US3627773A - 1,3,4,4A,5,9B-HEXAHYDRO-5-PHENYL-2H-INDENO{8 1,2-c{9 -PYRIDINES - Google Patents

Abstract

D R A W I N G

Description

ilnited States Patent [7 2] inventors Anton Ebnother 2 Barenbrunnenweg, 4144 Arleshelm; Jean-Michel Bastian, 5 Rhelnparkstrasse, 4127 Birslelden; Fulvio Gadlent, 45 Baselerstrasse, 4127 Birsielden, all 01 Switzerland [2]] Appl. No. 33,499 [22] Filed Apr. 30, 1970 [45] Patented 1971 A [73} Assignee Sandoz Ltd.

, Basee, Switzerland [32] Priorities May 6, 1969 [33] Switzerland [31] 6913/69;

June 9, 1969, Switzerland, No. 8747/69; Dec. 11, 1969, Switzerland, No. 18423/69; Feb. 5, 1970, Switzerland, No. 1650/70 [54] 1,3,4,4A,5,9B-HEXAHYDRO-S-PHENYL-ZH- lNDENO[1,2-C]-PYRIDINES 19 Claims, No Drawings 424/267 [51] int. Cl. C07d 39/00 [50] Field of Search 260/293.4

[56] References Cited I UNITED STATES PATENTS 3,408,353 10/1968 Jucker et a1. 260/293 7 3,462,443 8/1969 Paragamian 260/294 3,497,517 2/1970 Jucker et al. 260/293 3,499,895 3/1970 .lucker et a1. 260/247.5 3,513,168 5/1970 Jucker et a1. 260/290 3,573,316 3/1971 Ebnother et a1. 260/294.7

Primary Examiner-Henry R. J iles Assistant Examiner-G. Thomas Todd Attorneys-Gerald D. Sharkin, Robert S. Honor, Frederick H.

Weinfeldt, Richard E. Vila and Walter F Jewell ABSTRACT: The invention concerns new (4aRS,5SR,9bSR)-,

and (4aRS ,5 RS ,9bRS)-l ,3 ,4,4a,5 ,9bhexahydro-5-phenyl-2l-l-indeno[l ,2-c]pyn'dines of the l ,3,4,4A,5,9B-l'lEXAHYDRO-5-PHENYL-2H-HQDENOI l ,2- C ]-PYRIDINES IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS The present invention relates to new (4aRS,5SR,9bSR)-, (4aRS,5SR,9bRS)- and (4aRS,5RS,9bRS)- l ,3,4,4a,5,9b-hexahydro-5-phenyl-2H-indeno[ 1,2-c1pyridines of formula I,

in which R signifies hydrogen, a lower alkyl radical, fluorine,

bromine or chlorine, and each of R, R and R signifies hydrogen, a lower alkyl radical,

fluorine, bromine, chlorine, a lower alkoxy, a lower alkylthio or the trifluoromethyl radical, and to a process for the production thereof.

Compounds of formula I have the fundamental structure represented by fonnula lX.

The compounds I have three centers of asymmetry in the tricyclic ring system, i.e. the carbon atoms in positions 4a, 5 and 9b. Therefore, theoretically there may exist four isomers, which differ from each other by the position of the hydrogen atoms at the centers of asymmetry.

The nomenclature of R. S. Cahn, C. K. lngold and V. Prelog, Angewandte Chemie 78, 413 1966), is used.

Name Position of the hydrogen atoms (4aRS,5SR,9bSR) 4a/9b trans 4a/5 trans (MRSJSRBbRS) 40/9! cis 441/5 trans (MRSJRSfibRS) 4a/9b cis 4a/5 cis According to the invention the new indenopyridine derivatives of formula I are obtained by reacting a compound of formula ll,

III

in which R, and R have the above significance, and X signifies the acid radical of a reactive ester,

in a solvent which is inert under the reaction conditions and in the presence of a basic condensation agent.

When the put-pow of the invention is effected using one isomeric form of a compound of formula II as starting material, then the same isomeric form of a compound of formula I is obtained.

The invention is explained in detail below:

A compound of formula ll in a solvent which is inert under the reaction conditions, e.g. in a di(lower)alkyl-carboxylic acid amide such as dimethyl formamide, or in a lower alcohol such as ethanol, or in a chlorinated hydrocarbon such as chloroform, or in a ketone such as acetone, is reacted with a compound of formula III, preferably at an elevated temperature between 60 and C., in the presence of a basic condensation agent, the reaction having a duration of from onehalf to 24 hours, but normally 1 to 4 hours. Examples of suitable basic condensation agents are: alkali metal carbonates such as sodium or potassium carbonate, or lower tertiary alkyl amines such as triethyl amine, or an excess of an equivalent of the compound of fonnula II.

The lower alkyl radicals represented by the symbol R preferably have one to four, especially one to two carbon atoms, the lower alkyl, alkoxy and alkylthio radicals represented by the symbols R,, R, and R preferably have one to four, especially one to two carbon atoms.

