3 carbon atoms.

A compound of Formula I wherein R _{1 is} hydrogen is prepared by the following procedure.

The invention thus also relates to a process for the preparation of a cis compound of the general formula

8098Ϊ8 / 0932

wherein R ₁ ¹ 'is hydrogen, an alkyl group having 1 to 8 carbon atoms or a group of the formula

and R ₂ denotes hydrogen, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or an alkanoyloxy group having 1 to 3 carbons, which is characterized in that one is a compound of the general formula

(IV)

wherein RJ ¹ and R ₂ have the abovementioned meaning, are reacted with a reducing agent, where appropriate, the compounds of the formula III in which R ₁ ¹¹ is an alkyl group having 1 to 8 carbon atoms or a group of formula

is, to compounds of formula III, wherein R ₁ ¹¹ is hydrogen, splits, and optionally the compounds of formula III wherein R ₂ is an alkoxy group having 1 to 3 Kohlentoffatomen to give the compounds of formula II in which R_ represents a hydroxyl group, a Undergoes ether cleavage.

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A preferred group of compounds is that of compounds of the formula I in which R _{1 is} an alkyl group with 1 to 8 carbon atoms or a group of the formula CH ₂ R ₃ in which R is an alkenyl group with 2 to 7 carbon atoms or a cycloalkyl group with 3 to Means 6 carbon atoms. An even more preferred group of compounds within the last-mentioned preferred group are those of the formula I in which R "denotes a hydroxyl or methoxy group. A very particularly preferred group of intermediates are those of the formula III in which R. is hydrogen.

Throughout the specification and in the claims, the term "alkyl group having 1 to 8 carbon atoms" means both a group with a straight chain as well as a branched chain. Examples of typical alkyl groups having 1 to 8 carbon atoms are the 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 ones Groups.

The expression "group of the formula CH_R_, in which R _{3 is} an alkenyl group with 2 to 7 carbon atoms" is also to be understood as meaning both straight-chain and branched-chain alkenyl groups with 8 carbon atoms or below, such as, for example, the allyl, 3-butenyl, 2- Pentenyl, 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-heptenyl-, 6-octenyl-, 2-methyl-3- to understand heptenyl and related alkenyl groups.

In addition, the definition for R ₁ in formula I includes the group which is characterized by the formula CH ₃ R, in which R _{3 is} a cycloalkyl group having 3 to 6 carbon atoms. Such groups are, for example, the cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or

8 0 98 T8 / 0 <3f3 2

Cyclohexylmethyl group. R ₁ can also mean the 2-tetrahydrofurylmethyl, 3-tetrahydrofurylmethyl or 3-furylmethyl group.

In formula I, R _{1 can} also be a group of the formula

wherein η is 0, 1, 2 or 3 and m is 0 or 1, with the exception that when m is 0, η is other than 0; in which furthermore X _{denotes the radical CO 1} CHOH, CH = CH, S or 0, with the exception that when η denotes 0, X denotes a radical other than sulfur or oxygen; and R- and R _5, independently of one another, denote hydrogen, an alkyl group having 1 to 3 carbon atoms or a halogen radical. In this formula, the term "alkyl group having 1 to 3 carbon atoms" means, for example, the methyl, ethyl or propyl group. The term “halogen radical” is to be understood as meaning fluorine, chlorine, bromine or iodine. Examples of typical groups R. of the formula I are the benzyl, 2-phenylethyl, 3-phenylpropyl, 3-methylbenzyl, 4-chlorobenzyl, 2,4-dibromobenzyl, 2- (2-methyl-5- ethylphenyl) ethyl-, 3- (4-isopropylphenyl) propy1-, benzoylmethyl-, benzoylethyl-, 4-iodobenzoylmethyl-, 2-methyl-4-chlorobenzoylmethyl-, 2-phenyl-2-hydroxyethyl-, S-phenyl-S- hydroxypropyl-, 2- (4-F "luophenyl) -2-hyd.roxyethyl-, phenoxymethyl-, 3,5-diethylphenoxymethyl-, 3-phenylthiopropyl-, 2-methylphenylthiomethyl-, 3,5-dichlorophenylthiomethyl-, S-chlorine -S-bromophenylthiomethyl group or related groups.

The above-mentioned pyridine derivatives of the formula I are produced by first an amine, especially ammonia or a primary amine, with a cyclic anhydride, namely a 4a-aryl-tetrahydro-2,6-dioxocyclopent / c / pyran, according to the following implements generalized reaction scheme:

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>> ■

+ HN-R

2 1

wherein R ₁ and R _{2 have} the meaning given above. The 1,3-dioxo-4a-aryl-2,3,4,43,5,6,7,7 aoctahydro-1H-2-pyrindine, a cyclic imide, is then added to the oxo groups in 1- and 3-position reduced to a pyridine derivative of the formula III. In practice, it is preferred to use 4a-Ary1tetrahydro-2,6-dioxocyclopenta / c / pyrans in which the substituent on the aryl group, which is denoted by R- in the above-mentioned formulas, is hydrogen or an alkoxy group having 1 to 3 carbon atoms means. Among these alkoxy groups having 1 to 3 carbon atoms, the methoxy group is preferred because it can be demethylated to a hydroxyl group at later stages, as will be described below. When reacting an amine with the above-mentioned cyclic anhydride, it is similarly preferred to use amines, such as ammonia, alkylamines having 1 to 8 carbon atoms, in particular methylamine, and arylamines, in particular benzylamine. The 2-methyl- and 2-benzylpyrindine derivatives prepared in this way can easily be converted into the corresponding pyrindine unsubstituted in the 2-position, which in turn can easily be converted to other 2-substituted compounds of the formula I by alkylation and acylation. Such conversions are also described below.

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In the preparation of the 1,3-dioxo-4a-aryl-2 _r 3 _# 4 _# 4a, 5,6,7,7aoctahydro-1H-2-pyrindine according to the reaction scheme given above, the 4a-aryl-tetrahydro-2 _f 6-dioxo-cyclopenta- / c / pyran and the amine typically reacted in approximately equimolar amounts, although, if desired, an excess of one of the reactants can be used. The reaction can be carried out in one of the conventionally used non-reactive organic solvents such as aromatic solvents such as benzene, toluene, xylene, methoxybenzene and nitrobenzene, and in non-aromatic solvents such as chloroform, dichloromethane, dimethyl sulfoxide, nitromethane, acetone, tetrahydrofuran, dimethylformamide and dioxane. The reaction is typically carried out at elevated temperature, for example at temperatures from about 50 to about 200 ⁰ C and preferably from about 8O to about 150 ⁰ C. Since the reaction between the amine and the cyclic anhydride to the corresponding cyclic imide from the formation of Is accompanied by water, it can be advantageous to conduct the reaction in such a way that the water, as it forms, is removed from the reaction mixture. Any of the commonly used methods of keeping a reaction mixture dry can be used for this, such as the use of molecular sieves, or alternatively a Dean-Stark trap with reaction solvents such as benzene or toluene can be used. The reaction between the amine and the cyclic anhydride is normally complete within 24 to 72 hours; however, longer reaction times are not detrimental to the product formed and can be used if desired. The cyclic imide formed in this way, namely the 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine, can easily be isolated by the reaction solvent is removed, for example by evaporation under reduced pressure, and the product

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can further by customary methods, such as acid or Base extraction, recrystallization and chromatography.

As indicated above, the 4-aryl-tetrahydro-2,6-dioxocyclopenta / c / pyran with ammonia to the corresponding 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine are implemented, which is unsubstituted in the 2-position, or the pyran derivative can alternatively with a primary amine directly to a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine substituted in the 2-position implemented. It was further pointed out that, if desired, the To implement a pyran derivative with a primary amine to a pyridine derivative substituted in the 2-position, it is preferred that methylamine or benzylamine is used as such a primary amine. Such primary amines are preferred because they in their implementation with a 4-aryl-tetrahydro-2,6-dioxocyclopenta / c / pyran lead to a substituted in 2-position 1,3-dioxopyrindine derivative, which in its reduction gives a pyridine derivative substituted in the 2-position, in that the substituent in the 2-position can be easily removed, a pyridine derivative which is unsubstituted in the 2-position is obtained. The pyridine derivative which is unsubstituted in the 2-position is an extremely important intermediate in the manufacture of all other pyrindines of formula I, as further below is described. It should be noted, however, that although the preferred primary amines for reaction with the said Pyrane derivative are methyl- and benzylamine, but that practically any primary amine with the pyran derivative to the corresponding, 4a-aryl-2,3,4,4a-5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine substituted in the 2-position can be implemented. It is also pointed out that the last-mentioned compound, which is a 1,3-dioxopyrindine derivative,

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must be reduced at their 1- and 3-oxo group so that the pharmacologically valuable pyrindine according to formula I can be obtained. Preferably, therefore, any group included in the 2-position of such a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine stands, a group that is opposed to the reduction process, which is used to reduce the 1- and 3-0xogruppe are used, is practically insensitive. For groups that are not as resistant to a reduction are, it is preferred to proceed so that these groups by alkylation or acylation and subsequent Reduction of the pyrindine derivatives unsubstituted in the 2-position to be introduced.

