CA1055501A - 7-aza-6-alkoxy-1-tetralones derivatives and a process for making same - Google Patents

Abstract

Abstract of the Disclosure Novel compounds of the general formula IV

wherein R is an alkyl radical containing 1 to 7 carbon atoms or cycloalkyl group containing 4 to 8 carbon atoms are prepared by reacting a compound of the general formula V

with a compound of the general formula RI wherein R is an alkyl radical containing 1 to 7 carbon atoms or a cycloalkyl group containing 4 to 8 carbon atoms. These 7-aza-6-substit-uted-l-tetralones, for example 7-aza-6-methoxy-1-tetralone, are useful as intermediates in the preparation of novel steroids which have anti-viral activity and hypolipemic activity.

Description

The present invention relates to novel 2-aza-steroids, to a novel process for their preparation and to novel intermediates useful in the process. In parti-cular, it relates to a group of tetracyclic compounds having the following general structural formula.

H C
R' ~ (I) 0~
R

wherein R is an alkyl radical containing 1 to 7 carbon atoms or a cycloalkyl group containing 4 to 8 carbon atoms; R' is an alkyl radical containing 1 to 4 carbon atoms; and X is carbonyl or ~-hydroxymethylene.
The alkyl groups represented in the foregoing structural formula are typified by methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl and branched-chain isomers.
The cycloalkyl groups also represented in the foregoing structural formulas are typified by cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclo-octyl.
Those compounds are produccd rrom a novel group of intermediates represented by the following structural formulas

-2-1055S0~

~ II

R ~

H C

3 . OH
R' ~ b III

RO

wherein R is an alkyl radical having 1-7 carbon atoms or a cycloalkyl group having 4-8 carbon atoms inclusive, R' is an alkyl radical having 1-4 carbon atoms inclusive, X is a carbonylor ~-hydroxymethylene group, and the dotted line represents an optionally doubly bonded linkage.
The alkyl radicals in the foregoing structural formulas are typified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and the branched-chain isomers thereof.
The cycloalkyl groups represented herein have 4-8 carbon atoms inclusive and are illustrated by cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl and cyclooctyl.
For purpose of this invention the terms halo 1055~01 or halide refer to those derivatives of bromine, chlorine, fluorine or iodine.
The novel compounds of the present invention originate from a novel process which utilizes dihydrore-sorcinol as the starting material. That substance thusis allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-l-one. Reaction with cyanoacetamide and sodium hydride results in ~-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contac~ted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile. Elimination Or the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinol-inedione. Heating with an alkyl or cycloalkyl halide produces the corresponding 6-alkoxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexa-hydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetralone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione.