One process for the production of the compounds of formula ll is characterized in that a compound of formula Ila.

nifies the methyl or benzyl radical, is reacted with an ester of chloroformic acid offormula, 7

in which R, signifies a lower alkyl radical, a phenyl or benzyl radical, to give the corresponding urethane, and these urethanes are subsequently hydrolyzed.

The reaction of a compound of formula lla with a chloroformic acid ester of formula [V is preferably effected in a solvent which is inert under the reaction conditions, e.g. anhydrous benzene, and at the boiling temperature of the reaction mixtire. For this reaction chloroformic acid esters of formula lVa,

in which R, signifies a lower alkyl radical, are especially preferred as starting materials. The resulting urethanes may either be purified in manner known per se, or used as such for the subsequent urethane splitting.

The removal of the COOR, radical from the urethanes may be effected with an acid, e.g. a mineral acid such as hydrochlo- .l'iC acid, or a base, e.g. an alkali metal hydroxide such as potassium or sodium hydroxide, in a lower alcohol such as n-buitanol, preferably at the boiling temperature of the reaction mixture. Hydrolysis with an alkali metal hydroxide may result in a total or partial rearrangement of the (4aRS,5RS,9bRS) compounds into (4ARS,5SR,9bRS) compounds.

in which R, R, and R, have the above significance, or b. cyclizing a compound of formula Va,

3.1- I H OH I Q R1 Va in which R, and R, have the above significance, i to produce a compound of formula lib, 5

- i Nm in which R, and R, have the above significance, or 1 c. reducing a compound of formula IV,

, l N- i i 1 VIZ 1 in which R,, R, and R, have the above significance,

to produce a (4aRS,SRS,9bRS) compound of formula lla, or i d. heating a (4aRS,5RS,9bRS) compound of formula [la in alkaline medium to produce a (4aRS,SSR,9bRS) compound; of formula Ila Processes (a) and (b) mainly yield (4aRS,5S R,9bS R and (4aRS,5SR,9bRS) compounds, the relationship of the isome being dependent on the nature of the substituents R, and R,

The cyclization in accordance with processes a and b may be effected with polyphosphoric acid, optionally in the. presence of a solvent which inert under the reaction condi tions, e.g. a cyclic hydrocarbon such as benzene, toluene, xylene or tetralin, for a period of between l and 24 hours at a, temperature between and C.

A process used for the production of compounds of formula V i atae rizsd n h t a nm p i s t qt aalaii ao in which R, and R have the above significance,

VII

is gactedwith an organometallic compound of formula Vlll,

or of formula VIIIa,

-CH2-Li VIIIa 1 in which R, has the above significance, and X signifies chlorine or bromine,

in a solvent which is inert under the reaction conditions, and

the resulting complex ishydrolyzed.

For the reaction of compounds of formula Vll with compounds of formula Vlll or Vllla a cyclic or open-chain ether such as diethyl ether or tetrahydrofuran may, for example, be used as solvent which is inert under the reaction conditions, and the reaction is preferably effected at a temperature between 20 and 70 C. Benzyl magnesium bromide or benzyl lithium may, for example, be used as organometallic compound of formula VIII or Vllla.

Compounds of formula Vll may be produced by reacting a Z-phenyl-acrylic acid ester appropriately substituted on the phenyl radical with a 3-aminopropionic acid ester appropriately substituted on the nitrogen atom, cyclizing the addition product by treatment with a basic condensation agent,

and hydrolyzing and dec'arboxylating the resulting compound Compounds of formula Va may be obtained by reacting a compound of formula X,

in which R, and X have the above significance, in a solvent which is inert under the reaction conditions, hydrolyzing the reaction product and reducing the resulting compound of formula X1,

l XI

in which R, and R, have the above significance. i ssemsavnaieifi ni l a their vhamwbsica'ly lUlOM 0l87 tolerable acid addition salts are useful because they possess pharmacological activity in animals. More particularly, the compounds are useful as serotonin-antagonists, as indicated by the serotonin toxicity test in guinea pigs. The dosage administered will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, satisfactory results are obtained in test animals at doses from about 0.5 to about mg./kg. of body weight. As indicated by the said serotonin-antagonist proper-. ties, the compounds can be employed in the treatment of migraine, the total daily dose for larger mammals being from about 1 to about 30 mg. Divided dosage forms suitable for oral application contain about 0.3 to about 15 mg. of the compound admixed with a solid or liquid carrier or diluent.

The compounds are furthermore useful in the treatment of thrombosis as indicated by their properties in inhibiting hematoblast aggregation, this property being illustrated in the ADP-induced hematoblast aggregation test carried out in vitro. Doses administered will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, indicated doses in warm-blooded animals are between about 0.5 to about 10 mgJkg. body weight. For larger mammals the total daily dosage is in the range of from about 10 to about 400 mg., and dosage forms for oral application contain from about 3 to about 200 mg. of the compound admixed with solid or liquid carrier or diluent.

