US3033860A - Cyclopentanophenathreno-1, 3-oxazines - Google Patents

Description

a 3,033,860 CYCLOPENTANOPHENATHRENO-1,3-XAZINES Martin Eric Kuehne, Summit, N.J., assignor to Ciba Corporation, a corporation of New Jersey No Drawing. Filed Feb. 19, 1960, Ser. No. 9,699 i 16 Claims. (Cl. 260-23955) United States Patent on; v

in which R represents aliphatic hydrocarbon or substituted aliphatic hydrocarbon, R represents 0x0, functionally converted 0x0, or one of the groups of the formulae H(H), OH(H), OH(R in which R represents a lower aliphatic hydrocarbon, OAc(H), in which Ac represents an acyl radical, or OAc(R in which Ac and R have the previously given meaning, and R represents hydrogen, hydroxyl, acyloxy or lower alkyl, salts or quaternary ammonium compounds thereof, as well as process for the preparation of such compounds thereof, as well as process for the preparation of such compounds.

The radical R attached to the nitrogen atom of the oxazine nucleus represents an aliphatic hydrocarbon radical, such as, for example, alkyl, particularly lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl and the like, alkenyl, primarily lower alkenyl,

v 2-cyclopentenyl,

3,633,869 Patented May 8, 1962 ice e.g. allyl, Z-methyl-allyl, S-methyl-allyl and the like, cycloalkyl, which contains from three to seven ring car bon atoms, e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, cycloalkenyl, which contains from five to seven carbon atoms as ring members, e.g.

3-cyclopentenyl, Z-cyclohexenyl, 3- cyclohexenyl and the like, cycloalkyl-lower alkyl radicals, in which cycloalkyl contains from three to seven carbon atoms as ring members, e.g. cyclopropylmethyl, cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentylethyl, l-cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl, l-cyclohexylethyl, Z-cyclohexyiethyl, l 'cyclohexylpropyl, 3-cyclohexylpropyl and the like, cycloalkenyl-lower alkyl radicals, in which cycloalkenyl contains from five to seven ring carbon atoms, e.g. 2-cyclopentenylrnethyl, 3 cyclopentenylmethyl, 2 (2 cyclopentyl)-ethyl, 2-cyclohexenylmethyl, 3 -cyclohexenylmethyl, ,1-(3 -cyclohexenyl)-ethyl, 2-(2-cyclohexenyl)- ethyl, ,3-(2 cyclohexenyl)-propyl and the like, or any other aliphatic hydrocarbon radical.

Substituted aliphatic hydrocarbon radicals are, for example, those carrying functional groups. Such groups are primarily attached to lower alkyl radicals, such as, for example, methyl, ethyl, 1,1-dimethyl-cthyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl and the like. One or more than one functional group may be attached to any of the positions of the aliphatic hydrocarbon, particularly lower alkyl, radical available for substitution.

Functional groups are, for example, carboxy groups or functionally converted carboxy groups, such as carbolower alkoxy, e.g. carbomethoxy, carbethoxy and the like, carbamyl, particularly N-unsubstituted carbamyl, N-monosubstituted carbamyl, such as N-lower alkyl-carbamyl, e.g. N-methyl-carbamyl and the like, N,N-disubstituted carbamyl, such as N,N-di-lower alkyl-carbamyl, e.g. N,N-dimethyl-carbamyl and. the like, cyano or any other functionally converted carboxy group.

Other functional groups attached to an aliphatic radical are, for example, halogens, e.g. chloro, brorno and the like, as well as amino groups, particularly'N,N- disubstituted amino groups, particularly N,N-di-lower alkylamino, e.g. N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethy1amino, N,N-di-isopropylamino and the like, l-N,N-lower alkylene-imino group, in which the lower alkylene radical contains from four to' six carbon atoms, such as l-pyrrolidino, I-piperidino, 1-N,N- hexamethylene-imino and the like, l-N,N lower oxaalkylene-imino, in which oxa-alkylene contains preferably four carbon atoms, e.g. l-morpholino and the like, i