The reaction of the keto group of the 6-alkoxy and 6-cycloalkoxy 7-aza-1-tetralones with the lithium salt formed by adding butyl lithium to an appropriate halo substituted dimethylaminoalkene affords the corres-ponding N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-alkoxyisoquinol-8-yl]alk-2-en-1-yl)amine, or the appropriate cycloalkyloxy derivative. Typically, 7-aza-6-methoxy-1-tetralone is contacted with a solution contalning butyl lithium and 2-bromo-3-dimethylaminopro-pene to yield N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine.
The hydroxyl substituent is removed with a phosphorous oxyhalide, such as phosphorous oxychloride in pyridine or in concentrated sulfuric acid, to yield the N,N-dimethyl-N-(2-[5,6-dihydro-3-substituted-isoquinol-8-yl]alk-2-en-l-yl)amine. For example, N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-l-yl~amine is contacted with phosphorous oxychloride in pyridine to obtain N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl~prop-2-en-1-yl)amine. Quater-narization of the amines with an alkyl halide, e.g.
~ethyl iodide, yields the quaternary salts, which are subsequently reacted with silver oxide and then with 2-(lower alkyl)cyclopentane-1,3-dione to yield the appropriate 5,6-dihydro-3-substituted-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)alk-1-en-2-yl]isoquinoline.
In that manner, the aforementioned N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is treated with methyl iodide to afford the corresponding trimethyl ammonium iodide. Subsequent treatment with silver oxide and 2-(lower alkyl)cyclopentane-1,3-dione produces 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxo-cyclopent-2-yl)prop-1-en-2-yl]isoquinoline. Cycliza-tion of the diketones is effected conveniently with sulfuric acid to afford the corresponding dl-2-aza-3-substituted-11~-methylestra-1,3,5(10),8(14),9(11),15-lOSS50~
hexaen-17-ones. Representative thereoî is th~ ctiu~
of dl-2-aza-3-methoxy~ methylestra-1,3,5(10),8(14), 9(11),15-hexaen-17-one upon contacting the arorementioned isoqulnoline derivative with sulfuric acid.
Reduction of the 17-ketone moiety with a metallic hydride reducing agent, as for example, diisobutyl aluminum hydride, affords the 17~-ol. Catalytic hydro-genation, using a palladium-on-calcium carbonate catalyst effects saturation of the 15-double bond. Further catalytic reduction utilizing palladium-on-alumina affords those derivatives having the 1,3,5(10), and g(ll)-double bonds. T`ypically dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17-one is reduced with diisobutylaluminum hydride to the 17~-ol corresponding, and then subsequent hydrogenation as described above yields dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10), 8-tetraen-17~-ol. Reduction of the 8-double bond then can be accomplished with sodium metal in liquid ammonia to produce the instant compounds, e.g. dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10)-trien-17~-ol. A particularly preferred method of producing the instant compounds is to treat the tetraenes with sodium metal in liquid ammonia to produce the corresponding dl-2-aza-1~ -alkyl-3-substituted-estra-2,5(10)-dien-17~-ols, which then are rearomatized with dichlorodicyanobenzoquinone to yield the desired dl-2-aza-1~ -alkyl-3-substituted-estra-1,3,5(10)-trien-17~_ols.
Subsequent oxidation of the 17R-ols with sul-fur trioxide in pyridine or with c]lromic acid yields the 17~-ketones,e.g. dl-2-aza-3-methoxy-11-methylestra-1,3,5(10)-trien-17-one.

