US3210357A

US3210357A - Polyhydro-benzo [a] quinolizines

Info

Publication number: US3210357A
Application number: US276215A
Authority: US
Inventors: Taylor William Irving; Robison Michael Mullen
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1963-04-29
Filing date: 1963-04-29
Publication date: 1965-10-05
Anticipated expiration: 1982-10-05

Description

United States Patent 3,210,357 POLYHYDRO-BENZO [a] QUINOLIZINES William Irving Taylor, Summit, and Michael Mullen Robisou, Berkeley Heights, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 29, 1963, Ser. No. 276,215 20 Claims. (Cl. 260283) following formula:

11 \1 a 2 2 Ar.

in which the group A, together with the l-carbon atom and the llb-carbon atom of the 1,2,3,4,6,7-hexarydro- 11bH-benzo[a]quinolizine ring system, forms the cycloalkano portion having from five to ten ring members.

More particularly, the compounds of this invention are those of the formula:

NW R.

'(Cnno R. Rb

in which the group of the formula -(C H is alkylene which has from three to ten carbon atoms separating l-position of the 1,2,3,4,6,7-hexahydro-11bH-benzo[a]- 'quinolizine portion from the llb-position by three to eight carbon atoms, each of the groups R and R is hydrogen, hydroxyl, etherified hydroxyl, lower alkyl, or, when attached to adjacent positions and taken together, lower alkylene-dioxy, and each of the groups R,,, R R R R and R, is hydrogen or lower alkyl, or the salts thereof, as well as the N-oxides thereof, the salts of N- oxides thereof or the quaternary ammonium compounds thereof.

The cycloalkano portion, which has from five to ten, above all from five to eight, ring members, is preferably unsubstituted or may have lower alkyl groups as substituents, e.g. methyl, ethyl, n-propyl, isopropyl and the like. The group of the formula --(C,,H separating the 1-position of the 1,2,3,4,6,7-hexahydro-1lbH- benzo[a]quinolizine portion from the lib-position by three to eight carbon atoms, has from three to ten,

preferably from three to seven, carbon atoms (i.e., the

letter 11 is one of the integers from 3 to 10, preferably from 3 to 7). It is represented above all by 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, but may also be 1,7-heptylene or 1,8-octylene. These divalent radicals are preferably unsubstituted, or may be sub- 3,210,357 Patented Oct. 5, 1965 stituted by lower alkyl as mentioned before; such substituted divalent alkylene radicals may be represented by 1-methyl-1,3-propylene, 2-methyl-1,3-propylene, 2- isopropyl-1,3-propylene, 1,2-dimethyl-1,3-propylene, 1- methyl-1,4-butylene, 2-methyl-1,4-butylene, 2-ethyl-1,4- butylene, 1,Z-dimethyl-1,4-butylene, 1,2,3-trimethyl-1,4- butylene, 1-methyl-1,5-pentylene, 2,3-dimethyl-l,5-pentylene, 1 methyl 1,6-hexylene, 3,3-dimethyl-1,7-heptylene and the like.

The hexacyclic carbocyclic aryl portion of the l,2,3,4,6, 7-hexahydro-11bH-benzo[a]quinolizine ring system may be unsubstituted or substituted. substituents, such as the groups R, and R which may also represent hydrogen and may be attached to any of the positions available for substitution in the hexacyclic carbocyclic aryl portion, are primarily hydroxyl, etherified hydroxyl, represented above all by lower alkoxy, e.g., methoxy, ethoxy, npropyloxy, isopropyloxy, n-butyloxy and the like, as well as by lower alkenyloxy, e.g., vinyloxy, allyloxy, methylallyloxy and the like, carbocyclic aryloxy, e.g., phenyloxy and the like, or carbocyclic aryl-lower alkoxy, e.g., benzyloxy, l-phenylethyloxy, 2-phenylethyloxy and the like, or lower alkyl, e.g., methyl, ethyl, n-propyl, isopropyl and the like. When located at adjacent positions of the 1,2,3,4,6,7-hexahydro-l1bH-benzo[a]quinoli- Zine ring system and taken together, two substituents, such as R and R may be taken together and may represent lower alkylenedioxy, e.g. methylenedioxy, 1,1-ethylenedioxy, 1,2-ethylenedioxy and the like.

The remainder of the molecule is unsubstituted or may contain substituents, particularly aliphatic hydrocarbon groups, such as lower alkyl. The groups R,,, R R R R and R, are above all hydrogen, but may also represent lower alkyl, particularly methyl, as well as ethyl, npropyl, isopropyl and the like.

Salts of the compounds of this invention are acid addition salts, such as pharmaceutically acceptable, non-toxic acid addition salts with inorganic acids, e.g., hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g., acetic, propionic, malonic, succinic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, benzoic, salicylic, 2-acetoxybenzoic, nicotinic, isonicotinic acid and the like, or with organic sulfonic acids, e.g., methane sulfonic, ethane sulfonic, 2-hydroxyethane sulfonic, ethane 1,2-disulfonic, benzene sulfonic, toluene sulfonic, naphthalene 2-sulfonic acid and the like. Acid addition salts may also serve as intermediates for the preparation of other salts, such as the pharmaceutically acceptable, nontoxic acid addition salts, or in the purification of the free compounds, as well as for identification and characterization purposes. Salts particularly suitable for the latter are, for example, those with acidic organic nitro compounds, e.g., picric, picrolonic, flavianic acid and the like, with metal complex acids, e.g., phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like, or any other appropriate acid.

