DE2002499A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

Patent Attorneys O CYfYO / QQ

Dr. W. Schalk, Dipl.-Ing. P. Wirfh ^ ^UUZ ^

Dipl.-Ing. G. Dannenberg
Dr: V. Scbmied-Kowarzik.
Dr. P. Weinhaid, Dr. D. Gudel 6 Frankfuri / M., Gr. Eschenheimer Sh-. 39

SANDOZ AG.

Basel. -. -. Case 100-3042

Process for the preparation of new heterocyclic compounds

The invention relates to processes for the preparation of new compounds der'Formel I, wherein R .. for. Hydrogen, "an alkyl, alkenyl or alkynyl group or the henzyl group, R _n for a lower primary or secondary alkyl group and R-, for hydrogen, halogen or a lower alkyl group, Viwherein R _{1 is} not the methyl group when PU £ ü ? the methyl groups and R- stand for hydrogen.

According to the invention, the compounds of the formula I are obtained by

a) Compounds of the formula ± 1, in which R ^ is the benzyl group, represents an alkyl, alkenyl or alkynyl group and PU and R, Have the above meaning, 'where R ^ is not the methyl group

j. .

means when FU for the methyl group and R ^ for hydrogen

d j _T

stand, or compounds of the formula IV, wherein ..PC and R Have the above meaning, Rj- and 'PU each hydrogen or one mean lower alkyl group, where R, does not mean the methyl group, -if FU, Rp. and PU all stand for hydrogen, to the compounds of formula la, in which Hi, FU and .R ,. above Meaning-have, cyclized, or ~

b) Compounds of the formula Ib, wherein "FL for the methyl or

009831/1921
BATH ORIGINAL

- 2 - 100-

Benzyl group, and Rp and R-, have the above meaning by splitting off the methyl or benzyl group in the compounds of the formula Ic, in which Rp and R-. have the above meaning, transferred, or

c) Compounds of the formula Ic with compounds of the formula III, in which R, has the above meaning and Y is the acid radical

^X I

of a reactive ester, where R ₁ in the compounds of formula IH does not represent the methyl group, if in the compounds of formula Ic R "stands for the methyl group and R_ for hydrogen, condenses to the compounds of the formula Ia.

The cyclization according to process a) is preferably carried out with the aid of strong acids. Examples of such strong acids are hydrogen bromide, phosphoric acid or methanesulfonic acid. The cyclization is carried out at an elevated temperature, preferably between about 80 and 150 °, if appropriate in an inert gas atmosphere such as nitrogen.

The cyclization can, depending on the reaction conditions, lead directly to the end products of the formula Ia or through Elimination of water gives the intermediates of the formula IV, which are then subsequently cyclized.

The cleavage of the methyl or benzyl group from the compounds of the formula Ib according to process b) is preferably carried out in such a way that the compounds of the formula Ib are _{treated with a chloroformic acid ester of the formula V in which R 17 is} a lower alleyl group, the phenyl or bensyl group

009831/1921

BAD OfM &nM;"^;"^{> r} *

means to the urethanes of the formula Yi ₃ in which Rp, R, and R _{7 have the} above meanings, and these urethanes are "converted" into the "compounds of the formula Ie" by acidic or alkaline hydrolysis.

The reaction of the compounds of the formula Ib with the Chlorameisensäureestern of formula V is preferably carried out in a solvent inert under the reaction conditions _5, for example, in-an aromatic hydrocarbon, such as anhydrous benzene and carried out at elevated temperature, for example at the boiling point of the reaction mixture. For this reaction, the chloroformic acid esters of the formula Va, in which R _{7 is} a lower alkyl group, are especially preferred starting products. The urethanes of the formula VI obtained in this way can either be purified by methods known per se or used directly in the subsequent urethane cleavage.

The cleavage of the -COOR ^ group from the urethanes of Formula VI can be prepared with the help of acids, e.g. of mineral acids, such as hydrochloric acid © of the bases, e.g. alkali metal hydroxides, such as Potassium or sodium hydroxide, in one under the reaction conditions inert solvent, e.g. in a lower alcohol such as n-butanoi, preferably at boiling temperature of the reaction mixture are carried out.

The condensation of the compounds of the formula Ic with the compounds of the formula III according to process c) is preferably in a solvent which is inert under the reaction conditions, e.g. in a lower alcohol such as ethanol, in a chlorinated hydrocarbon such as chloroform, in one aromatic hydrocarbon such as xylene or in one

009831/1921

The (lower) alkylamide of a lower aliphatic carboxylic acid ν / ie dimethylformamide and in the presence of a basic Condensing agent, e.g. an alkali metal carbonate such as sodium or potassium carbonate, or a tertiary organic Base such as triethyiamine, or an excess of one Compound of formula Ic carried out. In the connections of the formula III, Y is in particular chlorine, bromine, iodine or a methane, benzene or toluenesulphonic acid group. the Condensation is preferably carried out at a slightly elevated temperature, if appropriate at the boiling point of the reaction mixture.

Acid addition salts can be prepared from the free bases in a known manner manufacture and vice versa.

The alkyl groups symbolized by R 1 preferably consist of 1 to 10, in particular 1 to 8, carbon atoms. The alkenyl and alkynyl groups symbolized by R 1 consist preferably of 3 to 6, in particular 3 to 4, carbon atoms. The by R _? symbolized lower primary or secondary alkyl groups preferably consist of 1 to 5, in particular 1 to 3 carbon atoms. The lower alkyl groups symbolized by R, consist preferably of 1 to 4, in particular 1 to 2, carbon atoms.

The compounds of the formula I and their pharmacologically compatible Acid addition acids with low toxicity Interesting pharmalccdynamic properties and skills hence it can be used as a remedy.

