Pyridine derivatives

The present invention relates to a process for the preparation of cis-4α-phenyloctahydro-1H-2-pyrindines, used as analgesic?, Of the general formula J:

and NR, wherein R-ι represents a linear alkyl group with 1-5 carbon atoms or 15 CH group₂R_3i where R₃ is a linear alehenyl group with 2 ... 3 carbon or tetrahydrofuryl atoms, and R₂ represents a hydrogen atom, a hydroxy or methoxy group. In the last 20 years, great efforts have been made in the field of the synthesis of certain drugs, such as, for example, analgesics capable of reducing the pain sensation.

Many of the painkillers existing in ₂₅currently have limited use due to the various undesirable side effects that frequently accompany their continuous administration. These side effects include mania and allergy. As us³⁰ Illustrative analgesics, which have recently been discovered, may be mentioned decahydroisoquinolines and, in particular, 4a-arylirnns-deca-hydroisoquinolines (Patent, Belgium, no. 802557).

Cis-4α-aryoctahydro-1H-2-pyrene The 2-substituted rings are somewhat structurally related to the above-mentioned isoquinoline derivatives. However, the compounds of formula I above could not be synthesized in the past. In the specialty literature, only simple, unsubstituted eyelid analogues are described. Thus, for example, Volodina and its partners have prepared certain octahydro-2-pyrindines, but none of these compounds were substituted at position 4a (Akad Doc. Nauk. USSR, 173 (2), pp. 342 ... 345 (1967), respectively Chemical Abstracts, vol. 67, 6034).

Also known is a process for obtaining a trans isomer of unsubstituted nitrogen tetrahydro-2-pyrindine by cycling inet-2- (2-aminoethyl) -cycloheptanes of Imethanol (M, Prochazka and collaborators of the trans isomer of azabicyclooctans. and azabicyclononans, Czech Collection Chem., Comm. 31 (9) 3824— · 3828, 1966).

LAW PRICE 17.95

The process, according to the invention, extends the range of octahydropyrindins in that an unsubstituted 4-α-phenyl octahydro-1H-2-pyrindine with the general formula ΙΪ:

\ | NH \ / \ Z in which R₂ has the above meanings, it is treated with a hal-Rq alkylating agent, wherein Hal is chlorine or bromine and R_t has the above significance, in dimethylformamide medium as a solvent, in the presence of an alkali meta] bicarbonate as an acid acceptor, the reaction having Ioc at reflux temperature and possibly followed by a deeterification when R₂ is methoxy to obtain a compound of formula I wherein R 1 is hydroxy, after which the product is self-separated.

The following are 10 examples of carrying out the process according to the invention.

Example 1. A solution of 2 g 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-iH-2-pyrindine in 30 ml of Ν, Ν-diethylformamide containing 1.23 g of Sodium bicarbonate is homogenized by stirring at 25 ° C in a mixture of 2-propene bromide dc. The reaction mixture was coded and heated to bmp reflux for 4 hours. After that, it was cooled to room temperature, filtered and concentrated as a oil under reduced pressure. The residual oil is dissolved in 300 ml of diethyl ether. The certified solution is washed with water, dried, and the solvent is removed by evaporation under low pressure, thus obtaining 4a-phenyl-2- (2-propenyl) -2,3,4,4a, 5,6,7, 7a-octahydro-1H-2-pyrindine as an oil. the oil thus formed is dissolved in 150 ml of fresh diethyl ether and passed through it: homhydrous acid in the form of gaseous bottles. The precipitated salt is collected by filtration and recrystallized from diisopropyl ether with isopropanol to give 1.3 g of 4a-lenyl-2 - (2 ~ propene!) Bromide - 2,3,4,4a, 5,6,7. , 7a-octahydro-1H-2-pyrindinium, melting point

185...187^.

Analytical calculations for Ο_ι7Η₂₄ΒγΝ (%):

- theoretically: C = - 63.36, - H - 7.51;

\ · 4,35;

- practically C - 63.63, - H - 7.24; N - 4.24,

Examples 2 ... 3. Following the procedure of Example 1, 1-alkylpyrindine derivatives are prepared by reacting 4a-phenyl "2,3,4,4a-5,6,7,7a-octahydro-1H-2-pyrindine with a suitable alkylating agent;

- 4a-phenyl-2-n-propyl-2,3, 4,4a, 5,6,7,7a- octahydro -ΙΗ-2-pyrindinium bromide, mp 245 ... 247 ° C.

Analytical calculations for C₁₇H2i; RrN {%):

- theoretically: C = · = 62.96; H = 8.08, · N - 4.32, - practically: C - 62.74; H, 8.22_;N, 4.23.

- dc 4a-phenyl-2-n-phenyl-2,3,4, 4a, 5,6,7,7a-oclahydro-1H-2 bromide at mp 24 ° C, 243 ° C.

Analytical calculations for C ^ H ^ BiM (%):

- theoretically: C - = 64.77, · H = = 8.58; N = 3.98 - practically: C - 65.04; H, 8.70; N - = 3.87.

Example 4. A solution of 1.6 g 4a- (3-meloxifenyl) -. 2 -nets 1-2,3,4,4a, 5,6,7,7a-octahydro- and H-2-pyrindine in 12 ml acetic acid containing 12 ml hydrochloric acid 48% aqueous is stirred and heated at reflux tini}) of 15! i. The reaction acid mixture is cooled to about 10 ° C and the pH adjusted to 10.2 by the addition of a 50% aqueous sodium hydroxide solution. The product insoluble in the aqueous alkaline solution is extracted from it in a solution of 90 ml n-butanol and 30 ml benzene. The organic solution is then separated, washed with water and dried. Evaporation of the excess solvent under low pressure results in a demethylated product as an oil, which is then crystallized from diethyl ether and ethylacelate to give 4a- (3-hydroxyphenyl) - 2-melons-2,3,4,4a, 5 , 6,7,7a-ocLahydro-1H-2-pyrindine, melting point

15l ... L53 ° C.

, Analytical calculations for C ^ EJNO {%); theoretically: C - 77.88; H = 9.15, N = 6.05;

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

Example 5. A solution of 1.5 g 4a- (3-hidiOxifeiiil) -2,3,4,4a_t5,6,7,7a-octahydro-1H-2-pyrindine in 15 ml of Ν, Ν-dimethylformamide containing 1.0 g of sodium bicarbonate and 0.95 g of 2-tetrahydrofurylmelyl bromide is heated to reflux for 4 hours. h. After cooling the reaction mixture 'Its 25'C, it is extracted several times with diethyl ether. The etherified extracts are combined, washed with water and dried. Evacuation of the solvent by evaporation under reduced pressure afforded 4a- (3-hydroxyphenes) - 2- (2-tetrahydrofurylmethyl) -2,3,4,4a, 5₍6,7,7a-oclabidro-H 2 -2-pyrindine as an oil. The oil thus formed is dissolved by filtration to obtain 1.0 g of 4a- {3-hydroxyphenyl) - 2 - (2-teas) bromide.^;trabidrofurylmethyl) -2,3,4,4a, -5,6,7,7a-octahydro-1H-2-pyrindinium, m.p. 19 ... 192 ° C.

Analytical calculations for C₁₉H₂₈NO₂Br (%):

- theoretically: C - = 59.69; H, 7.38; N, 3.66;

- practical: C = 59.89; H, 7.30; N - 3.78.