The compounds of this invention may also be in the form of their N-oxides, as well as the acid addition salts, particularly the pharmaceutically acceptable, non-toxic acid addition salts of such N-oxides.

Quaternary ammonium derivatives of the compounds of this invention are those with reactive esters formed by alcohols and strong acids. Examples of such esters are lower alkyl halides, e.g., methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, di-lower alkyl sulfates, e.g., dimethyl sulfate, die'thyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g., methyl or ethyl methane sulfonate or ethane sulfonate and the like, or lower alkyl aryl sulfonates, e.g., methyl p-toluene sulfonate and the like. Also included as quarternary ammonium compounds are the quaternary ammonium hydroxides, and the salts thereof with inorganic or with organic acids, such as those described above.

The compounds of this invention have antihypertensive properties and can be used as hypotensive agents in the treatment of hypertensive conditions. They are virtually free of side-effects, such as curare-type properties and the like.

Particularly useful are the compounds of the following formula:

in which the letter m stands for one of the integers 3, 4, and 6, and each of the groups R and R is hydrogen, lower alkoxy, or, when taken together, methylenedioxy, and the acid addition salts of such compounds.

The compounds of this invention may be used in the form of compositions for enteral or parenteral use, which contain the new compounds, their salts, N-oxides, salts of N-oxides or quaternary ammonium compounds in admixture with an organic or inorganic solid or liquid carrier. For making up these preparations, there are employed materials which do not react with the active ingredients, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, talc, vegetable oils, benzyl alcohol, stearyl alcohol, tragacanth, acacia, gums, propylene glycol, polyalkylene glycols, or any other known carriers for pharmaceutical preparations. The latter may be in solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, coloring agents. flavoring agents and the like. They may also contain, in combination, other useful substances.

The compounds of this invention are prepared, for example, by replacing in a polyhydro-benzo[a]cycloalkano- [iJquinolizine having a 4 oxo 1,2,3,4,6,7 hexahydro- 1lbH-benzo[a]quinolizine portion, in which the cycloalkano portion has from five to ten ring members, oxo by two hydrogen atoms, and, if desired, converting in a resulting compound a substituent attached to the hexacyclic carbocyclic aryl portion of the 1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine ring into another substituent, and/ or, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into an N-oxide or a quaternary ammonium compound thereof, and/ or, if desired, converting a resulting compound or an N-oxide into a salt thereof, and/ or, if desired, converting a resulting quaternary ammonium compound into another quaternary ammonium compound, and/ or, if desired, separating a resulting mixture into the single compounds.

Replacement of oxo in the starting material by two hydrogen atoms is achieved using procedures known for the conversion of the carbonyl portion of an amide grouping into methylene. Reagents of choice to accomplish the removal of the oxo group are aluminum hydrides, such as certain light metal aluminum hydrides, e.g., alkali metal aluminum hydrides, particularly lithium aluminum hydride and the like. These hydride reagents are used in the presence of diluents, particularly aliphatic ethers, e.g., diethyl ether and the like, or cycloaliphatic ethers, e.g., tetrahydrofuran and the like, preferably at an elevated temperature. Other reagents capable of replacing oxo by two hydrogens are certain borohydrides, e.g., sodium borohydride and the like, when used in the presence of an activator, e.g., aluminum chloride and the like, as well as alkali metals, e.g., sodium and the like, in the presence of lower alkanols, e.g., ethanol, n-butanol,

Rt R1 t nure R. b

in which R R R R R R R and the group of the formula -(C,,H have the previously given meaning, especially by those of the formula in which R and R and the letter m have the previously given meaning.

The starting materials are prepared, for example, by reacting a Z-phenyl-ethylamine compound, in which a hydroxyl group, substituting the phenyl portion, is protected by functional conversion, for example, by etherification and the like, with a 3-(2--oxo-cycloalkyl)- propionic acid compound, in which cycloalkyl has from live to ten ring members, or a functionally converted derivative thereof, and ring-closing, by treatment with a Lewis acid, the resulting 1-(2-phenyl-ethyl)-6-oXo-cyclo alkeno[b]piperidine compound, in which the cycloalkeno portion has from five to ten ring members and the double bond extends from the joint carbon atom of the bicyclic ring system, which is located adjacent to the piperidinenitrogen atom, to form the desired starting material; in the latter a functionally converted hydroxyl group, such as an etherified hydroxyl group may be converted into the free hydroxy group.

A functionally converted derivative of the above propionic acid intermediate is, for example, an ester thereof, such as a lower alkyl, e.g., methyl, ethyl and the like, ester, a tetra-hydropyranyl ester and the like. A functionally converted derivative of the starting material may also be a 3-(2-functionally converted oxo-cycloalkyl)- propionic acid, in which a functionally converted oxo group is primarily a ketalized oxo group, such as lower alkylenedioxy, e.g., 1,2-ethylenedioxy and the like.