The following list contains representative 4a-aryl-2,3,4,4a-5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine, which are routinely prepared directly by reacting an amine with a cyclic anhydride, as described above, and which subsequently reduced to pharmacologically valuable pyrindine derivatives, as described in detail below will.

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

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

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

4a- (3-ethoxyphenyl) -2- (3-phenylpropyl) -2,3,4,4a, 5,6,7,7aoctahydro-1,3-dioxo-1H-2-pyrindine,

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

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

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

4a-phenyl-2- / 2- (3-chlorophenyl) ethyV-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine,

4a- (3-methoxyphenyl) -2-cyclopropylmethy1-2,3,4,4a, 5,6,7,7aoctahydro-1,3-dioxo-1H-2-pyrindine,

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

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

4a-Phenyl-2- (3,4-dimethylpheny1) methy1-2,3,4,4a, 5, G, 7,7a-octahydro-1,3-dioxo-1H-2-pyrindine and

4a- (3-propoxyphenyl) -2- (4-phenylbuty1) -2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine.

As already mentioned, the 4a-aryl-2,3,4,4a, 5,6-7,7a-octahydro-1,3-dioxo-1H-2-pyrindines mentioned are of the general formula IV by reducing the 1- and 3-oxo groups to the 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines converted to formula III. This reduction can be carried out according to any of the usual reduction processes known to those skilled in the art are familiar. For example, the 1,3-Dioxopyrindinderivat with one of the acting as a reducing agent alkali hydrides, such as for example lithium aluminum hydride, sodium borohydride, lithium tri-tert.-butoxyaluminum hydride and lithium trimethoxyaluminum hydride, implemented. If desired, can

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reducing agents, such as zinc and acetic acid, or catalytic hydrogenation can also be used. The preferred method for reducing a 4a-aryl-2,3,4,4a, 5,6,7,7 aoctahydro-1,3-dioxo-1H-2-pyrindine of the formula IV is to use lithium aluminum hydride as the reducing agent. Typically a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine such as 4a-phenyl-2-methyl-2,3 , 4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine, reacted with about twice the molar amount of lithium aluminum hydride in an inert organic solvent. Inert organic solvents normally used in the reaction are, for example, tetrahydrofuran, diethyl ether, dioxane, diglycol dimethyl ether and related solvents. The reaction is normally carried out at a temperature of about 20 to about 100 ^° C. and, if this temperature is maintained, is routinely practically complete after about 4 to 20 hours. The product is normally obtained by first decomposing any unreacted reducing agent that may have remained in the reaction mixture. Such a decomposition is brought about, for example when using lithium aluminum hydride as reducing agent, by adding an ester to the reaction mixture which reacts easily with excess reducing agent. An ester such as ethyl acetate is usually used for this purpose. After the ester has been added to the reaction mixture, an aqueous ammonium chloride solution is typically added to the reaction mixture in order to coagulate inorganic salts formed during the reaction; then the product is 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 the reduced product

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is, namely a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine of formula III. This product is typically obtained in the form of an oil and, if desired, can be, for example easily further purified by distillation or chromatography or one can have such a compound in it Transfer acid addition salt, which can then be purified by recrystallization.

Compounds of formula I (as indicated by formula III), which in this way easily by reducing the 1- and 3-oxo groups a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxoilH-2-pyrindine can be obtained according to the methods described above are, for example, the following:

4a-phenyl-2,3,4,48,5,6,7,7a-octahydro-1H-2-pyrindine,

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

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

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

4a- (3-isopropoxyphenyl) -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-octahydro-1H-2-pyrindine,

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

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

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As mentioned above, the pyridine derivatives unsubstituted in the 2-position, in which R ₁ in formula III is hydrogen, are extremely important intermediates for the preparation of all pyridine derivatives according to formula I. Such compounds can easily be alkylated and acylated in the 2-position, whereby pharmacologically active octahydropyrindines of the formula I or, in the case of the N-acylated derivatives, intermediate products which can easily be converted into the active analgesics of the formula I. It is therefore often expedient to use the processes described above to prepare 4a-aryl-2 * 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines which are substituted in the 2-position and in which the substituent is located Can easily be removed in the 2-position, so that the corresponding octahydropyrindine derivatives unsubstituted in the 2-position are obtained. As already mentioned, the N-methyl and N-benzyl groups can easily be split off, so that the corresponding pyridine derivative which is unsubstituted in the 2-position is obtained. The 2-methylpyrindine derivatives prepared as described above can be reacted with a haloformic acid ester, such as phenyl or ethyl chloroformate, to give the corresponding carbamate in the 2-position of the pyrindine. This carbamate is then reacted with an aqueous base, such as sodium hydroxide solution, in order to split off the 2-carbamate radical and in this way to provide the corresponding pyridine derivative which is unsubstituted in the 2-position. One such method for splitting off an N-methyl group is that of Abel-Monen and Portoghese, described in J. Med. Chem., 15, 208 (1972).

The 4a-aryl-2-benzyl-2,3,4,4a, -5,6,7,7a-octahydro-iH-2-pyrindines mentioned above can be prepared analogously easily into the corresponding pyrindine derivatives unsubstituted in the 2-position by simple Convict debenzylation. Such debenzylation can be achieved by catalytic hydrogenation, whereby one for example as a catalyst 5% palladium, suspended

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Coal, used. Such debenzylation reactions are generally customary for the preparation of secondary amines and are described in detail in Härtung and Simonoff, Org. Reactions, 7, 277 (1953) and Loenard and Fuji, J. Amer. Chem. Soc, 85 , 3719 (1963).

As can be seen from the above discussion, the following pyrindine derivatives of the formula III which are unsubstituted in the 2-position, in which R ₁ ' ^{1 is} hydrogen, are also important intermediates for the preparation of the pyrindines according to formula I.

4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-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-isopropoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, 4a-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, 4a-phenyl-2-ethyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

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

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

The 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines which are unsubstituted in the 2-position and prepared in this way can according to normal procedures to pharmacologically active 2-substituted ones Pyridine derivatives are alkylated or acylated to form intermediates, which are readily converted into active analgesic

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Have pharmaceuticals transferred. For example, a 4a-aryl-2,3,4,4a, 5,6,7 _# 7a-octahydro-1H-2-pyrindine in the 2-position can be alkylated by reaction with practically any reactive derivative of an alkyl group. Such alkylating agents are compounds of the formula R - Z, in which R _{1 has} the meaning given above and Z denotes a group which is generally referred to as a group which can be split off easily. Such groups are, for example, the halogens, especially chlorine, bromine and iodine, and the p-toluenesulfonyl (tosyl), phenylsulfonyl, methanesulfonyl (mesyl), p-bromophenylsulfonyl (brosyl) and azido groups. The alkylating agent of the formula R ₁ -Z can be substituted in its alkyl moiety, for example with unsaturated, aryl or cycloalkyl groups. Thus, the expression "alkylating agents of the formula R ₁ -Z" also includes compounds such as methyl chloride, ethyl bromide, 5-methylheptyl tosylate, allyl bromide, 4-hexenyl iodide, 3-ethyl-4-pentenyl brosylate, cyclopropylmethyl chloride, cyclobutylmethyl iodide, cyclohexylmethyl mesylate, 3-tetrahydrofurylmethyl bromide, 2-furylmethyl azide, 2-phenylethyl chloride, 3-benzoylpropyl bromide, 2- (3-chlorophenylthio) ethyl azide, phenoxymethyl bromide, 3-isopropylphenylthiomide and to understand similar connections.

So it can be a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine with an alkylating agent to the corresponding 2-substituted one 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine reacted will. Such an alkylation reaction is common and can be carried out in such a way that the corresponding 4a-aryl-octahydro-1H-2-pyrindine with the corresponding Alkylating agent preferably reacted in an inert organic solvent. The alkylating agent is typically used in excess, for example in an excess from about 0.5 to 2.0 moles based on the pyridine derivative.