Examples 6 ... 8. Following the procedure of Example 5, 4a- (3-hydroxyphenyl) -2,3,4, -4a, 5,6,7,7a-octahydro- HH -2-pyrindine is reacted with allyl iodide in the presence of bicarbonate. sodium to obtain 4a- {3-hydroxyphenyl) -2 - (2-propenyl) -2,3,4,4a, 5,6,7,7a-oetahydro-1H -2-pyrindine, m.p. .108'C.

Analytical calculations for C_L7H₂₃NO (%):

- theoretically; C - 79.33, · H = 9.01; N, 5.44;

- practical: C ~ 79.29; H - 8.92; N - 5.44.

Similarly 4a- (3-methoxy.fc-nyl) -2,3, -4,4a, 5,6,7,7a-octa-hydro-1H -2-pyrindine is reacted with 4-iodopropane in the presence sodium bicarbonate to obtain 4a- (3-methoxy-nyl) -2-n-propyl-2, -3,4,4a, 5,6,7,7a-octahydro-H 2 -2-pyrindine, which was then converted to hydrobromide by reaction with gaseous hydrobromic acid in diethyl ether, melting point 107. J.99C,

Analytical calculations for C₁₈H_2SNOBr (%):

- theoretically; C - == 61.02; H = 7.97, N = 3.95;

- practical: C = 60.65, - H ~ 7.52; N - 4.97.

Similarly 4a- {3-meloxyphenyl-2,3,4, -4a, 5,6,7,7a-ocfa-hydro-1H-2-pyrindine reacted with 1-brompentan in the presence of sodium bicarbonate to obtain 4a- (3-methoxyphenyl) -2-n-pentyl-2,3, -4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. This compound is treated with gaseous bronihydric acid in diethyl ether to give 4a- (3-methoxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H -2 bromide. -pyrindinium in the form of a crystallized solid, melting point 179 ... Î8PC,

Analytical calculations for C._cH₃₂NOBr (%):

<td>- theoretically: N - 4.18 _;</td><td>C, 62.82;</td><td>H, 8.44_;</td>

<td>- practical: N - 4.02.</td><td>C ~ = 62.87, -</td><td>H, 7.98;</td>

<td>Example 9</td><td colspan="2">A solution of 2.0 g 4a- (3-</td>

-methoxyphenyl) -2-n-propyl) -2,3,4,4a, 5,6,7, -7a-octahydro-1H-2-pyrindine, prepared as described in Example 7, dissolved in 20 ml glacial acetic acid and 20 ml aqueous hydrobromic acid 48% are stirred and heated at reflux for 12 h. The reaction mixture is cooled and poured over 100 g of ice and the resulting aqueous solution is made. alkaline by the addition of aqueous sodium hydroxide at a pH of 10.2. The alkaline mixture obtained is 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 evaporation at low pressures afforded 1.3 g of 4a- | 3-hydroxyphenyl) -2-n-propyl-2,3,4,4a-5,6,7,7a-octahydro-HH -2-pyrindine as an oil. The oil is dissolved in diethyl ether and added to a solution of hydrogen gas bromide in diethyl ether. The hydrochloric salt of the above-mentioned compound is crystallized and recovered by filtration to give 2.1 g of 4a- (3-hydroxyphenyl) -2- / f-propyl-2,3,4,4a, -5,6 bromide. , 7, / a-octahid ro-3 Η-2-pyrene, melting point 235 ... 236'C.

Analytical calculations for

<td colspan="3">C, JU_(;NOBr (%):</td>

<td>- theoretically; C, N, 4.12;</td><td> 60,00 ;</td><td>H, 7.70;</td>

<td>- practical: C = N - 3.98.</td><td> 59,98 ;</td><td>H, 7.50;</td>

Example 10. Following the procedure set forth in Example 9, 4a- (3-methoxyethyl) -2-n-pentyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine is reacted with aqueous hydrobromic acid in glacial acetic acid to obtain 4a- (3-hydroxyphenyl) -2-n-pentyl-2,3,4,4a, 5,6,7_I7a-octahydro-1H-2-pyrindine, which is then converted to the corresponding hydrobromide, m.p. 171 ... 173 ° C.

Analytical calculations for C₂₃H₃₀NOBr (%):

- theoretically: C- 61.95; H, 8.21; N - 3.80;

- practical: C - 61.65; H, 7.93; N, 3.54.

Here are some examples of preparation of raw materials.

Example A. A solution of 130 g of 2-phenyl-2-ethoxycarbonylmethylcyclohexane in 2 000 ml of diethyl ether containing 56 g of ethyl formate and 11.5 g of sodium metal is stirred at 25 ° C for 48 h. The reaction of the mixture is then continued by adding 1000 ml of cold water and a layer of ether was removed. The aqueous layer is acidified to a pH of 6.5 by the addition of hydrochloric acid and further extracted with fresh diethyl ether. The ether extract is combined, washed with water and dried. Evaporation of the solvent under reduced pressure gives 98 g of 2-phenyl-2-ethoxycarbonylmethyl-6-formylcyclohexa / 2900 ΐ

• nine - with useful oil, boiling point - 158 ...

175 '«· la 0.6 nnnlig.

^it!./ Cprfcirie. aftairtice. for Ci7H-&gt;₀A₄ {%): theoretically: C ==. 70.81; H = 6.99, _- r ^ piţacțic .: C .--- 7.0.85 j 1. (. = · - · 6.77 .. c.Example. ILB · Uniting the procedure from e: X-ray,_:2- (3-metoxiieni)) - 2-ethoxycarbonyl. boilylmethylcyclohexanonac a was subjected to reaction with ethyl formate in the presence of metal rings to obtain 2- (3-me; doxirenyl) -2-ethoxycarbonylmethyl-6-formyl-cycloh-exane.

EXAMPLE C. A solution of 87.0 g of 2-sheet "cheohexane" in 100 ml of benzene is added first dropwise over 1 hour to the solution stirred by reflux of 28.0 µl of sodium amide in 400 nil benzene. . The reaction reaction is heated to the reUirx for about 2.5h and then cooled to an ice bath. The reaction mixture is cooled to a portion of 83.5 g of allyl iodide in 100 ml of benzene. The reaction mixture is heated to reflux: ha h and then • cooled to_;25 ° C and drop over

400 g of ice. The organic benzene layer is separated, washed with water and dried. Evaporation of the solvent yields 50 g of 2-phenyl- (2-propenyl) .- 'cycThdfyane', 'boiling point 114' 120'C: lu 0.1 .mmHg. . , '. '

.. ,,, 'ȚxețnpÎul D. A solution of .30 g 2-phenyl- _t.-â-t'-prQpenyl) -cyc1 Hexane in .6Q0 iin. Contains 3.4 g of sodium Sodium water and,,_r'8, of e ti Ifo r ut i at;. shake, 1 a.25C 'clear for 48 hours.' Mix 'the reaction', boil and add. apaches, at least 1 organic is separated. 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 etheric extract se^: it is combined, washed with water, dried and the solvent is evaporated off under reduced pressure to obtain a product as an oil. oil

- .. • thus.-obtained and distilled, to obtain 14.6 g of; · 2-ίρΐΐί1τ2- (2-ρι · ορ? Ηΐ1) -6 ..- formylcyclohexane.one, boiling point

125 ... l30'C at 0.1 tnmllg. '//'_:. EXAMPLE E. A solution of 50.0 g 2 -cyl ··. Nyl-2-etpxicar, b, opylmethyl-6-formylcyclohexanone -in, 500 µl of diethyl ether was stirred, 25'Cl · in , time, what. by picu_ rar a solution of rde, 24.8 g of, ·. diethylamine • in 100 ml of diethyl ether. time, 30 min. After shaking. of the mixture, reaction time d ·,¹ 2 h U 25 «, the solution, etc., cools to 8 *, and then the 33.5 g solution of p-toluene-sulfonylazide in 50 ml · diethyl ether is added dropwise over 15 min.