The first step of the above procedure for the manufacture of the starting materials, i.e., the elimination of the elements of water, is carried out by heating the mixture of two reactant-s, preferably dissolved in a highboiling, inert solvent, e.g., benzene, toluene, diethyleneglycol dimethylether, diphenyl ether and the like, if necessary, using a water separator; generated water may also be removed by evaporation, azeotropic distillation and the like. Dehydration may also be achieved by treatment with a dehydrating agent, such as phosphorus pentoxide and the like, if necessary, in the presence of an inert diluent, and/or at an elevated temperature.

A Lewis acid, causing the desired ring closure of a resulting 1-(2-phenyl-ethyl) 6 oxo-cycloalkeno [-bJpiperidine compound, in which the double bond of the cycloalkeno portion extends from a joint carbon atom of the bicyclic ring system, is primarily a strong Lewis acid, such as phosphoric acid, sulfuric acid, polypho-sphoric acid, boron trifluoride etherate and the like. Phosphoric acid, used in a mixture of a lower alkanol, particularly methanol, and water, is the preferred reagent. The above ring closure is preferably performed at an elevated temperature, if necessary, in the presence of an additional diluent, in a closed vessel, and/ or, in the atmosphere of an inert gas, e.g., nitrogen.

In the above starting material, a l-(2-phenyl-ethyl)-6- oxo-cycloalkeno[b]piperidine intermediate may not be formed directly and/ or may not be isolated. Thus, the reaction of a 2-phenyl-ethylamine compound with a 3-(2- oxo-cycloalkyl)-propionic acid compound, or a functional derivative thereof, particularly a functional oxo derivative, such as an ethylenedioxy derivative, thereof may yield an N-(Z-phenyl-ethyl)-3-(2-oxo-cycloalkyl)-propionic acid amide or a functional derivative thereof as the intermediate. This intermediate, when treated with an acid, such as one of the previously-mentioned Lewis acids, for example, phosphoric acid and the like, may be converted directly into the desired starting material without isolation of the 1-(2-phenyl-ethyl)-6-oxo-cycloalkeno[b] piperidine intermediate. In the course of the acid treatment, a functionally converted oxo-group, such as ethylenedioxy, may be converted into the free oxo group prior to the ring closure.

In the resulting starting material a functionally converted hydroxyl group, such as an etherified hydroxyl group, may be converted into the free hydroxyl group according to the procedure described below.

The compounds of this invention may also be prepared by replacing in a polyhydro-benzo[a]cycloalkano[i]quinolizine compound having a 6-oxo-l,2,3,4,6,7-hexahydrollbH-benzo[a]quinolizine portion, in which the cycloalkano portion has from five to ten ring members, oxo by two hydrogen atoms, and, if desired, carrying out the optional steps.

Replacement of the oxo group by two hydrogens is carried out as previously described, preferably by treatment with a light metal aluminum hydride reagent, such as an alkali metal aluminum hydride, e.g., lithium aluminum hydride and the like, in the presence of a suitable solvent, or by any other known methods capable of converting the carbonyl portion of an amide grouping into a methylene group.

The starting materials used in the above procedure are new and are intended to be included Within the scope of the invention. Preferred starting materials are those of the formula in which R R R R R R R, and the group of the formula (C,,H have the previously given meaning, particularly those of the formula in which R R and the letter In have the previouslygiven meaning.

The starting materials used in the above procedure may be prepared, for example, by converting in a [HZ-functionally converted oxo-cycloalkyl)-propionitrile, in which cycloalkyl has from five to ten ring members, and the functionally converted oxo group is preferably a ketalized oxo group, such as a lower alkylenedioxy group, e.g., 1,2-ethylenedioxy and the like, the cyano group into the aminomethyl group of the formula -CH NH by reduction. This reaction is carried out according to known methods, for example, by treatment of the intermediate compound with an aluminum hydride, such as a light metal aluminum hydride, for example, an alkali metal aluminum hydride, e.g., lithium aluminum hydride and the like, or with catalytically activated hydrogen, nascent hydrogen and the like. The resulting 3-(2-functionally converted oxo-cycloalkyl)-propylamine is then converted into an N-[3-(2-functionally converted oxo-cycloalkyl)- propyl] phenylacetic acid amide by treatment with a reactive derivative of a phenyl-acetic acid, in which a hydroxyl group substituting the phenyl portion is protected by functional conversion, for example, by etherification and the like; a reactive derivative of such acid is particularly a halide thereof, such as the chloride and the like, but may also be an ester thereof, e.g., a lower alkyl ester and the like. In the above N-substituted acetic acid amide compound, a functionally converted oxo group, such as a lower alkylene-dioxy group, is then liberated, for example, by treatment with an acid, e.g. p-toluene sulfonic acid and the like. The resulting N-[3-(2-oxo-cycloalkyl)- propyl] phenyl-acetic acid amide is then converted by dehydration into the N-(phenyl-acetyl)-cycloalkeno[b] piperidine, in which the double bond of the cycloalkeno portion extends from the joint carbon atom of the bicyclic ring system, which is located adjacent to the piperidinenitrogen atom, and ring-closed by treatment with a Lewis acid to yield the desired starting material; the two last steps are carried out as previously described. In the resulting starting material, a functionally converted hydroxyl group attached to the aromatic portion may be converted into the free hydroxyl group as described below.

