Pyridine derivatives

(M) Process for preparation 1 The invention relates to a process for the preparation of cis-4α-aryloctahydro-1H-2-piindines of general formula I:

<img file="RO77935A_D0001.tif" />

'\ z \ (I)

ÎWt,, 7 \ 7 «es to c / s-4a-ariIocțahi &lt;iro-lH-2-pirindine 2:

to nitrogen by cyclization of the trans-2- (2-year ethyl) - oyclopentylmethanol [M. Prochazka et al., The azomphbioieiooctane isomers and isomyceae isomers, Cpllect 5 tion Czech. Chem. Commuaî. 31 (9), ρ, μ. 3824 ... 3828, 1936].

The process, according to the invention, extends the range of octahydropyrindrines with new compounds in that an octahydropyrindine i of general formula II:

wherein R 1 represents a hydrogen atom, a 1-5 alkyl group of liming carbon atoms or a benzyl group, and R 1 represents a hydrogen atom or a methoxy group.

Many of the painkillers currently available have limited use, due to some¹ undesirable side effects to their continued administration, including mania and allergy. Some analgesics with the structure of decahydroizoquinoline are known, namely, 4a-aryl-irans-decahydroizoquinoline (Patent, Belgium, no. 8021557).

Some unsubstituted octahydro-2-ρίrindines at position 4a were prepared ('Chemical Abstracts, 67 · 6034, 1967).

Also known is a process for obtaining an unsubstituted trans octahedral hydro-2-pyrene isomer.

(Π)

N-hR, Z \ Z in which Ri and Ra have the above meanings are reduced with lithium-aluminum hydride in solvent medium, selected from tetr'ahidxofuran, ethanol, tolu, en and glacial acetic acid, at reflux temperature , whereupon, optionally, the alkyl group or the benzyl group at position 2 is removed, the methoxy group cp substituent on the phenyl ring is hydrolyzed to the dihydroxy group and the compound may be converted to a salt, in a known manner.

•77935

LEI PRICE 32.30

The following are 3 examples of the process according to the invention.

Example 1. A solution of 18 g 4a-phase] U-2-benzyl-2,3,4,4a, 5,6,7 // a - octahydrol, 3-ylhexoxo-iH-2-pLindine dissolved in 200 ml tetrahydrofuran was added dropwise in 90 min in a stirred suspension of 5.8 g lithium-aluminum hydride in 150 ml of tetrahydrofuran. After finishing. upon addition, the reaction mixture was heated at reflux for 5 h. While maintaining the temperature below 50 ° C of the mixture, add 50 ml of ethylacetate dropwise for 15 minutes, followed by the addition of 100 ml of aqueous ammonium chloride. The tetrahydrofuran was then added to the aqueous reaction mixture to separate the organic layer from the aqueous layer. The organic layer is decanted and concentrated under reduced pressure to obtain the product as an oil. The oil thus prepared was then dissolved in 500 ml diethyl ether. The etherified solution is washed with water, dried, and the solvent is evaporated off under reduced pressure to give 15 g 4a-phenyl-2-b, enzyl-2,3,4,5,4a, 56,7,7a -octahydro-1H-2 - pyrindine M⁺/ e 2,916 (origin peak), 213 (-77, tapes), and 200 (-91, tapes).

Example -2. Following the procedure of Example 1, 4a- (3-methoxy-enyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-nyrindine was reduced with lithium hydride. aluminum to obtain 4a- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7aoctahydro-1 Η-2-pyr indine.

As a solvent, ethanol, toluene, glacial acetic acid may also be used.

Example 3, A solution of 75 ml toluene containing 1.76 ml of liquid methylamine was cooled to -70 ° C in an ice-acetone bath and stirred, while a 1.0.4 g tetrahydrochloride solution. 4 (3-methoxyphenyl) - 2,6 - d / oxo-cyclopentane fc] p, iran in 125 ml toluene was added dropwise after 30 min. The reaction mixture is heated to room temperature and then at reflux for 20 hours, then cooled again to room temperature and concentrated as a low pressure oil. The oil thus formed is dissolved in 152 ml of 1 n sodium hydroxide solution and heated with stirring at 50 ° C for 15 min. The product is extracted from the alkaline reaction mixture in diethyl ether. The etherified extracts are combined, washed with water and dried. Evaporation of the solvent under low pressure afforded 8.3 g of 4a- (3-methoxyphenyl) -2-methyl-2,3,4, 4a, 5,6,7,7a-octahrdro-1H-2-pyrindine .

8.2 g reduction of 4a- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-oota⁵ hydro-1,3-d-oxo-iH-2-2-pyrindine in reaction with lithium-aluminum hydride, according to the process of Example 1, gives 4.6 g of 4a- (3-mephtoxyphenyl) - 2 - methyl-2,3,4,4a, 5,6,7,7a¹⁰ odtahi'dro-H-2-pyrindine; boiling point 133 ... 138 ° C at 0.55 torr.

Analytical calculations for CusHsNO, in »/»:

- theoretically: C-78.32; H, 9.45;

¹⁰ N-5.71;

- practical: C-78.13; 11-9.30, N = 5.68.

A solution of 4a- (3-methoxyphenyl) -2-nie20 th - 2,3,4,4a, 5,6,7,7a - oatahydro-1H-2-pyrindine in 100 ml of diethyl ether was stirred; During this time, bubble hydrochloric acid is passed through the respective solution. The reaction mixture was stirred for 30 min and then filtered. The solid product is recrystallized from diisoproplane digester and ... isopropanol to give 4a- (3-methoxyphenyl) - 2 methyl - 2,3,4,4a, 5,6,7,7a - octahydro-1H30 2-pyrindine chloride_; m.p. 175., 177 ° C.

Analytical calculations for CisHvHOCl, in%:

- theoretically: C = 68.19; H = 8.58 ·,

N, 4.97;

- practical: C = 68.00; H, 8.22;

N, 4.68.

The following is an indication of how ₄₀ removal of the benzyl group from position 2 and by hydrolysis of the methoxy group which is a substituent to the phenyl ring, to the hydroxy group,

A 21 g solution of 4a-phenyl-2-ben45 days - 2,3,4,4a, 5,6,7,7a - octahydro-11-1-2pyrrine in 172 ml ethanol was stirred, while 7 g of 5% palladium in carbon suspension is added in a portion. The reaction mixture is stirred in an at51) hydrogen gas mixture at 4.13 χ 10⁵dyne / cm² and heated to 60 ° C for 3 h. The reaction mixture is cooled to room temperature, filtered, and the solvent is evaporated by evapo55 rare under reduced pressure, to obtain 13.3 g of oil product. , oil which is distilled to obtain 4a-fem) I - 2,3,4,4a, 5,6,7,7a - octahydro-1 Η-2-pyrine.