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-1 / Γ-

Inert organic solvents which are customarily used in the reaction are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran and solvents such as benzene, dichloromethane, dimethylformamide, dimethyl sulfoxide, nitromethane or hexamethylphosphoric triamide. A base which serves as an acid acceptor is preferably present in the alkylation reaction, since the reaction between the pyridine derivative and the alkylating agent is generally accompanied by the formation of an acid, such as hydrochloric acid or p-toluenesulfonic acid, which can retain the unreacted 2-pyrindine derivative as a salt, Bases commonly used as acid acceptors in such reactions are, for example, sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine and pyridine. Typically about an equivalent of the base is used; however, the bases can also be used in excess, if desired. The alkylation reaction is normally carried out at an elevated temperature in the range from about 50 to 200 ^° C., and at this temperature the reaction is normally complete within about 1 to 10 hours; however, longer reaction times are not a disadvantage and can be used if desired. The product is typically recovered by simply adding water to the reaction mixture and then extracting the product into a water immiscible organic solvent such as benzene, ethyl acetate, dichloromethane, diethyl ether, chloroform or related solvents. After the solvent has been removed from the extracts, for example by evaporation under reduced pressure, the product obtained is the 2-substituted 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine , which is obtained either as an oil or as a solid at room temperature. The product obtained in this way can, if desired, further by customary processes,

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such as chromatography, recrystallization or distillation, are purified, or the pyrindine obtained can alternatively be converted into an acid addition salt by reaction with an inorganic or organic acid. Such salts are usually highly crystalline solids and easily convert to a solid salt of high purity Recrystallize. If desired, such a salt can then with a base, such as sodium hydroxide or potassium carbonate, be treated. What the purified 2-substituted 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is obtained as the free base.

As indicated above, the pyrindine derivatives unsubstituted in the 2-position, namely the 4a-aryl-octahydro-1H-2-pyrindines, can be converted into a 2-substituted pyrindine derivative which is either itself a pharmacologically valuable agent or which can easily be converted into such can be. For example, the reaction of a 4a-aryl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine with an alkylating agent such as 2-benzoylethyl iodide gives the corresponding 4a-aryl-2- (2 -benzoylethyl) -2,3,4,4a, 5,6,7,7a-octahydro-iH-2-pyrindine, which is an active analgesic. If desired, such a compound can be reduced at the benzoylcarbonyl group, for example by reaction with a reducing agent such as lithium aluminum hydride, after which the corresponding 4a-aryl-2- (3-hydroxy-3-phenyl) propyl-2,3, 4, 4a, 5 , 6,7,7a-octahydro-1H-2-pyrindine, which is also a valuable analgesic, is obtained. In addition, a pyridine derivative which is unsubstituted in the 2-position can be converted into an N-acylated pyridine derivative using any acylating agent, ie into a compound of the formula I in which R. is a group of the formula

O
-C-alkyl with 1 to 7 carbon atoms in the alkyl radical,

, or S-

80.S8.ie/-O.932

is. Such N-acylated pyrindines give, after reduction of the carbonyl group, 2-substituted pyrindine derivatives of the formula I, which are active analgesics. For example, a 4a-aryl-3-alkyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine can be acylated with any common acylating agent such as an acid halide or acid anhydride. Examples of commonly used acylating agents are acetyl chloride, pentanoyl chloride, 4-hexenoyl chloride, cyclobutylformyl bromide, 2- (tetrahydrofuryl) formyl chloride, benzoyl bromide, phenoxyacetyl iodide, 3,4-dimethylphenylacetyl chloride, 3- (2-fluorophenyl) propionyl chloride, Phenylthioacetyl bromide, 4-phenyl-3-butenoyl chloride, acetic anhydride and hexanoic acid anhydride. The acylation of the pyridine derivatives unsubstituted in the 2-position with an acylating agent such as those mentioned is carried out by reacting approximately equimolar amounts of the pyridine derivative and the acylating agent in an inert organic solvent such as dichloromethane, ethanol or tetrahydrofuran. The reaction is typically carried out in the presence of a base such as sodium bicarbonate, potassium carbonate or propylene oxide as the acid acceptor. It is best carried out at a temperature of about -20 to about 30 ^° C. and generally proceeds to completion within 1 to 8 hours. The product, for example a 4a-aryl-2,3,4,4a, 5,6,7-7a-octahydro-1H-2-pyrindine acylated in the 2-position, can easily be isolated by simply evaporating the reaction solvent removed. The product formed in this way is normally not purified further, but rather directly to a 2-substituted 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine of the formula I reduced. Such reduction of the N-acylcarbonyl group can be achieved by reducing the acylated pyridine derivative with a reducing agent such as lithium aluminum hydride or by catalytic hydrogenation.

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In addition, certain 2-substituted 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines of the formula I further modifications are made. For example, a 4a-arylpyrindine derivative in which the aryl group is a 3-hydroxyphenyl radical, can be prepared by converting from a 2- (3-hydroxyphenyl) -2-ethoxycarbonylmethyl-cyclohexanone and modify that connection using the various methods discussed above; but it can also to be preferred, a 2-substituted 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine and then the 3-methoxy group of such a 4a-aryl substituent to convert into a hydroxyl group. Such an overhead can easily be accomplished by that a 4a- (3-methoxyphenyl) pyrindine derivative with hydrogen bromide acid converts into acetic acid. Such a reaction is for the conversion of a methoxyphenyl group into a hydroxyphenyl group is common. The hydroxyl group such a 4a- (3-hydroxyphenyl) pyrindine can, if desired, with conventional alkanoylacylating agents 1 to 3 carbon atoms, such as acetyl chloride or propionyl anhydride, are acylated, the corresponding 4a- (3-alkanoyloxyphenyl) pyrindine derivatives are obtained.

As stated above, the 2-substituted 4a-aryloctahydro-IH-2-pyrindine derivatives of the formula I with an organic or inorganic acid to a crystalline one Are reacted salt, which is purified by recrystallization and then by reacting with a suitable Base, such as sodium hydroxide, can be recycled to the pyrindine free base. Certain acid addition salts are encompassed by formula I. In particular, these are the nontoxic, pharmaceutically acceptable acid addition salts

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comprising pyrindine bases described above. Such non-toxic pharmaceutically acceptable acid addition salts are prepared by a 2-substituted 4a-aryl-octahydro-1H-2-pyrindine of the formula I with an organic or inorganic acid. For the preparation of the pharmaceutically acceptable acid addition salts of the formula I. Commonly used acids are, for example, hydrogen halides acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, as well as acids such as sulfuric, phosphoric, Nitric and perchloric acids as well as phosphorous and nitrous acids and related acids. Organic acids commonly used for Preparation of pharmaceutically acceptable acid addition salts of the pyrindines according to formula I are used, for example Vinegar, propionic, p-toluenesulphone, chloroacetic, maleic, Wine, amber, oxal, lemon, milk, palmitic, stearic and benzoic acid and related acids. The pharmaceutically acceptable acid addition salts according to formula I can conveniently Way can be prepared by simply adding a 2-substituted 4a-aryl-octahydro-1H-2-pyrindine in a suitable Solvent, such as diethyl ether, ethyl acetate, acetone or ethanol, dissolves and this solution either with the equivalent amount or an excess of a suitable acid. The salt formed in this way crystallizes normally from the solution and can be recovered by filtration. It is so for its use as a pharmacological Medium suitable or can also be obtained by recrystallization from common solvents such as acetone or methanol, further cleaned.

The following list of 2-substituted cis-4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines is representative of compounds falling under Formula I.

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

4a- (3-methoxyphenyl) -2- (n-octyl) -2.3 _f 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-1H-2-pyrindine,

4a- (3-propoxyphenyl) -2- (2,3-dimethyl-4-hexenyl) -2,3,4,4a, 5,6,7-7a-octahydro-1H-2-pyrindine,

4a-phenyl-2- (5-heptenyl) -2,3,4,4a, 5,6,7,7a ~ octahydro-1H-2-pyrindinium acetate,

4a- (3-hydroxyphenyl) ^ - cyclopentylmethyl ^, 3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindinium oxalate,

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

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

4a- (3-hydroxyphenyl) -2- (2-methylphenoxymethyl) -2,3,4,4a, 5,6-7,7a-octahydro-1H-2-pyrindinium succinate,

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

4a- (3-ethoxyphenyl) -2- / 3- (3-methyl-4-bromophenyl) -3-hydroxy ^ / - propy1-2,3,4,4a, 5,6,7,7a-octahydro-1H -2-pyrindinium iodide,

4a-phenyl-2- / 3- (2-ethyl-6-methy lphenylthio) propyl ^ Z-2,3,4,4a, 5,6,7-7a-octahydro-1H-pyrindinium perchlorate,

4a- (3-hydroxyphenyl) -2- / 2- (3,4-dibromophenyl) -2-hydroxyyethyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine,

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4a-phenyl-2- (3-phenylthio) propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium citrate,

4a-phenyl-2- / 3- (2-isopropylphenyl) propy1 / -2,3,4,43,5,6,7,7 aoctahydro-1H-2-pyrindinium maleate,

4a- (3-ethoxyphenyl) -2- (2-phenyl-2-hydroxyethyl) -2,3,4,5,6,7,7 aoctahydro-IH-2-pyrindinium phosphate,

4a-phenyl-2- / 2- (4-chlorophenyl) -2-hydroxyethyl / -2,3,4, 4a-5,6,7,7a-octahydro-1H-2-pyrindinium methanesulfonate,

4a- (3-hydroxyphenyl) -2 / 3- (2-chloro-3-bromophenyl) -3-hydroxypropyl / - 2, 3,4,4a, 5,6,7,7a-octahydro-1H-2- pyrindine,

4a- (3-propoxyphenyl) -2- (2-ethylbenzoylethyl) -2,3,4,4a, 5,6,7,7 aoctahydro-IH-2-pyrindinium chloride,

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

4a-phenyl-2- / 3- (2-ethyl-5-bromophenyl) propy_l / -2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine and

4a- (3-Hydroxyphenyl) -2- / 2- (3,5-diethylphenoxy) ethyl / -2,3,4,4a-5,6,7,7a-octahydro-1H-2-pyrindinium stearate.