The above N- (phenyl-acetyl) -cycloalkeno [b piperidine, may also be prepared by liberating the functionally converted oxo group in a 3-(2-functionally converted oxocycloalkyl)-propylamine, ring-closing the 3-(2-oxo-cycloalkyl)-propylamine by dehydration, and reacting the resulting cycloalkeno[b]piperidine, with a reactive derivative of a phenylacetic acid, particularly a halide thereof.

In a resulting compound or in the starting material a substituent attached to the hexacyclic carbocyclic aryl portion of the 2,3,4,6,7-hexahydro-1lbH-benzohdquinolizine ring system may be converted into another group. A functionally converted hydroxyl group, particularly an etherified hydroxyl group, such as lower alkoxy or lower alkylenedioxy may be converted into hydroxyl by acidic hydrolysis, using, for example, a hydrohalic acid, e.g., hydrobromic, hydriodic acid, or any other suitable acidic reagent, e.g., pyridine hydrochloride. A phenyllower alkoxy group, particularly benzyloxy, may be converted into hydroxyl by hydrogenolysis, using hydrogen in the presence of a metal catalyst, e.g., palladium on charcoal and the like.

A resulting acid addition salt may be converted into the free compound, for example, by treatment with an alkaline reagent, such as an alkali metal hydroxide or an alkaline earth metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, an alkali metal carbonate or alkaline earth metal carbonate, e.g., sodium, potassium, magnesium or calcium carbonate or hydrogen carbonate and the like, ammonia or any other appropriate alkaline reagent, or with a suitable hydroxyl ion exchange preparation and the like.

A resulting acid addition salt may be converted into another salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, e.g., sodium, potassium, silver salt and the like, of an acid in the presence of a diluent in which a resulting inorganic compound is insoluble and is thus removed from the reaction medium. A salt may also be converted into another salt with the help of a suitable anion exchange preparation.

A resulting free compound may be converted into an acid addition salt by reacting it with an acid, such as one of those mentioned hereinbefore, for example, by

treating a solution of the free compound in a solvent or solvent mixture with the acid or a solution thereof, or with an anion exchange preparation, and isolating the desired salt. Salts may be obtained in the form of hydrates or may contain solvent of crystallization.

An N-oxide of a resulting compound may be prepared according to known methods, for example, by treating a solution of the free compound in an inert solvent with a peracid, such as an organic carboxylic peracid, e.g., peracetic, perbenzoic, perphthalic acid and the like, or another appropriate peracid, as Well as with any other suitable N-oxidation reagent, e.g., hydrogen peroxide and the like. The compounds of this invention may be converted into their quaternary ammonium derivatives, for example, by reaction with a reactive ester of an alcohol and a strong acid. Esters of that type are particularly those mentioned above yielding lower alkyl or phenyl-lower alkyl quaternary ammonium salts, such as halides, sulfates or sulfonates. If desired, the quaternizing reaction may be performed in the absence of presence of a solvent, while cooling, at room temperature or at an elevated temperature, under atmospheric or increased pressure, and/or in the atmosphere of an inert gas, e.g., nitrogen.

A resulting quatenary ammonium compound may be converted into another quaternary ammonium compound, such as a quaternary ammonium hydroxide; the latter may be obtained, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchange preparation, by electrodialysis or any other suitable procedure. From a resulting quaternary ammonium hydroxide compound, there may be prepared quaternary ammonium salts with acids, for example, with those outlined hereinbefore for the preparation of the acid addition salts, or with mono-lower alkyl sulfates, e.g., methyl sulfate, ethyl sulfate and the like. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of an intermediary quaternary ammonium hydroxide. Thus, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or with hydrochloric acid in anhydrous methanol to yield the quaternary ammonium chloride; or, upon treatment with a suitable anion exchange preparation a quaternary ammonium compound may be converted into another quaternary ammonium salt. Quaternary ammonium compounds may also be obtained as hydrates, or may contain solvent of crystallization.

The compounds of this invention may be obtained in the form of racemates, which may be resolved into the optically active dand l-forms according to known resolution procedures. For example, a solution of the free base of a racemic d,l-compound in an appropriate solvent may be treated with an optically active acid or a solution thereof. Especially useful as optically active acids are D-tartaric (also l-tartaric) and L-tartaric (also dtartaric) acid, as well as the optically active forms of malic, mandelic, camphor-lO-sulfonic, quinic, di-o-toluyltartaric acid and the like. A salt formed by the optically active acid with the optically active form of the base may then be isolated; from such salt, the free, optically active base may be obtained according to the methods outlined before, and a free, optically active compound may be converted into a salt, an N-oxide, a salt of an N-oxide or a quaternary ammonium compound according to the process mentioned before.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A solution of 8.59 g. of crude 11,12-dimethoxy-2,3,3a,4, 5,6,8,9-octahydro-1H benzo [a] cyclopenta[i] quinolizin- 6-one in 100 ml. of tetrahydrofuran is added to a solution of 6.0 g. of lithium aluminum hydride in 250 ml. of tetrahydrofuran, and the mixture is refluxed for five hours. After cooling in ice, Water is added to decompose the excess of lithium aluminum hydride; the solid material is filtered off and the filtrate is concentrated under reduced pressure. The remaining oil is dissolved in diethyl ether, and dry hydrogen chloride is passed into the solution. The desired 11,12-dimethoxy-2,3,3a,4,5,6, 8,9-octahydro-1H benzo[a]cyclopenta[i]quinolizine hydrochloride of the formula precipitates and is filtered off (yield: 6.66 g.), and melts at 256-258 (with decomposition).