⁶⁰ 4a (3-Methoxyphenyl) - 2-benzyl-2,3,4,4a, 5,6,7,7a-ootahid.ro - 1H-2 - pyrindine is hydrogenated in the presence of palladium suspended in manganese in accordance with the procedure of above to produce

4a- (3-methoxyphenyl) - 2,3,4,4a, 5,6,7,7a-oc77935 tetrahydro-ii-2-pyrindine; boiling point 145 ".160 ° C at 0.05 torr,

A solution of 8,4 g 4a- (3-methoxyphenyl) 2,3,4,4a_r5_r6,7,7a-octahydro - IH - 2 - pyrindine dissolved in 60 ml glacial acetic acid and 60 ml of 48% aqueous HBr solution was agitated and heated to reflux for 15 h, after cooling the reaction mixture to temperature to the chamber, it is mixed with 103 g of ice, and the pH of the resulting aqueous solution is adjusted to 10.2 plum addition of concentrated sodium hydroxide solution. This is then extracted with 400 ml of a mixture of three parts n-butanol and one part benzene. The extract is separated, washed several times with water, dried, and the solvent is removed by evaporation under reduced pressure to obtain the product as a crude solid. The solid thus formed is crystallized from eitlaceite to obtain 4.2 g of 4a- (3-hydroxyphenyl) -2,3, 4,4a, 5,6,7,7a-octahydro-1H-2-pinindine; melting point 18O ... 181 ° C.

Analytical calculations for CuHwNO, in Vo:

- theoretically: C = 77.38; H, 8.81;

N, 6.45;

- nractic: C = 77.56; H, 8.84;

N, 6.24.

A solution of 1.6 g 4a- (3-methoxyphenylmethyl - 2,3,4,4a, 5,6,7,7a - octahydro-1H2-pyrindine in 12 ml acetic acid containing 12 ml 48% hydrochloric acid / aqueous shake and warm to reflux for 15 h. The mixture¹ The reaction acid is cooled to about 10 ° C and the pH is adjusted to 10.2 by the addition of a 50% aqueous sodium hydroxide solution. The product is insoluble in alkaline aniseed solution and extracted from it in a solution of 90 ml η-butanol and 30 ml benzene. The organic solution is then separated, washed with water and dried. Evaporation of the excess solvent under low pressure led to the production of a demiltrated product in the form of an oil, which crystallized from diethyl ether and ethylacfa to obtain 4a13-hydroxyphenyl) -2-methane, 2,3,4,4a.5, 6. 7.7a - odtahydro-1H-2-pyrdine; melting point 151, .. 153^AC.

Analytical calculations for CisH? INO, in%:

- theoretically: C = 77.88; H, 9.15;

N, 6.05;

- practical: C- = 77.60; H, * 8.88; N, 5.76.

A solution of 2.0 g of 4a- (3-methoxyphenyl) - 2 - n - naphthyl-2,3,4,4a, 5,6,7,7,7a octahydro-1H-2-pyridine is dissolved in ml of glacial acetic acid and 20 ml of 48% aqueous hydrochloric acid, stirred and heated at reflux for 12 hours. The reaction mixture was cooled and poured over 100 g of ice, and the resulting aqueous solution was made alkaline by addition of aqueous sodium hydroxide. , at a pH of. 10.2. The obtained alkaline mixture was extracted with 200 ml of the mixture of three parts of n-butanol and one part benzene. The extracts are combined, washed with water and dried. Removal of the solvent by evaporating at low pressures afforded 1.3 g of 4a- (3-hydroxyphenyl) -2-n-propyl-2,3,4,4a, 5,6,7,7a octahydro-1H-. 2-piirindiiine as an oil. The oil is dissolved in diethyl ether and added to a solution of hydrobromic acid gas in the diethyl ether. The hydrochloric salt of the above-mentioned compound is crystallized and recovered by filtration to give 1.1 g of 4a- (3-hydroxyphenoyl) -2- n-propyl - 2.3,4,40,5,6,7, 78 pyrindinium octahydro-1H-2-bromide; melting point 235 .., 236³C.

Analytical calculation for CisEhsNOBr, in%:

theoretically: C = 60.00; H-7.70, N = 4.12 - practically: C = 59.98; H = 7.50 ·

N, 3.98.

Following the above procedure, 4a- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6, 7,7a-octahydro-1β-2-pyr.indine is reacted with hydrobromic acid aqueous in glacial acetic acid to obtain 4a- {3-hydroxyphenyl) - 2 - n - pentSl-2,3,4,4a, 5,6,7,7a-octahydro-IH - 2-pyrindea, which is then converted to the corresponding salt of hydrobromic acid; mp 171 ... 173 ° C.

Analytical calculations for C? OHwNOBr, in Vo - theoretically: C-61.95; H-8.21;

N, 3.80;

- practical: C = 61.65; 11 - 7.93;

N, 3.54.

Examples of raw material preparation are given below.

A. A solution of 130 g 2-phenyl-2-ethoxycarbonylmethylcyclohexane in 2 000 ml diethyl ether containing 56 g of ethyl formate and 11.5 g of sodium metal is stirred at a temperature of 2.5 ° C for 48 hours. Reaction The mixture is then continued by the addition of 1,030 ml of bile water and a layer of ether is removed. The aqueous layer is acidified to a pH of 6.5, by the addition of hydrochloric acid and extracted in conjunction with fresh diethyl ether. The ether extract is combined, washed with water and dried. Evaporation of the solvent under reduced pressure yields 98 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formyl.77935 cyclohexane ca. an oil; boiling point 158 ​​... 175 ° C at 0.6 torr.

Analytical calculations for CvHa&gt; Cb, in.%:

- theoretically: C -70.81; H, 6.99;

- practical: C-70.85; H = 6.77,

B. Following the procedure of Example A, the product 2- {3-methoxyphenyl) -2-ethoxycarbonylmethylcyclohexane was reacted with ethylformial in the presence of metal sodium to obtain 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6formanylcyclohexane.

C. A solution of 87.0 g 2-phenylcyclohex'anone in 100 ml of benzene is added dropwise over an hour to a stirred solution at reflux of 28.0 g of sodium amide in 400 ml of benzene. The reaction mixture was heated to reflux for about 2.5 h and then cooled to 0 ° C in an ice bath. The cooled reaction mixture is added, in a portion, to a solution of

83.5 g of allyiodide in 100 ml of benzene. The reaction mixture was heated to reflux for 1/2 h and then cooled to 25 ° C and dripped over 400 g of ice. The benzene layer is separated, washed with water and dried. Evaporation of the solvent gave 500 g of 2-phenyl- (2-propenyl) -eiclohexane with boiling point 114 ... 120 ° C at 0.1 torr,

D. A solution of 30 g 2-phenyl-2- {2-propenyl) -cyclohexane in 600 ml diethyl ether, containing 3.4 g of sodium metal and 11.8 g of ethyl formate, is stirred at 25 ° C. for 48 h. The reaction mixture is added to water and the organic citrate is separated and released. The aqueous layer is acidified to a pH of 2.5 by the addition of hydrochloric acid. The aqueous acid layer is extracted with fresh diethyl ether. The ether extract is combined, washed with water, dried and the solvent is evaporated off under reduced pressure to obtain an oil which is distilled to obtain 14.6 g of 2-phenyl-2- (2-propenyl). ) 6-fortn, ilcyclohexane with boiling point 125 ... 130 ° C has 0.1 torr.