They have saliaiuretische effectiveness, as reflected by Diuresevärsuone in the rat and the dog, and can ERSHIP so as Salidjuretics, verschiedenster in indications origins, eg edema in heart failure, in the 3chwan ~ Kephrooa-

009831/1921

thien / liver disease etc. are used. The ones to use Doses vary according to the nature of the administration and the condition to be treated. In general however, satisfactory results are obtained with a daily dose of 1.0 to ^ O mg / kg body weight; this day _ dose can be divided into 2 to 5 portions or as Retard form can be administered. For larger mammals the daily dose is around 5-50 mg. For oral applications the partial doses contain about 2 to 25 mg of the compounds of the formula I in addition to solid or liquid carriers or diluents. ■■ '"■" -, "" "■ ■;

The analytical properties of the compounds of the formula I and their acid addition salts manifest themselves, for example, in the "hot plate" test and through the inhibition of the phenyl-benzoquinone syndrome in mice. They can therefore be used as analgesics. "The doses to be used naturally vary depending on the type of administration and the condition to be treated. In general, however, satisfactory results are obtained with a daily dose of 1.0 to 30 mg / kg body weight, this daily dose can if necessary be administered in 2 to> ■ portions or as a sustained-release form. For larger mammals, the daily dose is about 10-100 mg. For oral administration, the partial doses contain about 5 to 50 mg of the compounds of the formula I in addition to solid or liquid Carriers or diluents.

Furthermore, they show a specific inhibition of offensive aggressive behavior (influencing offensive and defensive aggression in the mouse) and can therefore be used for behavioral disorders of psychopathic, oligophrenic or psychotic origin. The. The doses to be used naturally vary depending on the type of administration and the condition to be treated. Jm general, however, satisfactory results with a Ta ^ esdosis 0.07 to 2.5 mg / k ~ _c

009831/1921 BAD

- 6 - 100-3042

Maintain body weight; this daily dose can be used if necessary administered in 2 to 3 portions or as a sustained release form be «For larger mammals lies; the daily dose at about 5 to 100 mg. For oral applications, the partial doses contain about 2 to 50 mg of the compounds of Formula I in addition to solid or liquid carriers or diluents.

Finally, the compounds of the formula I and their acid addition salts also showed anti-inflammatory effects (traumatic edema in rats) and can be used as anti-inflammatory agents or exudation inhibitors for inflammation and for edema following contusions, distortions or fractures. The doses to be used naturally vary depending on the type of administration and the condition to be treated. In general, however, satisfactory results are obtained with a daily dose of 10 to J> 0 mg / kg body weight; If necessary, this daily dose can be administered in 2 to 3 portions or as a sustained-release form. For larger mammals, the daily dose is around 30 to 100 mg. For oral administration, the partial doses contain about 10 to 50 mg of the compounds of the formula I in addition to solid or liquid carriers or diluents.

The new compounds of the formula I or their physiologically acceptable acid addition salts can be used as medicaments alone or in a suitable remedy fora with pharmacological indifferent auxiliary substances are administered.

The compounds of the formula JI can be prepared by adding compounds of the formula VlI, wherein R ₁ , Rp * R-, un

j. t- j

Y obi ^ e I'edeutimn; own, with sodium borohydride in one

009831/1921

BATH ORIGINAL

Solvent, ^ ζ.Β «in a lower alcohol in Geraisch with water, reduced.

The compounds of the formula Ib used as starting materials in process to) represent a special case of the compounds of the formula I and can be obtained analogously to process a). However, starting from a ketone of the formula XII ₅ in which R-, and Rj, have the above meaning, by reaction with a 'compounds of the .Formel IX or Χ, in which Rp has the above meaning and X is.Halogen. Hydrolysis of the complexes formed to give the compounds of the formula XIII ₃ in which Rp, R- and R ₁ have the same meaning as above, and subsequent elimination of water, are prepared.

The general compounds of the formula VII can be prepared by reacting compounds of the formula VIII, in which R., _P has the above meaning, with compounds of the formula IX or X, the reaction products thus obtained to the compounds of the formula XI, in which Rp and R., Have the above meaning, hydrolyzed and this quaternized by reaction with compounds of the formula UE to 'the compounds of the formula VII

The ketones of the formula XlI are only partially known and can can be produced as follows: A lower alkyl ester of isonicotinic acid is used a compound of the formula XIV, in which R ^ has the above meaning and X represents chlorine or bromine, to the corresponding. ^ -Alkoxycarbönsrl-l-R ^ -pyridiniumhalogeniden um, e.g. by several hours' heating of the components in ethanol "from it tetrahydroisonicotinic acid ester is obtained by means of sodium borohydride Formula XV, in which Ru has the above meaning,

00 9831/1921. BATH ORIGINAL

2 JO 2 4 9 ϊ - 8 - 100-3042

This .e'cr-ahydroj sonicotinsäureester of the formula XV is ir_ ± a compound of the formula XVI, in which R-, which has ir: · "meaning, according to Grignard, hydrolyzed the Reakl. ^ Product and cyclized the resulting compound of Formula XVlI, in which R _x and Rk have the above meanings, by treatment with polyphosphoric acid or by hydrolysis to the free acid, preparation of the acid chloride and treatment with serf reiera aluminum chloride.

Some of the compounds of the formula VIII are unknown and can, for example, by reacting compounds of formula XVIIi wherein IL, has the above meaning, with compounds of Formula XV "τ and d-Ai-viU ff following hydrolysis of the formed Kemp ": xe be obtained

Also the production of the starting compounds is not described these are known or by methods known per se or analogous to those described here or can be produced analogously to processes known per se.

In de} ': following examples, the invention was explained more closely. l :: rer. Scope but in no way restrict it. -.-- :. ⁱ follow the partial instructions in degrees Celsius

009831/1921 BAD N

Example 1: ^

indeno [i; 2-c] pyridine, _ ■ "" ---.

A solution of 10 g of 1- (p-chlorophenyl) ~ 1- (1-methyl-L, 2,3,6-tetrahydropyridyl-4) ethan-1-ol in 60 ml of 85% phosphorus acid is added under nitrogen to 1 Heated to 100 ° for one hour. Then it is poured onto ice, made alkaline with potassium hydroxide and extracted with chloroform. After drying over -Magnesiumsulfat the chloroform solution is evaporated in vacuo, the residue in "dissolved ethanol and the solution acidified with ethereal hydrogen chloride, wherein" 8-chloro-l, 3 _J 4 _i -9b-tetrahydro-2,5-dimethyl-2H -indeno [l, 2-u] pyridine-hydr-β-chloride crystallizes. After recrystallization from isopropanol, it melts at 215-220 ° with decomposition. .