-The reaction mixture is allowed to warm to room temperature and is further stirred for 5 b. The reaction mixture is then washed with water and dried. Evaporation of the solvent under reduced pressure afforded -4.43.0 g of 2-phenyl-2-ethoxy-arbonylm'ethyl-6-diazocyclohexane as an oil. IR. (Grandson) 2 080 cm^-'¹ diazo group. ί. &lt;· &lt;- ··.

, Examples F ... G. Following the procedure of Example E, 2- (3-methoxyphenes {) - 2-ethoxycarbonylmethyl-6-iormylcyclohexanone is converted to 2- (3-methoxyphenyl-2,2-eloxycarbonylincyl-5-diazoci.clohexanon and 2- [enyl- 2- (27-Pi'onenyl) -6'-formylcyclohexanone is converted to .2- (2-propenyl) -phi-diazpycyclohexane. Example H. A 57 g solution of 2-phenyl-2-ethoxycarbonylmethyl-6-diacocycloh.exane shake at 25 ° C while bubble nitrogen gas is introduced through the reaction mixture. The solution is photolysed for 40 hours with a quartz lamp having a wavelength of 3000 Å. The solvent is then removed under reduced pressure to give a crude product or crude oil, which, dissolved in 500 ml of diethyl ether, · The ethereal solution is washed with water, and the aqueous solution of sodium bicarbonate is washed. with .. water and ..e. .show .. Evacuation of the solvent under reduced pressure, a, allowed to obtain, 27.4g of .._:2-phenyl-2-ethoxycarbonylmethyl · 1,2-ethoxycarbonyl-clopentan under forine. of oil. The oil is, in., Further .. purified by distillation, point. .. boiling 16 (1 ... 1.90'C at 0.02 mmHg.

Analytical calculations for C ^ H ^ CAj {%):

, theoretically; C 70.32 H - 7.64;

- practical: C = 70.30, - H = 7.36.

Examples L..J. Following the procedure dc in Example H, the 2- (3-methoxyphenyl-2-ethoxycarbonylmotyl-6-diszocyclohexane) is photolysed at a wavelength of 3,000 Å to obtain 2- (3-meloxifen · nyl) -2-ethoxy : arbonylmethyl-1, -methoxycarbonylcyclopentane, boiling point '190 ... 210 (...

Analytical calculations for C_J8H₂₄A_S(%):

- - theoretically: C - 67.48; H, 7.55;

- practical: C 67.61 _; H, 7.37.

Similarly, 2-phenyl-2- (2-propenyl) -6-diazocyclohexanone 'was irradiated with ultraviolet rays at a wavelength of 3,000 A from a quartz lamp in the presence of methanol to obtain 2-. phenyl-2- (2-propenyl) - 1-methoxycarbonylcyclopentane, boiling point 1 13, 1 15'C at 0.1 mmHg.

Analytical calculations for CjiJ-UoOj (%):

-τ- theoretically: C = 78.65; H, 8.25;

- practically-. C - «78.80_; 1I - 7.99.

Analytical calculations. because₁₉IUjOj (%):

- theoretically: C 68.24; 11 &lt;- = 7.84 ·,

- practical: C. 68.15, - H 7.57.

Example K. A solution of 2- (3-methoxyphenyl) - 2-ethoxycarbonylmtyl- 1-methoxycarbonylcyclopentane in 650 ml 1,4-dioxane containing 500 ml of 5% aqueous potassium hydroxide was stirred and heated at reflux for 12 h. After cooling 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 amounts. The ethereal extract is combined, washed with water and dried. Evaporation of the solvent under reduced pressure gives 38 g of 2- (3-methoxyphenyl) -2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane as crystallized solid, mp 175-180 ° C,

Examples Following the procedure from Example K, 2-phenyl-2-ethoxycarbonylcyclopentane was hydrolyzed to obtain 2-phenyl-2-hydroxyCarbonylmethyl-1 hydroxycarbonylcyclopentane, m.p. 205-208'C,

Analytical calculations for 0₁₄Ιί₁,; Ο₄ (%). · - theoretically; C, 67.73; H, 6.50_; - practically ; C, 67.70, - H, 6.32.

2-Phenyl-2- (2-propenyl) - 1-methoxycarbonylcyclopentane is hydrolyzed by reaction with aqueous potassium hydroxide to obtain 2-phenyl-2- (2-propenyl) -l-hydroxycarbonicyclopentane.

Example N. A solution of 25 g 2-phenyl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane in 150 ml of acetyl chloride is stirred and heated at reflux for 4 h. After cooling the reaction mixture to room temperature, excess solvent remove by evaporation under reduced pressure to afford 26 g of tetrahydro-4-phenyl-2,6-dioxocyclopenyl [c] pyran as an oil. The product is then further purified by distillation, boiling point 2O5 .., 2O7^CC at 0.25 mmHg.

Analytical calculations for Ci₄H_J5A₃(%):

- theoretically; C - 73.03, - H - 6.13, - practically: C = ~ 73.30_; H, 6.37.

Example O. Following the procedure of Example N, 2- {3-methoxyphenyl) -2-hydroxycarbonyl-1-hydroxycarbonylcyclopentane is dehydrated and cyclized by reaction with acetyl chloride to obtain tetrahydro-4- (3-methoxytenyl) - 2. , 6-dioxocyclopentafcjpiran, boiling point 2.00 ... 220 ° C.

Example P. In a stirred solution of

6.2 g of 2-phenyl-2- (2-propenylj-1-hydroxycarbonylcyclopentane in 100 ml of chloroform was added dropwise over 30 minutes to 30 g of thionyl chloride. The reaction mixture was then heated to reflux and stirred for a while. 15 h. After cooling the reaction mixture is evaporated under reduced pressure to remove the solvent and to obtain 7.4 g of 2-phenyl-2- (2-propenyl) -1-chlorocarbonylcycopentane.

Example Q. A solution of 10.7 g benzylamine in 100 ml toluene is stirred at 25 ° C while a solution of tetrahydro-4- (3-methoxyphenyl) - 2,6-dioxocyclopentacetpiran in 300 ml toluene is added dropwise. in an hour. After complete addition of the pyran derivative, the reaction mixture is stirred and heated at reflux for 3 days in a retort equipped with a Dean-Stark hatch for water discharge. After the reflux period, the reaction mixture is cooled to room temperature and the solvent is removed by evaporation under pressure, thus obtaining the product as a crude oil. The oil dissolves in 400 ml of sodium hydroxide solution In and the alkaline reaction mixture sc warms to 50^rC for 15 min, the aqueous alkaline mixture is then extracted with diethyl ether and the etherified extract is combined, washed with water, and thereafter. dry and the solvent is removed under reduced pressure to obtain the product as a solid residue. Recrystallization of the solid from diethyl ether allowed to obtain 4a- (3-methoxyphenyl) -2-benzyl-2,3,4, -4a, 5,6,7,7a-octahydro-1,3-dixo-1H-2 filled, mp 75, .. 77 ° C.