or 1-N,N-lo weraza-alkylene-imino, in which aza-alkylene contains from four to six carbon atoms, e.g. I-piperazino, 4-methyl-l-piperazino, and the like, N-acylamino groups, in which acyl represents the acyl radical of an organic carboxylic acid, for example, a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, acyl radicals, particularly those of organic carboxylic acids, such as lower alkanoic acid, e.g. acetic, 'propionic, butyric acid and the like, hydroxyl groups, esterfied hydroxyl, especially hydroxyl groups esterified with or ganic carboxylic acids, for example, lower aliphatic carboxylic acids, such .as lower alkanoic acids, e.g. acetic, propionic, pivalic acid and the like, etherified hydroxyl groups, represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, or etherified mercapto groups, for example, aliphatic hydro: carbon-mercapto, such as lower alkyl-'mercapto, e.g. methylmercapto, ethylmercapto, n-propylmercapto, isopropylrnercapto, n-butylmercapto, isobutylmercapto and the like, or any other functional group capable ofsubstituting aliphatic hydrocarbon. x

Substitu ted aliphatic hydrocarbons are primarily those containing carbocyclic aryl groups, such as inonocyclic carbocyclic aryl, e.g. phenyl or 'substituted'phenyl, or

bicyclic carbocyclic aryl, e.g. l-naphthyl or Z-naphthyl or substituted naphthyl radicals. Such carbocyclic arylsubstituted aliphatic hydrocarbon radicals may be represented primarily by monocyclic or bicyclic carbocyclic aryl-lower alkyl, such as phenyl-lower alkyl, e.g. benzyl,

l-phenylethyl, 2-phenylethyl, S-phenylpropyland the like, 1

. as well as l-napuhthylmethyl and the like, and these radicals, particularly phenyl-lower alkyl, substituted in the carbocyclic aryl portion. Substituents attached to the latter are, for example, lower alkyl, e.g methyl, ethyl substituent. .Substituents attached to carbocyclic aryl,

particularly monocyclic carbocyclic'aryl, portions may be attached to any of the available positions, whereby one or more than one of the same or of different substituents may be present.

Additional substituents of an aliphatic hydrocarbon radical are heterocyclic aryl radicals, which are particularly attached tolower'alkyl radicals. The heterocyclic radicals are primarily mouocyclic or bicyclic. heterocyclic aryl radicals, which may preferably contain from five to six atoms as ring members in the heterocyclic portion, such as monocyclic mono-azacyclic aryl, such as pyrryl, e.g. Z-pyrryl and the like, pyridyl, e.g. Z- yridyl, 3-pyridyl, l-pyridyl and the like, monocyclic diazacyclic aryl, such as pyridazinyl, e.g. 3-pyridazinyl and the like, pyrimidyl, e.g. Z-pyrirnidyl, 4-pyrimidyl and the like, pyrazinyl, e.g. 2-pyrazinyl and the like, bicyclic mono-azacyclic aryl, such as quinolyl, e.g. Z-quinolyl, 4-quinolyl, and the like, or isoquiuolyheg. l-isoquinolyl and the like, monocyclic monothiacyclic aryl, such as thienyl, e.g. Z-thienyl and e.gjmethyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, orhalogeno, e.g. fluoro, chloro, bromo, and the like.

, methacrylic, undecylenic acid and the like, alkynoic, such e.g. trifluoromethyl and the like, or any other suitable bonic acids, e.g. methoxy-carbonic, ethoxy-carbonic acid and the like, amino-carbonic acids (or carbamic acids), such as carbamic, N-lower alkyl-carbamic acid, e.g. N- rnethyl-carbamic and theglike, N,N-di-lower alkyl-carbamic acid, eg, N,N-dimethyl-carbamic and the like, N- carbocyclic aryl-carbamicacid, such as N-monocyclic or N-bicyclic' carbocyclic aryl-carbamic acid, e.g. N-phenylcarbamic, N-Zmaphthyl-carbamic acid and the like, alkanoic, particularly lower alkanoic, acids, e.g. (formic, acetic,propionic, butyric, pivalic, heptanoic acid and the like, alkenoic, such as lower 'alkenoic, acids,-e.g. acrylic,

as lower alkynoic, acids, e.g.propiolic acid and the like, alkane, such as lower alkan'e, dicarboxylic acids, e.g. succinic, glutaric acid and the like, cycloalkane .carboxylic acids, e.g. cyclohexane carboxylic acid and the like, or