The starting material can be produced as follows:

a) To a solution of methylmagnesium iodide (made from 9.6 g of magnesium turnings and 56.8 g of methyl iodide in 200 ml of ether), a solution of k ~ 5, l \ g of 4- (p-chrbenzoyl) is added at room temperature while stirring -pyridine is added dropwise to 130 ml of tetrahydrofuran. The suspension is stirred for a further 17 hours and then stirred into 300 ml of 10% ammonium chloride solution. It is extracted several times with chloroform, the extracts are dried with magnesium sulfate and evaporated. (p-Chlorophenyl) -l- (pyridyl-4) ethan-1-ol is recrystallized from isopropanol, 3mp. 155-160 °.

b) In a solution of 12.2 g of methyl iodide in 180 ml of methanol, 5 »0 ρ l- (p-chlorophenyl) -l- (pyridyl-4) ethan-l-ol are added in portions while cooling with ice. ^ The mixture is stirred k hours at 55 °> then evaporates completely in vacuo: the residue is taken up in 70 ml of methanol and there are

009831/1921 BAD ORlGi!

3Ä8

- 10 - 100-3042

with stirring, 7 k g of sodium borohydride in portions, the temperature should not rise above 50 °. The mixture is stirred for a further 17 hours at room temperature, then evaporated in vacuo, the residue is taken up in mass and extracted several times with chloroform. After drying the extracts over magnesium sulfate, these are evaporated and the residue is recrystallized from methanol. L- (p-chlorophenyl) -l- (l-methyl-1,2,3,6-tetrahydropyridyl-4) ethanol with a melting point of 181-183 ^{0 is obtained} .

Example 2: 1 _i 3,4,9b _I tetrahydro _:: 2 ₁ 5 _i 8-triniethyl-2H _:: indeno [I ₁ 2-c] pyridine

A solution of 10 g of l- (p-tolyl) -l- (l-ynethyl-1,2,3,6-tetrahydropyridyl-4) ethan-l-ol in 50 ml of 47% hydrobromic acid is refluxed under nitrogen for 6 hours. It is then diluted with 100 ml of water, the 1,3 * 4,9b-tetrahydro-2,5,8-trimethyl-2H-indeno [1,2-c] pyridine hydrobromide crystallized. After recrystallization from water, it melts at 221-222 ° with decomposition.

The starting material can be produced as follows:

a) 80 ml of thionyl chloride are slowly added to 25 g of isonicotinic acid, the mixture is refluxed for 1/2 hour and evaporated in vacuo. The residue is taken up in 2X> ml of toluene and 100 g of aluminum chloride are added in portions. Then _cooks% to ό hours at reflux, cooled, poured into 500 ml of ice and are 20% hydrochloric acid, a clear solution'm arises (about 200 ml). It is now made strongly alkaline (pH approx. 12) with 50% potassium hydroxide solution and extracted several times with chloroform. After drying, it is evaporated over magnesium sulfate and the remaining H- (p ~ -Volyl ^I ) pyridine is crystallized from benzene petroleum ether. ilmp. 10-97 °

009831/1921 BAD

- 11 .- _L 10ü -;> 042

2Q02493. "--V,." ■., ■■ ·. - -

b) To a solution of? iethylmagnesium iodide (made from 4 * 8 g of magnesium turnings and 24.4 g of methyl iodide in 200 ml Ether), the solution of 19 / Γ g of 4- (p-tolyl) pyri.din in 50 ml of absolute tetrahydrofuran is added dropwise at room temperature with stirring. The suspension is stirred for a further 17 hours and then in 150 ml of 10% ammonium chloride solution stirred in. It is extracted several times with chloroform, ■ dries the extracts with magnesium sulphate and evaporates them ... The l- (p-tolyl) -l- (pyridyl-4) ethanol-ol that remains is recrystallized from absolute ethanol., mp »

175-175 °. . ' μ

"■■ -. Si

g) In a solution of 13.4 g of methyl iodide in 180 ml of methanol, 5 * 0 g of 1- (p-tolyl) -l- (pyridyl-4) ethan-l -ol are added in portions while cooling with ice. Stirring is continued h hours at 55 ° _s, the reaction mixture evaporates in a vacuum gyji ⁴ 'dryness ₉ . takes up the residue in 80 ml of methanol

- '. and the solution is mixed in portions with 8.2 g of sodium borohydride while stirring, the temperature of the oil should not rise above 50 °. The mixture is then stirred for a further 17 hours at room temperature, then evaporated to dryness in vacuo, the residue is taken up in water and the solution is extracted several times with chloroform. After drying the. λ organic "phase. With magnesium sulfate this is evaporated and 'the residue is recrystallized from acetone." 1- (p-TolyI) -I- (1-raethy 1-1-, S ₉ J, 6-tetrahyciro.-pyridyi-4) ethan-l-ol with a melting point of 150-151 ° is obtained,

SMMiSi ^ l lί3ί. ^ί b9b ^ .Tetrahydr "o-5- ^ πethyl '-" 2H-indeno ■ [l · - _ί 2-c ■] pyridine' ■ - '■ "". "'

Solution of 21 gl _s 3.4 _J> 9b-Tetrahydro-2,5-dimethyl-2H-indelotlj2 ~ e] pyriaine in 90 fnl abs »benzene is added with stirring

009 831/1921

- 12 - 100 - ^ 042

68.8 g of ethyl chloroformate are added dropwise. The mixture is then heated to the boil for 4 hours then extracted the cooled to room temperature reactive solution twice with water and once with 2N hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated. The remaining one is distilled Residue in a high vacuum and the pure 2-ethoxycarbonyl-3> 4.9t> -tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine is obtained from Kp l4> l45 ° / 0.02 'Torr.

A solution of 117 g of 2-ethoxy carbonyl-1,3 »4,9b-tetrahydro-5-methyl-2H-indenc [1,2-c] pyridine in 120 ml of n-butanoi. mixed with 12 g of solid potassium hydroxide and 3 hours for Boiling heated. The reaction mixture is evaporated on a rotary evaporator a, the residue is taken up in water and the solution is extracted repeatedly with chloroform. The chloroform extracts are dried over magnesium sulfate and then evaporated. For transferring the crude base thus obtained the residue is dissolved in the hydrochloride in ethanol and added the calculated amount of ethanolic hydrochloric acid. The solution is evaporated to dryness and crystallized twice from ethanol / ether. The pure 1,2,4,9b-tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine hydrochloride has the m.p. 182-184 °.

The 1,3 »4,9b-tetrahydro-2,5-dimethyl-2H-indeno [1,3» 4,9b-tetrahydro-2,5-dimethyl-2H-indeno [1,2-c] pyridine used as starting material can be made as follows:

a) A suspension of 32.2 g of 1,3,4,4a, 5,9b-hexahydro-2-methyl-2H-indeno [i, 2-c] pyridin-5-one in 300 ml abs. Aether is added dropwise at -30 ° while passing 100 ml of a 4.4 quantities of an ethereal solution of methyllithium were added.