The 7-aza-1-tetralones having an alkoxy or cycloalkoxy substituer.t at the 6-position can also be converted to 2-azaestratrienes which do not have a substituent at the ll-position. Typical intermediates 1n such a conversion are:

7-Aza-6-methoxy-1-vinyl-1-tetralol 5,6,7,8-Tetrahydro-3-methoxy-8-[(2-methyl-1,3-dioxocyclopent-2-yl)ethylidene]isoquinoline.
dl-2-Aza-3-methoxyestra-1,3,5(10),8,14-pentaen-17-one.
dl-2-Aza-3-methoxyestra-1,3,5(10),8,14-pentaen-17~-ol.
dl-2-Aza-3-methoxyestra-1,3,5(10),8-tetraen-17-one.
dl-2-Aza-3-methoxyestra-1,3,5(10),8-tetraen-17~-ol.
The instant dl-2-aza-11-alkylestra-1,3,5(10)-trienes are valuable pharmacological agents as is evidenced by their anti-viral activity and hypolipemic activity. A suitable assay for detection of the anti-viral activity is described as follows:
Cell cultures of primary Rhesus monkey kidney maintained in 25 cc. plastic flasks and each containing test compound in concentrations of 625, 125, 25, 5, or 1~ g./ml. are prepared in pairs. These flasks and an identical pair of flasks containing no test compound are each inoculated with a dose of influenza virus type A (Strain 575) previously shown to produce maximum hemadsorption and minimum cytopathogenic effects after 3 a 24-hour incubation. Where the cultures contain test compound the viruses are added 1 hour after addition of the test compound to the culture. After 24 hour incuba-tion of the cultures the supernatant fluids are removed and 3.0 ml. of a 0.4% suspension of guinea pig erythro-cytes is added to each flask. The flasks are then in-cubated at 4C. in a horizontal position for 30 minutes.The flasks are rocked every 10 minutes during the incuba-tion period. After this incubation the red cell suspen-sion is decanted from each flask. The flasks are washed twice with 3.0 ml. of phosphate buffer solution (pH 7.4) to remove unabsorbed red cells and 3.0 ml. of distilled water is then added to lyse the absorbed cells. The flasks are then further incubated at 37 C. for 30 minutes in a horizontal position and the flasks are rocked every 10 minutes. After this incubation the fluid contents of the pairs of flasks are combined to form an assay unit and are placed at room temperature for 15-30 minutes to allow settling of the cellular debris.
A pair of control flasks identical with the above except for the absence of the test compound and virus inoculation are run concurrently. The resulting hemoglobin solutions from each assay unit are then read for optical density in a Beckman spectrophotometer at about 415 m~. A test compound is considered active if at any one of the tested levels it reduces the optical density reading by at least 50% relative to the virus control.
The hypolipidemic properties of the instant compounds is illustrated in the following assay:
Male Charles River rats (160-200 g.), having had free access to food and water, are administered a standard diet containing 2% DEAE - cellulose (Reeve Angel anion exchange resin) for 5 days. The rats then are sacrificed and their livers removed immediately.
The livers are homogenized in a medium consisting of 0.1 M potassium phosphate, pH 7.4, 0.004 m MgC12 and 0.03 M nicotinamide, and the microsomal-cytosol fraction obtained by centrifugation. 2.0 Ml. of the microsomal-cytosol fraction is incubated, at 37C. for 90 minutes for measurement of cholesterol biosynthesis, in a standard~assay mixture containing 10 micromoles of C14-labeled mevalonic acid, 2 micromoles nicotinamide adenine dinucleotide, 2 micromoles nicotinamide adenine dinucleo-tide phosphate, and 20 micromoles glucose-6-phosphate, and test compound, initially at 0.001 M, is added. All assays are run in duplicate with the assay to which no test compound is added serving as a control. Heat inac-tivated homogenate serves as blank for both control and test systems.
Reaction rate is determined per unit of time by the amount of C14 label incorporated into the lipid fraction from the radioactive mevalonic acid. Results are reported as % inhibition (i.e. (Reaction Rate for Test Compound/Reaction Rate for Control) x 100).
The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not be be construed as limiting the invention either in spirit or in scope as many modifications both in materials and methods will be apparent to those skilled in the art. In these examples temperatures are given in degrees Centigrade (C.) and .

quantities of materials in parts by weight unless otherwise noted. Nuclear magnetic resonance data was obtained on a Varian A 60-A or Varian T60 instrument.
Infrared spectra were recorded on a Beckman IR-12 grating spectrophotometer. Ultraviolet spectra were taken on a Beckman DX-2A.

-To a solution of 400 parts of dihydroresorcinol in 2000 ~arts by volume of chloroform was added 161.2 parts of phosphorus trichloride. The resulting reaction mixture was stirred and heated at the reflux temperature in a nitrogen atmosphere for about 3.5 hours. The mix-ture was then cooled and poured carefully into approximately 1000 parts of a mixture of ice and water. The layers were separated and the aqueous phase was extracted with ether.
Then ether extracts were combined with the chloroform layer. The resulting organic solution was washed successively with 5% aqueous sodium hydroxide solution and then dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure ~fforded the crude product. Purification of this crude product by distillation under reduced pressure gave 3-chloro-2-cyclohexen-1-one, boiling about 65 under 3mm.
pressure.