The compounds according to formula I have two centers of asymmetry, namely the 4a position and the 7a position. According to the invention includes both the known isomers and the racemic mixtures of these isomers which act as analgesic agonists or antagonic are pharmacologically valuable. However, only the cis isomers according to formula I are included, namely

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'**' 27A8A66

bS

those compounds in which the 4a-aryl group is on the same Side of the molecular plane, like the 7a-hydrogen atom. Thus of the invention are the pharmacologically active individual optically active cis isomers except for the racemic mixtures of the cis isomers. A racemic pair of cis-octahydropyrindines can after known processes are separated into its stereoisomers. In the event that the entire useful pharmacological Activity is based on a stereoisomer, the dl racemate is nevertheless valuable because it is the pharmacologically contains active isomers as a constitutive component.

The preparation of the 4a-aryloctahydropyrindines according to the formula I requires starting materials, many of which were previously unknown and not readily available. For the pyrindines according to formula I, 4a-Aryltetrahydro-2,6-dioxocyclopenta / c / pyrans are used as starting materials used. These starting materials are made from 2-arylcyclohexanones such as for example 2-phenyl cyclohexanone or 2- (3-methoxyphenyl) cyclohexanone, manufactured. For the preparation of the dioxocyclopentapyran derivatives the 2-Ary! cyclohexanone is in the 2-position by reaction with an alkyl haloacetate, such as, for example, ethyl chloroacetate, in the presence a base, such as sodium hydride, alkylated to give the corresponding 2-aryl-2-alkoxycarbonylmethylcyclohexanone. The 2-aryl-2-alkenyl-1-aminomethyl! Cyclopentane is prepared in an analogous manner first a 2-arylocyclohexanone in 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 the corresponding 2-aryl-2-alkenyl / cyclohexanone alkylated. Both the 2-aryl-2-alkoxycarbonylmethy! Cyclohexanones and the 2-aryl-2-alkenylcyclohexanones are then reacted in the 6-position with an alkyl formate, such as, for example, ethyl formate, in the presence of metallic sodium or

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Potassium formylated. The formylcyclohexanone derivatives are then reacted with p-toluenesulfonyl azide, whereby the 6-formyl group by a diazo group with formation of 2-aryl-2-alkoxycarbonyl-methyl-6-diazocyclohexanones or 2-aryl-2-alkenyl-6-diazocyclohexanones is replaced. These diazocyclohexanone derivatives are then exposed to light from a

Wavelength of about 30OO Å in an alcoholic solvent, such as methanol, photolyzed to produce a To bring about ring narrowing with simultaneous evolution of nitrogen and in this way to 2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentanes or 2-aryl-2-alkenyl-1-methoxycarbonylcyclopentanes. These connections will then hydrolyzed with aqueous alkali to give the corresponding di- or mono-acid. This results in the hydrolysis of a 2-aryl-2-alkoxycarbonyl-methyl-1-methoxycarbonylcyclopentane to the corresponding 2-Ary1-2-hydroxycarbonylmethyl-1-hydroxycarbony1-cyclopentane and analogously the hydrolysis of a 2-aryl-2-alkenyl-1-methoxycarbonylcyclopentane to the corresponding 2-aryl-2-alkenyl-1-hydroxycarbonylcyclopentane. The dicarboxylic acid, namely 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane, is then converted to the corresponding one by reaction with an acid halide, for example acetyl chloride Anhydride, a 4a-aryl-tetrahydro-2,6-dioxocyclopenta / c / -pyran, cyclized. These pyrans are the starting materials for the preparation of the pyrindines according to formula I.

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Certain 2-substituted 4a-aryl-octahydro-1H-2-pyrindines of formula I have found use in the treatment of pain and can accordingly be used to to produce analgesia in a patient who is in pain and in need of treatment. It it was also found that the pyrindine derivatives according to formula I have both properties of an analgesic agonist as well as that of an analgesic antagonist, d. that is, they are capable of analgesia in a mammal effect, while at the same time, because of the analgesic antagonistic effect, they have a greatly reduced tendency to create addiction exhibit. This ability of the compounds according to the invention to be both analgesic agonistic and antagonistic Producing effects in mammals is thus responsible for a decrease in the addictive properties of a drug responsible, which are caused by its opiate-like analgesic effect. The connections are thus particularly valuable because they provide anaigetics that cause minimal physical dependence symptoms. Certain compounds are also useful for combating the undesirable effects of opiates, such as of morphine.

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The analgesic effect of the compounds according to formula I is determined by investigations of these compounds in standard animal experiments has been determined routinely for determining analgesic effects of compounds under study can be used. Such experiments are, for example, the mouse curvature test and the rat tail twitch test.

As mentioned, the compounds according to formula I have shown analegetic activity in the standard mouse curvature test. In this procedure, the mice crouch by injecting acetic acid intraperitoneally. The level of analgesic activity of a drug is then determined by observing the inhibition of this curvature after the drug has been administered prior to acetic acid. Is 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5 _/ 6,7,7a-octahydro-1H-2-pyrindine in the form of its hydrochloride subcutaneously at a dose of 20 mg / kg body weight When given to a mouse in which writhing has already been created, a 100 percent reduction in writhing is observed. A subcutaneous dose of 10 mg / kg produces 96 percent inhibition of writhing. Similarly, when the abovementioned compound is administered orally, a 100 percent inhibition of writhing is achieved at a dose of 20 mg / kg and a 98 percent inhibition at a dose of 10 mg / kg. In addition, it has been found that naloxone completely prevents the inhibitory activity of the compound at a subcutaneous dose of 5 mg / kg, indicating that the compound is an opiate-type analgesic. In the studies using the rat tail twitch test, the above compound caused a significant increase in reaction time at a dose of 80 mg / kg, both subcutaneously and orally, and provided the same effect at oral doses as low as 20 mg / kg, where all measurements were taken 1/2 hour and 2 hours after dosing.

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The 4a- (3-hydroxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was obtained in an analogous manner examined. At a subcutaneous dose of 0.5 mg / kg, the compound caused a 75 percent inhibition of writhing in a test animal. At an oral dose of 10 mg / kg of the compound 98 percent inhibition of writhing was observed at the lapse of half an hour after the administration. Naloxone completely prevents the inhibitory effect of the compound at a subcutaneous dose of 0.5 mg / kg. The rat tail twitch test showed that the compound significantly increased the reaction time in succutaneous and oral administration of 20 rag / kg.

4a-Pheny1-2-methy1-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide, another compound according to formula I caused a 70 percent inhibition of writhing in one group from test animals at a dose of 100 mg / kg 1/2 hour after the administration. At an oral dose of 20 mg / kg the compound caused 58 percent inhibition at the lapse of 1 1/2 hours after dosing, with this effect was completely prevented in the presence of naloxone. The rat tail twitch test indicated that the compound caused only a moderate increase in the reaction time at a dose of 80 mg / kg.

In the mouse curvature test and the rat tail twitch test, the following effective doses (ED ₅₀ ), ie the doses which, compared with control animals, reduce the number of curvatures observed by 50%, were obtained for the following compounds according to formula I:

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HO

Tabel

example salt curvature
¹³⁰ SO Rat tail
twitch
^ED 5O 12th HCl 5 << 80 13th 0.4 0.2 14th HBr 1.0 1.0 15th HCl > 20 > 80 16 HBr 1.0 0.5 17th 20th > 80 18th 'HBr 50 > 80 19th HBr 20th - 20th HBr 20th > 80 21 HBr 1.0 << 80

The 2-substituted 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-iH-2-pyrindines according to formula I are in this way for the production of analgesia in mammals, such as humans, of use. These compounds can be administered to a mammal either orally or parenterally. Generally will it is preferred to use a pharmaceutically acceptable acid addition salt of the pyrine derivative when administering is done orally as these salts are easily formulated for convenient oral administration. For example be one or more pharmacologically active compounds according to Formula I either in the free base form or as a pharmaceutically acceptable acid addition salt for oral administration formulated to be admixed with a commonly used diluent, binder or carrier. Examples

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for such diluents and binders, the usual Used in pharmaceutical preparations are starch powder, cane sugar, cellulose, magnesium stearate. Lactose, calcium sulfate / sodium benzoate and similar substances. Such preparations can be used for a convenient Administration molded into tablets or enclosed in gelatin capsules. If desired, can the active compounds according to formula I additionally with one or more other known agents for effect of analgesia such as caffeine, acetaminophen or propoxyphene.