The starting material used in the above procedure is prepared as follows: A mixture of 38.1 g. of methyl 3- (2-oxocyclopentyl)-propionate and 39.6 g. of 3,4-dimethoxy-tryptamine in 300 m1. of toluene is refluxed in the presence of 5.0 g. of a cation exchange resin (styrenetype, sulfonic acid, in hydrogen form) for sixteen hours in a vessel equipped with a water separator. After cooling and filtering, the solution is concentrated and yields 24.1 g. of the crystalline N-[2-(3,4-dimethoxy-phenyl)- ethyl]-1,2,3,4,5,6-hexahydro-H-l-pyrindin-Z-one of the in which the double bond extends from the 7a-position of the l-pyrindine portion to the 4a-positi0n or the 7-position, and which melts at l04l07.

The above intermediate may also be prepared, for example, by refluxing 3.93 of 3-(2-oxo-cyclopentyl)-propionic acid and 4.5 g. of 3,4-dimethoxy-tryptamine in 40 ml. of xylene in the presence of 0.1 g. of p-toluene sulfonic acid; the generated water is removed with the help of a water separator. After seven hours, the resulting mixture is concentrated whereupon the desired intermediate precipitates and is filtered off.

A mixture of 10.47 g. of the latter in 13 ml. of water, 19.5 ml. of percent of phosphoric acid and 26 ml. of methanol is refluxed for 1 /2 hours. After cooling, it is diluted with ml. of water; the organic material is extracted with methylene chloride, and the organic phase is washed with Water and 2N aqueous sodium carbonate, and dried over magnesium sulfate. The organic solvent is evaporated, and the desired 11,12-

9 dimethoxy-2,3,3a,4,5,6,8,9-octahydro 1H benzo[a]cyclopenta[i] quinolizin-6-one of the formula is crystallized from diethyl ether, M.P. 113-116; yield: 8.59 g.

Example 2 To a hot solution of 15.78 g. of 11,12-dimethoxy-2,3, 3a,4,5,6,8,9-octahydro-1H benzo [a] cyclopenta [i] quinolizine in 700 ml. of acetone is added 12.8 g. of d-10- camphor sulfonic acid. The solution is concentrated to a volume of 550 ml. and is seeded with a crystal of the more insoluble salt obtained from a preliminary small scale resolution experiement. A total of 13.7 g. of solid material is filtered off and is recrystallized from acetone. A total of 9.68 g. of the more insoluble purified salt is obtained, which is converted into the free l-11,12-

dimethoxy-2,3,3a,4,5,6,8,9-octahydro 1H benzo[a]cyclopenta[i]quinolizine, [u] 60 (C, 0.98 in chloroform), from which the hydrochloride, M.P. 268-271 (with decomposition) is obtained; yield: 4.8 g. From the crystallization mother liquors, the more soluble salt is accumulated by fractional crystallization and converted into the d-ll,12-dimethoxy-2,3,3a,4,5,6,8,9-octahydro 1H-benzo[a]cyclopentalji]quinolizine, [11],; +52 (C, 3.0 in chloroform); its hydrochloride melts at 275-277 (with decomposition); yield: 4.5 g.

Example 3 A solution of 0.625 g. of 12,13 dirnethoxy 1,2,3,4, 4a,5,6,7,9,10 decahydro benzo[a]cyclohexa[i]quinolizin 7 one and 0.335 g. of lithium aluminum hydride in 35 ml. of dry tetrahydrofuran is refluxed for four hours while stirring. After chilling, the excess of the reducing reagent is decomposed by slowly adding 20 ml. of wa ter, and the mixture is poured into an aqueous solution of sodium potassium tartrate. The organic material is extracted with diethyl ether; the separated organic phase is evaporated, and the residue is added to 2 N aqueous sulfuric acid. The acidic solution is washed with diethyl ether and then made alkaline with a 10 percent aqueous solution of sodium hydroxide. The organic material is extracted with methylene chloride; the organic solution is washed with water and brine, dried and evaporated to yield 0.54 g. of an oily product, which is disaC- O- /WN 'HCl slowly crystallizes upon adding more diethyl ether; it melts at 253-254 (with decomposition).