009831/1921
BADORlGINAt

200249r;

After the / addition is complete, the mixture is stirred for 3 hours at -20 °, added das.Reaktionslösung with ice cooling and under Nitrogen-atmosphere-dropsvi.is.with.'QQ ml 20% Ammonium chloride solution and extracted with ether. The United A etfier extracts are 'about .'Magnesiumsulfat dried, the magnesium sulfate separated by filtration and evaporated the -Piltrat to dryness .. From the Residue, a crystalline crude product.

are obtained after recrystallization zvieimaligem aus.Di- "isopropy-läther..reines · 1,3, Λ ^ & 3 5 / _{9b-hexahydro-2,} 5-dimethyl-5 (2H) - _i indenoCl 2-c] pyridinol from Smp. Ί

b) A solution of '.14 g-1,3 * ^ * 4a> 5 »^ -Hexahydro-2., - 5- ^: d ^: imethy: l- - -5 (2ä) -indeno [i / 2 -c} pyrid; inol in 200 ml of 5U ethanolic hydrogen chloride solution is heated to boiling under reflux for 15 minutes 3 ^ 4,9b ~ T.etrahydrO ~ 2 ^
'hydrochloride; 2Θ3-205 of mp. ^{^::} (ΖβΓε.). - ■ '

Example 4; 1,3,4i> 9b-Tetrahydro-5-methyl-2-propargyl · -2H- - ■. indenotl, 2-c] pyridine ..,. "■ - ^ ',"} [''. ■ _ "

A mixture of 9.1, - .. g 1,3,4,9b-tetrahydro-5-ίriethyl · -i; ndeno [1 ,, 2-c] pyridine (base, prepared from the hydrochloride by treatment with potassium carbonate solution and Extraction with chloroform), 4.4 g of propargylic acid and 8.1 g of potassium carbonate in 60 ml of chloroform are heated to boiling for 50 hours while stirring. The Reaktiohsgemisehviird to, separation 'of inorganic salts filtered, washed with water and · di ^r e evaporated organic phase after drying over Kagnesiumsulfat.im Rotatiönsverdampfer; Dissolve the evaporation residue

00983j, fel§b

BADQFH6INAL

in ethanol, mixed with ethanolic hydrochloric acid up to clearly acidic reaction (pH about 3) and evaporates to dryness. After repeated recrystallization from ethanol / petroleum ether, the pure 1,3j-4- * 9b-tetrahydro-5-methyl-2-propargyl-2H ~ is obtained indeno [l, 2-c] pyridine hydrochloride with a melting point of 202-203 ° (decomp.)

Example 5: ^ i ^^^ g ^ g [l, 2-e] pyridine

A solution of 15Λ g · l-phenyl-l- (l-methyl-l, 2,3i6-tetrahydropyridyl-4) propan-l-ol in ΐβθ ml 85 foiger phosphoric acid is stirred for 2 hours to 100 ° and 1 hour 120 ° w heated. The contents of the flask are poured onto ice, made strongly alkaline with 40% sodium hydroxide solution (pH about 12) and extracted with benzene. The benzene extracts are dried over magnesium sulfate and evaporated in a rotary evaporator. The residue from evaporation is dissolved in acetone, the calculated amount of ethanolic hydrochloric acid is added and the mixture is again evaporated to dryness. To purify the crude hydrochloride, it is crystallized twice from acetone and once from a mixture of methanol / acetone. The pure 5-Aethylli3i (9t ⁾ -tetrahydro-2-methyl-2H-indeno [1 _jr 2-cjpyridine hydrochloride obtained in this way melts at Ιβ> -ΐ68 ^ο (decomp.).

The starting material can be produced as follows:

A solution of 35> 0 g of l-phenyl-l- (pyridyl-4) propan-l-ol in 525 ml of methanol are mixed with 41 ml of methyl iodide and during Heated to a gentle boil for 4 hours while stirring. One steams in a rotary evaporator to dryness, dissolve the residue in 850 ml of methanol and add in portions while stirring 36.6 g of sodium borohydride, the temperature being reduced by cooling is kept at about 30 °. The reaction mixture is during

009831/1921

Stirred for 4 hours at 50 ° and then to dryness evaporated »The residue is taken up in water and the solution extracted repeatedly with chloroform. After drying over magnesium sulfate, the combined extracts are "evaporated and the crude product recrystallized from benzene. Mp. 130-132 °." v. ■

Example 6t "1, -3 * 4,9b-Tetrahydro-S-iso ^ ropyl ^ -methyl ^ H-indeno

According to the process described in Example 5, S-methyl-1-phenyl-1-Cl-methyl-1 ^^ Jiö-tetrahydropyri- || is obtained from iS ** h dyl - ^} - propan-l-ol and 160 ml of 85% phosphoric acid, the compound mentioned in the title, "Hydrochloride Snip. -l80-rl83 ^o (decomp.)

The starting material can be prepared according to the method described in Example 5 (preparation of the starting material) by converting 83 _? 5 g of 2-methyl-l-phenyl-l- (pyridyl-4) propan-l-ol with 2 ml of methyl iodine in 1200 ral methanol and reduction of the N-methylpyridinium j bdide thus obtained with 8% g Sodium hydride can be obtained in 20 OO ml of methanol. M.p. 112-114 ° from benzene.

Example T; 1 ^ ι2Ά ^

inäeno [l ₅ 2-cTpyridin

Bach's method described in Example 5 is obtained from -'20. g 2-M6thyl-l-phenyL-l ^ (l ■ -methyl-l _ί 2 _i) 3,6-tetrahydropyridyl-4) propene-1 in 200 ml 85% phosphoric acid r, 3, ^ i9t> -Tetrahydro- ^ isopropyl-g-niethyl-aH-indenoLr ^ -clpyriöin. Mp. A HyärpGhloriäs 180-183 ⁰ (decomp.)