The active compounds according to formula I can also be used as sterile aqueous or non-aqueous solutions, suspensions and Emulsions can be formulated for convenient parenteral administration. Non-aqueous vehicles commonly used in such Formulations used are, for example, propylene glycol, vegetable oils such as olive oil, as well various organic esters such as ethyl oleate. Useful aqueous solutions for oral and parenteral administration are for example isotonic salt solutions.

The exact dosage of the active ingredient, i.e. H. the amount of one or more of the pharmacologically active, 2-substituted 4a-Aryl-octanydro-1H-2-pyrindine of the formula I, which a mammal, e.g. B. a human, can be administered via a vary relatively wide range, it being necessary that the preparations a proportional proportion contain one or more of the active ingredients according to formula I, so that a suitable dosage is achieved. One such dosage depends on the particular therapeutic effect desired and the particular mode of administration employed and the duration of treatment as well as the exact situation to be treated. Typically the dosages will be the active compounds according to formula I in a range from about 1.0 to about 25 mg / kg body weight and day, appropriately subdivided for administration once to four times a day. Preferred oral dosages are generally in the range of about 2 to about 50 mg / kg.

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The following examples serve to further illustrate the invention.

Starting materials Example A

A solution of 130 g of 2-phenyl-2-ethoxycarbonylmethylcyclohexanone in 20OO ml of diethyl ether containing 56 g of ethyl formate and 11.5 g of metallic sodium was ^{stirred at 25 °} C. for 48 hours. The reaction mixture was then added to 100 ml of ice water and the ethereal phase was removed. The aqueous phase was acidified to pH 6.5 by adding 1N hydrochloric acid and extracted further with fresh diethyl ether. The ethereal extracts were combined, washed with water and dried. Evaporation of the solvent under reduced pressure gave 98 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexanone in the form of an oil with a boiling point of 158 ° to 175 ° C./0.5 mm Hg.

Analysis, C ₁₇ H ₃₀ O ₄ :

calculated: C, 70.81; H 6.99;
Found: C, 70.85; H 6.77.

Example B.

According to the procedure given in Example A, 2- (3-methoxyphenyl) -2-ethoxycarbonylmethylcyclohexanone was obtained with ethyl formate in the presence of metallic sodium to give 2- (3-methoxphenyl) -2-ethoxycarbonyl-methyl-6-formy! cyclohexanone implemented.

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Examples

A solution of 87.0 g of 2-pheny / cyclohexanone in 100 ml of benzene was added dropwise over one hour to a stirred, refluxed solution of 28.0 g of sodium amide in 400 ml of benzene. The reaction mixture was heated for a further 2.5 hours under reflux and then cooled in an ice bath to 0 ⁰ C. A solution of 83.5 g of allyl iodide in 100 ml of benzene was added all at once to the cold reaction mixture. The reaction mixture was heated under reflux for 1/2 hour and then cooled to 25 ⁰ C and poured onto ice 4OO g. The organic benzene phase was separated off, washed with water and dried. Evaporation of the solvent gave 50 g of 2-phenyl-2- (2-propenyl) -cyclohexanone with a b.p. 114 to 120 ° C./0.1 mm Hg.

Example D

A solution of 30 g of 2-phenyl-2- (2-propenyl) cyclohexenone in 600 ml of diethyl ether containing 3.4 g of metallic sodium and 11.8 g of ethyl formate was ^{stirred at 25 °} C. for 48 hours. The reaction mixture was then poured into water and the organic phase was separated off and stored. The aqueous phase was acidified to a pH of 2.5 by adding aqueous hydrochloric acid. The aqueous-acidic phase was extracted with fresh ethyl ether. The ethereal extracts were combined, washed with water, dried and the solvent removed by evaporation under reduced pressure to give the product as an oil. The 01 was distilled to give 14.6 g of 2-Pheriy1-2- (2-propenyl) -6-formy! Cyclohexanone, bp. 125 to 130 ^e C / 0.1 mm Hg.

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ti,

Example E.

A solution of 50.0 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formy cyclohexanone! And 5OO ml of diethyl ether was stirred at 25 ⁰ C, while was added dropwise a solution of 24.8 g of diethylamine in 100 ml of diethyl ether over 30 minutes. After stirring the reaction mixture for 2 hours at 25 ^° C., the solution was ^{cooled to 5 °} C. and then a solution of 33.5 g of p-toluenesulfonyl azide in 50 ml of diethyl ether was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for an additional 5 hours. The reaction mixture was 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; IR (neet) 2080 cm, diazo group.

Examples F - G

Following the procedure of Example E, 2- (3-methoxyphenyl) 2-ethoxycarbonylmethyl-6-formylcyclohexanone was obtained in 2- (3-methoxyphenyl) ^ - ethoxycarbonylmethyl-S-diazocyclohexanone and 2-phenyl-2- (2-propenyl) -6-formylcyclohexanone in 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone convicted.

Example H

A solution of 57 g of 2-phenyl-2-ethoxycarbonylmethyl-6-diazocyclohexanon in 500 ml of anhydrous methanol was stirred at 25 ⁰ C while being bubbled through the reaction mixture nitrogen. The solution was 40 hours with a

Quartz lamp with a wavelength of 3000 A photolyzed. The solvent was then removed under reduced pressure, the product was obtained as a crude oil which was dissolved in 500 ml of diethyl ether. The ethereal solution

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ts

was washed with aqueous sodium bicarbonate and with water and dried. Removal of the solvent under reduced pressure gave 27.4 g of 2-phenyl-2-ethoxycarbonylmethyl-1-methoxycaronylcyclopentane as an oil, which was further purified by distillation; Bp. 160 to 190 ° C / 0.22 mm Hg.

Analysis, C ₁ -H ₂₂ O-:

calculated: C 70.32; H 7.64; found: C, 70.30; H 7.36.

Examples I - J Following the procedure of Example H, 2- (3-methoxyphenyl) -

Z-ethoxycarbonylmethyl-δ-diazocyclohexanone at 30OO A to

2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-i-methoxycarbonyl Cyclopentane from bp 19O to 210 ° C photolyzed.

Analysis, C ^ H ₂ .0 ₅ :

calculated: C, 67.48; H 7.55; found: C, 67.61; H 7.37.

In an analogous manner was 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone with ultraviolet light of 30OO A using a Quartz lamp irradiated in the presence of methanol, with 2-phenyl-2- {2-propenyl) -1-methoxycarbonylcyclopentane from bp 113 to 115 "0 / 0.1 mm Hg was obtained.

Analysis, C ₁ -H ₂₀ O ₂ :

Calculated: C 78.65; H 8.25; found: C, 78.80; H 7.99.

Analysis, C ₁₉ H ₂₅ O ₅ :

calculated: C, 68.24; H 7.84; Found: C, 68.15; H 7.57.

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Example K

A solution of 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-imethoxycarbonylcyclopentane in 650 ml of 1,4-dioxane, which contained 500 ml of 5 percent aqueous potassium hydroxide solution, was stirred and refluxed for 12 hours. After cooling the reaction mixture to room temperature, 500 ml of water were added. The reaction mixture was acidified by adding 2N hydrochloric acid and the aqueous-acidic mixture was extracted several times with equal volumes of diethyl ether. The ethereal extracts were combined, washed with water and dried. Evaporation of the solvent under reduced pressure gave 38 g of 2- (3-methoxyphenyl) -2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane in the form of a crystalline solid with a melting point of 175 to 180 ^° C.

Examples L - M

According to the method of Example K 2-phenyl-2-methoxycarbonylcyclopentane ethoxycarbonylmethy1-1 was hydrolyzed to 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentan mp. 2o5 to 208 ⁰ C.

Analysis, C ₁₄ H ₁₆ O ₄ :

calculated: C, 67.73; H 6.50;
found: C, 67.70; H 6.32.

2-Phenyl-2- (2-propenyl) -1-methoxycarbonylcyclopentane was with aqueous potassium hydroxide solution to 2-phenyl-2- (2-propenyl) -1-hydroxycarbonylcyclopentane hydrolyzed.

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Example N

A solution of 25 g of 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane in 150 ml of acetyl chloride was stirred and refluxed for 4 hours. After cooling the reaction mixture to room temperature, excess solvent was removed by evaporation under reduced pressure, to give 26 g of tetrahydro-4-phenyl-2 _r 6-dioxocyclopenta / c / pyran in the form of an oil. The product was further purified by distillation; Bp. 205 to 207 ° C / O, 25 mm Hg.