To a mixture of 58 parts Or sodium hydride and 1800 parts by volume of ethylene glycol dimethyl ether, under nitrogen, was added, at room temperature over a period of about 30 minutes, 198 parts of cyanoacetamide.
That mixture was heated at reflux temperature for about 30 minutes and allowed to cool. On cooling 145.2 parts of 3-chloro-2-cyclohexen-1-one was added over a period of 15 minutes. The mixture was stirred and heated at reflux temperature for about 1 hour, then cooled. To this cooled mixture was added dropwise a solution of 20 parts by volume of methanol and 10 parts by volume of water. ~fter this addition, 500 parts of water was added. The organic solvents were removed by distillation under reduced pressure. Acidification of the residual aqueous solution to pH 1-2 resulted in the precipitation of a product. This product was isolated by filtration, washed with cold water, and dried. Purification of this crude product by recrystallization from ethanol-water-ethyl acetate, afforded a-cyano-3-oxo-1-cyclohexen-1-acetamide, melting at 181-183.

To a solution consisting of 40 parts of a-cyano-3-oxo-1-cyclohexen-1-acetamide in 125 parts by volume of dimethylformamide, in an atmosphere of nitrogen, was added dropwise, over a period of 10-15 minutes, 40 parts of dimethylformamide diethyl acetal. After the reaction mixture was stirred at room temperature for about 18 hours, 10 parts of water was added. The organic solvents were removed by distillation under reduced pressure. The residual oil~product was ex-tracted with dilute aqueous sodium hydroxide. The extract was washed several times with chloroform and then flltered to remove a small amount of insoluble material.
Neutralization of the alkaline solution by the addition of dilute hydrochloric acid resulted in the precipitation of a product. Purification of this product by recrystalli-zation from aqueous acetone afforded 2,3,5,6,7,8-hexa-hydro-3,8-dioxo-4-isoquinolinecarbonitrile, melting above 290.

A solution of 28.4 parts of 2,3,5,6,7,8-hexa-hydro-3,8-dioxo-4-isoquinolinecarbonitrile in 500 parts by volume of 48% hydrobromic acid was heated at the reflux temperature in the absence of light for about 7 hours. After the heating period, the solvent was re-moved by distillation under reduced pressure. The resulting residue was partitioned between chloroform and aqueous sodium chloride, and the layers were then separated. The aqueous phase was extracted several times with chloroform and then was combined with the original chloroform layer. This organic solution was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate and stripped of its solvent under reduced pressure to afford the crude product. The original aqueous layer was neutralized by the additlon of sodium bicarbonate, and extracted with chloroform. Evaporation of that chloroform extract to dryness afforded additional crude product.
The combined crude product was purified by recrystalli-zation from aqueous acetone, thus affording pure lOS5501 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione, melting at about 246-248 with decomposition.

To a solution of 2.6 parts of 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione in 375 parts by volume of dry benzene was added 2.3 parts of silver carbonate and 5 parts by volume of methyl iodide. The resulting mix-ture was heated at the reflux temperature in the absence of light~ under an atmosphere of nitrogen, for about

4 hours. At the end of that time the mixture was cooled and filtered through diatomaceous earth to afford an organic solution which was extracted several times with 6 N hydrochloric acid. Those acidic extracts were washed with chloroform, made alkaline by the addition of aqueous sodium hydroxide and extracted with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The re-sulting crude product was purified by recrystallization from water to yield 7-aza-6-methoxy-1-tetralone, melting at about 55.5-57.
The aforementioned chloroform washings were evaporated to dryness under reduced pressure and the residual oil was extracted with benzene. The resulting organic solution was diluted with hexane to the point of incipient turbidity, and then decolorized with activated carbon. The decolorized solution was diluted with hexane. Cooling of this solution afforded crystal-line 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione, meltlng at about 94-97.