The compounds of fonnula l or their physiologically tolerable acid addition salts may be used as medicaments on their own or in the fonn of appropriate medicinal preparations with pharmacologically inert adjuvants.

Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes or in a manner analogous to the processes described herein or to processes known per se.

in the following nonlimitative examples all temperatures are indicated in degrees Centigrade and are uncorrected.

EXAMPLE I A solution of 7.9 g. of phenacyl chloride in 50 cc. of dimethyl formamide is added dropwise at room temperature to a suspension of 14.4 g. of (4aRS,5SR,9bSR)-l,3,4,4a,5,9b-

hexahydro-7-methyl-5-p-tolyl-2H-indeno[ l,2-c]pyridine and 10.9 g. of sodium carbonate in l00 cc. of dimethyl formamide. The reaction mixture is subsequently heated in an oil bath of 130 for 2 hours, is then cooled to room temperature and poured on 500 g. of ice. The aqueous phase is shaken out thrice with 500 cc. amounts of diethyl ether, the ether phase is washed with water, dried over magnesium sulfate, purified with animal charcoal and concentrated to a volume of about 200 cc. at reduced pressure. After cooling in a refrigerator the title compound crystallizes. m.p. 85-86.

The following compounds of formula I may be obtained in a manner analogous to that described in example 1 (examples 2 to [7):

EXAMPLE l8 8.5 g. of anhydrous sodium carbonate are added to a solution of 10.0 g. of (4aRS,5SR,9bSR)-l,3,4,4a,5,9b-hexahydro- 5-phenyl-2H-indeno[ l ,2-c]pyridine in cc. of N,N-dimethyl formamide, and the mixture is heated to l2.4 g. of phenacyl chloride are added portionwise at the same temperature during the course of 2 hours, the reaction mixture is stirred at the same temperature for a further 30 minutes, is cooled to 20 and is poured into 200 cc. of a 20 percent common salt solution. The precipitated product is extracted with methylene chloride, the organic solution is washed with water, dried over sodium sulfate and the solvent is removed by distillation at reduced pressure. The oily residue is then dissolved in 100 cc. of ethanol, the pH value of the resulting solution is ad- .justed to 3 with hydrochloric acid in ethanol, and 10 cc. of ether are added. The mixture is allowed to stand at 0, whereupon the precipitated hydrochloride of the title compound, haying a m.p. of 250-2 5 5 is filtered off.

This hydrochloride is suspended in 100 cc. of water and 300 cc. of methylene chloride, the suspension is made alkaline with a caustic soda solution, the organic phase is separated and the aqueous phase is again shaken out twice with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and the solvent is removed by evaporation at reduced pressure. The residue is crystallized ahydro-Z-phenacyl-S-phenyl-ZH-indeno[ l,2-c]pyridine, having a m.p. of l03.3-105: i .s obtained. F U m The compounds used as starting materials may be obtained as follows:

EXAMPLE l9 (4aRS,5 SR,9bSR l ,3,4,4a,5 ,9b-hexahydro-7-methyl-5-ptolyl-2H-indenol l ,2-clpyridine (for example l A solution of 28 g. of chloroforrnic acid ethyl ester in 40 cc. of benzene is added dropwise at room temperature during the course of 10 minutes to a solution of 19 g. of (4aRS,5SR,9 bSR l ,3 ,4,4a,5,9b-hexahydro-2,7-dimethyl-5-p-tolyl-2H-indeno[ l,2-c]pyridine in cc. of benzene. The reaction mixture is then heated at reflux for 3 hours, is subsequently cooled to 20 washed with 2 N hydrochloric acid and with water and dried over sodium sulfate. After removing the solvent by distil- ;lation at reduced pressure, the residue is dissolved in l50 cc. of n-butanol, 73 g. of potassium hydroxide are added and the mixture is stirred in an oil bath of 130 for l zfihours. After cooling to 70 the mixture is diluted with 300 cc. of benzene Configuration Phys. chem. constants g mmmnmmmmm a: cum mmmmmmmrmmmm 4aRS, 5BR, QbSR-.. M.P. 95-100".

4e38, 6BR, QbRS... M.P. of the hydrogen fumarate 190491". 4aRS, 58R, 9bSR M.P. 138-139".

4aRS, 5BR, ObSR... M.P. 147-148.

MRS, 5BR, ObSR... M.P. 128-129".

MRS, 5BR, QbSR-.. M.P. 106407".

4sRS, 58R, 9bSR M.P. 121-123".

aRS, 58R, QbSR... M.P. 127-120".

aRS, 58R, DbSR-.. M.P. 112-114.

4aRS, 55R, QbSR... M.P. 108-110".