E. A 50.0 g solution of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclobobexane in 500 ml diethyl ether is stirred at 25 ° C, while a solution of 24.8 g diethylamine in 100 ml diethyl ether is added dropwise. for 30 min. After stirring the reaction mixture at 25 ° C for 2 h, the solution is cooled to 8 ° C, and then a solution of

33.5 g of p-toluenesulfonylazide in 50 ml of diethyl ether was added dropwise over 15 min. The reaction mixture was allowed to warm to room temperature and stirred for a further 11 hours

h. The reaction mixture was washed with water and dried. Evaporation of the solvent under reduced pressure afforded 43.0 g of 2-phenyl-2-ethoxycarbonylmethyl-6-diaaocyclohexane as an oil. IR (net) 2,080 cm¹ diazo group.

F. and G. Following the process of Example E, the product 2- (3-methoxyphenyl) 2-ethoxycarbon; ilmeI-6-formylcyclohexanone is converted to 2- (3-methoxy-phenyl) -2-ethoxycarbonylnethyl-6-di. azocyclohexane and 2-phenyl-2- (2-propenyl) 6-formylcyclohexanone in 2-phonon-2 (2-propyl nyl) -6-dazocyclohexane.

H. A 57 g solution of 2-phenyl -2-ethoxycarbonylmethyl-6-diazocyclohexane is stirred at 25 ° C, while bubble nitrogen gas is introduced through the reaction mixture. The solution is photolysed for 40 hours with a quartz lamp with a wavelength of 3,000 A. The solvent is then removed under reduced pressure to produce a crude product, which is dissolved in 500 ml of diethyl ether. The ethereal solution is washed with water, aqueous sodium bicarbonate solution and dried. Evacuation of the solvent under reduced pressure afforded 27.4 g of 2-phenyl-2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane under oil sheets. The oil is further purified by distillation, - put ', boiling 16O ... 19O ° C at 0.02 torr.

Analytical calculations for CvHrOi, in%:

—Theoretical: C = 70.32; H, 7.64;

- practical: C-70.30; H = 7.36.

Ϊ. and J. Following the process of Example H, 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-6-diazocyclohexanone is photolysed at a wavelength of 3,000 A to obtain 2- (3-methoxyphenyl) -2 ethoxycarbonylmethylpiperidin it-metoxicarbonilciclopantan; boiling point 9 ° C to 21 ° C.

Analytical calculations for CisHnOs, in 0/0:

- theoretically: C -67,48; H, 7.55;

—- practically: C - 67.61; H, 7.37.

Similarly, 2-phenyl-2- (2-propenyl) 6-diazocyclohexane is irradiated with 3,000 A wavelength ultraviolet rays from a quartz lamp in the presence of methanol to obtain 2-phenyl - 2 - (2 -propenyl) -l-methoxy carbons cyclopentane; boiling point 113 ... 115 ° C at Ot torr.

Analytical calculations for C16H20O3, in ° / o:

- theoretically: C = 78.65; H = 8.25;

- practical: C = 78.80; H = 7.99.

K. A solution of 2- (3-methoxyphenyl) -2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopenitan in 650 ml of 1,4 dioxane containing 500 ml of 5% aqueous potassium hydroxide is stirred and heated at reflux for 12 h. Cool the reaction mixture to room temperature, add 500 ml of water. The reaction mixture is then acidified by the addition of hydrochloric acid 2n, after which the aqueous acid mixture is extracted several times with volumes of diethyl ether in equal quantities. The aqueous extract was combined, washed with water and dried, Evaporation of the solvent under reduced pressure gave 38 g of 2- (3-methoxyphenyl) -2-hydroxycarbonylmethyl-1-hydroxycarbonylldyclopentane as crystallized solid; mp 175 ... 180 ° C.

Analytica l calculations for C ^ HaOs, in%:

- theoretically: C = 68.24; H, 7.84;

- practical: C = 68.15; H, 7.57.

L. and M. Following the process of Example K, 2-phenyl-2-ethoxycarbonylmethyl-1-methoxycarbonylcyclopentane was hydrolyzed to obtain 2-phenyl-2-hydroxycarbonylm'yl-1-hydroxycarbonylcycloproputane; mp 2O5 ... 2O8 ° C.

Analytical calculations for CuHuOi, in o / o:

-— theoretically; C, 67.73; and 1 - 0.50;

- practical: C = 67.70; 11 - 6.32,

2-Phenyl-2- (2-propenyl) -1- methoxycarbonylcyclopentane was hydrolyzed by reaction with aqueous potassium hydroxide to obtain 2-phenyl-2- (2-propenyl) -1-hydroxyarbonylcyclopentane.

N. A solution of 25 g 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopemtan in 150 ml of acetyl chloride is stirred and heated at reflux for 4 h. After cooling the reaction mixture to room tempe rature, the excess solvent is cooled. It is removed by evaporation under reduced pressure, allowing to obtain 26 g of tetrahydro-4-phenyl-2,6-dioxocyclopentaclpyrane as an oil. The product is then further purified by distillation; boiling point 205, .. 207 ° C at 0.25 torr.

Analytical calculations for ChH-sCL, in%:

- theoretically: C-73.03; H, 6.13; practical: C = 73.30; H, 6.37.

O. Following the process of Example N. 2- (3-methoxyphenyl) -2-hydroxycarbonyl-1-hydroxyarbonylcyclopentane is dehydrated and cyclized by reaction with acetyl chloride to obtain tetrahydro-4- (3-methoxyphenyl). -2.6d / -oxo-cyclopentafc] piiran; boiling point 200 ... 220⁹C

P. To a stirred 6.2 q solution of 2-phenyl - 2 - (2-propenyl) -l-hydroxycarbonyl nylcyclopentane in 100 ml chloroform, 30 g thionyl chloride is added dropwise over 30 minutes. The reaction mixture was heated to reflux and stirred for 15 h. After cooling, the reaction mixture was evaporated under reduced pressure to remove the solvent and to obtain 7.4 g of 2-phenyl - 2 - {2-propenyl ) -L-clorcarbonilciclopentan.