Analytical calculations for C ^ H ^ NOj (%);

- theoretically; C, 75.62; H, 6.63; N, 4.01;

- practically; C = 75.40, · H = 6.58; N - 3.78.

Example R. The product tetrahydro-4-phenyl-2,6-dioxocyclopento [c] pyran with benzylamine is reacted according to the procedure of Example Q to obtain 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-oeLahydro-i, 3-dioxo-HH -2-pyrindine, m.p. 77 ... 79 ° C.

Analytical calculations for C_youH₂iNO₂ (%):

- theoretically: C - 78.97, - H - 6.63 _;

- 4.39-, - practically; C - 78.73, - H = 6.65; N - 4.26.

Example S. A solution of 18 g 4a-enri-2-benzyl -2,3,4,4a, 5,6,7,7a-octahydro-1,3-dioxo- HH -2-pyrindine dissolved in 200 ml tetrahydrofuran dropwise over 90 minutes in a stirred suspension of 5.8 g lithium aluminum hydride in 50 ml of tetrahydrofuran. After the addition is complete, the reaction mixture is heated to reflux for 5 hours. In cc time¹ keep the temperature below 50 ° C of the mixture, add 50 ml of ethyl72900 i!

acetate by drip tim.p for 15 min, followed by addition of 100 m] aqueous ammonium chloride. Further tetrahydrofuran is 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 is then dissolved in 500 ml diethyl ether. The etherified solution was washed with water, dried, and the solvent was evaporated under reduced pressure to give 15 g of 4a-phenyl-2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro - IH -2-pyrindine. M + A? 291 (peak origin), 213 (-77, phenyl), 200 (-91, bonios).

Example T. Following the procedure of Example S, 4a- (3-methoxyphenyl) -2-henzyl-2,3,4,4a, 5,6,7,7a-octahydro-IH -2-pyrindine is reduced by hydride of lithium aluminum to obtain 4a- {3-methoxyphenyl) -2-benzyl-2,3_r4,4; i, 5,6,7₍7a-octahydro-1H-2-pyrindine,

Example U. A solution of 21 g 4a-phenyl -2,3,4,4a, 5.6_r7,7a-octahydro- IH -2-pyrindine in 172 ml ethanol is stirred while 7 µl of 5% palladium in suspension on coal is added in a portion. The reaction mixture is stirred in an atmosphere of hydrogen gas at 4.13XiO^s dyrt /&gt; cm² and heated to 60C for 3 h. The reaction mixture was cooled to room temperature, filtered, and the solvent was evaporated off under reduced pressure to afford 13.3 g of an oil product, the oil being distilled for to obtain 4a-phenyl-2,3,4,4a, 5, -6,7,7a-octahydro- IH -2-pyrindine.

Example V. 4a- (3-Methoxyphenyl) -2-benzyl-2,3,4,4a, 5,6,7,7a-octahydro-IH -2-pyrindine is hydrogenated in the presence of palladium in manganese suspension in accordance with the procedure from Example U to produce 4a- (3-methoxy, phenyl)) - 2,3,4,4a, 5,6,7,7a-octahydro- IH -2-pyrindine, boiling point I45 ... 16O ° C at 0.05 mmHg,

Example W. A solution of 8.4 g of -4a - (3-methoxyphenyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine dissolved in 60 ml glacial acetic acid and 60 ml of 48% aqueous HBr is stirred and heated at reflux for 16 h. After cooling the reaction mixture to room temperature, it is mixed with 100 g of ice, and the pH-u-Ι of the resulting aqueous solution is adjusted to 10 , 2 by adding concentrated sodium hydroxide solution. It 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. The mixture is dried and the solvent is evaporated off10

G0 re under reduced pressure to obtain the product as a crude solid. The solid thus formed is crystallized from ethylacetate to give 4.2 g of 4a- (3-hydroxyphenyl) -2,3,4,4a, 5,6,7,7a, -octahydro-ΙΗ-2-pyrindine, the melting 180 181 ° C.

Analytical calculations for C_UH₁₉NO (%):

- theoretically: C - = 77.38, - H 8.81 _;N - 6.45 _; - practical: C - 77.56 _; H - 8.84 _;N, 6.24.

A preferred group of compounds consists of those compounds of formula I, wherein the symbol Rj represents an alkyl group of 1-5 carbon atoms or a -CPLR group₃ wherein the symbol R₃ represents an alkenyl group with 2 to 3 carbon atoms. A group of compounds, which is part of the above group, but which is preferred to a greater extent, consists of those compounds of formula 1, wherein the symbol R₂ represents a hydroxy group or a methoxy group.

In the spirit in which it is used herein and in the appended claims, the notion of "alkyl group with 1 ... 5 carbon atoms refers to both linear alkyl groups and branched alkyl groups, which possess a number of alkyl atoms. carbon equal to 5 or less. As examples of representative alkyl groups with 1-5 carbon atoms, mention may be made of methyl, ethyl, propyl, butyl isopropyl, isobutyl, pentyl, 2-methyl-butyl, and related groups. Group - CH₂R₃, wherein the symbol R₃ represents an alkenyl group with 2 ... 3 carbon atoms refers to both linear and branched alkenyl groups, which have a number of carbon atoms equal to 3 or less and which include allyl, α-methylalyl groups and related alkenyl groups.

The pyrindine 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 a 4-phenyltetrahydro-2,6-dioxo-cyclopenta [c] -peran, according to the generalized scheme below:

U₂ Vo _a 4-HNR, - * z \ /

II o

reaction

<img file="RO72900A_D0001.tif" />

(. I

NO, in which the symbols R-, and R2 have the meanings mentioned above. Compound '

thus obtained, namely, 1,3-dioxo-4a-phenyl-1-2,3,4,4a_r5,6,7,7a-oct.hydro- HH -2-pyrindine, which represents a cyclic imide, is then reduced to the oxo groups at positions 1 and 3 to give a pyrene derivative of formula II. In practice, it is preferred to use 4-cr / a-phenyl-letrahydro-2,6-dioxocyclopenta [c] pyranes, wherein the substituent linked to the aryl group, which is defined in the formulas above by the symbol R₂, represents a hydrogen atom, or an alkoxy group having 1-3 carbon atoms. Of these alkoxy groups I - 3 carbon atoms, the methoxy group is preferred, as this group is readily demethylated at a later stage 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, alkylamines with 1 ... 8 carbon atoms and especially methyl amine, as well as arylamines and , in particular, benzylamine. The 2-methyl derivatives and the 2-benzyl derivatives pyindin thus obtained are readily transformed into the corresponding unsubstituted 2-pyrindine, which is readily subjected to an alkylation and acylation reaction to produce other compounds or formula I, which are substituted. in position 2. These transformations will be described in more detail in the following.