Analysis, ^c i4 ^H i5 ° 3 ^!

Calculated: C, 73.03; H 6.13;
found: C, 73.30; H 6.37.

Example 0

Following the procedure of Example N, 2- (3-methoxyphenyl) -2-hydroxycarbonyl-i-hydroxycarbonylcyclopentane was obtained by reaction with acetyl chloride to give tetrahydro-4- (3-methoxyphenyl) -2,6-dioxocyclopenta / c / pyran of bp 200 to 220 ⁰ C dehydrated and cyclized.

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 were added dropwise with stirring over a period of 30 minutes. The reaction mixture was then refluxed and stirred for 15 hours. After cooling the reaction

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Mixture, the solvent was reduced by evaporation under The pressure was removed, and 7.4 g of 2-phenyl-2- (2-propenyl) -1-chlorocarbonylcyclopentane were obtained.

Example Q

A solution of 10.7 g of benzylamine in 100 ml of toluene was mixed with a solution of tetrahydro-4- (3-methoxyphenyl) -2,6-dioxocyclopenta / c / pyran in 300 ml of toluene ^{at 25 ° C. dropwise over the course of 1 hour} offset. After the addition of the pyran derivative was complete, the reaction mixture was stirred and refluxed for three days in a flask fitted with a Dean-Stark trap to remove water. After refluxing, the reaction mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to give the product as a crude oil. The oil was dissolved in 400 ml of 1 η sodium hydroxide solution, and the alkaline reaction mixture was ^{heated to 50 °} C. for 15 minutes. It was then extracted with diethyl ether and the ethereal extracts were combined, washed with water and dried; the solvent was then removed under reduced pressure and the product was obtained as a solid residue. Recrystallization of the residue from diethyl ether gave 4a- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-iH-2-pyrindine of mp. 75 to 77 ⁰ C.

Analysis, ^C 22 ^H 23 ^NO 3 ^:

Calculated: C 75.62; H 6.63; N 4.01; found: C, 75.40; H 6.58; N 3.78.

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example

Tetrahydro-4-phenyl-2,6-dioxocyclopenta / c / pyran was according to the procedure of Example Q with benzylamine to 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7 ^ a-octahydro- i, 3-dioxo-1H-2-pyrindine of mp. 77 to 79 ⁰ C implemented.

Analysis, ^C 2i ^H 21 ^NO 2 ^:

Calculated: C 78.97; H 6.63; N 4.39; found: C, 78.73; H 6.65; N 4.26.

End products example 1

A solution of 18 g of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7aoctahydro-1,3-dioxo-1H-2-pyrindine in 200 ml of tetrahydrofuran was stirred for 90 minutes Suspension of 5.8 g of lithium aluminum hydride in 15Ό ml of tetrahydrofuran was added dropwise. When the addition was complete, the reaction mixture was refluxed for 10 hours. While the temperature of the reaction mixture was kept below 50 ⁰ C, 50 ml Essigester were added dropwise over 15 minutes, and then 100 mL of aqueous ammonium chloride. Further tetrahydrofuran was then added to the aqueous reaction mixture in order to achieve separation between the organic and aqueous phases. The organic phase was decanted and concentrated under reduced pressure to give the product as an oil. The oil thus obtained was dissolved in 500 ml of diethyl ether. The ethereal solution was with

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Washed with water, dried and the solvent removed by evaporation under reduced pressure to give 15 g of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine . M ⁺ / e 291 (molecular ion), 213 (-77, phenyl) and 200 (-91, benzyl).

Example 2

According to the procedure of Example 1 was 4a- (3-methoxyphenyl) · 2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine by reaction with lithium aluminum hydride to give 4a- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine reduced.

Example 3

A solution of 21 g of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine in 172 ml of ethanol was stirred all at once with 7 g of 5 percent palladium / carbon catalyst offset. The reaction mixture was below 4.13 χ

6 2

10 dynes / cm of hydrogen ^{heated to 60 °} C. for 3 hours with stirring. The reaction mixture was cooled to room temperature, filtered and the solvent removed by evaporation under reduced pressure to give 13.3 g of the product as an oil. The oil was distilled to give 4a-phenyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine.

Example 4

Following the procedure described in Example 3, 4a- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was obtained via palladium / carbon to 4a- (3-methoxyphenyl) -

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2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine from »b.p. 145 to 16O ° C / O5 πββ Hg hydrogenated.

Example 5

A solution of 8.4 g of 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindine in 60 ml of glacial acetic acid and 60 ml of 48 percent aqueous hydrogen bromide was 15 Hours under Stir and reflux. After cooling the reaction mixture to room temperature, it became 100 g Ice was added, and the pH of the aqueous solution obtained was increased by adding concentrated sodium hydroxide solution 10.2 set. The alkaline reaction mixture was then with 400 ml of a mixture of three parts n-butanol and a part of benzene extracted. The extract was separated, washed several times with water and dried, and the solvent was evaporated removed under reduced pressure to give the product as a crude solid. This was made from ethyl acetate recrystallized, and 4.2 g of 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine of melting point 180 bis were obtained 181 ° C.

Analysis, C..H..gN0:

calculated: C, 77.38; H 8.81; N 6.45; Found: C, 77.56; H 8.84; N 6.24.

Example 6

A solution of 2 g of 4a-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 bicarbonate 1.23 g of 2-propenyl bromide were added all at once with stirring at 25 ^{° C.} That

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The reaction mixture was stirred and refluxed for 4 hours. After cooling to room temperature, it was filtered and concentrated under reduced pressure to an oil. The oil obtained was dissolved in 300 ml of diethyl ether. The ethereal solution was washed with water and dried, and the solvent was then removed by evaporation under reduced pressure to give 4a-phenyl-2- (2-propeny1) -2,3,4,4a, 5,6,7 , 7a-octahydro-1H-2-pyrindine in the form of an oil. This was dissolved in 150 ml of fresh diethyl ether and gaseous hydrogen bromide was allowed to flow through the ethereal solution. The precipitated salt was filtered off and recrystallized from diisopropyl ether and isopropanol, and 1.3 g of 4a-phenyl-2- (2-propenyl) -2,3,4, 4a, 5, 6, y ^ aoctahydro-IH ^ - pyrindinium bromide, mp. 185 to 187 ⁰ C.

Analysis,

calculated: C, 63.36; H 7.51; N 4.35; Found: C, 63.63; H 7.24; N 4.24.

Examples 7-8

Following the procedure of Example 6, the following 1-alkylpyrindine derivatives were prepared by reacting 4a-phenyl-2,3,4,4a, 5,6 _/ 7,7a-octahydro-1H-2-pyrindine with an appropriate alkylating agent.

4a-phenyl-2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide; mp. 245-247 ⁰ C.

Analysis C ₁₇ H ₃₆ BrN:

calculated: C, 62.96; H 8.08; N 4.32; found: C, 62.74; H 8.22; N 4.23.

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4a-phenyl-2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindiniuni bromide from Pp 240 -. 243 ⁰ C.

analysis

calculated C, 64.77; H 8.58; N 3.98; found: C 65.04; H 8.7O; Ν 3.87.

Be is ρ i e 1 9

A solution of 3, Og 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 10 ml of 88 percent formic acid was added dropwise with stirring at 20 ° C. for 15 Minutes with 10 ml of 38 percent formaldehyde. The reaction mixture was then heated to 95 ° C. for 8 hours. After cooling the reaction mixture to 25 ⁰ C for 30 minutes 1OO ml 4 η hydrochloric acid were added dropwise. The aqueous acidic reaction mixture was evaporated under reduced pressure to give an oily residue. The oil was then dissolved in 100 ml of water and the aqueous solution was made alkaline by adding 50 percent strength sodium hydroxide solution. The product precipitated from the aqueous alkaline solution was extracted with diethyl ether. The ethereal extracts were combined, washed with water and dried, and the solvent was removed under reduced pressure, whereupon 4a-phenyl-2-methyl-2,3,4,4a, 5,6,7-7a-octahydro-iH -2-pyrindine received in the form of an oil. This oil was dissolved in 150 ml of diethyl ether. A solution of 10 ml of 48 percent hydrogen bromide in 10 ml of ethanol was added dropwise over 10 minutes to the ethereal solution at 25 ^{° C. while stirring.} The product precipitated out of solution and was collected by filtration. The solid precipitate became from diisopropyl ether

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and isopropanol recrystallized, and 2.7 g of 4a-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide of melting point 209 to 210 were obtained ⁰ C.