Q, A solution of 10.7 g of bemzylamine in 100 ml of toluene is stirred at 25 ° C, while a solution of tetrahydro-4- (3-methoxyphenyl) - 2,6-dioxocyclopentate] pyran in 300 ml of toluene is added via dripping for one hour. After complete addition of the pyran derivative, the reaction mixture is stirred and heated at reflux for three days in a retort equipped with a Dean-Stark hatch, to remove water. After the reflux period, the reaction mixture is cooled to room temperature and the solvent is evacuated by evaporation under reduced pressure, thus obtaining the product as a crude oil. The oil dissolves in 3400 ml of solution

- Sodium hydroxide ln and the alkaline reaction mixture is heated to 50 ° C for 15 min. The aqueous alkaline mixture is then extracted with diethyl ether and the etherified extract is combined, washed w ith water and dried, and the solvent is removed under reduced pressu re to obtain the product as a solid residue. Recrystallization of the solid from diethyl ether allows to obtain 4- (3-methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-di-oxo-1H-2-pyrindine, · Mp 75 ... 77 ° C.

Ice calculations for CaHaNO?, In.%:

- theoretically: C = 75.62; ii -6.63;

N, 4.01;

- practical: C -75.40; H, 6.58;

N, 3.78.

A. The product tetrahydro-4-phenyl-2,6-df-oxo-cyclopenta [benzylamine chlorpan] is subjected to the reaction. according to the process of Example Q, to obtain 4a-phenyl-2-benzyl-2,3,4,4a, 5,6.7, 7a-octahydro-1,3-di-oxo-1H-2-pyrindine; mp 77 ... 79 ° C.

Analytical calculations for CaHțiNO ', in o / o ·.' - theoretically: C -78.97; H, 6.63;

N, 4.39;

- Cyclic: C = 78.73; H, 6.65;

N, 4.26.

A preferred group of compounds consists of those compounds of formula I, wherein the symbol R 1 represents an alkyl group of 1-5 carbon atoms.

A group of compounds, which is part of the above but preferred group of urea, consists of those compounds of formula I wherein the symbol R 2 represents a hydroxy group or a methoxy group. A preferred group of compounds contains those compounds of fortune I in which the symbol R 1 represents a hydrogen atom.

'In the spirit in which it is used herein, the notion of alkyl group with 1 ... S carbon atoms refers both to the linear alkyl groups and to the branched alkyl groups, which have a number of carbon atoms equal to 8 or smaller. As examples of alkyl groups with 1 ... 8 representative carbon atoms, mention may be made of the methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, 3-methylpentiyl, 1,2-dimethylpenyl, 2-methylbulti, 3-Ethylpentyl, n-octyl, 2-methylheptyl, iso-heptyl, 3-ethylhexyl, 1- - trimethylpentyl.

The pyrene derivatives of formula I above are produced by the reaction in the first step of an amine (specifically ammonia or a primary amine) with a cyclic anhydride, namely, with a 4-aryltetrahydro-2,6-. cb'-oxocyclopenta [c] pyran, according to the generalized reaction scheme below:

'\ ^z\ ru / wo

, / \ z + Κ, Ν — R,

N-R

OO

In which the symbols Rs and R2 have the meanings mentioned above. The compound thus obtained, namely, 1,3-dioxo-4a-aryl - 2,3,4,4a, 5,6,7,7a - octahydrolH-2-pyrindine, which represents a cyclic imide, is then reduced to oxo groups of positions 1 and 3, to give a derivative of the pyrene of formula I. In practice, it is preferred to use 4-α / pharyltetrahydro-2,6-di-oxo-cyclopent 50 [cjpyranes, wherein the subtype of the aryl group bond, which is defined in the above formulas by the symbol R?, represents a hydrogen atom or an alkoxy group with i., 3 carbon atoms, 55 Of these alkoxy groups with 1 ... 3 carbon atoms, the methoxy group is preferred, as this group is slightly added in a subsequent step towards to give a hydroxyl group, as described below. In the case of the reaction of an amine with the above mentioned cyclic anhydride, it is also preferred to use amines, such as ammonia, 65 alkylamines with 1 ... 8 carbon atoms and especially methylamine, as well as aramlamines and in particular benzylamine. The 2-methyl derivatives and the 2-benzenesI-derivatives of the pyrene thus obtained are readily transformed into the corresponding unsubstituted 2-pyrene. In the preparation of f, 3-d; -oxo4a-ar'yl-2,3,4,4a, 5,6,7,7a-octahydro-iH2-pyrindines by the above-mentioned reaction scheme, 4-aryl-tetrahydrob 2 , 6-df-oxo-cyclopenta [c] pyran and amine are typically combined in approximately equimolar amounts, although it is possible to use an excess of any reactant, if desired. The reaction can be carried out in any commonly used non-reactive organic solvent, such as aromatic solvents such as benzene, toluene, xylene, methoxybenzene and nitrobenzene, as well as non-aromatic solvents, such as, for example, chloroform, methylene chloride, dimethylsulfoxide, nitride. acetone, tetrahydrofuran, dimethylformamide and dioxane. The reaction is typically carried out at elevated temperature, for example, at a temperature of between about 50 and about 200 ° C and preferably between about 80 and about 150 ° C. Since the reaction between the amine and the cyclic anhydride, in order to form the corresponding cyclic imide, is accompanied by the formation of water, it may be appropriate to carry out the reaction, thus preventing the water from being removed from the reaction mixture as it is born. For this purpose, it is possible to use any of the techniques commonly used to maintain an anhydrous reaction mixture, for example, by using molecular sieves; alternatively, in the case of reaction solvents, such as benzene and toluene, it is possible to use a Dean-Stark separator for this purpose. The reaction between the amine and the cyclic anhydride normally ends completely within a period of time. 24 ... 72 h. However, longer reaction times are not harmful to the reaction product being subjected to formation, so they can be used if desired. The cyclic imide formed, namely, 4aaril-2_r3,4,4a.5,6,7,7a-octahydro-1,3-dioxo-1H-2-nirindine is readily isolated by removal of the reaction solvent, for example by evaporation under reduced pressure, and the reaction product may be further purified by common methods, such as acid or base extraction, crystallization and chromatography. As mentioned above, 4-aryltetrahydro-2,6-ci; oxo-cyclopenta [cjpiran may be reacted with ammonia to give 4-aryl2,3,4,4a, 5,6,7,7a-octahydro - the corresponding 1,3-di-oxo-2-pyrindine which is unsubstituted at position 2; alternatively, the pyran derivative can be reacted with a primary amine to obtain a 4a-aryl-2,3,4 directly_r4a, 5,6,7,7aoctahydro-1,3-di-oxo-1H-2-pyrindine 2-substituted. It has also been established that when it is desired to subject the reaction of the pyran derivative to a primary amine to obtain a 2-substituted plrindine, it is preferable that this primary amine be methylamine or benzylamine. These primary amines are preferred because, when subjected to a reaction with 4-α-ryltetrahydro-2,6-dioxo-cyclopentamethylpyrane, they give a 2-substituted 1,3-dioxo-pyrindine, which, when reduced, leads to to a 2-substituted pyrene derivative, whose substituent at position 2 can be readily removed to obtain a 2-substituted pyrene derivative. However, it should be noted that although the preferred primary amines for the reaction with the above derivative of pyran are methylamine and benzylamine, in essence, the pyran derivative can be reacted with any primary amine to give 4α-aryl-2. , 3,4,4a, 5,6,7,7a-octahydro-1,3-di-oxo-ΙΗ-2-pyrindine 2 substituted corresponding. It will also be mentioned that, since the last mentioned compound is a derivative of 1,3-di-oxo-pyrindine, this compound must be subjected to the reduction of the oxo groups of positions 1 and 3, in order to obtain the pyrinines of the formula I, pharmacologically useful. For this reason, it is preferable as an eventual group bound in position 2 of such 4a - aryl - 2,3,4,4a, 5,6,7,7a-octahydro-1, 3d / -oxo-1H-2 - 2-substituted pyridines to represent a group which is resistant to the reduction methods used to reduce the oxo groups of positions 1 and 3. In the case of groups which are not so resistant to reduction, it is appropriate to introduce resistant groups by alkylation or acylation (followed by reduction) of the 2-unsubstituted derivatives of pyrene.