In the preparation of 1,3-dioxo-4a-feml-2,3, 4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines by the above-mentioned reaction scheme, 4-phenyltetrahydro-2, 6-dioxocyclopenta tc] 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 may 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, dichloromethane, dimethylsulfoxide, nitr. , tetrahydrofuran, dimethylformamide and dioxane. The reaction is typically carried out at elevated temperatures, for example at a temperature of between about 50 and about 200 ° C and preferably about 80 to about 150 ° C. Because the reaction between the amine and the cyclic anhydride for the purpose of forming the corresponding cyclic anhydride is accompanied by the formation of water, it may be appropriate to perform the reaction so that the water is removed from the reaction mixture as it gives rise, for this purpose, it is possible to use any of the commonly used techniques! for maintaining an anhydrous reaction amesH tec, for example by using molecular sieves; alternatively, in the case of reaction solvents, such as benzene and toluene, it is possible to resort to this purpose. a Dean-Stark separator, The reaction between the amine and the cyclic anhydride normally ends completely within a period of 24 ... 72 h. However, longer reaction times are not detrimental to the reaction product being formed as such. they can be used if desired. The cyclic imide thus formed, namely 4a-phenyl-2,3,4,4a, 5,6,7,7a-o.ctahydro-1,3-dixo-1H-2-pyrindine, is readily isolated by removal of the reaction solvent, for example by evaporation under reduced pressure, and the reaction product can be further purified by ordinary methods, such as extraction with an acid or base, crystallization and chromatography.

4a-Phenyl-1, 2,3,4,43,5,6,7,7a-octahydro-1,

3-dioxo-1H-2-pyrindines are converted to 4-asphenyl-2,3,4,4a, 5_r6,7,7a-octahydro-1H -2-prindines of formula II 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, 1,3-dixoxo-derivative of pyrindine may be reacted with any reduction agent based on alkali metal hydrides, such as lithium-aluminum hydride, sodium boride, sodium lithium-irides-butoxy-aluminum hydride. and lithium-trimeioxy-aluminum hydride, if desired, may also be used for other reducing agents such as zinc and acetic acid and catalytic hydrogenation. The preferred process for reducing a 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1,3-dixo-1H-2-pyrene involves the use of lithium-aluminum hydride as the reducing agent. Representatively, a 4a-phenyl-2,3,4,4a, 5.6_r7_r7a-octahydro-1,3-dioxo-1H-2-pyrindine, such as, for example, 4a-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1 , 3-dioxo-1H-2-pyrindine is reacted with an amount of about one-third molar volume of lithium-aluminum hydride in an inert organic solvent, as inert organic solvents, commonly used for this reaction, letrahydrofuran, ethyl ether, dioxane, diglime and hardened solvents may be mentioned. The reaction is normally carried out at a temperature between about 20 and 100'C; then when it is carried out at such a temperature, the reaction is usually practically complete after a period of about 4 ... 20 h. The reaction product is normally recovered by decomposing in the first stage of any unreacted reducing agent, which may remain in the reaction mixture. If the reducing agent is, for example, lithium-aluminum hydride, this decomposition is achieved by introducing - in the reaction mixture - an ester, which reacts readily with any 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 an organic solvent. suitably, 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, namely 4a-fcnil-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine of formula II. This product is representative in the form of oil and is slightly further purified (if desired) by methods such as disl.i. laying and eromatography; alternatively, the reaction product can be converted to an addition salt with an acid, which can then be purified by recrystallization.

Compounds of formula II, which are thus easily obtained by reducing the oxo groups of positions 1 and 3 of a 4a-phenyl-2,3, 4,4a, 5,6,7,7a-octahydro-1, 3-dioxo-1H -2-pyrene-dine by the processes described above include, but are not limited to:

- 4a-Phenyl-2,3,4,4a, 5_f6_r7,7a-ociahydro-ΙΗ-2-pyrindine;

- 4a- (3-Methoxyphenyl) -2,3,4,4a5,6,7,7a-octahydro-1H-2-pyrindine, - 4a- (3-Ethoxyphenyl) -2-meth1-2,3_it4,4a, 5, 6,7,7a-octahidTO-1H-2-pyrindine;

- 4a-Phenyl-2-ethyl-2,3,4,4a, 5, G, 7,7a-ociahydro-1H-2-pyrindine;

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

- 4a-Phenyl-2-isobutyl-2,3,4,4a-5, G, 7,7a-octahydro-1H-2-pyrindine, - - 4a- (3-Methoxyphenes!) - 2 - :( 4- ethylhexy!) - 2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine, - 4a- (3-Ethoxyphenyl) -2- (3-chlorhenzyl) -2,3_r4,4a, 5,6,7,7a-octahydro-2-pyrindine-H.

As mentioned above, the very important intermediates, in order to prepare all the derivatives of the pyrene of formula I are represented by the derivatives of the 2-unsubstituted pyrene, namely those (6 compounds of the formula I, in which the symbol Rt represents a hydrogen atom. These compounds can be easily alkylated or acylated at position 2 to give the pharmacologically active oclahydropyrindins of formula I.

For this reason, it is often appropriate, in accordance with the procedures described above, to prepare 4a-phonon-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines 2-substituted , wherein the substituent at position 2 can be readily removed to obtain the corresponding unsubstituted octahydropyrindines in position 2. The N-methyl and N-benzyl groups are readily cleaved to give the corresponding unsubstituted pyrene derivative at position 2. Thus, 2-methyl-pyrene derivatives may be reacted with an ester of a haloformic acid, such as, for example, phenyl chlorformate or ethyl chlorformate to give the corresponding carbamate at position 2 of the pyrene. This carbamate is then treated with an aqueous base, such as sodium hydroxide, to split the carbamate residue at position 2, in order to produce the corresponding unsubstituted pyrene derivative at position 2. This method for splitting an N-methyl group was described by Abel-Monen and Portuguese in Med. Chem., 15, p. 208 (1972).

Similarly, the aforementioned 4a-phenyl-2-benzyl-2,3,4, 4a, 5,6,7,7a-octahydro- H 2 -2-pyrene] is readily transformed into the corresponding unsubstituted pyrene at position 2 through simple debentures. This differentiation can be achieved by catalytic hydrogenation, using, for example, a palladium-based catalyst applied to coal (with a palladium content. of 5%), These differentiation reactions are quite general for the preparation of secondary amines and are described in detail by Hartung and Simonoff in Org. Reactions, 7, 277 (1953) and by Leonard and Fuji in J. Amer. Chem. Soc., 85, p. 3719 (1963). As can be easily deduced from the foregoing discussions, the pyrindinpie 2-unsubstitutes of formula II (in which the symbol Rt represents a hydrogen atom) mentioned below are also important intermediates for the preparation of pyrindine of formula I.

- 4a-Phon and 1-2,3,4,4a, 5, G, 7,7a-octahydro-1H-2-pyrindine, - - - 4a- (3-Methoxyphenyl) -2,3,4,4a, 5.6_I7,7a, octahydro-1H-2-pyrindine;

- 4a- (3-Ethoxyphenyl) -2,3,4,4a, 5₁6,7,7a-ot · tahi dro-1 Η-2-pyrene;

- 4a- (3-isopropoxyphenite) -2,3,4,4a, 5,6,7,

7a-octahydro-1H-2-pyrin dina.