Analysis,

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

Example 10

A cold solution (0 to 5 ⁰ C) of 3.0 g of 4a-phenyl-2,3,4,4a, 5,6, 7,7a-octahydro-1H-2-pyrindine in 47 ml of methanol with a content of 14 ml of water and 2.6 g of potassium carbonate were admixed all at once with 2.6 g of phenylacetyl chloride. The reaction mixture was ^{stirred at 0 to 5 °} C. for ^{30 minutes and then warmed to 25 °} C. and stirred at this temperature for a further hour. The reaction mixture was concentrated under reduced pressure to give an oily residue. The oil was dissolved in 500 ml of diethyl ether and washed with dilute aqueous sodium bicarbonate and with water. After the ethereal solution had been dried, the solvent was removed under reduced pressure, and 4a-phenyl-2-phenylacetyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, the the acylation described occurred in the form of a UI.

The oil was dissolved in 25 ml of tetrahydrofuran and while 30 minutes to a stirred suspension of 3.0 g of lithium aluminum hydride added dropwise in 150 ml of tetrahydrofuran. To

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When the addition was complete, the reaction mixture was stirred and refluxed for 4 hours. After cooling the reaction mixture to 3O ⁰ C 60 ml Essigester and then 1OO ml of saturated aqueous ammonium tartrate was added. The organic phase was separated off by decantation and the aqueous phase was extracted with diethyl ether. The organic solutions were combined and evaporated under reduced pressure to give the product as a crude oil. This was dissolved in 400 ml of diethyl ether, washed with water and dried. Removal of the solvent by evaporation under reduced pressure gave 4a-pheny1-2- (2-phenylethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine as an oil. This oil was dissolved in 150 ml of diethyl ether and added to a solution of 10 ml of 48 percent hydrogen bromide in 10 ml of ethanol. The hydrobromide of the above pyrindine precipitated out of solution and was recrystallized from diisopropyl ether and isopropanol; to give 2.4 g of 4a-phenyl-2- (2-phenylethyl) -2,3,4-4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide; mp. 269-270 ⁰ C.

Analysis,

calculated: C, 68.39; H 7.30; N 3.63; found: C, 68.61; H 7.57; N 3.69.

Example 11

Following the procedure of Example 10, there was obtained 4a-phenyl-2,3,4,4a, 5-6,7,7a-octahydro-1H-2-pyrindine with cyclopropanecarboxylic acid chloride to give 4a-phenyl-2-cyclopropanecarbonyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine acylated. Reduction of the acylated pyrine intermediate with lithium aluminum hydride gave

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the corresponding 2-Alkylpyrindin, which after reaction with hydrobromic the 4a-phenyl-2-cyclopropylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindiniumbromid of mp. 240-241 ⁰ C.

Analysis,

calculated: C, 64.28; H 7.79; N 4.16; Found: C, 64.54; H 7.51; N 4.13.

Example 12

A solution of 75 ml of toluene containing 1.76 ml of liquid methylamine was cooled in a bath of dry ice and acetone to -70 ⁰ C and g with stirring with a solution of 10.4 tetrahydro-4- (3-methoxyphenyl) -2,6-dioxocyclopenta / c / pyran in 125 ml of toluene was added dropwise over 30 minutes. The reaction mixture was warmed to room temperature and then refluxed for 22 hours. The reaction mixture was cooled again to room temperature and evaporated under reduced pressure to an oil. The oil was dissolved in 152 ml of 1 η sodium hydroxide solution and ^{heated to 50 °} C. for 15 minutes with stirring. The product was extracted from the aqueous-alkaline reaction mixture with diethyl ether. The ethereal extracts were combined, washed with water and dried. Evaporation of the solvent under reduced pressure gave 8.3 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5-6,7,7a-octahydro-1,3-dioxo-iH-2 -pyrindine.

Reduction of 8.2 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a-5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine with lithium aluminum hydride according to the procedure given in Example 1 gave 4.6 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine from bp 133 to 138 ° C / O, 25 mm Hg.

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Analysis, C ₁₆ H ₂₃ NO:

Calculated: C, 78.32; H 9.45; N 5.71; Found: C, 78.13; H 9.30; N 5.68.

A solution of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5-6,7,7a-octahydro-1H-2-pyrindine in 100 ml of diethyl ether was flowed through with stirring by hydrogen chloride gas. The reaction mixture was stirred for 30 minutes and then filtered. The solid product was recrystallized from diisopropyl ether and isopropanol, and 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium chloride was obtained from m.p. 175 to 177 ⁰ C.

Analysis,

calculated: C, 68.19; H 8.58; N 4.97; found: C, 68.00; H 8.22; N 4.68.

Example 13

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 with a content of 12 ml of 48 percent strength aqueous hydrobromic acid was refluxed for 15 hours with stirring. The acidic reaction mixture was ^{cooled to about 10 °} C. and the pH was adjusted to 10.2 by adding 50 percent strength sodium hydroxide solution. The product was insoluble in aqueous alkaline solution and was extracted therefrom into a mixture of 90 ml of n-butanol and 30 ml of benzene. The organic solution was then separated off, washed with water and dried. Evaporation of the excess solvent under reduced pressure gave the demethylated product in the form of an oil, which was converted from diethyl ether and ethyl acetate.

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was crystallized, after which, 5,6,7,7a-octahydro-1H-2-pyrindine, mp. 151 to 153 ⁰ C was 4a- (3-hydroxyphenyl) -2-methyl-2,3,4,4a.

Analysis, C ₁₅ H ₃₁ NO:

Calculated: C, 77.88; H 9.15; N 6.05; found: C, 77.60; H 8.88; N 5.76.

Example 14

To a solution of 2.17 g of the 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines prepared as described in Example 5 in 50 ml Ν , Ν-Dimethylformamide containing 3.95 g of triethylamine were added dropwise with stirring at room temperature 3.87 g of phenylacetyl chloride over 15 minutes. After the addition was complete, the reaction mixture was ^{heated to 70 °} C. for two hours and then poured into 200 ml of water. The aqueous reaction mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with saturated aqueous sodium chloride solution and water and dried. Removal of the solvent by evaporation under reduced pressure gave 4a- (3-hydroxyphenyl} -2- (2-phenylacetyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine product was dissolved in 50 ml of tetrahydrofuran and added dropwise with stirring over 30 minutes with a solution of 4.0 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The reaction mixture was then heated for 4 hours at reflux temperature and then cooled to about 25 ⁰ C. with stirring 25 ml of ethyl acetate and then a saturated aqueous ammonium tartrate solution were added to the reaction mixture

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filtered and the filtrate by evaporation of the solvent concentrated under reduced pressure. The obtained product was dissolved in diethyl ether and washed with water and dried. Removal of the solvent gave 4a- (3-hydroxyphenyl) -2- (2-phenylethyl) -2,3,4,43,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil was in 150 ml Dissolved diethyl ether and mixed with a 50 percent solution of 48 percent hydrogen bromide in ethanol while stirring. The hydrobromide of the above product crystallized out and was filtered off and recrystallized from ethyl acetate, and 1.3 g of 4a- (3-hydroxyphenyl) -2- (2-phenylethyl) -2,3,4,4a, 5,6, 7,7a-octahydro-1H-2-pyrindinium bromide of m.p. 135-137 ° C.

Analysis, C ₂₂ ^H 28 ^NBrO %

calculated: C, 65.67; H 7.01; N 3.48; Found: C, 65.41; H 7.12; N 3.66.

Example 15

Following the procedure given in Example 14, 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was obtained with cyclopropylcarboxylic acid chloride in the presence of potassium carbonate to give 4a- (3 -Hydroxyphenyl) -2- (cyclopropylcarbonyl) -2,3,4 _# 4a, 5,6,7,7a-octahydro-1H-2-pyrindine converted. The last-mentioned compound was reduced with lithium aluminum hydride to 4ä- (3-Hydroxypheriyl) -2-cyclopropylmethyl-2,3,4-4a, 5,6,7,7a-octahydro-1H-2-pyrindine, which with hydrogen chloride gas in diethyl ether in the hydrochloride of melting point 256 to 258 ^° C. was transferred.

Analysis, C ^ HjgNOCl:

calculated: C, 70.22; H 8.51; N 4.55; Cl 11.52; Found: C, 69.93; H 8.25; N 4.72; Cl 11.52.

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Example 16

A solution of 1.5 g of 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine in 15 ml Ν, Ν-dimethylformamide with

containing 1.0 g of sodium bicarbonate and 0.95 g of 2-tetrahydrofurylmethyl bromide was refluxed for 4 hours. After the reaction mixture had cooled to about 25 ^° C., the mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure gave 4a- (3-hydroxyphenyl) 2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine as a Oil. The oil was dissolved in diethyl ether and added to a solution of gaseous hydrogen bromide in diethyl ether. The product crystallizes out of the solution and was filtered off, 1.0 g of 4a- (3-hydroxyphenyl) -2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5,6,7,7 aoctahydro-IH -2-pyrindinium bromide, mp. 190 to 192 ⁰ C received. ^β

Analysis, C ₁₉ H ₂ QNO ₂ Br:

calculated: C, 59.69; H 7.38; N 3.66; found: C, 59.89; H 7.40; N 3.78.