To 43 parts of 2-bromo-3-dimethylaminopropene in 650 parts of toluene, cooled to about -10 under an atmosphere of nitrogen, was added 130 parts by volume of 2.04 N butyl lithium in hexane solution at a rate so as to maintain a temperature below -5 during the addition.
After stirring for about 10 minutes, 9.8 parts of 7-aza-6-methoxy-1-tetralone which was dissolved in 22 parts of benzene was added over a 10 minute period. After this addition the reaction mixture was allowed to reach a temperature of approximately 5 by removal of the cooling bath. The reaction mixture was now quenched by the addition of 150 parts by volume of a saturated ammonium chloride solution. The two phases which formed were separated and the aqueous solution was extracted with benzene. The combined extracts were subsequently ex-tracted themselves with 5 portions of 5% aqueous formic acid solution. The acidic extracts were backwashed once with benzene before neutralization to pH 7 with aqueous ammonia and extraction with chloroform. The extracts were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. Upon solvent removal, a crude product was obtained as an oil.
The oil was dissolved in ether, and n-hexane was added until the solution became turbid. The solution then was filtered through diatomaceous earth. Pure N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxy_ isoquinol 8-yl]prop-2-en-1-yl)amine, melting at about 66-68 was obtained upon reducing the volume of the solution and allowing the mixture to stand at room temperature.

To 7.1 parts of N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-l-yl)amine in 31 parts of benzene and 34.5 parts of pyridine~was added 4.5 parts of phosphorous oxychloride, dropwise and at room temperature. This solution was stirred at room temperature for several hours, then cooled in an ice bath. 25 Parts of water was added slowly followed by enough 5% aqueous sodium hydroxide solution to bring the pH of the solution to about 10.
After the addition of ether, the organic and aqueous layers separated. The aqueous layer was extracted with ether and the extracts were washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Approximately 200 parts of n-hexane was added to the solution, followed by a portion of charcoal. Filtration of this mixture through diatomaceous earth gave a light yellow solution which, upon solvent removal, afforded a yellow oil.
This oil was distilled and the distillate was taken up into methanol-water. Upon standing this solu-tion yielded crystalline N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl~prop-2-en-1-yl)amine melting at about 42-45.

A solutlon of 0.04 part of N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine and 0.5 part by volume of concentrated sulfuric acid was allowed to stand at room temperature for about 30 minutes. This reaction mixture was added to water and made alkaline with aqueous ammonia. The solu-tion was extracted with ether and the etheral extracts were washed with saturated sodium chloride solution, dried ovèr anhydrous sodium sulfate and evaporated under reduced pressure to yield N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine, identical to the product of Example 7 A.

To a solution containing 4.3 parts of N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine in 88 parts of benzene was added 10 parts by volume of methyl iodide. The mixture was allowed to stand at room temperature for 3.5 hours. The precipitate which formed was filtered, washed with additional benzene, and dried. This procedure afforded a crude product which, upon recrystallization from acetone-ethyl acetate, gave pure N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxy-isoquinol-8-yl]prop-2-en-1-yl)ammonium iodide, melting at about 165-169~.

~05550~

5.8 Parts of N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)ammonium iodide was dissolved in a mixture of 64 parts of methanol and 20 parts of water, and treated with 1.9 parts of silver oxide. This solution was stirred in the absence of light for 1 hour and then filtered through diatomaceous earth. The filtrate was treated with 2.0 parts of 2-methylcyclopentane-1,3-dione. The solvent was removed under reduced pressure at about 50. The oily residue which remained was taken up into 26 parts of dioxane.
Then 132 parts of xylene was added, followed by 4 parts by volume of triethylamine. The solution was heated to reflux temperature and refluxed overnight under a nitro-gen atmosphere. After the overnight heating period, asolution of 5% aqueous sodium hydroxide was added.
The layers which formed separated; the organic phase was washed with saturated sodium chloride and then ex-tracted with 2.5% aqueous formic acid. The acidic extracts were backwashed with benzene and combined.
These combined extracts were washed with a saturated sodium chlorine solution, and dried over anhydrous sodium sulfate. Removal of the solvent gave an oil which crystallized upon scratching to give a crude product. Pure 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline was ob-tained upon recrystallization from acetone.