ί 7

These unsubstituted 4a-aryl-2,3,4,4a, 5,6,7,7a-octahidi'o-1H-2-pyrindines in position 2 thus prepared can be alkylated by ordinary processes to give pyrindines. 2-substituted pharmacologically active, or may be acylated to produce intermediates, which are then easily transformed into active analgesia. Thus, for example, a 4a-phenyl -2,3,4,4a, 5,6,7,7a-o.ctahydro-1H -2-pyrindine can be alkylated at position 2 by reaction with any reactive derivative of a group. alkyl. These alkylating agents are composed of compounds of formula Ri — Z, in which the symbol R_t it has the meanings mentioned above, and the symbol Z represents one of the groups, which are considered as groups, which leave the molecule slightly. The groups, which are best known as the groups which left the molecule lightly, include the halogen atoms and especially the chlorine, bromine and iodine atoms, as well as the p-toluenesulfonyl (tosyl), phenylsulfonyl, methanesulfonyl (mesyl) groups, p-bromophenylsulfonyl (brosyl) and azido. It will be mentioned that when - in the present description - an alkylating agent with the formula Rq — Z is spoken of, it should be understood that the alkyl residue of this alkylating agent may also be unsaturated substituents. , aryl groups and cycloalkyl groups. Thus, the expression "alkylating agent of the formula R] -Z includes compounds such as methyl chloride, ethyl bromide, dc 5-methyl-heptyl tosylate, aylyl bromide, 4-hexenyl-p-bromo-phenylsulfonate iodide. of 3-ethyl-4-pentanil, cyclopropylmethyl chloride, cyclobutylmethyl iodide, cyclohexylmethyl methanesulfonate, 3-tetrahydrofurylmethyl bromide, 2furylmethylazide, 2-phenylethyl chloride, 3-benzoylpropyl, 2- (3-chloro) bromide -ethylazide, phenoxymethyl bromide, 3-Isopropyl-phenylthiomelyl bromide and other related compounds.

Thus, a 4a-phenyl-2,3,4,4a_r5,6,7,7a-octahydro-1H-2-pyrindine can be treated with an alkylating agent to give 4a-phenyl-2,3,4,4a, 5,6,7,7a-octahydro-1H- Suitable substituted 2-pyrindine 2. Such an alkylation reaction is quite general and can be carried out by treating the appropriate 4a-aryl-octahydride-O-H-2-pyrindine with the corresponding alkylating agent, preferably in an inert organic solvent, typically the alkylating agent. it uses excessively, for example, in a molar excess of about 0.5 ... 2.0 in relation to the piindrin derivative. Inert organic solvents commonly used for this reaction include ethers, such as ethyl ether, dioxane, tetrahydrofuran, as well as other solvents, such as, for example, benzene, methylene chloride, dimethylformamide, dimethylsulfoxide, nitromethane and hexamethylene. phosphoric. In the penyr mixture, the alkylation reaction is preferably introduced as a base, which acts as an acid acceptor, since the reaction between the pyrene derivative and the alkylating agent is generally accompanied by the formation of an acid, such as the acid. hydrochloric acid or p-toluenesulfonic acid, which can be combined with the possibly non-reaction 2-pyrindine derivative to give a salt. Bases commonly used as acid acceptors for such a reaction include sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, and pyridine, typically about an equivalent amount of base is used. However, if this is desired, the excess base may be used. The alkylation reaction is normally carried out at a high temperature of between about 50 and 200 ^ 0, at such a temperature the reaction is usually practically complete within a period of about 1 ... 10 hours. However, the durations longer reaction times are not harmful and can be used if desired. The reaction product is usually recovered by the simple addition of. water in the reaction mixture and by extraction of the reaction product from the mixture using a water-immiscible organic solvent, such as benzene, ethyl acetate, methylene chloride, ethyl ether, chloroform or related solvents. After removal of the solvent from the extracts, for example, by evaporation under reduced pressure, the reaction product is obtained, namely 4a-phenyl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-1H- 2-pyrindine, which exists - at room temperature - either in the form of an oil, as a solid substance. The product thus formed can be further purified, if desired, by ordinary methods, such as chromatography, crystallization or distillation. Alternatively, the obtained pyrindine can be converted into an addition salt with an acid by reaction with an inorganic or organic acid, typically these salts are very crystalline solids and are easily recrystallized to give a high purity solid salt. If this is desired, the salt may then be treated with a base, such as sodium hydroxide or patassium carbonate, to split the salt in order to obtain 4a-phenyl2,3,4,4a, Purified 5,6,7,7a-octahydro-1H-2-pyrindine-2-substituent in free base form.

Sc will also mention that certain 4a-phenyl-2,3,4,4a, 5,6,7,7a- octahydro- tII-2-pyrindine-2-substituted formulas may be subject to further modifications. Thus, for example, although a 4α-FeQyl-pyrindine, in which the phenyl group represents a 3-hydroxy-phenyl group, it can be prepared starting from 2- (3-hydroxyphenyl) -2-ethoxycarbonyl methylcyclohexane and modifying this compound by various processes. discussed above, it might be preferable to first prepare a 4a- (3-methoxyphenyl) -23,4,4a, 5,6,7,7 a- octahydro- ΙΗ-2-pyrindine-2- substitute it and then convert the 3-methoxy group of the 4a-phenyl substituent into a hydroxy group. This transformation is easily accomplished by treating 4a- (3-methoxy-phenyl) -pyrindine derivative with hydrobromic acid in acetic acid. This reaction is general for the conversion of a methoxyphenyl group into a hydroxyphenyl group.

As noted above, the 4a-phenyl-2-substituted product of octahydro-1H-2-pyrindine of formula ί may react with an organic or inorganic acid such that a crystallized salt can be obtained which can be purified by crystallization and which can then be converted to free pyrene base 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 1. Specifically, non-toxic, pharmaceutically acceptable acid salts of the pyrindine bases described above are added here. Such pharmaceutically acceptable acidic addition salts are prepared by reacting 4a-phenyl-2-substituted-octahydro-1H-2-pyrindine of formula I with an organic or inorganic acid. The acids commonly used for the preparation of pharmaceutically acceptable acid addition salts of formula I include hydrogen halide acids, such as hydrochloric acid, hydrochloric acid, iodic acid, and acids such as sulfuric acid , nitrogen, phosphoric, perchloric, phosphorous, nitrogen and related acids. Organic acids commonly used for the preparation of pharmaceutically acceptable acid addition salts of the pyrindines of formula I include acetic, propionic, paratoiuensulfonic, chloroacetic, maleic, tartaric, succinic, oxaiic, citric, lactic, palmitic, stearic, benzoic acid and related acids. The pharmaceutically acceptable acid addition salts of the formula may be prepared in the conventional manner

2t by simply dissolving the product 4a-phenyl-2-substituted-octahydro- ΙΗ-2-pyryridine in a suitable solvent, such as diethyl ether, ethyl acetate, acetone, or ethanol, and by adding to such solutions either a an equivalent or excess amount of convenient acid. The salt thus formed normally crystallizes out of the solution and may be re-filtered and as a result is ready for use as a pharmaceutical agent, or may be purified in. further by recrystallization from a common solvent such as acetone and methanol.