The starting material used in the above procedure is prepared as follows: A mixture of 37.0 g. of methyl 3- (2-oxocyclohexyl)-propionate, 12.0 g. of ethylene glycol and 2.0 g. of a cation exchange resin (styrene-type, sulfonic acid, in hydrogen form) in ml. of benzene is refluxed for 21 hours; the generated water is separated in a water separator. The reaction mixture is filtered, the filtrate is evaporated and the residue, containing the methyl 3 (2 ethylenedioxy cyclohexyl) propionate is added to 15.0 g. of sodium hydroxide in 40 ml. of ethanol and 40 ml. of water. The mixture is refluxed for 1 /2 hours, then cooled to 0, and neutralized with 35 ml. of cold 6 N aqueous sulfuric acid. After saturation with sodium chloride, the organic material is extracted with diethyl ether; the organic phase is separated, Washed with brine, dried and evaporated to dryness. The desired 3-(Z-ethylenedioxy-cyclohexyl)-propionic acid is obtained by distilling the residue and collected at 144- l51/0.5 mm; yield: 30 g.

A mixture of 18.1 g. of 2-(3,4-dime'thoxy-phenyl)- ethylamine, 21.4 g. of 3-(Z-ethylenedioxy-cyclohexyl)- propionic acid and 2.0 g. of a cation exchange resin (styrene-type, sulfonic acid, in hydrogen form) is heated in an oil bath, the temperature being raised to over a period of two hours. After maintaining this temperature for four hours, the reaction mixture is cooled, dissolved in diethyl ether and filtered. The filtrate is extracted twice with cold 5 percent hydrochloric acid and twice with a 5 percent aqueous solution of sodium carbonate, washed with brine, dried and evaporated. The oily residue (yield: 29.3 g.) is diluted with diethyl ether; the solution is allowed to stand while cooling to yield approximately 2.0 g. of a crystalline material, which is filtered off and washed with diethyl ether. After recrystallizations from methanol, the N-[2-(3,4-dimethoxyphenyl) ethyl]3 (2 ethylenedioxy cyclohexyl) propionic acid amide melts at 101-103 :as the hemihydrate. Special data of the above oily residue suggest that the latter is contaminated with the N-[2-(3,4-dimethoxy phenyl) ethyl] 1,2,3,4,5,6 hexahydro 7H,H-quinolin-2-one of the formula in which the double bond extends from the 8aposition of the quinoline portion to the 4a-position or the 8-position, or with the desired starting material.

The latter is obtained by heating a mixture of 1.3 g. of the N- [2- (3 ,4-dimethoxy-phenyl) ethyl] 3 2-ethylenedioxycyclohexyl)-propionic acid amide, 1.2 ml. of 85 percent phosphoric acid, 1 ml. of methanol and 0.8 ml. of water on the steam bath for two hours; during this period, most of the methanol is allowed to evaporate. After cooling, 10 ml. of water is added; the organic material is extracted into methylene chloride, and the organic phase is washed with an aqueous solution of sodium carbonate, water and brine, dried and evaporated to yield 0.98 g. of a gummy material, which is chromatographed on aluminum oxide (neutral, activity IIIII). The fractions eluted with a 3:1-mixture of henzene and diethyl ether are combined (yield: 0.74 g.), sublimed and collected at l20125/ about 0.5 mm. as a glassy material. It analyzes correctly for the desired ll 12,13 dimethoxy 1,2,3,4,4a,5,6,7,9,10 decahydro benzo[a]cyclohexa[i]-quinolizine of the formula and has the correct infrared absorption spectrum; yield: 0.705 g.

Example 4 A mixture of 8.5 g. of 2,3,3a,4,5,6,8,9-octahydro-1H- benzo[a]cyclopenta[i]quinolizin 6 one and 5.8 g. of lithium aluminum hydride in tetrahydrofuran is refluxed for three hours. Water is added to decompose the complex; the resulting mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in methylene chloride; the basic material is extracted into dilute sulfuric acid. The acidic layer is basified with 2 N aqueous sodium hydroxide and extracted with methylene chloride; the organic layer is separated, dried and evaporated to dryness. The crude 2,3,3a,4,5,6,8,9-octahydro-lH-benzo[a]cyclopenta[i]quinolizine of the formula (yield: 4.45 g.) is dissolved in diethyl ether, and the organic solution is treated with dry hydrogen chloride gas. The resulting 2,3,3a,4,5,6,8,9-octahydro-1H-benzo[a]cyclopenta[i]quinolizine hydrochloride melts at 194196.

The starting material used in the above procedure is prepared as follows: A mixture of 5.0 g. of 2-phenylethyl-amine and 6.4 g. of 3-(2-oxo-cyclopentyl)-propionic acid in 150 ml. of toluene is refluxed for ten hours in the presence of 0.1 g. of p-toluene sulfonic acid; the generated water is separated in a water separator. The reaction mixture is evaporated to dryness, the residue is taken up into chloroform, and the organic solution is Washed with dilute hydrochloric acid and dilute sodium hydroxide. After being dried over magnesium sulfate, the organic solution is evaporated to yield 9.9 g. of the oily N-(Z-phenylethyl)-1,2,3,4,5,6-hexahydro H-l-pyridin-2-one of the formula in which the double bond extends from the 7a-position of the l-pyrindine portion to the la-position or to the 7-position; the crude intermediate is used without further purification.

A mixture of 9.9 g. of N-(2-phenyl-ethyl)-1,2,3,4,5,6- hexahydro-H-l-pyrindin-Z-one and 60 g. of polyphosphoric acid is heated at 130 for thirteen hours. After cooling, ice and water are added, and the organic material is extracted with chloroform. The organic solution is washed with aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to dryness. The rewhich is crystallized from diethyl ether, melts at 9l-92 and is used Without further purification.