,cycloalkyl-lower alkanoic .acids, e.g. B-cyclopentyl-propicnic, cyclohexylacetic acid and the like. Acyl radicals may also be those of substituted lower alkanoic acids, such as, for example, haloge'no-lower alkanoic acids, e.g. chloroacetic, dichloroacetic, trifluoroace tic, trichloroacetic acid and the like, lower alkoxy-lower alkanoic acids,

e.g. methoxyacetic acid and the like, or amino-lower alkanoic acids, particularly N,N.-di-lower alkyl-aminolower alkanoic acids, e.g. N,N-dimethylamino-acetic, 3- N,N-diethylamino-propionic acid and the like, or N,N-

' alkylene-imiuo-lower alkanoic acids, e.g. 3-(1-piperidino)- V propionic acid and the like.

-the like, or mouocyclic mono-oxacyclic aryl, such as furyl,

Apart from representing two hydrogen atoms, the group R attachedto the l7-position of the steroid portion of the molecule, represents an OX0 group or a functionally converted OX0 group; the'latter type may be represented by an oxime of the formula =N-OH or =N-OAc,

in which Ac represents acyl, more specifically defined hereinbelow,v a semicarbazone of the formula V N-NHCO NH a thiosemicarbazone of the formula =NNH-CS -NH 7 Other acyl radicals maybe those of carbocyclic aryl carboxylic acids, especially monocyclic carbocyclic-aryl carboxylic acids, e.g. benzoic, 4-methyl-benzoic, .4-methoxy-benzoic, 3,4,5-trimethoxy- .benzoic, 4-0-ethoxy-carbonyl-syringic, 3,4-dichloro-ben zoic, 3-nitro-benzoic, 3-N,Ndimethylamino-benzoic acid and the like, or bicyclic aryl carboxylic acids, e.g. l-naphthoic, Z-naphthoic acid and the like, carbocyclic aryl-lower aliphatic carboxylic acids, such as-monocyclic carbocyclic aryl-lower alkanoic acids, e.g. phenylacetic, diphenylacetic, 3-phenyl-propionic, 4-methoxyphenylacetic acid and the like, or nionocyclic carbocyclic aryl-lower alkenoic acids, e.g. cinnamic, 4-chloro-cinnarm'c, 3,4,5-trimethoxybenzoic acid and the like, heterocyclic aryl carboxylic acids, such as .monocyclic heterocyclic aryl carboxylic acids, e.g. nicotinic, isonicotinic, Z-furoic, Z-thienoic acid and the like, or heterocyclic aryl-lower aliphatic carboxylic acids, such as-rnonocyclic heterocyclic aryl-lower alkanoic acids, e.g. Z-pyridyl-acetic, Z-thienyl-acetic acid and the like.

Lower aliphatic hydrocarbon radicals representingthe group R are primarily represented by lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, lower alkenyl, such as vinylic lower alkenyl, e.g. vinyl, 1-

propenyl and the like, or allylic lower'alkenyl, e.g. allyl,

Z-methyl-allyl, Z-butenyl and the like, for lower alkynyl, e.g. ethynyl, lj-propy'n'ylandthe like.

The group R represents hydrogen, hydroxy, functionally converted hydroxy, particularly esterified hydroxy of the formula OAc, in which Ac has the above-given meaning, or lower alkyl, e.g. methyl, ethyl and the like.

The radical R may also stand for OH(H), outta in'which R represents an aliphatic hydrocarbon, particularly a lower aliphatic hydrocarbon, radical, especially lower alkyl, lower alkenyl or lower alkynyl, to be defined hereiubelow, OAc(H), in which Ac represents an acyl radical, particularly the acyl radical of an organic car- .boXylic acid tobe defined more specifically hereinbelow, or ()ActfR in which Ac and R have the previously given meaning.

The acyl radical Ac in the above formulae stands particularly for the acyl radical of a therapeutically acceptable organic carboxylic acid containing from one to' twelve carbon atoms. Such acids may be represented by aliphatic carbcxylic acids, such as lower alkoxy-car- Salts of the .cornpoundsof this invention are particularly therapeutically acceptable acid addition salts with inorganic acids, particularly mineral acids, e.g. hydrochloric, hydrobromic,- sulfuriqphospho'ric acids and the like, with organic carboxylic acids, e.g. formic, acetic, propionic, glycoiic, lactic, pyruvic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic, furnaric, rnalic, tartaric, citric, benzoic, cinna-mic, maudelic, salicylic, 4 amino'salicylic, Z-phenoxybenzdic, 2-acetoxybenzoic, and the like, or organic sulfonic acids, e.g. methane sulfonic,

ethane sulfonic,.hydroxyethane sulfonic, p-toluene sulfonic acid and the like.