The following is a list of the products c 's-4-phenyl-2-substituted -2,3,4,43,5,6,7,7a-oclahydro-1H-2-pyrindine:

- 4a-Phenyl-2- (3-ethylpentyl) -2,3,4,4a, 5,6, 7,7a-octahydro-1β-2-pyrindine;

- 4a- (3-Methoxyphenyl) -2- (n-octyl) -2,3,4, 4a, 5,6,7,7a-oc tahydro-ΙΗ-2-pyrindine bromide;

- 4a_r(3-hydroxyphenyl) -2- (2-propenyl) -2,

3,4.4a, 5,6,7,7, -ocLahIdro-1H-2-pyrrine;

- 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-pyrindine acetate;

- 4a- (3-Hydroxyphenyl) -2-cyclopentylmethyl - 2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine oxalate, - - 4a- (3-Propoxyphenyl) -2- (2,3-dimethyl-4-hexenyl) -2,3,4,48,5,6,7,78- octahydro-1H-2-pyrindium;

- 4ά- (3-Είοχΐ · ίθηί1) -2- (2-ΙβΐΓ8ΜάΓθίηrilmethyl) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine, na;

- 4a- (3-Hydroxyphenyl) -2- (2-methylphenoxymethyl) -2,3,4,4a, 5,6,7_it7a-octane! Dro-1H-2-pyrene succinate;

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

- 4a- (3-Methoxyphenyl) -2- {3,5-dichlorobfc-benzoylmethyl) -2,3,4,4a, 5,6,7,7a-octahydro -ΙΗ-2-pyrindine;

- 4a- (3-Ethoxyphenyl) -2- [3- (3-methyl-4-bromophenyl) -3-hydroxy] -propyl-2,3,4,48,5, 6,7,7a-octahydro-1H -2-pyrindine iodide, · - 4a-Phenite-2-f3- {2-ethyl-6-methylphenylthio) -propyl] -2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2 - perchlorate pyrene;

- 4a- (3-Hydroxyphenyl) -2-f2- {3-dibromlenyl) -2-hydroxy] -ethyl-2,3,4,4a, 5,6,7,7a-octahydro-1β-2-pyrindine ;

- 4a-Phenyl-2- (3-phenylthio) - propyl-2,3₁4, 4a, 5,6,7,7a-octahydro-1H-2-pyrindine citrate;

- 4a-Feiul-2-i3- (2-isopropylphcnyl] -2, 3,4,4a, 5,6,7,7a-oc tahydro-ΙΗ-2-pyrindine moiety;

- 4a- (3-Ethoxyphenyl) 2- (2-phenyl-2-hydroxyethyl) -2,3_r4,4a, 5,6,7,7a-octahydto-IH-2-pyrindine phosphate;

7Κ900 .- :: 75:; 4a-Phenyl-2-Ț [2 * - · (4 &lt;; 1ρΓ · ίθηbl) -2-hydr'O- ··.

. .xieti.lj-2,3.4,4a, 5,6,7, '/ a - &lt;) Cl &lt;ihydro-tl Î.-2,_?-piriij £ Li Jia_?oiptaneuli9jşial, -I, 'n / ·, ··. _;; - Vc. :,,&gt;&gt; r-,! 4a- (3-Hydro.oxifepyl) -2-f3 + 2τίί1θΓ73 '· b., -; ϋΐΌΕ (ΐ: 1θπί]) .- 3- ^ ί (ί.ΓΡΧ: ίρ. ΐΡΡ: ΐ1] · ί2 · ϋ3,4,4α; 5.6; ί .- • AlZa-pctahidiO-1H ^ pyridine · chloride ·;:&gt;

-:¹ Î f&gt; -4aa (3-E t ό xi phenyl) 72 ^J[3- (2-e1o rf e ni 1 tio) -propylp2i3; 4; 4fl, 5,6,7,7a-oct-ahidro- '^:

-H. 1-2-pirÎiKline ·} ·,.

&lt;-V '4a-i -ropoxyphenyl-2- (2-ethylbenzeneylethyl)], 3,4,4a; 5,6,7; 7a-ol: tahydro-1H-2-p-: · wavelength chloride : '“·' +4 -%^::* 243 .4â-FehH '- (2-oxoethyl-5 (br0'mf0ni1) -^:;·

-prdj3tll'2₎3,4₁-4a^,,^!5₁'6,7, 7-dc^&gt;tâhidro-^:1 1 Γ · 2 · '

-pyrindine; /^ISI'·'- ^Λ b · ''. 4 a - '(3 -Hi t) r oxy f en i 1) -2- [2- (3,5-diphi-phenoxy) -ethyl] -2,3,4 / 4', 5,^:6.7; 7a-ocLahydro-1-pyrindine / stearate. ' ..

/ Compounds that have the formula I.pu asymmetric centers, .especially - position .4a, and..position 7a. This invention comprises the preparation, both of the separated isomers, as well as of the racemic mixtures of -7 such isomers, which are, of course, pharmacologically useful; as analgesics) (medicines) / antagonists., or hu. However, only cis isomers of formula I are also taken into account. In particular, those in which the 4a-phenyl group is oriented to the same side of the plane of the molecule from the hydrogen atom 7a. This invention, as a result, comprises the optically-individual isomers as pharmacologically active. in addition to the cis -isomers of racemic mixtures. Such racemic pairs of c-s-Octahydropyrindine [iotine] should be observed in stereoisomeric components. by procedures ·, well known in this field, in the event that the entire pharmacological activity - the useful one resides in a stereoisomer, the respective racemate is still useful through what it contains, as a constituent part, of the active isomer from the point of . pharmacological view, 'Preparation of ța-phenyl-tetrahydropifindiiΊόίΊόί with the formula. I, it requires 'raw materials, many of them', which 'some'. they are ruthless and not easy ', available ·. Use a 4a-phenyl-tetrabidro-2,6-dibxocycopence product / fc] pirate 'yes' raw material.

For, the preparation of dioxoc'yclopențapra • pului, .. respectively, of its derivatives, the product, 2.-feni3cÎclp.hexanol. is .aljchiîat, 1a. position..2 by reaction, .cp. a. alkyl, fwloacelal,, as, would be elylchloraceLat, in the presence, .. μηρί bases, c. such as sodium hydride. by, horses; obtain the corresponding product, / 2-phenyl-2-alkoxycarbonylmethylcyclohexane. Similarly, in the preparation of "2-phenyl-2-alkenyl-t-aminomethylcyclopentanes, a, 2-phenylohexaiion is first alkylated. At ,, position 2a

-their reaction · with an alkenyl -bathogen, as no · iodide. aiil.or .bronuii a rin '. · 2-Ιηι.tenii dn: prezeiițamuneiubaZe, now di Indrura d &lt;&gt; sodium, .to obtain ί .iîn:. product - icorespuhza'tor, c 2-k'ni 1 -2-dlclienilcicloheXtinoiw. Both 2-diethyl-2-alkoxycarbonylmethylcielobexanonelepcite and 2-phenyl-2-alkenes^;, 'lciclohexaaaonene. : Formylated silica then at position 6a by the reaction: with alkyl-tetylt-formate 'the presence of metal soda or potassium. Formylcyclohexane derivatives are then treated with p-to.luensulfonylazide, performing. , I find this way • replacement of G-formylulujucugo.igrupăcdiazo to, respectively, make 2-phenyl-2-al. coxi carbonylinetitl-6 ^ diazocyclohexanone. and., 2 ~ fem.l-2-alkenyl-6rdiaz.o, ~ eic: lohexanpne,. Such derivatives_:diazocyclo.hex-anions are then photolysed with a light: which has a wavelength of about 3000 A in an alcoholic solvent, such as. mela.new, to effect, a contraction · ring with the expulsion / concomitant expulsion of the gases and, to obtain 2-phenyl-2-alkoxycarbonylmethyl-1, -methoxycarbouil. but cl a pen ta ni ş 1, r cs pec ţi v 2 - fgn.il? 2-_Þ of he pd-t-meloxycarbopylcyclopentanes /, as well. de-esterify,, .ad.ică hydra; for you,. r-wt. with alkalis. a. mail. ' to, get., diat iduI. coies · ppnzulor and / the inoxacid resjieifiv. In the specific moiety / Αμ + οΙίζΑ / 2-phenyl-2-moieties: arhonyl-iin&gt; ii] I-myeloxycarbonyl cycloputa 11 id 11 i, leads. 1 a..to obtain, upui, product. suitably, 2-'-phenyl-27-hydroxycarbonyl, bonylmef ii-1-hydroxycarbonylsVcyclopehtan'. '', in a similar fashion, hydrolysis / 2-phenyl-2-alkenyl-t-methoxycarbonylcylcopenane,! leads, 1a Obtaining a suitable, corresponding.-fe.nil-2-alkenyl-. Ι, -ΕίάΓΟ.χιςμΓΒοηίΡρίρΙρρβηίάη ,,: i&gt; yakciul ,,. especially. 2-phenyl-2, HL, droxicarbonilmetil-._: 1 -, - bidroxycarbonylcir lopei'iLanuI, · is then. cyclized by the reaction, for example, cn_: chloro.uru; .. of .acetyl .for ·, to obtain · _ţ anhydride) / cpreşpoițo a re ,,,,, a. 4a-f en i 1 te tr ahi dr o-2,6-di oxo cyclopentamide). pi ram, These ·: .pirani-. .they are raw materials for preparing the rindins. ... ,. ·.