In the following, we mention a few representative 4a - aryls - 2,3.4,4a, 5,6,7,7a-octahydro - 1,3 - dr-oxo-1H-2-pyrindines, of formula I, which are specifically expressed accustomed directly by the reaction of an amine with a cyclic anhydride, as described above, which is then reduced to give pharmacologically useful pyrene derivatives of formula I:

H-4a-Phenyl-2,3,4,4a, 5,6,7,7a-octab, hydro-1, 3-dr-oxo-1H-2-pyrindine;

- 4a - Phenyl-2-methyl-2,3,4,4a, 5,6, 7,7a-octahydro-1,3-di-oxo-1H-2-pyrene, - 4a- (3-Methoxyphenyl) - 2-n-pentr-2,3,4,4a, 5,6,7,7a-ootahydro-1,3-di-oxolH-2-pyrindine;

- 4a- (3-Ethoxyphenyl) - 2 - (3-phenylpropyl) - 2,3,4,4a, 5,6,7,7a - octahydro-1,3di-oxo-1H-2-pyrene ·, - · 4a-Phenyl-2-phenylmethyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-di-oxo-1H-2-pyrindine;

- 4a- (3-Propoxyphenyl) - 2-n-propyl 2,3,4,4a, 5,6,?, 7a-octahydro-1,3-di-oxoΙΗ-2-piyrindine;

- 4a-Phenyl-2 - [2- (3-Chlorophenyl) -ethyl] 2,3,4,4a, 5,6,7,7a-octahydro-1,3-di-oxoΙΗ-2-pyrindine;

- 4a- (3-Methoxyphenyl) -2-phenylmeiyl 2,3,4,4a, 5,6,7,7a-octahydro-1,3-di-oxolH-2-pyrindime;

- 4a - (3-Methoxyphenyl) - 2,3,4,43,5,6,7, 7a-octahydro-1,3-di-oxo-ΙΗ-2-pyridine;

- 4a - Phenyl - 2 - (3,4-dimethylphenyl) methyl - 2,3,4,43,5,6,7,7a - octahydro-1,3di-oxo-1H-2-pyrindine and - 4a- ( 3-Propoxyphenyl) - 2 - (4-phenylbuiyl) - 2,3,4,4a, 5,6,7,7a - octahydro-1,3-di-oxo-ΙΗ-2-pyrindine.

As mentioned above, 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3 dI-oxo-1-yl-2-pyrene of formula II. mentioned above, it is converted to 4a-aryl - 2,3,4,4a, 5,6,7,7a - octahydro-1H2-pyrene of formula 1, by reducing the oxo groups of positions 1 and 3. This reduction can be achieved by any ordinary method of reduction, which is known to those skilled in the art. Thus, for example, 1,3dr-oxo-derivative of pyrindine may be reacted with any reduction agent based on alkali metal hydrides, such as lithium-aluminum hydride, sodium borohydride, lithium-tri-ion hydride -butoxialuminiu. and lithium-thiomethoxy aluminum aluminum hydride. If this is desired in the cafe, it is also possible to use other reducing agents, such as zinc and acetic acid, and catalytic hydrogenation. The preferred process for reducing a 4a-aryl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-di-oxo-1H-2-pyrindine of formula II, involves the use of lithium hydride. aluminum, as a reducing agent. Representatively, a 4a - aryl - 2,3,4,4a, 5,6,7,7a-o'-hydrohydro-1,3-oxo-1H-2-pyrindine, such as, for example, 4a- phenyl-2-methyl-2,3,4,4a, 5.

6,7,7a-octahydro-1,3-di-oxo · 1H-2-pyridylidia, is reacted with an approximately double molar amount of lithium-aluminum hydride in an inert organic solvent. As inert organic solvents, which are commonly used for this reaction, tetrahydrofuran, ethyl ether, dioxane and related solvents may be mentioned. The reaction is normally carried out at a temperature between about 20 and about 100 ° C; when it is carried out at such a temperature, the reaction is usually practically complete, after a period of time of approx.

4 ... 20 h. The reaction product is normally recovered by decomposing in the first step of the eventual unreacted reducing agent, which may remain in the reaction mixture, if the reducing agent is represented, for example, by lithium aluminum hydride, this decomposition is achieved by the introduction - in the reaction mixture - of an ester, it reacts easily with the possible excess reducing agent. For this purpose, an ester, such as ethyl acetate, is usually used. After the ester is added to the reaction mixture, the latter is typically treated with an aqueous ammonium chloride solution to coagulate any inorganic salts formed during the reaction, and the desired reaction product is then extracted from the mixture with a suitable organic solvent, such as ethyl acetate or tetrahydrofuran. The organic extracts are then combined and concentrated by evaporation of the solvent to obtain the reduced reaction product, ie. 4a-aryl-2,3. 4,4a, 5,6,7,7a-ootahydro-IH-2-pyrindine of formula I. This noodle is representative in the form of oil and is more easily purified (if desired) by methods such as distillation and chromatography; alternatively, the reaction product may be converted to an addition salt with an acid, which can then be purified by recrystallization.

