N-alkyl indenopyridines therapeutics

PATENT DESCRIPTION

<img file="PL80561B1_D0001.tif" />

Additional patent to patent No. _

Reported: 05.05.1970 (P. 140430)

MKP C07d 39/00 C07d 29/38

OFFICE

PATENT

PRL

Priority: 07.05.1969 for claims 2 and 3 Switzerland

The application was announced on 10.05.1973

Patent description published: 30.01.1976

-and

Int. CL.²

C07D 221/02

IS LLNIA

Patent Office fol, i) fck. ._fi|

Creators of the invention: Anton Ebnóther, Jean-Michel Bastian, Erwin Rissi Patent holder: Sandoz AktiengeseUschaft, Basel (Switzerland)

Method for the production of new tetrahydroindenopyridine derivatives in the form of acid addition salts ♦

and

The present invention relates to a process for the preparation of new tetrahydroindenopyridine derivatives of the formula I in which R1 is a hydrogen atom, a lower alkyl radical, a fluorine, bromine or chlorine atom, R₂ represents a cyano group, a group of formula -COOR₅in which R₅ is hydrogen or a lower alkyl radical or R₂ is a group of formula 11 in which R₅ has the abovementioned meaning, and R_e is hydrogen or a lower alkyl radical or R₆ and R_e together with the nitrogen atom form a heterocyclic ring containing

5-7 segments, Rj and R₄ are hydrogen or lower alkyl radicals, and n is an integer from 0 to 3 in the form of acid addition salts.

According to the invention, new indenopyra derivatives. The dyes of formula I in the form of acid addition salts are obtained in such a way that the water is separated from the compound of formula II in which Ri, R₂, R₃, R₄ in have the abovementioned meaning, and in the case when R₂ is a cyano group, a group of formula COOR? in which R | is a lower alkyl radical or R₂ is a group of formulas 11 in which R₅ and R₆ have the abovementioned meaning, optionally simultaneously with the cleavage of water, or subsequently, the substituent R is carried out₂ into a carboxy group by hydrolysis, or in the case where R₂ is a cyano, carboxy group or group of formula! 1, in which R₅ and R_e'have the abovementioned meaning simultaneously with the cleavage of water or subsequent esterification.

The compounds of formula I are stable in the form of acid addition salts. If, however, they appear as free bases, then there is rearrangement with the double bond shifting from position 4a, 5 to position 4a, 9b. Therefore, it is preferable to use strong acids for the cleavage of water which, with compounds of formula I, give crystalline salts, or chlorides, bromides or iodides of strong acids, whose reaction products formed during the cleavage of water give crystalline salts with compounds of formula 1. For the cleavage of water you can only use chlorides, ₁₅ bromides or iodides of strong acids when Rt is not a COOH group, because in this case the carboxyl group reacts to form the corresponding acid halide group.

Examples of strong acids suitable for cleaving water are mineral acids (e.g. in aqueous or alcoholic solution), such as hydrochloric, hydrobromic, hydroiodic, sulfuric or organic acids, for example.

. organic sulfonic acids such as methanesulfonic, benzenesulfonic and naphthalene-1,5-disulfonic acid. Thionyl chloride, for example, can be used as strong acid halide.

For cleavage, water is treated with strong acids or strong chlorides, bromides or iodides, hydroxy compounds,

561

561 formula 2 in the form of free acids or their acid addition salts, for example hydrochlorides, within about 1 minute to 24 hours, preferably within 15 minutes to 2 hours, in the temperature range from room temperature to the boiling point of the reaction mixture, optionally in the medium solvent inert under the reaction conditions. The reaction mixture is then evaporated to dryness and optionally the acid addition salts obtained of the compounds and formula I are purified in a known manner.

Depending on the reaction conditions, during the splitting of water, the substituent at the nitrogen atom may remain unchanged or also react. For example, compounds represented by the formula la in which Ri, R₈, R₄ and n are as defined above, can be obtained not only from compounds of formula 2a in which R_b Rs, R₄ and n have the abovementioned meaning but also from compounds of formula 2b in which R_x, R₈, R₄ in have the abovementioned meaning, and R₇ is a lower alkyl radical or compounds of formula 2c and 2d_? in which R_x, R₈, R₄ in have the abovementioned meaning.