4aRS, 5R8, QbRS... M.P. of the hydrochloride 237240 (decom.). 4e38, 5BR, 9bRS comp.). aRS, 58R, 9bRS... M.P. of the hydrogen fumarate 4aRS, 5SR,9bRS M.P. of the hydrogen comp.). 4aRB, 5SR,9bRS M.P. of the hydrogen fumarate 192194 (deoomp. 4-0CH 4aRB,5SR,9bRS M.P. of) the hydrogen furnarate 210212 (de- M.P. of the hydrogen lumarate 193-196" (de- (decom fumarate 197202 81ocomp.

- (4aRS,5RS,9bRS)-1,3,4,

and washed with water until neutral. After drying over mag,- nesium sulfate the solvent is removed by distillation, whereby the title compound distils over at l94/0.01 mm. of Hg. The compound obtained in crystalline form from ethanol/water (6:4) has a m.p. of45-46.

The following compounds of formula 11 may be obtained in a manner analogous tothat described in example 19 (examples 20 to 23):

EXAMPLE 28- (4aRS,5RS,9bRS )-1 ,3,4,4a,5,9b-hexahydro-2-methyl-5- phenyl-2l-l-indeno{ l,2-c]pyridine (for examples 24 and 29) a solution of 30 g. of l,3,4,9b -tetrahydro-2-methyl-5-phenyl-2-indeno[l,2-c]pyridine in 200 cc. of glacial acetic acid is i elsssatslli ea fil how with? rlst s Oxide catalyst and R2 Configuration Phys. chem. constants For Ex.

4-01 4aRS, 58R, QbSR... B.P. 210 /1106 mm. of Hg 2. 4Cl 4aRS, 68R, SbRS... B.P. 175l80/0.01 mm. of Hg 3, 15, 16, 17. 4-011; 4aRS, 5SR, 9bRS M.P. of the hydrogen iumarate 210213 14. H 4aRS, 5SR, QbSR... M.P. of the hydrochloride 292-29 4-11 and 18.

EXAMPLE 2 hydrogen at an initial pressure of 6 atmospheres. The catalyst (4aRS,5RS9bRS)-l ,3 ,4,4a,5,9b-hexahydro-5-phenyl-2H- indeno[ l ,2-c ]pyridine (for example 12) A solution of 12 g. of (4aRS,5RS,9bRS)-l,3,4,4a,5,9b-hexahydro-2-methyl-5-phenyl-2-indeno[ l ,2-c1pyridine in 120 cc. of absolute benzene is added dropwise at 70--75 during the course of half an hour to a solution of 15 g. of chloroforrnic acid ethyl ester in 60 cc. of benzene. The mixture is then boiled at reflux for 2%hours, is cooled, some precipitated 5,9b-hexahydro-2-methyl-5- phenyl-ZH-indenoI l ,2-clpyridine hydrochloride is filtered off and the filtrate is concentrated by evaporation. The resulting oily, crude (4aRS,5RS,9bRS)-2-ethoxycarbonyl-l,3,4,4a,5,9; b-hcxahydro-2-mcthyl-5-phenyl-2l-l-indeno[ 1 ,2-c]pyridine is boiled at reflux for 16 hours with a mixture of 75 cc. of glacial acetic acid and 75 cc. of concentrated hydrochloric acid. The mixture is evaporated to dryness in a vacuum, the residue is dissolved in a small amount of isopropanol and ether is added, whereupon the hydrochloride of (4aRS,5RS,9 bRS)- 1 ,3,4,4a,5 ,9bc-hexahydro5-phenyl-2l-l-indeno[ 1 ,2-c ]pyridine crystallizes. it is recrystallized from isopropanol/ethcr and then has a m.p. of 230-232 (decomp.).

The following compound of formula 11 may be obtained in a manner analogous to that described in example 24 (example 25):

is then filtered off, the solution is concentrated by evaporation in a vacuum, the residue is divided between a dilute caustic soda solution and methylene chloride, the methylene chloride solution is dried over magnesium sulfate and concentrated by evaporation. The resulting base is dissolved in isopropanol and a solution of hydrogen chloride in ether is added, whereupon (4aRS,5 RS,9bRS )-1 ,3 ,4 ,4a,5 ,9b-hexahydro-2-methyl-5-phenyl-2l-l-indeno[1,2-c1pyridine hydrochloride crystallizes. After recrystallization from isopropanol the compound has a m.p. of 270-272+ (decomp.

EXAMPLE 29 (4aRS,5SR,9bRS)-l,3,4,4a,5,9b-hexahydro-2-methyl-5- phenyl-ZH-indenol l,2-c]pyridine (for example 25) Exam- For ple R1 R2 Configuration Phys. chem. constants Ex. 25.-." H H 4sRS, ESR, QbRS... M.P. of the hydrochloride 287289 (dec.) 13

EXAMPLE 26 (4aRS,5RS,9bSR)- l ,3,4,4a.5 ,9b-hexadro-2,7-dimethyl-5-ptolyl-2Hindeno[ l ,2-c]pyridine (for example 19) deno[ 1,2-c1pyridine distils over at 165-l70/0.l mm. of H The compound obtained in crystalline form from acetonitrilc' has a m.p. of 106-l07.