Compounds of formula I, which are thus easily obtained by reducing the oxo groups from notions 1 and 3 of a 4a-aryl-2,3 4. 4a, 5,6.7.7a-octahydro-1,3-di-oxo-lH2- pyrindines by the process described above. include, but are not limited to:

- 4a- Phonyl - 2.3,4,4a, 5,6,7,7,7a - octahydro-1H-pyrindine;

- 4a- (3-Methoxyphenyl) - 23,4,4a, 5,6,7, 7a-octahydro-1H-2-pyrindine, · - 4- (3-Ethoxyphemyl) -2-methyl-2,3,4 , 4a5,6,7,7a - octahydro-1 Η-2-pyrindine {- 4a - Phenyl - 2-ethyl-2,3,4,4a, 5.6_r7, 7a-octahydro-1H-2-pyrindine;

- 4a- (3-Isopropoxyphenyl) -2-benzyl 2,3,4,43,5,6,7,7a-octahydro-ΐΗ-2-φϊπηdin;

- 4a - Phenyl -2- isobutyl-2,3,4,4a, 5,6, 7,7a-octahydro-1H-2-pyrindine;

- 4 &lt;a- (3-Methoxyphenyl) - 2 - (4-ethylhexyl) - 2,3,4,4a, 5,6,7,7a - octahydro-1H-2-pyrindine and - 4a- (3-Ethoxyphenyl) ) - 2 - (3-chlorobenzyl) - 2,3,4,4a, 5,6,7,7a - octahydro-1H-2-pyridine.

For this reason, it is appropriate, in accordance with the process described above, to prepare substituted 4-aryl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindines 2, in which the substituent at position 2 can be readily removed, so as to obtain the corresponding unsubstituted octahydropyreneins at position 2. As mentioned above, the N-methyl and N-benizyl groups are readily cleaved, to give the corresponding unsubstituted captive derivative at position 2. . Thus, the 2-methyl-derivatives of pyrindines, which are prepared in the manner described above, may be reacted with an ester of a haloformic acid, such as, for example, phenyl chlorate formate or ethyl chloroformate, to give carbamates corresponding to position 2 of the pyrene. This carbamate is then treated with an aqueous base, such as sodium hydroxide, to split the carbamate residue from position 2, in order to produce the corresponding pyrene derivative.^iteluted at position 2. This method for cleavage of an N-methyl group has been described in the literature [Abei-Monen and Portoghese, J. Med. Chem., 15. p. 208 (1972)].

Similarly, 4α-aryl-2-benzyl-2,3_;4, 4a, 5,6,7,7a-ootahydro - 1H-2 - pyrinines mentioned above are readily transformed into the corresponding iridinated unsubstituted in position 2 by simple mole. This debenzylation can be performed by catalytic hydrogenation, using, for example, a palladium-based catalyst applied to coal (with a palladium content of 5%), These debenzylation reactions are quite general for the preparation of secondary amines and are described in detail in the literature [Hartung and Simonoff Org. Reactions, 7, p. 277 (1953); Leonard and Fuji J. Amer. Chem. Soc., 85, pp. 3 719 (1963)]. As can easily be deduced from the foregoing discussions, the 2-unsubstituted pyridines of formula I (in which the symbol R 1 represents a (hydrogen) atom, mentioned below, are also important pyridines:

- 4a-Phenyl - 2,3,4,43,5,6,7,73-octahydiro-1H-2-pyrindine;

- 4a- (3-Methoxyphenyl) - 2,3,4_r4a, 5,6,7, 7a-octahydro-1H-2-pyrindine;

- 4a- (3-Ethoxyphenyl) - 2,3,4,43,5,6,7,7aocl.hydro-II-2-pyryridine;

- 4a- (3-Isopropoxyphenyl) - 2,3,4,4a, 5,6, 7,7'a-ocitahydro-1H-2-pyrindine;

- 4a- Phenyl-2-methyl-2,3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindine;

- 4a-Phenyl-2-ethyl-2,3,4,4a, 5_r6,7,7aootahydro-1H-2-pyrindine, · - 4a- (3-Methoxyphenylj-2-n-pentyl2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindma and - 4a (3-Methoxyphenyl) - 2-isopropyl 2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindhia.

It will also be noted that certain 4'-aryl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindins of formula I may be subject to further modifications . Thus, for example, it might be preferable to first prepare a 4α- {3-methoxyphenyl) -2-substituted -2,3,4,4a.5,6 7,7a-octahydro-IH-2-pyrindine and the 3-methoxy group of the 4α-aryl substituent is then iranformed into a hydroxy group. This transformation is easily accomplished by treating 4a- (3-methoxyphen.ilj-derivative of pyrindine with hydrobromic acid in acetic acid. This reaction is general for converting a methoxyphenyl group into a hydroxyphenyl group.

As pointed out above, the 4a-aryl-2-substituted product with the octahydro-IH-2-pyrindine derivatives of formula I can react with an organic or inorganic acid so as to obtain a crystalline salt which can be purified. by crystallization and which is then converted to free-base pyrindine by a convenient treatment with a base, such as sodium hydroxide. Undoubtedly, the addition of acid salts is necessary to make the compound of formula I. Specifically, non-toxic, pharmaceutically acceptable acid salts of the pyrindine bases described above are prepared. Such pharmaceutically acceptable acidic addition salts are prepared by reacting 4α-aryl-2-substituted-octahydro-1H-2-pyrindine of formula I with an organic or inorganic acid. Acids commonly used for the preparation of pharmaceutically acceptable acid addition salts of formula I include halogenated acids, such as hydrochloric acid, hydrochloric acid, hydrochloric acid, and acids such as sulfuric, nitric acid, mentioned phosphoric, perchloric, phosphorous, nitrogen and acids. Organic acids commonly used for the preparation of pharmaceutically acceptable acidic addition salts of pyrene of formula I include acetic, propionic, p-toluenesulfonic acid, chloracetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic, benzoic and others. The pharmaceutically acceptable acid salts of formula I may be conventionally prepared by simply dissolving 4-aryl-2-substituted-octahydro-1H-pyrindine in a suitable solvent, such as diethyl ether, ethyl acetate, acetone or ethanol, and by adding to such solutions an equivalent or excess amount of convenient acid. The salt thus formed normally crystallizes and can be recovered by filtration and, as a result, is ready for use as a pharmaceutical agent, or may be further purified by recrystallization from a common solvent, such as acetone and methanol.

The following is a list of representative cis-4a-aryl-2-substituted products - 2,3,4,4a, 5,6,7, 7a-octahydro - ΙΗ-2-pyrindine:

- 4a-Phenyl - 2 - (3-ethylpentyl) -2,3,4, 4a, 5,6,7_IH-7a-octahydro-2-pyrindine;

- 4a- (3-Meioxyphenyl) - 2 - (n-octylj2,3,4.4a, 5,6,7,7a-octenhydrobromide of pyrindinium;

- 4a-f3-Hydroxyphemyl) - 2 - (2-methylphenoxymethyl) - 2,3,4,4a, 5,6.7,7a - octahydro-2-pyrininium succinate;

- · 4a-Phenyl - 2 - (2-phenoxyethyl) -2,3,4,4a, 5,6,7,7a - octahydro-1H-2-pyrindle;

- 4a- (3-Methoxyphenyl) - 2 - (3,5-dchlorobenzoylmethyl) - 2,3,4,4a, 5,6,7,7a - ootahydro-1H-2-pyrindine;

—- 4a (3-Ethoxyphenyl) -2 - [3- (3-methyl-4-bromfemyl) -3-hydroxy] -propyl-2,3.4,4a, 5,6,7,7a-octahydro-ΙΗ-2 pyrindinium iodide;