In the case where the desired end products are compounds represented by the formula Ib in which R_x, R₈, R₄, R₇ and n are as defined above, then the water is cleaved off with acids or chlorides, bromides or iodides of strong acids, preferably in an anhydrous environment, for example in the corresponding anhydrous alcohol. At the same time, the optionally present amide or cyano group can be pre-hydrolysed to the carboxyl group and then esterified. Esterification of the amide, cyano or carboxyl group can also occur simultaneously with the separation of water.

The process according to the invention can be carried out, for example, as follows.

The hydroxy compound of formula II is heated to reflux for about 1/2 hour with strong acid or with strong acid chloride, bromide or iodide. The obtained acid addition salt of the compound of formula 1 precipitates under the crystalline precipitate most often already during heating or cooling of the reaction mixture. Otherwise, the reaction solution is evaporated to start (crystallization or dryness). The crude product which has been filtered off or remaining after evaporation can be purified by known methods.

Lower alkyl radicals marked with symbols R_x, R₈, and R₄ preferably contain 1-4 carbon atoms and are especially a methyl radical. Alkyl radicals marked with symbols R₅ and R₆ preferably contain 1-6, especially 1-3 carbon atoms.

The starting products of formula 2 are new and cannot be obtained in such a way that a) compounds of formula 3 in which R_x has the abovementioned meaning, it is reacted in the presence of a basic condensing medium with compounds of formula 4 in which R₂, R₈, R₄ and n have the abovementioned meanings, and Hal is a chlorine, bromine or iodine atom, or b) for the preparation of compounds of formula 2e in which R_x, R₂, R₈ and R₄ have the abovementioned meaning, compounds of formula 3 are reacted with acrylic acid or with derivatives of acrylic acid of formula 5 in which R₂, Rs and R₄ have the abovementioned meaning.

The reaction according to a ') is carried out, for example, in such a way that the compound of formula 3 is reacted with the compound of formula 4 in the presence of a basic condensing agent and a solvent inert under the reaction conditions, for example in a carboxylic acid dialkylamide with lower alkyl radicals such as dimethylformamide, at elevated temperature, for example 130 ° C, the reaction being completed after about 2 hours. As the basic condensing agent, for example, an alkali metal carbonate, such as sodium or potassium carbonate, or an equivalent of the compound of Formula 3 may be used in excess. The reaction product can be purified by known methods or further processed without further purification.

The reaction of the compound of formula 3 with the compound of formula 5 according to b ') can be carried out, for example, at elevated temperature, preferably at the reflux temperature of the reaction mixture, optionally in a medium inert under the reaction conditions, for example in a lower alcohol such as methanol or ethanol. The reaction is carried out in about 2-16 hours. The product obtained can be isolated by known methods and purified, for example by crystallization or simply further processed.

The starting products used to prepare compounds of formula II are partially known; they can be prepared as follows.

Compounds of formula 3 can be prepared by reaction of a tetrahydroisononicotinic acid ester of formula 6 in which R₈ is a methyl or benzyl radical with a magnesium compound of formula 7 in which R_x has the abovementioned meaning; then, by hydrolysis of the obtained product is obtained. compounds of the formula 8 in which R_xand R₈ have the abovementioned meaning. Compounds of formula 9 in which R is obtained from these compounds_x and R₆ have the abovementioned meaning, either directly by heating with polyphosphoric acid or by hydrolysis to free carboxylic acids, preparation of acid chloride, for example with thionyl chloride and cyclization with Friedel-Crafts catalysts such as anhydrous aluminum chloride.

Compounds of formula 10 in which R1 and R₈ have the abovementioned meaning, obtained by the selective reduction of the carbonyl group of formula 9 to CHOH.

Compounds of formula 3 can be obtained when in the compound of formula 10 the OH group is protected by converting it into an easily cleavable ester or ether, then the resulting compound is converted by reaction with a chloroformic acid ester into the corresponding urethane, from which the protective group is again separated , and the urethane group is hydrolyzed simultaneously with cleavage

561 protecting group or subsequently in an alkaline environment.