Example 5 A mixture of 7.6 g. of 11,12-methylenedioxy-2,3,3a, 4,5,6,8,9-octahydro 1H benzo[a]cyclopenta[i]quinolizin-6-one and 5.0 g. of lithium aluminum hydride in ml. of tetrahydrofuran is refluxed for three hours. Water is added to decompose the complex; the inorganic material is filtered off and the filtrate is concentrated. The residue is dissolved in dilute sulfuric acid; the acidic solution is washed with methylene chloride, basified with a 2 N aqueous sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated to yield 5.4 g. of the crude 11,12 methylenedioxy-2,3,3a,4,5,6,8,9-octahydrolH-benzo[a]eyclopenta[i]quinolizine of the formula which is converted into the hydrochloride by gassing a diethyl ether solution thereof with dry hydrogen chloride. The 11,12-methylenedioxy 2,3,3a,4,5,6,8,9-octahydrolH-benzo [a] cyclopenta [i] quinolizine hydrochloride melts at 264266.

The starting material used in the above procedure is prepared as follows: A mixture of 7.4 g. of 2-(3,4-methylenedioxy-phenyl)-ethylamine and 7.0 g. of 3-(2-0xoy cyclopentyl)-propionic acid in ml. of toluene conin which the double bond extends from 7a-position of the l-pyrindine portion to the 4a-position or the 7-position, and which melts at 9092 after crystallization from diethyl ether.

A mixture of 10.0 g. of the above N-[2-(3,4-methylenedioxy-phenyl -ethyl] -1,2,3 ,4,5 ,6-hexahydro-H-1 pyridin- 2-one in 26 ml. of methanol, 13 ml. of water and 20 ml. of polyphosphoric acid is heated for three hours on a steam bath. The solution is extracted with methylene chloride; the organic phase is washed with 2 N aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to yield 6.0 g. of the desired 11,12-methylene- 1 3 dioxy-2,3,3a,4,5,6,8,9-octahydro-1H benzo[a]cyclopenta [i]quinolizin-6-one of the formula which melts at 128-130 after crystallization from hexane and recrystallization from a mixture of diethyl ether and acetone.

Example 6 A mixture of 5.0 g. of 2,3,3a,4,5,6,8,9-octahydro-1H- benzo[a]cyclopenta[i]quinolizin-8-one and 3.5 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran is refluxed for three hours. The resulting complex is decomposed by adding water, the inorganic precipitate is filtered ofi and the filtrate is concentrated to dryness. The residue is dissolved in dilute sulfuric acid; the acidic solution is washed with methylene chloride and basified with a 2 N aqueous sodium hydroxide soltuion. The organic material is then extracted with methylene chloride; the organic phase is dried over magnesium sulfate and evaporated. The crude 2,3,3a,4,5,6,8,9-octahydrolH-benzo[a]cyclopenta[i]quinolizine (yield: 3.6 g.) is converted into its hydrochloride by treating a diethyl ether solution of the free base with dry gaseous hydrogen chloride; the desired 2,3,3a,4,5,6,'8,9-octahydro-lH-benzo[a] cyclopenta[i]quinolizine hydrochloride melts at l94-l96 and is identical with the product obtained according to the procedure described in Example 4.

The starting material used in the above procedure is prepared as follows: To an ice-cold solution of 3-(2-ethylenedioxycyclopentyl)-propylamine in 25 ml. of pyridine is added 5.6 g. of phenylacetyl chloride; the reaction mixture is allowed to stand for 3 /2 hours and is then diluted with water. After being acidified with dilute hydrochloric acid, the mixture is stirred for an additional 3 /2 hours and is then extracted with methylene chloride. The organic phase is washed with dilute hydrochloric acid and dilute aqueous sodium hydroxide, is dried over magnesium sulfate and concentrated to dryness to yield the N [3 (2 oxo cyclopentyl) propyl1phenylacetic acid amide, within melts at 110 after crystallization from diethyl ether.

A mixture of 6.7 g. of N-[3-(2-oxo-cyclopentyl)- propyl]phenylacetic acid amide in 60 g. of polyphosphoric acid is heated at 130 for fifteen hours. After being treated with ice and water, the organic material is extracted with methylene chloride; the organic phase is washed with dilute aqueous sodium hydroxide, dried over magnesium sulfate, and concentrated to dryness. The desired 2,3,3a,4,5,6,8,9-octahydro 1H benzo[a]cyclopenta [i]quinolizin-8-one of the formula 3a,4,5,6,8,9-octahydro-1H benzo[a]cyclopenta[i]quinolizine, 10-ethyl-1,2,3,4,4a,5,6,7,9,10 decahydro-benzo[a] cyclohexa[i]quinolizine, 12 benzyloxy 1,2,3,4,4a,5,6, 7,9, l0-decahydro-benzo [a] cyclohexa [i] quinolizine (from which the 12 hydroxy 1,2,3,4,4a,5,6,7,9,10 decahydrobenzo[a]cyclohexa[i]quinolizine can be obtained by hy drogenolysis in the presence of a palladium catalyst), 11- phenyloxy-2,3 ,3a,4,5,6,8,9-octahydro-1H benzo [a] cyclopenta[i]quinolizine, 8-methyl-2,-3,3a,4,5,6,3,9 octahydrolH-benzolja] cyclopenta [i] quinolizine and the like.