^ The starting material can be produced as follows

00-9831 / t'921

BATH ORIGINAL

- 16 - 100-3042

20 g ^ -Methyl-l-phenyl-l-U-methyl-l ^^ o-tetrahydropyridyl ~ 4) propan-l-ol are treated with 200 ml of 47% hydrobromic acid at room temperature for 2 1/2 hours. The reaction mixture is evaporated to dryness, the residue is taken up in water and until it is strongly alkaline Reaction (pH 11) mixed with potassium carbonate. The released base is extracted with ether, the extracts dried over magnesium sulfate and evaporated. After purifying the residue by distillation at reduced Pressure is added to an ethereal solution of the base with the saturated ethereal solution of the calculated amount of maleic acid. The product which crystallizes spontaneously is purified by crystallization from acetone / ether. Smp. Des Hydrogen maleate 107-109 °.

Example 8: 2 - (> Butynyl) -1, 3 _i 4 _i Qb ₌ tetrahydro-5-methyl _:: 2H _:: indeno [1,2-c] pyridine

A suspension of 10 g of 1,3, 4,9t> tetrahydro-5-methyl-2H-indeno [l, 2-c] pyrldin and 8.2 g of potassium carbonate in 50 ml of dimethylformamide is added dropwise at a temperature of 50 ° with a solution of 8.8 g of l-mesyloxy-j5-butyne in 10 ml of dimethylformamide was added. The reaction mixture is stirred for 7 hours at 50 ° and then 150 ml of water are added. After saturation with potassium carbonate, the reaction mixture is extracted with benzene, the benzene extracts are dried over magnesium sulphate and the solvent is then evaporated off under reduced pressure. The remaining residue is dissolved in 20 ml of ethanol and the calculated amount of ethanolic hydrochloric acid is added to the solution. The crystals obtained after standing in the refrigerator for a long time are recrystallized again from ethanol for further purification. The pure 2 - (> butynyl) -1, 3,4,9b-tetrahydro-2H-indeno [1,2-c] pyridine hydrochloride with a melting point of 202-205 ° (decomp.) Is obtained in this way.

00983 1/1921

Example 9;

The substance can be made in the following ways: a) 200 ml of phosphoric acid are at a temperature of

40 ° in portions with 20 g of raw l-

a-methyl-a'-phenyl-4-pyridinemethanol is added. The mixture is then stirred for 40 minutes at βθ °, poured into water and made alkaline with sodium hydroxide solution. It is extracted repeatedly with chloroform, the combined extracts are washed with water, dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The residue is dissolved in ether * ^ j, the solution with an ethereal solution of the ^berechne-; offset ~ th amount of fumaric acid, and the precipitated hydrogen fumarate purified by recrystallization from ethanol. The pure 2-ethyl-l, 5,4,9b-tetrahydro-5-methyl'-2H-indeno [1,2-c] pyridine hydrogen furnarate melts at 156-158 °.,

The 1-ethyl-1,2,5,6-tetrahydroa-methyl-a-phenyl-4-pyridinemethanol used as the starting material can be obtained in the following ways:

A solution of 48 g of a-methyl-a-phenyl-4-pyridinemethanol in 50 ml of methanol are mixed with 188 g of ethyl iodide and if |

refluxed for 9 hours. It is evaporated to dryness in a rotary evaporator, the residue is dissolved in 1000 ml of methanol / water (4; 1) and, while stirring, 4 _Λ 6 g of sodium borohydride are added in portions, the temperature being kept at about J> 0 ° by cooling . The reaction mixture is stirred for 5 1/2 hours at 50 ° and then evaporated to dryness. The residue is taken up in water and extracted repeatedly with chloroform. After drying over magnesium sulfate, the combined extracts are evaporated. The ethanol solution of the residue is

009831/1921

- 18 - 100-3042

2002A99

Neten amount of fumaric acid added and evaporated. To Twice crystallization from ethanol gives the pure, neutral fumarate with a melting point of 172-174 °.

Analogous to the method described in Example 9 &) can the following connections can also be established:

1,2,4,9b-Tetrahydro-2-isobutyl-5-methyl-2H-indeno [1,2-c] pyridine

1 »5i ^» 9b-Tetrahydro-5-methyl-2-pentyl-2H-indeno [1,2-c] pyridine 1,5 » ² ^ 9b-Tetrahydro-5-methyl-2-octyl-2H-indeno [ 1,2-c] pyridine-1,2,4,9b-tetrahydro-5-methyl-2H-indeno [1,2-c]

pyridine.

b) The procedure is as described under a), except that 1-ethyl-1,2,3,6-tetrahydro-4- (a-methylenobenzyl) pyridine is used as the Starting product. The hydrogen fumarate of those mentioned in the title Compound melts at 156-158 °.

The 1-ethyl-1,2,3,6-tetrahydro-4- (ü-methylenberi2yl) pyridine used as the starting product can be produced as follows:

A solution of 20 g of 1-ethyl-1,2, ^ »ö-tetrahydro-a-methyla-phenyl-4-pyridinemethanol in 200 ml of 2N hydrochloric acid is heated to 100 ° for 1/2 hour. One evaporates under reduced Pressure to dryness and sets the base by treatment with potassium carbonate solution and extraction with ether free. After adding the calculated amount, the crude product is converted into maleic acid by crystallization from acetone / ether

009831/1921

_ 19 -

the pure l-ethyl-1,2,3,6-tetrahydro-4- (a-methylenebenzyl) pyridine hydrogen maleate from Srnp. 70-72 ° obtained.

Example 10; 1,3,4,9b-tetrahydro-2-isopropyl-5; n ^ ethyl _; ■ 2H-

The substance can be made in the following ways:

a) The procedure is as in Example 9 * but using 20 g of 1-isopropyl-1,2,3i6-tetrahydro-a-methyl-a ~ phenyl-4-pyridine-methanol in 200 ml of phosphoric acid and stirring for 90 minutes at 30 °. The Hydrogenfurnarat melts at 177-178 ⁰ after recrystallization from ethanol.

The starting material is analogous to the starting material in Example 9 from 50 g of a-methyl-a-phenyl- ^ pyridinemethanol, 427 g of isopropyl iodide in 1000 ml of isopropanol (17 hours reflux) and subsequent reduction with 56.8 g sodium borohydride in 800 ml methanol / v / water 4: 1 (6 hours 50 °).

Neutral fumarate: m.p. = 16I-162 ⁰ from ethanol / ether.

b) The procedure is as in Example 9 * but 10 g of l-isopropyl-1,2,3 * 6-tetrahydro-4- (a-methylenebenzyl) pyridine in 100 ml of phosphoric acid are used and the mixture is stirred for 90 minutes at room temperature. The hydrogen furnarate melts at 177-178 ° after recrystallization from ethanol.