The following compound of formula lla may be obtained in yl-2l-l-indeno[ l,2-c]pyridine hydrochloride crystallizes. After crystallization from isopropanol the compound has a m.p. of 287289 (decomp.

EXAMPLE 3O (4aRS,5SR,9bSR)-7-chloro-5 -p-chlorophenyl-l ,3,4,4a,5,9b-

hexahydro-Z-methyl-ZH-indeno[ l ,2-c1pyridine (for example i g. of 4-(p-chloro-a-hydroxybenzyl)-3-p-chlorophenyll-methyl-piperidine are added portionwise within 15 minutes to 800 g. of polyphosphoric acid preheated to The reaction mixture is then stirred at the same temperature for 8 hours and is subsequently poured on a mixture of 3 kg. of ice and 1,500 cc. of methylene chloride while stirring. The mixture is subsequently made neutral with a concentrated caustic soda solution, the organic phase is separated and the aqueous phase is shaken out thrice with 1,000 cc. amounts of methylene chloride. The organic extracts are washed with a manner analogous to that described in example 26 (example 70 water, dried over yfpw y and the V V F -Fn r? m by MRS, 53R, llbSR M.P. 83

I distillation at reduced pressure. The oily residue is distilled in a high vacuum, whereby the primary fraction distils over as an oil at l95-200/0.0l mm. of Hg. The portion obtained in crystalline form from acetonitrile is a mixture of isomers having a m.p. of 95-l A fumarate, having a m.p. of 224225 is obtained from this mixture with fumaric acid in ethanol. This salt is divided between diethyl ether and a 2 N caustic soda solution, the ether phase is dried over magnesium sulfate and the solvent is removed, whereby (4aRS,5SR,9bSR)-7- chloro-S-p-chlorophenyll ,3 ,4,4a,5 ,9b-hexahydro-2-methyl- 2H-indeno[ l,2-c]pyridine is obtained. After recrystallization from n-hexane the compound has a m.p. of l l2-l 14.

EXAMPLE 31 l 5 (4aRS,5SR,9bRS )-7-chloro-5-p-chlorophenyll ,3,4,4a,5,9b hexahydro-2H-indeno[ l,2-c]pyridine (for example 21 The process is effected as described in example 30. After separating the fumarate, the mother liquor of the fumarate is completely concentrated by evaporation at reduced pressure and the residue is divided between diethyl ether and a 2 N caustic soda solution. After drying and concentrating the ether phase, the residue is recrystallized from n-hexane, whereby (4aRS,5SR,9bRS)-7-chloro-S-p-chlorophenyll ,3 ,4,4a,5 ,9b-hexahydro-2-methyl-2H-indenol l ,2-c ]pyridine, having a m.p. of l22l25, is obtained.

EXAMPLE 32 (4aRS,5SR,9bRS l ,3 ,4,4a,5 ,9b-hexahydro-2,7 iimethyl-5- p-tolyl-2l-l-indeno[ l ,2-c ]pyridine (for example 22) EXAMPLE 33 4-(a-hydroxy-p-methylbenzyl l -methyl-3-p-tolyl-piperidine (for example 26) a. 7.3 g. of magnesium are covered with a layer of absolute tetrahydrofuran, and a few crystals of iodine are added. A solution of 51.3 g. of p-bromotoluene in 100 cc. of absolute tetrahydrofuran is then added dropwise at such a rate that the reaction is kept going. The reaction mixture is then heated at reflux for 1% hours, and a solution of 16.9 g. of l,2,3,6- tetrahydro-l-methyl-isonicotinic acid ethyl ester in 50 cc. of 7 absolute tetrahydrofuran is added to the resulting Grignard solution at reflux temperature. The reaction mixture is subsequently heated at reflux for one hour and 15 minutes, is then cooled to 10 and added with stirring to a mixture of 40 g. of ammonium chloride, 50 cc. of water, 50 g. of ice and 500 cc. of methylene chloride. After separating the organic phase, the aqueous phase is again shaken out thrice with 300 cc. of 65 methylene chloride, the combined extracts are dried over magnesium sulfate and the solvent is removed by distillation. The oily residue is distilled in a high vacuum, whereby l-. methyl-4-p-toluoyl-3-p-tolyl-piperidine distils over at 205-' 2l0/0.05 mm. of Hg. The compound obtained in crystalline form from diethyl ether/pentane has a m.p. of l07l08.

b. A solution of 28.5 g. of sodium borohydride in 100 cc. of water, stabilized with 6 cc. of a 5 N caustic soda solution, is added dropwise to a mlution of 92.l g. of l-methyll-ptoluoyl-3-p-tolyl-piperidine in 600 cc. of etha ioljyitltirrgg minutes, at such a rate that the internal temperature does not exceed 40. The reaction mixture is then stirred at 70 for Slhours, is subsequently evaporated to dryness at reduced pressure, and the residue is divided between 300 cc. of water and 300 cc. of chloroform. The organic phase is separated and the aqueous phase is again extracted twice with cc. amounts of chloroform. The combined extracts are dried over magnesium sulfate, the solvent is removed by distillation at reduced pressure, and the residue, is. 4-( a-hydroxy-p-methylbenzyl)-l-methyl-3-p-tolyl-piperdine, is recrystallized from diethyl ether/pentane. m.p. l20-l 23.