~05550~

A solution containlng 0.75 parts of 2.methyl-cyclopentane-1,3-dione in 19 parts of dimethylformamide was treated sequentially with 1.0 part by volume of tri-ethylamine and 1.9 parts of N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl) ammonium iodide. The resulting homogeneous solution was heated at approximately 135 for 4 3/4 hours. It was allowed to cool to room temperature and the solvent was removed ~nder reduced pressure. The remaining material was diluted with water-ether and enough 5% sodium hydroxide solutioh was added to bring the pH to 10. The aqueous and organic layers were separated and the aqueous layer was extracted with ether. The extracts were washed sequentially with 5% sodium hydroxide solution, 2.5%
- aqueous formic acid solution and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate.
Upon solvent removal, an oil remained which was taken into ether. Then n-hexane was added until the solution became turbid. Charcoal was added and the mixture was filtered. Solvent was removed under reduced pressure to yield an oil which crystallized upon standing. Re-crystallization of this material from acetone-water gave pure 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxo^
cyclopent-2-yl)prop-1-en-2-yl~isoquinoline, which was identical to the product obtained in Example 9 A.

~ossso~

To 40 parts by volume of concentrated sulfuric acid which was cooled to about -5 with a cooling bath, was added 2.4 parts of 5,6-dihydro-3-methoxy-8-[3-(2 methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoqvinoline, portionwise at a rate such that the temperature does not exceed 10. After the additions were completed, the cooling bath was removed and the solution was allowed to warm to room temperature. The solution then was added to 100 part`s of water which was cooled in an ice bath, and made alkaline with ammonium hydroxide to afford a pre-cipitate which was recovered by filtration. This material was recrystallized from acetone to give a pure compound, dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10), 8(14),9(11),15-hexaen-17-one3 meltingat about 197-198.5.

A solution of 2.1 parts of dl-2-aza-3-methoxy-ll~-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17-one in 66 parts of benzene and 36 parts of ethyl ether, cooled to 0, was treated with 12 parts of a 20% diisobutyl alu-minum hydride in a toluene solution. The reducing agent was added dropwise over a 10 minute period. The ini-tially heterogeneous solution becarl~e homogeneous and was stirred for about 15 minutes before destroying the re-ducing agent with isopropyl alcohol. Water, acidified with a small quantity of hydrochloric acid, was added to form 2 layers. The slightly acidic aqueous layer was extracted with benzene and the pH of this aqueous l~)S5501 solution was adjusted to approximately 6.5 to 7 with ammonium hydroxide. The aqueous layer was extracted with chloroform. The extracts were combined. Upon solvent removal, an oil remined which was triturated with methanol to give a crude crystalline product. Pure dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10),8(14), 9(11),15-hexaen-17~-ol, melting at about 95-100, was obtained upon recrystallization from methanol.

.

` EXAMPLE 12 A mixture consisting of 1.0 part of dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17~-ol, 200 parts by volume of benzene, and 0.5 part of 5% palladium-on-calcium carbonate catalyst was stirred in a hydrogen atmosphere at room temperature and atmospheric pressure until approximately a molecular equivalent of hydrogen had been absorbed. The solvent was removed under reduced pressure to yield an oil which was taken up into denatured ethanol. Upon cooling, dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10),8(14),9(11)-pentaen-17~-ol formed as yellow crystals. That material exhibited maxima in the ultraviolet spectrum in methanol at about 291 milimicrons with a molecular extinction coefficient of about 6860, 242 milimicrons with a molecular extinction coefficient of about 21,900 and 247 milimicrons with a molecular extinction co-efficient of about 20,900. It further was characterized by maxima in the nuclear magnetic resonance spectrum in deuterio chloroform at about 55, 122, 135, 237, 243 and 488 Hertz.

'105550~

To a solution of 3.7 parts of dl-2-aza-3-methoxy-ll~-methylestra-1,3,5(10),8(14),9(11)-pentaen-17~-ol in 79 parts of ethanol was added 1.8 parts of 5% palladium-on-alumina catalyst and that mixture was shaken with hydrogen until a molecular equivalent of hydrogen had been absorbed. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give an oil, which when taken up in methanol and cooled yielded crystalline dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10),8-tetraen-17~-ol, melting at about 164-167.5.