The 1-isopropyl-1,2,3,6-tetrahydro-4- (a-methylenebensyl) pyridine used as the starting material is produced as follows:

A solution of 20 g of 1-isopropyl-1, 2,3..6-tetrahydro-amethyl-a-phenyl-4-pyridinemethanol in 200 ml of 2H hydrochloric acid

009831/1921 BAO ORIGINAL

- 20 - 100-3042

is heated to 100 ° for 1 hour. It is evaporated to dryness under reduced pressure and treated by treatment free the base with potassium carbonate solution and extraction with ether. After distillation of the crude product (bp l40 ° / 0.02 Torr) after adding the calculated amount of fumaric acid by crystallization from ethanol, the pure 1,2,3,6-tetrahydro-1-isopropyl-4- (a-methylenebenzyl) pyridine hydrogen fumarate is obtained obtained from m.p. 157-159 »5 °.

The following compounds can also be produced analogously to the process described in Example 10b):

2-ethyl-l, 3,4,9b-tetrahydro-5-methyl-2H-indeno [l, 2-c] pyridine, 1,3,4,9b-Tetrahydro-2-isobutyl-5-methyl-2H-indeno [1,2-c] pyridine,

If3,4,9b-tetrahydro-5-methyl-2-pentyl-2H-indeno [1,2-c] pyridine,

l »3» 4,9b-tetrahydro-5-methyl-2-octyl-2H-indeno [l, 2-c] pyridine,

2- (2-Butynyl) -1, 3,4,9b-tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine.

Example 11: 1,3,4,9b-Tetrahydro-2-isobutyl-5-methyl-2H-indenofl, 2-c] pyridine

A suspension of 15 g of 1,3 »4,9b-tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine and 12.8 g of potassium carbonate in 100 ml of dimethylformamide is at a temperature of 60 ° A solution of 10.6 g of isobutyl bromide in 50 ml of dimethylformamide was added dropwise. The reaction mixture is stirred for 3 hours at 60 ° and then treated with 150 ml of water. After saturation with potassium carbonate, this becomes The reaction mixture was extracted with benzene, the benzene extracts were dried over magnesium sulfate and then the solvent evaporated under reduced pressure. The remaining residue is dissolved in 20 ml of Ethahol and the solution is added

009831/1921

the calculated amount of fumaric acid. The crystals obtained after standing in the refrigerator for a long time are recrystallized again from ethanol for further purification. Is obtained as the pure 1, j5,4,9b-tetrahydro-2-isobutyl-5-methyl ~ 2H-indeno [l, 2-c] pyridine-hydrogen fumarate, mp. 178-180 ^0th

The following compounds can also be prepared analogously to the process described in Example 11:

2-ethyl-l, 5,4,9b-tetrahydro-5-methyl-2H-indeno [l, 2-c] pyridine,

l> 5 »4,9b-tetrahydro-2-isopropyl-5-methyl-2H-indeno [l _i 2-c] pyridine.

Example 12; 1,3,4,9b-Tetrahydro-5-methyl-2-peiityl-2H-indeno

The procedure is as in Example 11, except that 8.7 g of l »3i4,9b-tetrahydro-5-methyl-2H-indeno [l, 2-c] pyridine, 7.8 g potassium carbonate and 9.5 g pentyl iodide in total 100 ml of dimethylformamide and the reaction mixture is stirred for 5 hours at 6o °.

The hydrochloride of the compound mentioned in the title melts at 222-224 ° after recrystallization from ethanol.

Example 13: l »3 _i i [i§b _I tetrahydro-5-methyl 2 _{:: :: octyl:; ::} 2H indeno

The procedure is as in Example 11, except that 8.0 g * 3 * 4,9b-tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine, 7 * 2 g of potassium carbonate and 8.4 g are used Octyl bromide in a total of 100 ml of dimethylformamide and the reaction mixture is stirred for 5 hours at 6o °.

The hydrochloride of the compound mentioned in the title melts at 211-214 °.

009831/1921

Example l4;

The procedure is as in Example 11, except that 18.5 g of 1,3,4,9b-tetrahydro-5-methyl-2H-indeno [l, 2-c] pyridine, 13.8 g potassium carbonate and 8.9 g l-chloro-2-butyne in total 150 ml of dimethylformamide and the reaction mixture is stirred for 7 hours at 50 °.

The hydrochloride of the compound mentioned in the title melts at 195-197 ° (decomp.) After recrystallization from methanol / Acetone.

Example 15: Ιι ^ ι ^ ΐ ^ i ^^ [1,2-c] pyridine

4.7 g l, 3,4,4a, 5 »9b-hexahydro-2,5,7-trimethyl-5 (2H) -indeno [l, 2-c] pyridinol are mixed with 50 ml of 2.7 N methanolic hydrogen chloride Boiled under reflux for 30 minutes. It is then evaporated in vacuo and the residue is crystallized twice from isopropanol. The hydrochloride of the compound mentioned in the title melts at 218-220 ° with decomposition.

The raw material is produced as follows:

The solution of 10g of 1,3,4,9b-tetrahydro-2,7-dimethyl-2K-indeno [1,2-c] pyridin-5-one in 50 ml abs. Tetrahydrofuran is added dropwise at -30 ° with 24 ml of 1.92 molar ethereal methyllithium solution added. The mixture is stirred for a further 3 hours at -20 °, then poured into 50 ml of saturated ammonium chloride solution and separates off the organic phase after the addition of ether. Shake out twice more with ether and evaporate after drying over magnesium sulphate and chromatographed the residue on silica gel. First, unreacted starting material is treated with chloroform, which contains 1 μS of methanol,

009831/1921

then the reaction product with chloroform / methanol 4: 1 eluted. After evaporation of the solvent remains 1,3,4,4a, 5,9b-Hexahydro ~ 2,5,7-trimethyl-5 (2H) indeno [1,2-c] pyridinol as a viscous oil that can be used without further purification.

Example 16; Ti

6.4 g of 7-chloro-1,3,4,4a, 5,9b-hexahydro-2,5-dimethyl-5 (2H) -indeno [1,2-c] pyridinol are mixed with 65 ml of 2.7 N methanolic i Hydrogen chloride refluxed for 30 minutes. Then it is evaporated to dryness in vacuo and the crystallized Residue twice from isopropanol. The hydrochloride of the compound named in the title melts at 225-226 ° Decomposition. It is hygroscopic and absorbs 1/2 mole of crystal water when lying in the air.