Quaternary ammonium derivatives of the compounds of this invention are particularly lower alkyl quaternary ammoniurnsaltssuchas those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bro-.

s,oss,seo

mide or iodide and the like, di-lower alkyl-sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate and the like, lower alkyl lower hydroxyalkane sulfonates, e.g. methyl Z-hydroxyethane sulfonate and the like, lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate and the like. Also included as quaternary ammonium compounds are lower alkyl quaternary ammonium compounds with other inorganic or organic acids, such as with those described hereinbefore as being suitable for the preparation of acid addition salts.

Compounds of the present invention have estrogenic or uterotrophic effects, which are manifested in growth stimulation of the uterus in animal tests. They can, therefore, be used in the control of uterine bleeding, symptoms of menopause, threatened abortion and the like.

A preferred group of compounds may be represented by the formulae:

0 H: N/ I 2 0 O H C H:

and

'allgyl substituted by carbamyl, in which lower alkyl contains from one to seven, primarily from one to four, carbon atoms, cycloalkyl containing from three to seven,

particularly from five to six, ring carbon atoms, monocyclic carbocyclic aryl-lower alkyl, particularly phenyllower alkyl, in which lower alkyl contains from one to seven, particularly from one to four, carbon atoms,

monocyclic monoheterocyclic-lower alkyl, particularly twelve carbon atoms, particularly of a lower alkanoic acid containing from one to seven, particularly from one to four, carbon atoms, OH(R in which R, stands for lower alkyl containing from one to four carbon atoms,

lower alkenyl containing from one to four carbon atoms or lower alkynyl containing from one to four carbon atoms, OAc'(R in which R, and Ac have the previously given meaning, or :0, and R stands for hydrogen or hydroxy, therapeutically acceptable acid addition salts or lower alkyl thereof.

This group of compounds may be represented by the compounds of the formulae:

quaternary ammonium compounds in whichvR" represents lower alkyl, containing from one -to seven, particularly-from one to four, carbon atoms,

cycloalkyl containing from five to six ring carbon atoms, phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, or pyridyl-lower alkyl, in which' lower alkyl contains from one to four carbon atoms, R stands for OH(H), OH(lower alkyl), in which lower alkyl contains from one to four carbon atoms, O'H(lower alkenyl), in which lower alkenyl contains from one to four carbon atoms, OH(1ower alkynyl), in which lower alkynyl contains from one to four carbon atoms, or =0, the therapeutically acceptable mineral acid addition salts and the lower alkyl quaternary ammonium halides, sulfates and sulfonates thereof.

mula;

V V H H1 fill in which R" has the previously given meaning, 3'-R"- 2',4' dihydro 17a ethynyl 17ft hydroxy l,3,5()- estratrieno[2,3 e]:1',3-oxazines of the formula:

rw-N Hu l in which R has the previously given meaning are specific groups of compounds with outstanding estrogenic activities. In the above formulae R" stands primarily for four carbon atoms, cycloalkyl, containing preferably a from five to sixjriug carbon atoms, and phenyl-lower' alkyl, in which lower alkyl contains preferably from one to four carbon atoms.

1,35,5(10)-estratrieno[3,4-e] l','3-oxazines' of a the forpolyalkylene glycols or any other known carrier for medicaments. The pharmaceutical preparations maybe inrthe 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 1 like, salts for varying the osmotic pressure, buffers, or

no lower alkyl, such as lower alkyl containingtfrom oneto 7' The new compounds of this invention may be used as 'rnedicaments in the form of pharmaceutical preparations,

which contain the new compounds, the salts or the quaternary ammonium compounds thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier. 'For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches,

stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils,benzyl alcohols, gums, propylene glycol,

other, auxiliary substances.

The compounds of the present invention may also be used on inter-mediates for the preparation of other useful compounds.

The compounds .of the present invention may be prepared, for example, by reactingone of the compounds of the formula:v

and

in which R has the above-given meaning, and with at least two equivalent amounts of formaldehyde or a re active derivative thereof, and, if necessary, separating a resulting mixture of compounds into single compounds and/or, if desired, converting a resulting salt into the free compound and/or, if desired, converting a resulting compound into a salt or. quaternary ammonium com-' pound thereof.