Preferably, the method according to the invention is such that: in the case of the preparation of acid addition salts with 1,3,4,9b-tetrahydro-2 (2H) -indeno [1,2-c] pyridinenopropionic acid, from 1,3,4,4a, 5,9b-hexahydro-5 acid -hydroxy-2 (2H) -indeno [1,2-c] pyridinopropionic acid, water is cleaved off, in the case of the preparation of acid addition salts with 1,4,4,9b-tetrahydro-2 (2H) -indeno [1,2- c] pyridinopropionic acid, 1, 3, 4, 4, 5,9b-6-hydroxy-5-hydroxy-2 (2H) -indeno [1,2-c] pyridinopropionic acid methyl ester or 1, 3, 4a, 5, 9b-hexahydro-5-hydroxy-2 (2H) -indeno [1,2-c] pyridinopropionitrile or 1,3,4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indeno [1, 2-c] pyridinopropionamide is boiled with hydrochloric acid.

Pharmacologically acceptable acid addition salts of compounds of formula I possess interesting pharmacodynamic properties at low toxicity and can therefore be used as therapeutic agents.

They show anti-inflammatory effects, as shown in animal studies (infectious edema in rats). The doses of the new compounds vary depending on the type of treatment and the patient's condition. In general, however, satisfactory results have been obtained in test animals at doses

3-30 mg / kg body weight. These doses can be given naturally in 2-3 parts or also in a prolonged form. The daily dose is about 5-30 mg for larger mammals. When used orally, the doses partly contain about 2-15 mg of the acid addition salt of the compounds of formula I in addition to solid or liquid carriers. They also have protective properties against ulcers, as demonstrated in rat studies (lobutazone-induced peptic ulcer test). Naturally, the doses used change depending on the type of treatment and the patient's condition. In general, however, satisfactory results are obtained with doses of 5-20 mg / kg body weight; these doses can be administered as needed in 2 or 3 parts or also in a prolonged form. For larger mammals, the daily dose is about 10-50 mg. When used orally, the doses partly contain about 3-25 mg of the acid addition salt of compounds of Formula 1 in addition to solid or liquid carriers.

The action of new compounds that lower blood pressure is evident when testing the blood circulation of a drugged dog. Naturally, the doses used vary depending on the type of administration and the condition being treated. In general, however, satisfactory results are obtained in test animals at doses of 0.5-10 mg-kg body weight. These doses can be given as needed in 2-3 parts, or also in a prolonged form. The daily dose is 3-10 mg for larger mammals. When used orally, partial doses contain about 1-25 mg of the acid addition salt of the compound of Formula 1 in addition to solid and liquid carriers.

These compounds also have an appetite-suppressant effect, as it turned out in the rat by testing feed intake. Naturally, the doses used vary depending on the type of administration and the condition being treated. In general, however, satisfactory results are obtained in test animals at doses of 3-30 mg / kg body weight. These doses can be given as needed in 2-3 parts, or also in a prolonged form.

For larger mammals, daily doses are around 10-50 mg. When used orally, partial doses contain about 3-25 mg of the acid addition salt of the compound of Formula 1 in addition to solid or liquid carriers.

As therapeutic agents, physiologically acceptable acid addition salts of compounds of formula I can be used alone or in a suitable drug form with pharmacologically inert auxiliary materials.

Unless the production of the starting products used is described, they are known or can be prepared by known methods, or analogously to those described herein or analogously to known methods.

In the following examples, which explain in more detail the method according to the invention without limiting its scope, all temperature data are given in degrees Celsius and are uncorrected.

Example I. 1,3,4,9b-tetrahydro-2 (2H) -indeno (1,2-c) -pyridinopropionic acid methyl ester hydrochloride. 10 g of 1,3,4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indeno (1,2-c) pyridinopropionic acid methyl ester in 100 ml of methanol is heated to boiling for 2 hours hydrogen chloride. Then it is evaporated under reduced pressure, the residue is recrystallized first from an acetone / ether mixture and then twice from methanol. The title compound melts with decomposition at 183 ° -185XL

Example II Analogously, as described in Example 1, the following compound of formula 1 can be obtained:

<td>At- Quad</td><td>ri</td><td>r₂</td><td>r₃</td><td>R ..</td><td>n</td><td>Physico-chemical constants</td>

<td>II</td><td>H</td><td>COO-C₂h₅AND</td><td>H 1</td><td>H</td><td> 0</td><td>Hydrochloride melting point 176 ° -178 ° and decomposed)</td>

Example III. 1,4,4,9b-tetrahydrogen-2 (2H) -indeno (1,2-c) pyridinopropionamide hydrochloride.