The starting material is prepared as follows: The solution of 20 g of 7-chloro-l, 3,4,9b-tetrahydro-2-methyl-2H-irideno [l_.2-c] pyridin-5-one in 100 ml Section. Tetrahydrofuran is added dropwise at -30 ° with 44 ml of 1.92 molar ethereal methyllithium solution. The mixture is stirred for a further 3 hours at -20 °, then 90 ml of saturated ammonium chloride solution is added dropwise with cooling and the mixture is extracted several times with ether. After drying over magnesium sulfate, it is evaporated and the residue is chromatographed on silica gel. First, unreacted starting material is eluted with chloroform containing 2% methanol, then the reaction product is eluted with chloroform / methanol 4: 1. After evaporation of the solvent there remains 7-chloro-1,3,4,4a, 5,9b-hexahydro-2,5-. dimethyl-5 (2H) -indeno [l, 2-c] pyridinol as a viscous oil, which is processed further without further purification.

009831/1921

Example 1 7 _; 7-ethyl-l, 5,4 , 9b-tetrahydro-2,5-dimethyl-2H-indeno [l _i 2-c] pyridine

A solution of 6.8 g of 7-ethyl-1,3,4, ha., 5> 9 ^ -hexahydro-2,5-dimethyl-5 (2H) -indeno [1,2-c] pyridinol in 100 ml 5N ethanolic hydrochloric acid is heated to boiling for 15 minutes. The solution is then concentrated to dryness and the residue, the hydrochloride of the compound mentioned in the title. recrystallized from isopropanol / ether. M.p. 220-225 °.

The 7-ethyl-1,3 »4,4a, 5» 9 ^D- hexahydro-2,5-dimethyl-5 (2H) -indeno [1,2-c] pyridinol used as starting material is prepared as follows:

a) 12.2 g of magnesium are mixed with 40 ml of abs. Tetrahydrofuran overlaid and etched with a few crystals of iodine. A solution of 9 ² > 3 g of p-ethylbromobenzene in 60 ml of abs is then added dropwise. Tetrahydrofuran and 100 ml of abs. Toluene so quickly that the reaction continues. The reaction mixture is then refluxed for a further 2 hours, the resulting Grignard solution is cooled to -15 ° and within 20 minutes with a solution of J53> 8 g of ethyl 1,2,3 * 6-tetrahydro-1-methylisonicotinate in 100 ml of abs. Toluene is added, the reaction mixture is then stirred for a further 5½ hours at -15 ° and then poured into a mixture of 200 g of ammonium chloride. Poured 200 ml of water and 200 g of ice. The aqueous phase is extracted three times with 200 ml of methylene chloride each time, the combined methylene chloride extracts are dried over magnesium sulfate and the solvent is completely distilled off under reduced pressure. The oily residue is distilled in a high vacuum, the 3-p-ethylphenyl-1-methyl-4-piperidinecarboxylic acid ethyl ester passing over at 146-15O ° / 0.06 Torr.

009831/1921

- 25 - 100-3042

b) A mixture of 4o, 5 g of 3-p-ethylphenyl-1-methyl-4-piperidinecarboiic acid ethyl ester and 320 g of polyphosphoric acid are heated under nitrogen in an oil bath at 180 ° for 30 minutes. The reaction mixture is then poured onto 1500 g of ice / water, while cooling with solid sodium hydroxide, it is alkaline placed and the aqueous phase extracted three times with 500 ml of diethyl ether each time. The combined ether extracts are dried over magnesium sulfate, purified over animal charcoal and the solvent is distilled off. The oily residue is distilled in a high vacuum, the 7-ethyll * 3i ^ i9b-tetrahydro-2-methyl-2H-indeno [1,2-c] pyridin-5-one passes at 147-15O ° / 0.2 torr.

c) To 10 g of 7-ethyl-1,3,4,9b-tetrahydro-2-methyl-2H-indeno

[l, 2-c] pyridin-5-one in 100 ml of abs. Aether is dripped under nitrogen 21.8 ml of a 4.4 igen essential Solution of methyllithium at -70 °. After stirring for 3 hours at the same temperature, the reaction mixture is poured to 90 ml of a saturated ammonium chloride solution and extracted three times with 50 ml of ether each time. The United Ether extracts are dried over magnesium sulfate, the The solvent is distilled off and the oily residue, the 7-ethyl-1,3,4,4a, 5,9b-hexahydro-2,5-dimethyl-5 (2H) -indeno [1,2-c] pyridinol by chromatography on silica gel (0.05-0.2 mm) of any starting material still present separated. After recrystallization from diisopropyl ether, the compound melts at 103-104 °.

Ex iel l · 8: 7-Fluoro _^: l, 3 »4,9b-tetrahydro-2H 2,5rdiΓrlethyl _Γ - indeno [1,2-c] pyridine

A solution of 6.3 g of 7-1 " ¹¹ IuOr-I ^ 4,4a, 5,9b-hexahydro-2,5-dimethyl-5 (2H) -indenoLl, 2 ~ c] pyridinol in 100 ml of 5N ethanolic shear Hydrochloric acid is heated to boiling for 15 minutes

009831/1921 BAD ORtOINAi.

- 26 - 100-3042

20 02A99

The solution is then concentrated to dryness and the The residue, the hydrochloride of the compound mentioned in the title, recrystallized from isopropanol. Srnp. 236-240 ° (dec.).

The 7-fluoro-1,3,4,4a, 5,9bhexahydro-2,5-dimethyl-5 (2H) -indeno [1,2-c] pyridinol used as starting material is made as follows:

a) 12.2 g of magnesium are covered with 40 ml of absolute tetrahydrofuran and etched iodine with some crystals. A solution of 87.5 g of 4-bromofluorobenzene in 60 ml is then added dropwise Section. Tetrahydrofuran and 100 ml of abs. Toluene so quickly that the reaction continues. Then you proceed like described in Example 1 a). The oily residue is distilled in a high vacuum, the 3-p-fluorophenyl-1-methyl-4-piperidinecarboxylic acid ethyl ester passes at 115-120 ° / 0.1 Torr.

b) A mixture of 40 g of jS-p-fluorophenyl-l-methyl - ^ - piperidinecarboxylic acid ethyl ester and 320 g of polyphosphoric acid is taken under Nitrogen heated in an oil bath at 180 ° for 30 minutes. Thereon the procedure is as described in Example 1 b). The oily residue is distilled in a high vacuum, the 7-fluoro-1,2,4,9b-tetrahydro-2-methyl-2H-indeno [1,2-c] pyridin-5-one at 122 ° / 0.1 torr.

c) To 17 g of 7-fluoro-l, 3, ² l, 9b-tetrahydro-2-methyl-2H-indeno [l, 2-c] pyridin-5-one in 150 ml of abs. 58.5 ml of a 4.4 / Sigen ethereal solution of methyllithium at -70 ° are instilled in ether under nitrogen. The procedure is then as described in Example 1 c). The combined ether extracts are dried over magnesium sulfate, the solvent distilled off and the oily residue containing 7-fluoro-l, 3,4, ^I IA, 5,9b-hexahydro-2,5-dirncthyl-5 (2H) indeno [l , 2-c] pyridinol from ether / pentane recrystallized Ll crt. 114-117 °.