Example 7 To a solution of 0.03 g. of 11,12-methylenedioxy-2,3, 321,4,5 ,6,8,9-octahydro- 1H benzo [a] cyclopenta [i] quinolizine in 1.5 ml. of methanol is treated with 0.025 g. of picric acid in 0.5 ml. of methanol. The mixture is allowed to stand whereupon the desired 11,12-methylenedioxy-2,3,3 a,4,5,6,8,9-octahydro-1H benzo[a]cyclopenta [i1quinolizine picrate precipitates; it melts at 2l3-2 l4 after recrystallization from methanol.

What is claimed is:

1. A member selected from the group consisting of a compound of the formula in which the group of the formula -(C H- is alkylene having from three to ten carbon atoms separating the 1-position of the 1,2,3,4,6,7-hexahydro-11bH-benzo[a] quinolizine portion from the llb-position by three to eight carbon atoms, each of the groups R; and R is a member selected from the group consisting of hydrogen, hydroxyl, lower alkoxy, lower alkyl, and, when attached to adjacent positions and taken together, lower alkylenedioxy, and each of the groups R,,, R R R R and R is a member selected from the group consisting of hydrogen and lower alkyl, an acid addition salt thereof, an N-oxide thereof, an acid addition salt of an N-o xide thereof, a lower alkyl quaternary ammonium salt thereof and a phenyl-lower alkyl quaternary ammonium salt thereof.

2. A compound of the formula Rag W in which the letter In is the integer 3, and each of the groups R and R is lower alkoxy.

3. A compound of the formula in which the letter In is the integer 4, and each of the groups R and R is lower alkoxy.

4. A member selected from the group consisting of 1l,l2-dimethoxy-2,3,3a,4,5,6,8,9 octahydro 1H benzo [a]cyclopenta[i]quinolizine and an acid addition salt thereof.

5. A member selected from the group consisting of l-l1,12-dimethoxy-2,3,3a,4,5,6,8,9-octahydro 1H benzo [a]cyclopenta[i]quinolizine and an acid addition salt thereof.

in which the group of the formula -(C H is alkylene having from three to ten carbon atoms separating the 1-position of the 4-oxo-1,2,3,4,6,7-hexahydro-1lbH-benzo [a]quinolizine portion from the llb-position by three to eight carbon atoms, each of the groups R and R is a member selected from the group consisting of hydrogen, hydroxyl, lower alkoxy, lower alkyl, and, when attached to adjacent positions and taken together, lower alkylenedioxy, and each of the groups R R R R and R is a member selected from the group consisting of hydrogen and lower alkyl.

11. A compound of the formula I (or-12 in which the letter In is the integer 3, and each of the groups R and R is lower alkoxy.

12. 11,12-Dimethoxy-2,3,3a,4,5,6,8,9 octahydro 1H- benzo [a] cyclopenta [i] quinolizine-6-one.

13. 12,13-Dimethoxy-1,2,3,4,4a,5,6,7,9,10 decahydrobenzo [a] cyclohexa [i] quinolizine-7-one.

14. 2,3,3 a,4,5,6,8,9 octahydro-1H-benz0[a] cyclopenta [i] quinolizine-6-one.

15. 11,12 Methylenedioxy-2,3,3 a,4,5,6,8,9-octahydro- 1H-benzo [a] cyclopenta [i] quinolizine-o-one.

16. A compound of the formula tit in which the group of the formula (C H is alkylene having from three to ten carbon atoms separating the 1-position of the 1,2,3,4,6,7-hexahydro-11bH-benzo[a] quinolizine portion from the llb-position by three to eight carbon atoms, each of the groups R and R is a member selected from the group consisting of hydrogen, hydroxyl, lower alkoxy, lower alkyl, and, when attached to adjacent positions and taken together, lower alkylenedioxy, and each of the groups Ra, R R R and R is a member selected from the group consisting of hydrogen and lower alkyl.

17. A compound of the formula in which the letter m is the integer 3, and each of the groups R and R is lower alkoxy.

18. 2,3,3a,4,5,6,8,9 octahydro-lH-benzo[a]cyclopenta [i] quinolizine-8-one.

19. A compound of the formula in which the letter In is the integer 4, and each of the groups R and R is lower alkoxy. 20. A compound of the formula in which the letter m is the integer 4, and each of the groups R and R is lower alkoxy.

References Cited by the Examiner Hartung, Industrial and Engineering Chemistry, vol. 37, pages 126-127 (1945).

Morton, The Chemistry of Heterocyclic Compounds, p. VI of the preface (1946).

IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 210 ,357 October 5 1965 William Irving Taylor et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 15, lines 57 to 66, the formula should appear as shown below instead of as in the patent:

Hanan) Ra b column 16, line 54 for "R2", first occurrence, read R1 a Signed and sealed this 9th day of August 1966 (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attestlng Officer Commissioner of Patents

Claims

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA

16. A COMPOUND OF THE FORMULA