For a solution of 17.9 gl, 3,4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indene ^J(1,2-c) -pyridinopropionamide in 350 ml of chloroform is added dropwise with 10 ml of thionyl chloride. The mixture is healed with an ipoid reflux condenser for 30 minutes, whereupon the initially precipitated resin goes into solution then evaporated under reduced pressure and the residue is boiled with 150 ml of isopropanol. After

561 cooling, the title compound is filtered off and recrystallized twice from methanol. The product has a melting point of 224 ° -226 ° (with decomposition).

Example IV 1,2, 3,4,9b-tetrahydro-2 (2H) -indeno (1,2-c) pyridinopropionic acid hydrochloride.

gl, 3,4,4a, 5,9b-hexahydro-5H-hydroxy-2 (2H) -indeno (1,2-c), pyridine propionic acid is boiled under reflux with 100 ml of a 2 N hydrochloric acid solution for 15 minutes. The mixture is allowed to cool, the title compound is filtered off and recrystallized from water. The melting point of the product is 285 ° -287 ° (with decomposition).

Example V. 1,2,4,9b-tetrahydro-2 (2H) -indeno (1,2-c) -pyridine propionyl trichloride hydrochloride.

Gl, 3,4,4a, 5,9b-hexahydrogenO-5-hydroxy-2 (2H) -indeno (1,2-c) pyridinopropionitrile is boiled under reflux with 100 ml of a 2 N hydrochloric acid solution for 15 minutes. It is then evaporated under reduced pressure, evaporated again with ethanol and the residue recrystallized twice from ethanol. The title compound melts with decomposition at 297 ° -300 °.

Example VI. 1,4,4,9b-tetrahydro-N-methyl-2 (2H) -indene- (1,2-c) -pyridinopropionamide hydrochloride.

gl, 3,4,4a, 5,9b-hexahydro-5-hydroxy-N-methyl-2 (2H) -indene- (1,2-c) pyridinopropionamide is boiled under reflux with 120 ml of 2N hydrochloric acid solution within 15 minutes. It is then cooled, basified with solid sodium carbonate and shaken repeatedly with ethyl acetate. The extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is dissolved in acetone and the solution is acidified with an ethereal hydrogen chloride solution, whereupon the title compound crystallises after some time. It melts (with decomposition) after recrystallization from acetone at 186 ° -⁵ 188°.

Example VII. 1,4,4,9b-tetrahydro-2 (2H) -indene- (1,2-c) pyridinopropionic acid hydrochloride.

g of crude 1,4,4,4a, 5,9b-hexahydro-5H-hydroxy-2 (2H) -indene- (1,2-c) -pyridinopropionic acid methyl ester is boiled under reflux with 200 ml of a 2N hydrochloric acid solution within 20 minutes. It is allowed to cool, the title compound is filtered off and recrystallized from water. The melting point of the product is 285 ° -287 ° (with decomposition).

By analogy, as described in Example VII, the following compounds of formula 1 can be obtained (examples: VIII to XVI):

<td>Example</td><td>ri</td><td>r₂</td><td>rg</td><td>ri</td><td>n</td><td>Physico-chemical constants</td>

<td>VIII</td><td>H</td><td>COOH</td><td>H</td><td>H</td><td> 3</td><td>Melting point of hydrochloride 235 ° - 237 ° (with decomposition)</td>

<td>IX</td><td>cl</td><td>COOH</td><td>H</td><td>H</td><td> 0</td><td>Melting point of hydrochloride 235 ° - 238 ° (with decomposition)</td>

<td>X</td><td>CH₃</td><td>COOH</td><td>H</td><td>H</td><td> 0</td><td>Melting point of hydrochloride 234 ° - 236 ° (with decomposition)</td>

<td>XI</td><td>c₂h₅</td><td>COOH</td><td>H</td><td>H</td><td> 0</td><td>Melting point of hydrochloride 243 ° - 246 ° (with decomposition)</td>