- 4a-Phenyl - 2 - [3- (2-ethyl-6-methylphenyl) -nropyl] - 2,3,4,4a, 5,6,7,7a, - octenhydro-1H-2-pyrindinium perchlorate;

- 4a- (3-Hydroxyphenyl) - 2 - [2- (3,4-dibromophenyl) -2-hydroxy] -ethyl-2,3.4,4a, 5.6, 7.7a-octahydro-1H-2-pyrindine ;

- 4a-Phenyl - 2 - (3-phenylthio) -propyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-citrate pyreneine;

- 4a-Phenyl - 2 - [3- (2-isopropylphenyl) propyl] -2,3,4,4a, 5,6,7,7 &lt;a-octahydro-IH 2-maleate of pyrindinium;

1-.9-4a- (3-Ethoxyphenyl) -2- (2-phenyl-2-hydroxyethyl) -2,3,4,4a, 5,6,7,7a-octahydrol H-2-pyrindinium phosphate - 4a-Phenyl - 2 - [2- (4-chlorophenyl) -2-hydroxyethyl] - 2,3,4,43,5,6,7,7a -. ootahydroΐΉ-2-pyridinium meibansulfonate;

- 4a- (3-Hydroxyphenyl) - 2- t3- (2-chloro-3-bromophenyl) -3-hydroxypropyl] -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-chloride pirkid'in iu;

- 4a- (3-Ethoxyphenyl) - 2 - [3- (2-chlorophenylthio) -propyl] - 2,3,4,4a, 5,6,7,7a - octahydro-1H-2-pyrindine;

- 4a- (Propoxyphenyl) - 2 - (2-ethylbenzoethyl) - 2,3,4,4a, 5.6_r7_rPyrindinium 7a-octahydro-1,2-chloride ·, - 4a-Phenyl - 2 - [3- (2-ethyl-5-bromophenyl) -propyl] - 2,3,4,4a, 5,6,7,7a - octahydro-2-pyrinidine and - · 4a- (3-hydroxyphenyl) - 2 - [2- (3,5-diethylphenoxy) -ethyl] - 2,3,4,4a, 5,6,7,7a - octahydro- H-2-pyrene stearate.

The compounds of formula I have asymmetric centers, especially the fourth position 4a and the seventh position 7a. This invention encompasses both separate isomers, as well as racemic shoulder strains, such isomers that are syntactically useful from a pharmacological point of view as analgesic antagonists to their nts.

However, only the cis-isomers of formula I are taken into account, and especially those in which the group 4 is oriented to the same side of the plane of the molecule from the hydrogen atom 7a. This invention as a result. it comprises the optically individual cis isomers, pharmacologically additive, in addition to the cis isomers of racemic mixtures. Such racemic pairs of Cis-octahydropyrinditne may be separated into stereoisomeric components by methods well known in the art. I take the eventuality in which all the useful pharmacological activity resides in a stereoisomer, the respective racemate still remains useful through what it contains, having a constituent of the pharmacologically active isomer.

Preparation 4a - aryl octahydropyrindines of formula I require many starting materials, some of which are not readily available. The pyridines with form I use a 4a-aryl-tetrahydro-2,6-df-dxo-cyclopene + a [c] piTa as the starting material. For the preparation of dioxo-cyclopentapyrane or derivatives thereof, 2-arylcyclohexartone is alkylated at position 2 by reaction with uu alkylloacetate, such as ethylchloroacetate, in the presence of a base, such as sodium hydride, by giving. the corresponding product 2-anyl-2- &amp; lycoxycarbonylmeIcyclohexaneone is obtained. Similarly, in the preparation of 2-uryl-2-alkenyl-1-aminomethylcyclopopeites, a 2-arylcyclohexane is first alkylated at position 2 by its reaction with an alkenyl halide, such as allyl iodide or 2-butenyl bromide, in the presence of a base, such as sodium hydride, to obtain a suitable product, 2-aryl-2-alkenyl cyclohexane bona. Both 2-aryl-2-alkoxycadbonylmethylcyclohexanones and 2-aryl-2-alkenylcycloh-exonones are then formulated at the 6th position by reaction with alkyl (or ethyl-formate in the presence of metal sodium or poitasis). with p-toluenesulfonylazide, thereby substituting 6-formyl with a diazo group, to produce 2-aryl-2-alkoxycarbonyl-ethyl-6-diazocyclohexamone and 2-aryl-2-alkenyl-6-diazocyclohexane. Such didzocyclohexanonic derivatives are then photolysed with a light having a wavelength of about 3,000 ′ in an alcoholic solvent, such as methanol to effect an annular contraction in the concomitant expulsion of nitrogen gas and to obtain 2 -aryl-2-alkoxycarbonylmethyl-1-methoxy carb onylcyclopentanes and 2-aryl-2-alkenyl-1-methoxycarb-nylcyclopentanes respectively. Such compounds are then deesterified, i.e. hydrolyzed by reaction with alkalis in water, to obtain the corresponding diacid and the respective monoacid. Specifically, 2-aryl-2-methoxycarbonylmethyl-1-methoxycarbonylcyclopentane hydrolysis results in a suitable product, 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane. Similarly, hydrolysis of 2-aryl-2alkenyl-1-methoxycarbonylcyclopentane results in a suitable product, 2-aryl-2-alkenyl-hydroxycarbonylcycopsantan, Diacid, especially 2-aryl-2-hydroxyarbonylmethyl-1-cyclohexycarbonyl, and then hydroxycarbonyl. reaction with a halogenated agenl, such as acetyl chloride, to obtain the corresponding anhydride, a 4α-aryl-tetrahydro-2,6-di-oxocyclopenta {c] pyran. These piranhas are starting materials for the preparation of pyrinines.

Certain 4a-aryl-2-substituted-ootahydro-iH-2-pyrenes of formula ί have been found to be useful in the treatment of pain and, therefore, may be used for analgesia, in subjects suffering from pain and in need of treatment. . In addition, the pyrin77935 derivatives of the formula I teeth have proanalgesic, as well as anti-analgesic properties, and thus are able to achieve pain relief in mammals, while, due to their amylo-analgesic activity, they lead to a large decrease in liability. Such ability of the compounds described above to determine both the analgesic phenomenon, as well as its antagonist in the mammalian domain, results in the decrease of any secmidal properties of a particular drug determined by the sleeping pills similar to the analgesic one. The compounds are thus useful because they produce the analgesic effect with only a small physical dependence on the weakness (risk). Certain compounds are additionally useful in combating the undesirable effects produced by narcotics, such as morphine.

The analgesic activity possessed by the compounds of formula I was determined by testing them on the standard animal, commonly used to measure the analgesic action attributed to these compounds. Also analyzes include the mouse test.