009831/1921

BATH ORIGINAL

Example 19: 2-Benzyl _: -1,3,4 _i 9b-tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine

A suspension of 13 »5 · g 1 * 3, 4,9b-tetrahydro-5-methyl-2H-indeno [1,2-e] pyridine (base, prepared from the hydrochloride by treatment with potassium carbonate solution and extraction with chloroform) and 15.1 g of potassium carbonate in 70 ml of dimethylformamide are added dropwise at 60 ° with stirring with a solution of 15 * 0 g of benzyl bromide in 60 ml of dimethylformamide. The reaction is allowed to continue for 3 ^1/2 hours at 60 °, the reaction mixture is then poured into 1000 ml of 2% potassium carbonate solution and extracted repeatedly with benzene. The crude base remaining after the solvent has evaporated is dissolved in acetone and the calculated amount of ethanolic hydrochloric acid is added. The precipitated hydrochloride is recrystallized from methanol for purification. M.p. 224-226 ° (dec.).

Example 20t

A suspension of 18.0 g of 1,3,4,9b-tetrahydro-5-methyl-2H-indeno [1,2-c] pyridine hydrochloride and 28.1 g of potassium carbonate in 200 ml of dimethylformamide is added dropwise with stirring at 50 ° with the solution of 11.8 g of allyl bromide in 50 ml of dimethylformamide offset within 15 minutes. The reaction is allowed to continue for an hour at 50 ° and the mixture is poured onto it Reaction mixture in benzene. It is extracted three times with water, the organic phase is dried over magnesium sulfate and evaporated the solvent off. The residue is taken up in acetone. and mixed with the calculated amount of ethanolic hydrochloric acid. It is allowed to crystallize and the hydrochloride of the title substance is obtained with a melting point of 206-208 ° (decomp.).

009831/1921

^ Λ f

- 28 -

100-3042

R.

NR ₁

R,

R.

■ N-R,

Yes

R,

-NO ₁

R,

Ic

R.

NO

II

Ro OH

III

R ₃

NO:

IV

5 «6

009831/1921

100-3042

Cl-COOR ₇ V ya

R.

• N-C.ÖOH,

VI

•NO"

VII

VIII

R ₂ -Mg-X IX

R ₂ -Li

XI

009831/1921

100- ^ 042

R.

NR ₁

XII

R-

NO,

R ₂ OH XIII XIV

AlkylOOC

NR ₁ XV

MgBr

R. XVI

XVII

AlkylOOC

Cl-OC

XVIII

009831/1921

Claims (1)

Patent claims: 1 / Process for the preparation of new compounds of the formula I, in which R, for hydrogen, the benzyl group, an alkyl, alkenyl, or alkynyl group> R ₂ for a lower primary or secondary alkyl group and R-, for hydrogen, halogen or a stand lower alkyl group, where R, is not the methyl group when Rp is the methyl group and R ^, are hydrogen, characterized in that one a) Compounds of the formula II, in which R, for the benzyl group is an alkyl, alkenyl or alkynyl group, R _p and R-, have the above meaning, where R _{1 is} not the methyl group, if R ^ for the methyl group and R- , stand for hydrogen, or compounds of the formula IV, viorin R ₁ . and R ^, have the above meaning, Rp. and Rg each denote hydrogen or a lower alkyl group, while R ₁ does not denote the methyl group when R ^, R, - and R ^ all represent hydrogen, to the compounds of the formula Ia, in which R-, Rp and R ^ have the above meaning, eyclisiert, or b) Compounds of the formula Ib, wherein R ₁ . represents the methyl or benzyl group, and R ₂ and R _{7 have the} above meaning, converted into the compounds of the formula Ic, in which Rp and R ^ have the above ^ meaning, by cleavage of the methyl or benzyl group, or - c) compounds of the formula Ic with compounds of the formula III in which Rr has the above meaning and Y stands for the SMurerest of a reactive ester> where R ₁ in ^ the compounds of the formula III is not the methyl group, 009831/1921 2002A99 -52- 100-3042 if in the compounds of formula Ic JU for the methyl group and PU stands for hydrogen, condensed to give compounds of the formula Ia. 2. The method according to claim 1, variant a), characterized in that that the cyclization is carried out with strong acids. J. The method according to claim 1, variant b), characterized in that that the compounds of the formula Ib with a chloroformic acid ester of the formula V, wherein FU is a lower Alkyl group, which means phenyl or benzyl group, converts to the corresponding urethanes and these by acidic or alkaline hydrolysis converted into the compounds of the formula Ic. 009831/1921 - ■■ '■■ 1 = 2 = 1- 4. Compounds of the formula I in which R, for the ~ Benzy! Group, Hydrogen, an alkyl, alkenyl or alkynyl group, Rg for a lower primary or secondary alkyl group and R-. stand for hydrogen, halogen or a lower alkyl group, where R, does not mean the methyl group when Rp stands for the Methyl group and R- stand for hydrogen. 5. 1 * 3 * 4.9t ⁾ -Tetrahydro-2-isopropyl-5-niethyl-2H-indenotl, 2 ~ c] pyridine. 6. Remedies, characterized in that 'it is whole or partially compounds of the formula I in which R, for the benzyl group, Hydrogen, an alkyl, alkenyl or alkynyl group, Rg for a lower primary or secondary alkyl group and R_, stand for hydrogen, halogen or a lower alkyl group, where R- does not mean the methyl group, when Rg stands for the methyl group and R- for hydrogen, contains, ' 3700 / SR / SH. SOHZ AG. I) i) 8 3 1/10 BADORtQlNAL