<td>XII</td><td>H</td><td>COOH</td><td>H '</td><td>H</td><td> 2</td><td>Melting point of hydrochloride 185 ° (with decomposition)</td>

<td>XIII</td><td>H</td><td>COOH</td><td>H</td><td>H</td><td> 1</td><td>Melting temperature . hydrochloride 255 ° - 258 ° (with decomposition)</td>

<td>XIV</td><td>H</td><td>COOH</td><td>ch₃</td><td>H</td><td> 1</td><td>Hydrochloride melting point 150 ° - 180 (with decomposition)</td>

<td>XV</td><td>H</td><td>COOH</td><td>ch₃</td><td>H</td><td> 0</td><td>190 ° -192 ° hydrochloride melting point (with decomposition)</td>

<td>XVI</td><td>H</td><td>COOH</td><td>H</td><td>CHG</td><td> 0</td><td>Melting point of hydrochloride 225 ° - 227 ° (with decomposition)</td>

For further work-up of the reaction mixture in Examples 15 and 16, the resulting solution is evaporated to dryness and the residue is recrystallized.

Example XVII. 1, 3,4,9b-tetrahydro-2 (2H) -indene, 2-c) pyridinopropionic acid methyl ester hydrochloride.

'' A solution of 9.5 g of 1,2,4,9b-tetrahydro-2 (2H) -indeno (1,2-c) pyridinopropionic acid hydrochloride (prepared according to Example 4) in 150 ml of methanol is boiled under reflux , introducing hydrogen chloride; in 2 hours. It is then concentrated to about 25 ml and, after cooling, the title compound is filtered off.

It melts with decomposition after recrystallization from methanol at 183 ° -185 °.

Example XVIII. By analogy, as described in Example 17, the following can also be obtained compound 1 :

561

<td>Example</td><td>ri</td><td>r₂</td><td>ra</td><td>r₄</td><td>n</td><td>Physico-chemical constants</td>

<td>XVIII</td><td>H</td><td>COO-C₂k₅</td><td>H</td><td>H</td><td> 0</td><td>The hydrochloride melting point (with decomposition) 176 ° -178 °</td>

Example XIX. 1, 3,4,9b-tetrahydro-2 (2H) -indeno- (1,2-c) pyridinopropionic acid methyl ester hydrochloride.

The title compound can be obtained as described in Example 17 if instead of 1,4, 3,4b-tetrahydro-2 (2H) -indeno- (1,2-c) pyridinopropionic acid hydrochloride, 3,4 , 4a, 5.9b-sixAvk&gt; doro-5-hydroxy-2 (2H) -indene- (1,2-c) pyridinoprofionic. The hydrochloride melting point is 183 ° -185 ° (with decomposition).

Example XX. 1,3,4, 9b-tetrahydro-2 (2H) -indene- (1,2-c) pyridinopropionic acid hydrochloride.

The title compound can be obtained by boiling 1,1,4,4a, 9b-hexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyridinopropionitrile or hydrochloride 1,4,4,9b - tetrahydro-2 (2H) -indene, 2-c) -pyridinopropionitrile (for preparation see example V) within 2.5 hours with a 5 N solution ¹⁵ hydrochloric acid. The reaction mixture is worked up as described in Example VII. The hydrochloride melting point is 285 ° -287 ° (with decomposition).

Similarly, as described in Example 1, ex²⁰ starting from the corresponding 1,3,4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyridinififryl, * the following compounds of formula 1 can also be obtained (Examples XXI -XXIII):

<td>Example</td><td>ri</td><td>• on₂</td><td>ra</td><td>^R&lt;</td><td>n</td><td>Physico-chemical constants</td>

<td>XXI</td><td>H</td><td>COOH</td><td>H</td><td>H</td><td> 1</td><td>The hydrochloride melting point 255 ° —258 ° (with decomposition)</td>

<td>XXII</td><td>H</td><td>COOH</td><td>ch₃</td><td>H</td><td> 0</td><td>Melting point of the hydrochloride 190 ° -192 ° (with decomposition).</td>

<td>XXIII</td><td>H</td><td>COOH</td><td>H</td><td>CH_S</td><td> 0</td><td>The hydrochloride melting point 225 ° -227 ° (with decomposition)</td>

Example XXIV. 1,3, 4,9b-tetrahydro-2 (2H) -indene- (1,2-c) -pyridinopropionic acid hydrochloride.