As indicated above, the compounds of formula I have demonstrated analgesic activity, when tested in guinea pigs, with registration. In this procedure, the test is performed by injecting acetic acid into the intraparitoneal area of ​​the mouse. The degree of analgesic activity possessed by the drug is then determined by observing the inhibition of the subject, when the drug is administered before the administration of acetic acid. When 4a- (3-meloxifeml) -2-methyl-2,3,4,4a hydrochloride, 5,6,7,7,7a octahydro-1H-2-pyrindine was administered subcutaneously in an amount of 20 mg / kg body weight mouse, a 100% reduction in mouse tilt was observed. A subcutaneous dose of 10 mg / kg produces 96% inhibition of such strokes. Similarly, an oral dose of a compound mentioned above produces a 100% inhibition of strokes at a dose of 20 mg / kg and a 98% inhibition at a dose of 10 mg / kg. In addition, the total prevention of the inhibitory action of the compound at a subcutaneous dose of 5 mg / kg was found, thus indicating that the analgesic is of narcotic type. When shock tests were performed, the above-mentioned compound produced an immortal increase in reaction time at doses of 80 mg / kg, both subcutaneously and orally, and produced the same effect as in oral doses up to mg / kg, measurements were made at 30 minutes and 2 hours after injection or administration.

Similarly, the product 4a- (3-hydroxyphenyl) - 2-methyl-2, 3,4,4a was tested_r5,6,7,7a - octahydro-1H-2-pyrindine. At a subcutaneous dose of 0.5 mg / kg, the compound resulted in a 75% inhibition of stroke in an animal test. With an oral dose of 10 mg / kg of this compound, an inhibition of strokes of 98% was observed after 30 minutes of administration. The total prevention of the inhibitory action of the compound was observed at a subcutaneous dose of 0.5 mg / kg. Shock test assays showed that the compound causes a significant increase in reaction time at subcutaneous doses of 20 mg / kg.

Another compound, 4^itα-phenyl-2-methyl-3,3,3,4, 4a, 5,6,7,7a-oc&gt; tetrahydro-1H-2 - pyrindinium bromide, produced a 70% inhibition of strokes in a group of test animals at a dose of 100 mg / kg after half an hour after administration. At an oral dose of 20. mg / kg, the compound resulted in an inhibition of 58% after ί h and 30 minutes after administration, an effect that was completely prevented in the presence of naloxone. Shock tests indicated that the compound causes only a moderate increase in reaction time at a dose level of 80 mg / kg.

The following EDm data (dose that decreases the number of twists observed at 50% in comparison with the control ones) were obtained in the mouse and shock tests, given in the table below.

<td>Example no.</td><td>The salt</td><td>writhing, EDjo</td><td>Shock, Eda</td>

<td> 0</td><td>HCl</td><td> £</td><td> 80</td>

<td> 7</td><td> —</td><td> 0,4</td><td> 0,2</td>

<td> 8</td><td>HBr</td><td> 20</td><td> &gt;80</td>

<td> 9</td><td>HBr</td><td> 1,0</td><td> »80</td>

The product of formula I, 4a-aryl-2-substituted - 2,3,4,4a, 5,6,7,7a - octahydro-1H-2-pyrene.ine is thus useful in producing the analgesic effect in peanuts and aids, such as and Pa man. Such compounds may be administered orally or. by mouth, as well as by injection. In general, it is preferable to use pharmacologically acceptable addition salts when dosing pirlndine derivatives, when they are administered orally '.

7®

Of*_;example / .upț ^ Î or, px mu ^ ti ^ c.om-. put pharmacologically ^ acțîyi'χύ ^ fhrmuia 'i / ^ fig, Cf »basej ^ U [3 ^ Ș,; fjp cș''o^itj, Saj-e_youaci8a '' dq pharmacologic ^ bcgpțăjbila, ', νρτ ^ fi .add pehțțh' aapuinÎswțe ^ *¹; oral *, cp.'pricar'e. ^ diait ^ rp '., £ iluăjitii,' / excipidhți, f ull '. pppțătpfii \ .uÎițițâfif..în ^. m'qd ^ pbi ^ nuiț / 'Examples of genieni.enqa' dî'fgpnțT xspu / șl · excipipnți ,. ' use in, mod^-'accustomed to pteparafeie ,. pharmacological include ^ p'hlbere.dJe mentioned, suczQzp. / cellulose /. 'star / i'at.de. ^ âgnez'iu,' lactQzâ.sulfap of palei u,;, calcium benzoate. ' and. dilpafțfii 'adeg-. you .. .. Asergehqa cprapozifii 'ppț' sâ either be pțo.delaie ,,. îh, tabl-elte or ', introduced in, tablets. telescopic deggline '.pen4h admipistrarg .. ^ .ρ / iyehionaf a., if.' se 'dpieșiș, compounds, .activV with j formplh I,' ppt to, be ^ combed add with upiil 'sap, i $ ai, many, known pgents. to perform, analgez.igi ,,. as is the case,_{/ t}, acetaminophen, and propoxifene. ,.

, .The active chickens with / with the formula Γ may be additionally presented with aqueous solutions. suspensions and emulsions for, o_;build me up. convenient on the way? substances_ţof. vehicles, used parts, in mod. ordinary, .ÎLp._!also_j presentations include 'prppilenglicpjui. ^ vegetable oils, such as ti, plelie / dp. olives, as well as different), eg terj, gabiei, as is the ethyl oleate. Solutions.₍aqueous ulUUziate. oral,₍and. parenteral include ό 'solution, salineJzophonic .. ...... .... ...

, The precise weight of the ingr ^ dieniȚiÎuf âcțiy ,. that is, the gauntlet. from one or more, 4a-afXl-- .2 supșțitu.it-gcfahiâro-lH'2-pirindine, active from. point, d₍e, pharmacological evidence, of formula I, administered

20'

30 'mammal, such as a pmau subject, for example,' may. either, Y. arrigta on a wider or relatively wide range, it being necessary to obtain an optimum dosage of these constituents. Such convenient dosages will depend on the particular therapeutic effect desired, the particular route of administration used and the duration of treatment,_and;as well as on the condition, precise 50 treaty. Typically, the dosages of the active compounds of formula I will vary in the range from about 1.0 to about 25 mg / kg of; grerifâțe / 'cbfjA aninfSf · pd-zi;' - diVizat · îri / rhod 'aiied ^ Kț * p &amp; iiffn atiiminisf ¥ afd^{! i}of^f'Idl;^J, at '4'ρΡΡρη / ζί DozajdÎ ^ oPajld-pre ^ fetate' variety '¹ ϊιϊΪγ-ό hen '¹ dd lâ 2^Jla5 (.i tffg / kg?

. The process'¹according to the invention ',' pre int '/ avâlîțajuÎ' preparation, uhef 'new compound compound'¹ with properties 'anăl.gezice', lacking hedrirife, 'which is the sleeping pill' or 'narcotic.'