The following compounds of formula Va may be produced in a manner analogous to that described in example 33 (examples 34 and 35):

EXAMPLE 34 (for example 30 and 31) a. 4-p-chlorobenzoyl-3-p-chlorophe nyl- 1 -methylpiperidine,m.p. ll8-l20.

b. 4-(a-hydroxy-p-chlorobenzoyl-3-p chlorophenyll methyl-piperdine, m.p. 1 42.

EXAMPLE 35 (for example 27) 4-benzoyl-l-methyl-3-phenyl-piperidine, tap.

' /0.05 mm. of Hg.

b. 4-(a-hydroxybenzyl)-l-methyl-3-phenyl-piperidine, rn.p. l53-l 57.

EXAMPLE 36 (4-aRS,5RS,9bRS l ,3,4,4a,5 ,9b-hexahydro-2,7-dimethyl-5- p-tolyl-2H-indeno[ l,2-c]pyridine (for example 3 2) a. A solution of 42 g. of 4-bromotoluene in 350 cc. of absolute diethyl ether is added dropwise within 10 minutes in an atmosphere of nitrogen to 3.5 g. of lithium wire cut in small pieces in 350 cc. of absolute diethyl ether. The mixture is subsequently heated at reflux for lihours, is then cooled to --70 and a solution of 26.9 g. of l,3,4,9b-tetrahydro-2,7-dimethyl- 2l-l-indeno[l,2-c]pyridin-5(4aH)-one in 250 cc. of absolute diethyl ether is added within 30 minutes. Theinternal temperature of the solution is allowed to rise to 0, stirring is continued at this temperature for 4 hours, and the reaction mixture is poured on 1,500 g. of ice and 1,500 g. of water, the aqueous phase is extracted with 6,000 cc. of chloroform, the extract is dried over magnesium sulfate and is almost completely concentrated by evaporation at reduced pressure.

deno[l,2-c]pyridinol crystallizes from chloroform diethyl ether. m.p. 2 l02l2.

b. 30.7 g. of l,3,4,4a,5,9b-hexahydro-2,7-dimethyl-5-p tolyl-5(2H)-indeno[l,2-c]pyridinol are heated at reflux for 2 hours in 200 cc. of 2.5 N hydrochloric acid in methanol. The solution is then completely concentrated by evaporation at reduced pressure. l,3,4,9b-tetrahydro-2,7-dimethyl-5-p-tolyl- 2-indeno[l,2-c]pyridine hydrochloride, having a m.p. of 243245 (decomp. is obtained from alcohol/diethyl ether.

The free base is obtained by dividing the hydrochloride between a 2 N caustic soda solution and chloroform, drying the chloroform extract over magnesium sulfate and concentrating at reduced pressure to,a light yellow oil.

c. A solution of 26.4 g. of l,3,4,9b-tetrahydro-2,7-dimethyl- 5-p-tolyl-2H-indeno[ l,2-c]pyridine in 200 cc. of glacial acetic acid is hydrogenated with 0.6 g. of platinum oxide at 40 and 4 atmospheres for 42 hours. After reduction is complete, the catalyst is filtered off and the filtrate is completely concentrated by evaporation at reduced pressure. The residue is :talren up in 300 cc. of water, is made alkaline with dilute :caustic soda solution and shaken out thrice with 200 cc. amounts of diethyl ether. The combined ether extracts are washed with water until neutral, are dried over magnesium sulfate and the solvent is comiplaely removed by distillation.