Starting from zl, 3,4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyridinopropionamide or 1,3,4,9b-tetrahydrogen-2 (2H) hydrochloride ) -indene- (1,2-c) -pyridinopropionamide, the title compound can be obtained in analogy as described in Example XX. Hydrochloride melting point: 285 ° -287 ° (decomposed).

Compounds used as starting materials can be obtained as follows:

Example XXV. 1,3, 4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyridinopropionic acid methyl ester (for example I, VII).

40 gl, 3,4,4a, 5,9b-hexahydro-5 (2H) -indeno- (1,2-c) -pyridinol, 36 g acrylic acid methyl ester and 400 ml methanol are boiled under reflux for 16 hours . The mixture is then evaporated under reduced pressure, the residue dissolved in ether and shaken three times with sodium carbonate solution. The ether layer after drying over magnesium sulfate is evaporated. The residue is crude l, 3,4,4a, 5,9b-hexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyridinopropionic acid methyl ester in the form of a brown oil. It is clean enough for further processing.

In analogy to Example XXV, the following compounds of formula 2 (Examples XXVI-XXXVII) may be obtained:

<td>Example</td><td>ri</td><td>r₂</td><td>R</td><td>r₄</td><td>η</td><td>Physico-chemical constants</td><td>to the example</td>

<td>XXVI</td><td>H</td><td>COOH</td><td>, Η</td><td>Η</td><td> 0</td><td>melting point 215 ° -218 ° (with timetable)</td><td>IV and XIX</td>

<td>XXVII</td><td>H</td><td>CO-NH-CH₃</td><td>Η</td><td>Η</td><td> 0</td><td>mp 127 ° -129 ° (with timetable)</td><td>VI</td>

<td>XXVIII.</td><td>H</td><td>CN</td><td>Η</td><td>Η</td><td> 0</td><td>melting point 84 ° -86 ° (with timetable)</td><td>V and XX</td>

<td>XXIX</td><td>H</td><td>COO'C₂H₅</td><td>Η</td><td>Η</td><td> 0</td><td>Continue working without ' purification</td><td>II</td>

<td>XXX</td><td>H</td><td>at * nh₂</td><td>Η-</td><td>Η</td><td> 0</td><td>mp 146 ° -148 ° (with timetable)</td><td>III and XXIV</td>

<td>ΧΧΧΓ</td><td>cl</td><td>coo-ch₃</td><td>Η</td><td>Η</td><td> 0</td><td>further processed without purification</td><td>IX</td>

561

<td>Example</td><td>R₄</td><td>R₂</td><td>r₈</td><td>r₄</td><td>n</td><td>Physico-chemical constants</td><td>to the example</td>

<td>XXXII</td><td>ch₈</td><td>COO-CH₈</td><td>H</td><td>H</td><td> 0</td><td>further processed without purification</td><td>X</td>

<td>XXXIII</td><td>C₂H₅</td><td>coo-ch₈</td><td>H</td><td>H</td><td> 0</td><td>further processed without purification</td><td>XI</td>

<td>XXXIV</td><td>H</td><td>COO-C₂h₅</td><td>ch₃</td><td>H</td><td> 0</td><td>further processed without purification</td><td>XV</td>

<td>XXXV</td><td>H</td><td>COO-C₂h₅</td><td>H</td><td>ch₃</td><td> 0</td><td>further processed without purification</td><td>XVI</td>

<td>XXXVI</td><td>H</td><td>CN</td><td>ch₃</td><td>H</td><td> 0</td><td>further processed without purification</td><td>XXII</td>

<td>XXXVII</td><td>H</td><td>CN</td><td>H</td><td>ch₃</td><td> 0</td><td>further processed without purification</td><td>XXIII</td>

Example XXXVIII. 1, 3.4, 4a, 5.9b acid methyl ester^jhexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyro-capron (to Example VIII).