' The reaction is preferably carried out in the presence of diluents, particularly water-miscible, polar solvents, for example, alcohols, such as lower alkanols, e.g. methanol, ethanol, n-propanol, isopropanol and the like, others, e.'g. ,tetrahydrofuran, p-.dioxane, diethyleneglycol dimethylether and the like, ketones, e.g. acetone, ethyl methyl ketone and the like, 'carboxylic acid amides, e.g. formamide, N,N-dimethylformamide and the like, or water or mixtures of such solvents, as well as less polar solvents, such as aliphatic hydrocarbons, e.g. pentane, hexane and the like, carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, or any other suitable solvents.

Usually the amine and the phenol are given to the solution of the formaldehyde, which may be used as an aqueous solution thereof, or in the form of a polymer thereof, e.g. para-formaldehyde, trioxymethylene and the like, or'of an acetal thereof with a lower alkanol, e.g. methanol, ethanol and the'like, such as a di-lower alkoxymethane, e.g. dimethoxymethane, diethoxymethane and the like. The reaction may be carried out in the presence I of a condensing reagent, for example, a base, such as an alkali metal hydroxide, e. g. lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. If necessary, the reaction mixture maybe heated, for example,

9 on the steam bath to about 80-90", if desired, in the atmosphere of an inert gas, e.g. nitrogen.

The resulting benzoxazine compound may crystallize upon cooling, or it may be isolated, for example, by diluting the solution with a solvent differing from the one used during the reaction and, if necessary, extracting the product, or by evaporating the solution and crystallizing the residue. The reaction product is purified according to known methods, for example, by crystallization, recrystallization, adsorption, for example, or aluminum oxide, or another suitable adsorbent, and elution, or any other suitable purification method.

A resulting mixture of compounds may be separated on the basis of physico-chemical differences, such as solubility differences; crystallization from solvents or solvent mixtures, or any other suitable separation method may be used.

The starting materials used in the above reaction are known, or if new, may be prepared according to known procedures. I

The compounds of this invention can be obtained in the form of the free bases was the salts thereof. A salt may be converted into the free base, for example, by reaction with an alkaline reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, or ammonia, or with an anion exchange resin. A free base may be converted into its therapeutically useful acid addition salts by reaction with one of the inorganic or organic acids outlined hereinbefore; for example, a solution of the free base in a solvent, such as a lower alkanol, e.g. methanol, ethanol, propahol, isopropanol and the like, a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like, an ether, e.g. diethylether and the like, a halogenated aliphatic hydrocarbon, e.g. methylene chloride and the like or in a mixture of solvents may be reacted with the acid or a solution thereof and the desired salt may then be isolated.

Quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by re acting the tertiary base with an ester formed by an alcohol and a strong inorganic or organic acid. Such acids are more especially mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or

bocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate and the like. The quaternizing reaction may be performed in the absence or in the presence of a solvent, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, butanol, pentanol and the like, a lower alkanone, e.g. acetone, methyl ethyl ketone and the like, an organic acid amide, e.g. formamide, dimethylformamide and the like, a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene and the like, a halogenated hydrocarbon, e.g. methylene chloride and the like,- an ether, e.g. diethyl ether and the like, or any other equivalent solvent.

Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, 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 exchanger, or by electrodialysis. From any resulting quaternary ammonium base there may be prepared therapeutically suitable quaternary .45 strong organic acids, e.g. p-toluene sulfonic acid and the This solution (Woelrn, basic, activity II); the column is developed with which melts at l00-101 from the aboves olvent.

by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as the hydrates; monoor poly-quaternary ammonium compounds may be formed depending on the number of tertiary amino groups.