The oily residue is then converted into the hydrochloride with the calculated amount of hydrochloric acid in ethanol. m.p. 2 2 s same EXAMPLE 3 7 (4aRS,5SR,9bSR)-1,3 ,4,4a,5 ,9bhexahydro-2-methyl-5- phenyl-2l-l-indenoI 1 ,2-c ]pyridine (for example 23) 2. The compound of claim i. which is (4aRS,5SR,9bSR)- 1 ,3 ,4-,4a,5 ,9b-hexahydro-7-methy1-2- a. 4-benzy1-l-methy1-3-pheny1-piperidinol-4. 15.6 g. of magnesium are covered with a layer of 120 cc. of absolute ether, a crystal of iodine and'about 5 cc. of a solution of 81.4 g. of benzyl bromidein 400 cc. of absolute other are added, and the mixture is heated until the reaction commences. The remainder of the above benzyl bromide solution is then added dropwise at such a rate that the solution boils continuously, and the solution is subsequently heated at reflux! for a further 4 hours. A solution of 61.6 g. of 1-methyl-3-phen-' y1-piperidone-4 in 300 cc. of absolute ether is added dropwise at to this benzyl magnesium bromide solution while stirring well, the reaction mixture is stirred at room temperature for a further 3 hours and is then allowed to stand at room tem-f perature over night. The reaction mixture is then poured with stirring into a solution of 240g. of ammonium chloride in 1,500 cc. of ice water, the entire material is filtered through, diatomaceous earth, the organic phase is separated and the aqueous solution is again shaken out with ether. The com-. bined ether solutions are washed with water, dried over potassium carbonate and concentrated by evaporation at reduced. pressure. The residue is crystallized from n-hexane and yields 4-benzy1'l-methy13-phenyl-piperidinol-4, having a m.p. of 102-l04. b. (4aRS,5SR,9bSR)-1,3,4,4a,5,9lrhexahydro-2-methy1-5- pheny1-2-indeno[ 1 ,2-c lpyridine.

A mixture of 200 g. of polyphosphoric acidand 200 cc. of xylene is preheated to 130, and a solution of 19 g. of 4- benzyl-1-methy1-3-phenyl-piperidinol-4 in 40 cc. of xylene is added within 30 minutes while stirring vigorously. The reac-S tion mixture is stirred at 130 for 10 minutes, is cooled to 90 and poured on 600 cc. of ice water. The organic phase is separated, the aqueous portion is washed once with ether and is then saturated with potassium carbonate. The basic aqueous suspension is extracted with methylene chloride, the extract is washed with water and dried over potassium carbonate, whereupon the solvent is removed by evaporation at reduced, pressure. The residue is distilled in a high vacuum, wherebyi (4aRS,5S1R,9bSR)- 1 ,3,4,4a,5,9b-hexahydro-2-methyl-5-phenyl-2H-indeno[ 1,2-c1pyridine distils over as an oil at 150 155/O.3 mm. of Hg. m.p. 82-83 from hexane.

What is claimed is:

l. A (4aRS,5S R,9bSR)-, (4aRS,5SR,9bRS or (4aRS,5R; S,9bRS)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2l-l-indeno[ 1,2- c]pyridine of the formula:

wherein R is hydrogen, lower alkyl, fluorine, bromine or chlorineend ash 9? a- Ra an Metastases-lawman 4. The compound of claim 1 which is 3. The compound of claim 1 which is (4aRS,5SR,9bSR)-7-chloro-5-p-chlorophenyl- 1 ,3,4,4a,5 ,9b hexahydro-Z-phenacyl-ZH-indeno[ 1,2-

(4aRS,5SR,9bRS)-7-chloro-5-p-chloropheny1- l ,3 ,4,4a,5,9h-hexahydro-Z-phenacyl-2H-indeno1 1 ,2- .Eh 5. The compound of claim .1 which is (4aRS,5SR,9bSR)-2-( 4bromophenacy1)- 1 ,3,4,4a,5 ,9b-

he tahydro-S-pheny1-21-l-indeno[ 1,2-c]pyridine. 6. The compound of claim 1 which is (4aRS,5SR,9bSR)-2-(4-chlorophenacy1)-1,3,4,4a,5 ,9b-

hexahydro-S-pheny1-2H-indeno[ 1,2-c1pyridine.

The compound of claim 1 which is (4aRS,$SR,9bSR)- l ,3 ,4 ,4a,5 ,9b-2-(2,5 -dich1orophenacy1 1,3,4,4a,5,9h-hexahydro-S-phenyl-21-1-indeno[ 1 ,2-

Q. The compound of claim 1 which is (4aRS,5SR,9bSR)- 1 ,3 ,4,4a,5,9-hexahydro-2-( 2-methy1- P hr nsesql13 :9!Pyridi V 9. The compound of claim l which is Mali-15,5 SR,9bSR)- 1 ,3 ,4,4a,5 ,9b-2-( 4-methy1-phenacy1-5- s w -w n rs lfiflrxi iae.

1 1. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(3-methylphenacyD-S-phenyl-l ,3,4,4 a, 5, 9 1-1-indeno[ 1 ,2-c ]pyridine. Q

12.The compound of claim 1 which is phenacyl)-5-pheny1-21-1-indeno[ 1,2-c]pyridine.

13. The compound of claim 1 which is (4aRS,5RS,9bRS l ,3 ,4,4a,5 ,9b-hexahydro-Z-phenacyl-S- phenyl-2-indeno[ 1,2-clpyridine. V

MQThe compound of claim 1 which is (4aRS5SR,9bRS )-1 ,3,4,4a,5 ,9b-hexahydro-Z-phenacyl-S- pheny1-21-l-indeno[ l ,2-c ]pyridine.