Examples 17-19

Following the procedure described in Example 16, 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine was obtained with allyl iodide in the presence of sodium bicarbonate to give 4a- (3 hydroxyphenyl) -2- (2-propenyl) -2,3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindine, mp. 106 to 108 ⁰ C implemented.

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Analysis, C ₁₇ H ₂

Calculated: C 79.33; H 9.01; N 5.44; Found: C, 79.29; H 8.92; N 5.44.

In an analogous manner, the 4a- (3-methoxyphenyl) -2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine prepared according to Example 4 was converted to 4a with 1-iodopropane in the presence of sodium bicarbonate - (3-Methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindine reacted, which is then converted into the hydrobromide of melting point by reaction with gaseous hydrogen bromide in diethyl ether 197 to 199 ⁰ C was transferred.

Analysis, C ₁₈ H ₂₈ NOBr:

calculated: C, 61.02; H 7.97; N 3.95; Found: C, 60.65; H 7.52; N 4.07.

In an analogous manner, 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7aoctahydro-iH-2-pyrindine with 1-bromopentane in the presence of sodium bicarbonate to 4a- (3-methoxyphenyl) - 2-n-pentyl-2,3,4,4a-5,6,7,7a-octahydro-1H-2-pyrindine reacted. This compound was converted into 4a- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindinium bromide with gaseous hydrogen bromide in diethyl ether, a crystalline solid of melting point 179 to 181 ^° C., transferred.

Analysis, C ₃₀ H ₃₂ NOBr:

calculated: C, 62.82; H 8.44; N 4.18; found: C, 62.87; H 7.98; N 4.02.

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Example 20

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, which, as in Example 18, in 20 ml of glacial acetic acid and 20 ml of 48 percent aqueous hydrobromic acid was heated with stirring and under reflux for 12 hours. The reaction mixture was then cooled and poured over 100 g of ice and the aqueous solution obtained was made alkaline to a pH of 10.2 by adding aqueous sodium hydroxide solution. The aqueous alkaline mixture was extracted with 200 ml of a mixture of three parts of n-butanol and one part of benzene. The extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure gave 1.3 g of 4a- (3-hydroxyphenyl) -2-n-propyl-2,3,4 _/ 4a, 5,6,7,7 aoctahydro-1H-2-pyrindine in the form of an oil. The oil was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The hydrobromide of the compound mentioned crystallized out and was filtered off, giving 1.1 g of 4a- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a-octahydro-1H -2-pyrindinium bromide, mp. 235-236 ⁰ C obtained.

Analysis, C ₁₅ H ₂₆ NOBr:

calculated: C 60, 00; H 7.70; N 4.12; found: C, 59.98; H 7.50; N 3.98.

Example 21

Following the procedure described in Example 20, there was obtained 4a- (3 x methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine with aqueous hydrobromic acid in glacial acetic acid

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4a- (3-hydroxyphenyl) -2-n -pentyl-2,3,4,43,5,6,7,7a-octahydro-1H-2-pyrindine implemented, which was then converted into the corresponding hydrobromide of melting point 171 to 173 ° C.

Analysis, C ^^ H ^ NOBr:

calculated: C 61.95; H 8.21; N 3.80; Found: C, 61.65; H 7.93; N 3.54.

809818/0932

Claims (22)

Claims 1. cis compound of the general formula Hydrogen, an alkyl radical with 1 to 8 carbon atoms, the group CH ₃ R ^ or the group _y »=» y / 4 means in which R. an alkenyl group with 2 to 7 carbon atoms, Cycloalkyl group with 3 to 6 carbon atoms, furyl or tetrahydrofuryl group means; * ₄ and R ₅ independently of one another represent hydrogen, an alkyl group having 1 to 3 carbon atoms or a halogen atom; η is 0, 1, 2 or 3; m is 0 or 1 except that when m is, η does not have the value 0; 809818/0932 X is one of the radicals CO, CHOH, CH = CH, S or Is 0 with the exception that when η is 0, X is neither sulfur nor oxygen means; and R_ hydrogen, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or an alkanoyloxy group having 1 to 3 carbon atoms; as well as the non-toxic pharmaceutically acceptable acid addition salts of that. 2. A compound according to claim 1, characterized in that R _{1 is} an alkyl radical having 1 to 8 carbon atoms or a group of the formula CH ₃ R ₃ , wherein R-, an alkenyl group having 2 to 7 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms means. 3. A compound according to claim 2, characterized in that R _{2 is} a hydroxyl or methoxy group. 4. A compound according to claim 1, characterized in that R _{2 is} a hydroxyl group. 5. A compound according to claim I, characterized in that R _{1 is} hydrogen. 809818/0932 6. 4a- (3-methoxyphenyl) -2-benzy1-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. 7. 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. 8. 4a- (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. 9. 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. 10. 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-pyrindine. 11. 4a- (3-hydroxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. 12. 4a- (3-Hydroxyphenyl) -2- (2-phenylethyl) -2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine. 13. 4a- (3-Hydroxyphenyl) -2-cyclopropylmethyl-2,3,4,4a, 5,6,7-7a-octahydro-1H-2-pyrindine. 14. 4a- (3-Hydroxyphenyl) -2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. 809818/0932 * 27Α8Λ66 15. 4a- (3-Hydroxyphenyl) -2- (2-propenyl) -2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine. 16. 4a- (3-methoxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine. 17. 4a- (3-Methoxyphenyl) -2-n -pentyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine. 18. 4a- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7 aoctahydro-1H-2-pyrindine. 19. 4a- (3-Hydroxyphenyl) -2-n -pentyl-2,3,4,43,5,6,7,7 aoctahydro-1H-2-pyrindine. 20. Process for the preparation of a cis compound of general formula (ID 809818/0932 R ₁ 'is an alkyl group having 1 to 8 carbon atoms or a radical of the formula CH ₂ R ₃ or - (CH ₂ ) - 'R means in which R is an alkenyl group of 2 to 7 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, a puryl or tetrahydrofuryl group; R ₄ and R ₅ independently of one another represent hydrogen, an alkyl group having 1 to 3 carbon atoms or a halogen group; η is 0, 1, 2 or 3; m is 0 or 1 except that if m is O, η is not 0; X is a radical of the formula CO, CHOH, CH = CH, S or 0 means with the exception that when η is 0, X is not sulfur or oxygen means, and R is hydrogen, a hydroxyl group, an alkoxy group with up to 3 carbon atoms or an alkanoyloxy group with 1 to 3 carbon atoms, ßO981 8/0932 as well as their non-toxic, pharmaceutically acceptable acid addition salts, characterized in that a compound of the general formula (III), in which R _{2 has} the meaning given above and R ₁ ″ is hydrogen, reacts with an alkylating agent to give a compound of the formula II, in which R ₁ 'is an alkyl group having 1 to 8 carbon atoms or a group of the formula CH ₃ R ₃ , in which R _{3 is} an alkenyl group with 2 to 7 carbon atoms, or with an acylating agent with subsequent reduction to a compound of the formula II, in which R ₁ 'is a group of the formula CH ₃ R ₃ , in which R _{3 is} a cycloalkyl group with 3 to 6 carbon atoms, a furyl or tetrahydrofuryl group or a group of the formula / -> C ^# ~~ R denotes, in which n, m, R- and R _{5 have} the meanings given above, optionally carries out an ether cleavage if R_ is an alkoxy group having 1 to 3 carbon atoms, in order to obtain a compound of the formula II in which R_ is a hydroxyl group and optionally acylated a compound of the formula II in which R _{2 is} a hydroxyl group to give a compound of the formula II in which R _{2 is} an alkanoyloxy group having 1 to 3 carbon atoms. 8Q9818 / 0932 21. Process for the preparation of a cis compound of the general formula Α ν (III) wherein R ₁ ¹¹ is hydrogen, an alkyl group having 1 to 8 carbon atoms or a group of formula is, and R _{2 is} hydrogen, a hydroxyl group, an alkoxy group with 1 to 3 carbon atoms or an alkanoyloxy group with 1 to 3 carbon atoms, characterized in that a compound of the general formula Cr- (IV), \ A> v wherein R ₁ ' ¹ and R _{2 have} the meanings given above, reacts with a reducing agent, optionally the compounds SQ9818 / 0932 of the formula III, in which R ₁ ' ^{1 is} an alkyl group having 1 to 8 carbon atoms or a group of the formula means, subjected to a cleavage in order to obtain the compounds of the formula III in which R .. '' signifies hydrogen, and optionally the compounds of the formula III in which R ~ signifies an alkoxy group having 1 to 3 carbon atoms, an ether cleavage to obtain the compounds of the formula II, in which R _{2 is} a hydroxyl group. 22. A pharmaceutical agent containing a carrier and a compound according to claim 1 as an active ingredient. (D 809818/0932