Certain 4a, phenyl-octahydro-1H-2-pinndiiie-2-subsf Huite with -I formula have found their usefulness in the treatment of pain and as a result may be used for analgesia in the case. subjects suffering from pain and · chre-need treatment. In addition, the derivatives of pyridines of the formula I have been found to have both properties: proanalgesic, as well as anti-analgesic; and so they are able to achieve - soothe pain in mammals! whereas, due to the antiangesic activity, it leads to a great decrease of the reliability, As well as your ability of the compounds described above, to determine both the analgesic phenomenon, as well as its antagonism in mammals, and consequently the decrease of any secondary properties of a particular drug caused by the somniferous action similar to the analgesic one. Compounds are thus particularly useful because they produce the analgesic effect with only a small physical dependence on the liabilities (risk). Some of these compounds are, in addition, useful in combating the undesirable effects of narcotics, such as morphine,

The analgesic activity possessed by the compounds of formula I was determined - by testing them on standard animals commonly used to measure the analgesic action attributed to these compounds. Such analyzes include the registration test on mice.

The compounds of formula I have demonstrated analgesic activity when tested in guinea pigs. In this procedure, the test is performed by injecting acetic acid into the interperitoneal 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 prior to the administration of acetic acid. To 4a- (3-methoxyphenyl) - '2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-' ΓΗ -2-pyrindine, when subcutaneous hydrochloride was administered in an amount of 20 mg / kg body weight mouse saw a 100% reduction in mouse tilt. A subcutaneous dose of 10 mg / kg produces 96% inhibition of such shunts. Similarly, an oral dose of the above-mentioned compound produces a 100% inhibition of trills at a dose of 20 mg / kg and a 90% 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 indicating that the analgesic is of a narcotic type. When tested on mice, the above-mentioned compound produced a significant increase in reaction time at doses whose level was 80 mg / kg, both subcutaneously and orally, and produced the same effect as oral doses. up to 200 mg / 'kg, all measurements being performed at i /₂ h and 2 h after injection or administration.

Similarly, the product 4a- (3-hydroxyphenyl) -2-meLyl-2,3,4,4a, -5,6,7,7a-octahydro-IH -2-pyrindine was tested. At a subcutaneous dose of 0.5 mg / kg, the compound resulted in a 75% inhibition of stroke in an animal test. At an oral dose of 10 mg / kg of this compound, an inhibition of 98% circulating G4 was observed after 72 hours after administration. The total prevention of the inhibitory action of the compound was observed at a subcutaneous dose of 0.5 mg / kg. Shock test tests have. showed that the compound causes a significant increase in reaction time at subcutaneous and oral doses of 20 mg / kg.

An alpha compound of formula I, 4a-phenyl-2-methyl-ZjSA-αSAT2α-octahydro-IH -2-pyrindine bromide produced a 70% inhibition of strokes in a group. test animals at a dose of 100 mg / kg after half an hour from. administration. At an oral dose of 20 mg / kg, the compound caused a 50% inhibition after U /₂ h 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 at a dose level of 80 mg / kg.

The following EDt data (i (dose that decreases the number of movements observed at 50% compared to control)) were obtained in the mouse and shock tests, presented in the table.

<td>Example number</td><td>A &lt;D 0 co</td><td>ω IT. Ό^: £ o &gt; Q Mili</td><td>• Q A A IIj U A {/&gt;</td>

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

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

<td> 6</td><td> ·</td><td> 20</td><td> &gt;80</td>

<td> 7</td><td>HBr</td><td> 50</td><td> &gt;80</td>

<td> 8</td><td>-HBr</td><td> 20</td><td> -</td>

<td> 9</td><td>HBr</td><td> 20</td><td> &gt;80</td>

<td> 10</td><td>HBr</td><td>L0</td><td> »80</td>

The product of formula I, 4a-phenyl-2,3,4, -4a, 5,6,7,7a-octahydro-IH -2-pyrindine-2-substituted is thus useful in producing the analgesic effect in the mammoth domain. , as I know n.an. Such compounds can be administered both orally and by injection. In general, it is preferable to use pharmacologically acceptable addition salts of pyrene derivatives when they are administered orally. For example, one or more pharmacologically active compounds of formula I, either as a free base or as a pharmacologically acceptable acidic salt, will be mixed for oral administration with any of the diluents, - exceptions or carry 72000 compounds with analgesic properties, missing of unwanted side effects, such as sleeping or narcotic action.

the flowers you usually use. Examples of such diluents or '/' and excipients commonly used in pharmacological preparations include starch powder, sucrose, cellulose, magnesium stearate,₅lactose, calcium sulphate, calcium benzoate and diluents. Such compositions may be molded into tablets or introduced into telescopic gelatin tablets for conventional administration. If desired, the active compounds of formula I may additionally be combined with one or more agents known to perform analgesia, such as caffeine, acetaminophen and propoxyphen.

The active compounds of formula I may be presented as sterile or non-aqueous aqueous solutions, suspensions and emulsions for convenient oral administration. The non-aqueous carrier substances used in such presentations include propylene glycol, vegetable oils, such as olive oil, and various organic esters, such as ethyl oleate. Oral and parenteral aqueous solutions include an isotonic saline solution.

Accurate dosage of the active ingredient, (the amount of one or more 4-phenyl octahydro- IH -2-pyrindine-2-substitutes ³⁰pharmacologically active tweets of formula I) administered to the mammal, such as a human subject, for example, may be varied over a wide or relatively wide range, as ³⁵cesarean section for optimal dosage. Such convenient dosages will depend on the particular therapeutic effect desired, the particular route of administration used and the duration of treatment.⁴⁰ment, as well as the precise condition to be treated. Typically the dosages of the active compounds of formula I will vary in a range from about 1.0 to about 25 mg / kg of body weight per day, depending on⁴⁵appropriately targeted for administration 4 times daily. Preferred oral dosages range from 2 to 50 mg / kg.

The process according to the invention has the advantage of preparing a new range of