To 50 parts by volume of freshly distilled ammonia, cooled to -78 under a nitrogen atmosphere, was added 0.55 part of sodium metal in small pieces. The mixture was stirred for approximately 15-30 minutes, then 0.30 parts of dl-2-aza-3-methoxy-llB-methylestra-1,3, 5(10),8-tetraen-17~-ol in l8 parts of tetrahydrofuran was added to the deep blue solution over a 5 minute period.
The reaction mixture was stirred at -78 for about 30 minutes, then 2.0 parts of ammonium chloride was added. The cooling bath was removed and the reaction mixture was allowed to warm to about -33 at which point the ammonia was distilled off. A portion of ether was added as the ammonia evaporated. After evaporation, a saturated sodium chloride solution was added, and the ether layer was separated from the aqueous phase. The organic phase was washed with additional sodium chloride 105550~.
solution and dried over anhydrous sodium sulfate. Upon solvent removal, desired product and crude dl-2-aza-3-methoxy-11~-methylestra-2,5(10)-diene-17~-ol remained as an oil. The crude oil was taken up in a mlxture of 5 parts by volume of acetone and 5 parts by volume of benzene, and to this solution was added 0.250 part Or di-chlorodicyanobenzoquinone. The reaction mixture was stirred at room temperature for about 15 minutes, after which time 25 parts by volume of a 10~ sodium bisulfite solution and a portion of ether were added. The two layers were separated and the organic phase was washed with 5% sodium hydroxide solution and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The dried solution was treated with activated charcoal and filtered through diatomaceous earth. Solvent removal gave an oil which, upon crystallization from methanol and re-crystallization from ether-methanol, gave pure dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10)-trien-17~-ol, melting at about 168-169.

0.10 Part of dl-2-aza-3-methoxy-11~-methylestra-1,3,5(10)-trien-17~-ol in 1 part by volume of dimethylsul-foxide containing 0.25 part by volume of triethylamine was vigorously stirred, then treated with 0.15 part of sulfur trioxide-pyridine salt. The reaction mixture was stirred for 20 minutes to afford an oil, which upon continued stirring became a red solid. The solid was recovered and recrystallized from methanol to give dl-2-aza-3-methoxy-ll~-methylestra-1,3,5(10)-trien-17-one, melting at approximately 155-160.

1~55501 Substitution of an equivalent quantity of ethyl iodide, cyclopentyl iodide or cyclohexyl iodide for the methyl iodide utilized in the procedure of Example 5 afforded respectively, 7-aza-6-ethoxy-1-tetralone, 7-aza-6-cyclopentyloxy-l-tetralone and 7-aza-6-cyclohexyloxy-l-tetralone.

The products described in Example 16 are treated according to the procedures outlined in Examples

6-10 to yield, respectively, dl-2-aza-3-ethoxy-11~-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17-one;
dl-2-aza-3-cyclopentyloxy-11~-methylestra-1,3,5(10~,8(14), 9(11),15-hexaen-17-one; and dl-2-aza-3-cyclohexyloxy-11~-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17-one.

The compounds of Example 17 were treated accord-ing to the procedure described in Example 11 to afford, respectively, dl-2-aza-3-ethoxy-11~-methylestra-1,3,5(10), 8(14),9(11),15-hexaen-17~-ol,~ dl-2-aza-3-cyclopentyloxy-11~-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17~-ol and dl-2-aza-3-cyclohexyloxy-11~-methylestra-1,3,5(10), 8(14),9(11),15-hexaen-17~-ol.

The compounds of Example 18 were treated accord-ing to the procedure described in Example 12 to afford, 105SS0~
respectively, dl-2-aza-3-ethoxy-llB-methylestra-1,3,5(10), 8(14),9(11)-pentaen-17~-ol; dl-2-aza-3-cyclopentyloxy-ll~-methylestra-1,3,5(10),8(14),9(11)-pentaen-17~-ol;
and dl-2-aza-3-cyclohexyloxy-11~-methylestra-1,3,5(10), 8(14),9(11)-pentaen-17~-ol.