16.8 g of sodium carbonate are added to a solution of 15 g, 3,4,4a, 5,9b-hexahydro-5- (2H) -indeno- (1,2-c) -pyridinol in 290 ml of dimethylformamide, then dropwise added a solution of 16.6 g of 6-bromocaproic acid methyl ester and then heated for 2 hours at 130 °. Then it is cooled, poured into 1000 ml of ice water, extracted three times with methylene chloride, the combined extracts are dried, dried over magnesium sulfate and evaporated. The residue is recrystallized twice from a mixture of isopropanol / pentane. 1,2,4, 4a, 5,9b ^ hexahydro-5-hydroxy-2 (2H) -indene- (1,2-c) -pyridinecaproic acid methyl ester melts at 84 ° -86 °.

Similarly, as described in the example

XXXVIII, the following compounds of formula 2 (Examples XXXIX-XLII) can be obtained.

<td>Example</td><td>ri</td><td>r₂</td><td>R »</td><td>r₄</td><td>n</td><td>Physico-chemical constants</td><td>down example</td>

<td>XXXIX</td><td>H</td><td>COO-C₂h₅</td><td>CH_S</td><td>H</td><td> 1</td><td>further processed without purification</td><td>XIV</td>

<td>XL</td><td>H</td><td>COO-C₂h₅</td><td>H</td><td>H</td><td> 2</td><td>further processed without purification</td><td>XII</td>

<td>XLI</td><td>H</td><td>COO-C₂h₅</td><td>H</td><td>H</td><td> 1</td><td>further processed without purification</td><td>XIII</td>

<td>XLII</td><td>H</td><td>CN</td><td>H</td><td>H</td><td> 1</td><td>further processed without purification</td><td>XXI</td>

Example XLIII. 7-chloro-1,3,4,4a, 5,9b-hexahydro-5 (2H) -indene- (1,2-c) -pyridinol (to Example XXXI).

To a solution of 40 g of 7-chloro-1,3,4,4a, 5,9b-hexahydro-2-methylO-5- (2H) -indene- (1,2-c) -pyridinol in 200 ml of pyridine is added dropwise , 5 g acetic anhydride and leave at room temperature for 15 hours. The solution is then evaporated in vacuo, the residue dissolved in water and extracted three times with methylene chloride. After drying over magnesium sulfate, evaporation and the remaining crude, resinous 5-acetoxy-7Hloro-1,3,4,4a, 5,9b-hexahydro-2-methyl-2H-indeno (1,2-c) -pyridine is dissolved in 300 ml of benzene. 70 g of chloroformic acid ethyl ester are added dropwise to this solution with stirring, then the mixture is boiled under reflux for 3 hours, the precipitate is filtered off, the filtrate is shaken first with water, then with 1 N hydrochloric acid solution and finally with saturated sodium chloride solution. The benzene layer is dried over magnesium sulfate and evaporated. As a residue, 5-acetoxy-2-ethoxycarbo is obtained₄₀ nyl-7-chloro-1,4,4,4a, 5,9b-hexahydro-2H-indeno- (1 ', 2-c) -pyridine in the form of a thick oil, which slowly crystallizes on prolonged standing.

g 5-acetoxy-2-ethoxycarbonyl-7-chloro-1,3,4, 4a, 5,9b-hexahydro-2H-indene- (1,2-c) -pyridine⁴⁵ is refluxed for 9 hours with a solution of 35 g of potassium hydroxide in 350 ml of butanol. After cooling, the mixture is poured into 500 ml of saturated sodium chloride solution and shaken three times with chloroform. After

Drying over magnesium sulfate evaporates the residue obtained 7-chloro-1,3, 4,4a, 5,9b-hexahydrogen-5 (2H) -indeno- [1,2-c] pyridinol, recrystallized from isopropanol. Melting point 197 ° -199 ° C.

⁵⁵ Similarly, as described in Example XLIII, the following compounds of formula 3 (Example XLIV and XUV) can also be obtained:

<td>Example No.</td><td>ri</td><td>Physico-chemical constants</td><td>to the example No.</td>

<td>XLIV</td><td>CH</td><td>mp 168 ° -170 °</td><td>XXXII</td>

<td>XLV</td><td>CJH₅</td><td>melting point of A 128-130 °</td><td>XXXIII</td>

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