15. The compound of claim 1 which is (4aRS,5 SR,9bRS )-1 ,3,4,4a,5 ,9b-hexahydro-7-methy1-2- phenacyl-5-p-tolyl-2l-1-indenol l,2-c]pyridine.

16. The compound of claim 1 which is (4aRS,5 SR,9bRS)-1 ,3 ,4,4a,5 ,9b-hexahydro-2-p-methoxyphenacyl-ZH-indenoI 1 ,2-c ]pyridine.

117. The compound of claim 1 which is (4aRS,5SR,9blRS)-7-chloro-5-p-ch1orophenyl- 1 ,3,4,4a,5 ,9b-hexahydro-Z-m-methy1phenacyl-2H-indeno[ 1 ,2-c1pyridine.

18. The compound of claim 1 which is (4aRS,SSR,9bRS)-7-ch1oro5-p-chlorophenyl-2-( 3 ,4-

dimethoxyphenacynl ,3 ,4,4a,5 ,9b-hexhydro-2H-indeno[ 1 ,2-c]pyridine.

119. The compound of claim 1. which is (4aRS,5 SR,9bSlR)- 1 ,3,4,4a,5 ,9b-hexahydro-2-phenacyl-5- phenacy1-2H-indeno[ l,2c]pyridine.

Claims (18)

1. 2. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-7-methyl-2-phenacyl-5-p-tolyl-2H -indeno(1,2-c)pyridine.
2. 3. The compound of claim 1 which is (4aRS,5SR,9bSR)-7-chloro-5-p-chlorophenyl-1,3,4,4a,5,9b-hexahydrO-2-phenacyl-2H-indeno(1,2-c)pyridine.
3. 4. The compound of claim 1 which is (4aRS,5SR,9bRS)-7-chloro-5-p-chlorophenyl-1,3,4,4a,5,9b-hexahydro-2-phenacyl-2H-indeno(1,2-c)pyridine.
4. 5. The compound of claim 1 which is (4aRS,5SR,9bSR)-2-(4-bromophenacyl)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2H -indeno(1,2-c)pyridine.
5. 6. The compound of claim 1 which is (4aRS,5SR,9bSR)-2-(4-chlorophenacyl)-1,3,4,4a,5,9b-hexahydro-5-phenyl-2H -indeno(1,2-c)pyridine.
6. 7. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-2-(2,5-dichlorophenacyl)-1,3,4,4a, 5,9b-hexahydro-5-phenyl-2H-indeno(1,2-c)pyridine.
7. 8. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9-hexahydro-2-(2-methyl-phenacyl)-5-phenyl-2H -indeno(1,2-c)pyridine.
8. 9. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(3-methyl-phenacyl)-5-phenyl-2H -indeno(1,2-c)pyridine.
9. 10. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-2-(4-methyl-phenacyl-5-phenyl-2H-indeno(1,2 -c)pyridine.
10. 11. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(3-methyl-phenacyl)-5-phenyl -1,3,4,4 a, 5, 9 H-indeno(1,2-c)pyridine.
11. 12. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-(4-methyl-phenacyl)-5-phenyl-2H -indeno(1,2-c)pyridine.
12. 13. The compound of claim 1 which is (4aRS,5RS,9bRS)-1,3,4,4a,5,9b-hexahydro-2-phenacyl-5-phenyl-2-indeno(1,2 -c)pyridine.
13. 14. The compound of claim 1 which is (4aRS5SR,9bRS)-1,3,4,4a,5,9b-hexahydro-2-phenacyl-5-phenyl-2H-indeno(1,2 -c)pyridine.
14. 15. The compound of claim 1 which is (4aRS,5SR,9bRS)-1,3,4,4a,5,9b-hexahydro-7-methyl-2-phenacyl-5-p-tolyl-2H -indeno(1,2-c)pyridine.
15. 16. The compound of claim 1 which is (4aRS,5SR,9bRS)-1,3,4,4a,5,9b-hexahydro-2-p-methoxyphenacyl-2H-indeno(1,2 -c)pyridine.
16. 17. The compound of claim 1 which is (4aRS,5SR,9bRS)-7-chloro-5-p-chlorophenyl-1,3,4,4a,5,9b-hexahydro-2-m -methylphenacyl-2H-indeno(1,2-c)pyridine.
17. 18. The compound of claim 1 which is (4aRS,5SR,9bRS)-7-chloro5-p-chlorophenyl-2-(3,4-dimethoxyphenacyl) -1,3,4,4a,5,9b-hexhydro-2H-indeno(1,2-c)pyridine.
18. 19. The compound of claim 1 which is (4aRS,5SR,9bSR)-1,3,4,4a,5,9b-hexahydro-2-phenacyl-5-phenacyl-2H-indeno(1,2 -c)pyridine.