The compounds of Example 19 were treated accord-ing to the procedures described in Examples 13 and 14 to afford, respectively, initially the intermediates dl-2-aza-3-ethoxy-ll~-methylestra-2~5(lo)-dien-]7~-ol;
dl-2-aza-3-cyclopentyloxy-11~-methylestra-2,5(10)-dien-17~-ol; and dl-2-aza-3-cyclohexyloxy-11~-methylestra-2,5(10)-dien-17~-ol, and then the instant dl-2-aza-3-ethoxy-ll~-methylestra-1,3,5(10)-trien-17~-ol; dl-2-aza-3-cyclopentyloxy-11~-methylestra-1,3,5(10)-trien-17~-ol; and dl-2-aza-3-cyclohexyloxy-11~-methylestra-1,3,5(10)-trien-17~-ol.

The products of Example 20 were treated accord-ing to the procedure of Example 15 to afford, respectively, dl-2-aza-3-ethoxy-11~-methylestra-1,3,5(10)-trien-17-one, dl-2-aza-3-cyclopentyloxy-11~-methylestra-1,3,5(10)-trien 17-one, dl-2-aza-3-cyclohexyloxy-11~-methylestra-1,3,5(10)-trien-17-one.

_z~

lOSSSOl Pharmaceutical formulations were prepared in the following manner with amounts indicating the relatlve amount per tablet. Thus, 750 mgs of 2-aza-3-methoxy-11~-methylestra-1,3,5(10)-trien-17~-ol was dissolved in iso-propyl alcohol-water mixture and distributed on 160 mgs. of lactose. The mixture was air dried and passed through a 40 mesh screen. 50 Mgs. of corn starch and 30 mgs. of polyvinylpyrrolidone were added to the drug substance-lactose mixture, mixed thoroughly and passed through a 40 mesh screen. The mixture was then granulated with isopropyl, spread on trays, and dried at 120F. for 16 hours. The dried granulation was then screened. The granules were mixed thoroughly with 10 mgs. of magnesium stearate and the mixture was compressed into tablets. The tablets weigh 1000 mg. and contained 750 mg. of active ingredient per tablet.
In the preparation of tablets from the compounds of the present invention, a variety of excipients can be used. These are summarized as follows: sugars such as lactose, sucrose, mannitol, or sorbitol; starches such as corn starch, tapioca starch, or potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, or methyl cellulose; gelatin; calcium phosphates such as dicalcium phosphate or tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate; stearic acid vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn lOSSSOl oil; surfactants (nonionic, cationic, anionic); ethylene glycol polymers; beta-cyclodextrin; fatty alcohols; hydro-lyzed cereal solids; as well as other non-toxic compatible fillers, binders, disintegrants, and lubricants commonly used in pharmaceutical formulations.

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the general formula IV

wherein R is an alkyl radical containing 1 to 7 carbon atoms or cycloalkyl group containing 4 to 8 carbon atoms which is characterized by reacting a compound of the general formula V

with a compound of the general formula RI

wherein R is an alkyl radical containing 1 to 7 carbon atoms or a cycloalkyl group containg 4 to 8 carbon atoms.

2. The process according to Claim 1 wherein the alkyl or cycloalkyl iodide used is methyl iodide.

3. The process according to Claim 1 for the preparation of 7-aza-6-methoxy-1-tetralone which is characterized by reacting 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione with methyl iodide.

4. A compound of the formula IV

wherein R is an alkyl radical containing 1 to 7 carbon atoms or cycloalkyl group containing 4 to 8 carbon atoms, whenever prepared by the process of Claim 1.

5. A compound of the formula IV as defined in claim 4, whenever prepared by the process of claim 2.

6. 7-Aza-6-methoxy-1-tetralone, whenever prepared by the process of Claim 3.