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 u'sed'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 Tea cold solution of 0.65 g. of trioxymethylene and .a trace of potassium hydroxide in 35 ml. of n-propanol is added 1.1 g. of benzylamine, followed by 3.0 g. of 17u-ethynyl-estradioL. The mixture is refluxed for fifteen hours under an atmosphere of nitrogen, the solvent is I evaporated under reduced pressure and the residue is dissolved in a 2:1-mixture of benzene and petroleum ether. is chromatographed on aluminum oxide the initial solvent mixture to yield 2.8 g. of crude material. The latter is dissolved in a mixture of methylene chloride and heptane, which is gradually evaporated until crystallization occurs. A total of 1.4 g. of crystalline product is filtered 011?, which is recrystallized from the methylene chloride-heptaue mixture to yield 1.1 g. of 3 benzyl 2.,4' dihydro 17a ethynyl 17B hydroxy-1,3,5(10)-estratrieno[2,3-e]-1',3'-oxazine of the formula:

:'--- ozon after repeated recrystallizations Paper chromatography on W1- .paper, treated with a 121- ture of formamide and methanol containing one per cent of benzoic acid, shows Rf=25 in mobilephase A (chloroform saturated with formamide) and Rf=50 in mobile phase B (lzl-mixture of benzene and chloroform, containing two percent of pyridine); the compound is detected by treatment of the paper with antimony trichloride or platinum hexachloride.

After removal of the previously mentioned 1.4 g. of crude crystallizate, the filtrate is further evaporated and 0.4 g. of 3'-benzyl-2,4dihydro 17a ethynyl-l7/9-hy- .11 drew-15,5110Lestratrieno [3 ,4-e] 1 ,3 '-oxazine of the formula: V

i Egg is recovered in amorphous form; paper chromatograph on the above-mentioned paper shows Rf=90 in mobile phase A and Rf='85 in mobile phase B.

Example 2 A total of 1.0 g. :of cyclohexylamine'is added to a cold solution of 0.65 g. of trioxymethylene and a trace of potassium hydroxide in 35 ml. of propanol, which is followed by 3L0 gLof 1 7a-ethynyl-estradio1. The reaction mixture is refluxed for fifteen hours under an atmosphere of nitrogen, md worked up .as shown in Example 1. The initial eluate from the chromatogram yields 3.3 g. of

crude material, which 'is dissolved in cyclohexane and rechromatographed on 50 g. of a magnesia silica gel prep- .aration as described in-U;S. Patent No; 2,393,625 The .first fractions are crystallized from heptane giving 0.59 g. :of crystalline material, 0.33 -g. :of a gummy crystalline product and 0.74. g. of .amorphousmaterial; an additional amount of 0.521 g. of amorphous material is obtained-by -further ;elution'with a lzl-mixture ofbenzene and cyclohexane. The initial crystalline material is recrystallized from .heptane to yield the 3'-cyclohexyl-2',4'-dihydro- 17a ethynyl-17B hydroxy 1,3,5(10) -'estratrieno- [3,4 e]-1",3'-oxazine of the formula! melting at 141- 143; Rf=35 in mobile phase A (see Example 1).

The above-mentioned amorphous material-is combined and reprecipitated from heptane yielding 1.2 g. of 3-cyclo- 'hexyl 2',4' dihyclro 17a ethynyl 17B hydroxy- 1,3,5 (10)-estratrieno[2,3-e]-1',3-oxazine of the formula:

. .7 -12 V with an Rf= in mobile phase A (see Example 1) and Rf=30 in mobile phase B (see Example 1).

Example 3 To a cold solution of 0.65 g. of trioxymethylene and a trace of potassium hydroxide in 35 ml. of n-propanol is added 1.22 g. of'Z-phenylethylamine, followed by 3.0 g. of l7a-ethynyl-estradiol. The reaction mixture is treated and worked up as shown in- Example 1. The first eluate fractions of the chromatogram yields 2.2 g. of material,

which is dissolved in methylene chloride; the solution is slowly evaporated until crystallization occurs. 0.38 g. of 2,4'-dihydro-l7a-ethynyl 17ft hydroxy-3'-(2-phenylethyl) -l,3,S l0)-estratrieno[3,4-e]l ,3'-oxazine of the formula -ozon is recovered and .melts at 141-142 after repeated recrystallization; Rf=40 in mobile phase B (see Example 1.).

The methylene chloride filtrate after the removal of the crystalline material yields 1.8 g. of the amorphous 2,4"- dihydro- 17a ethynyl 175 hydroxy 3 (2- V phenylethyl) -.1,3,5(10) estr'atrieno[2,3 e] 1,3' oxazine of the formula:

estratrieno [2,3 -e] -1-,3'-oxazine, V 2,4'-dihydro-3 '-isopropyl- 1,7/3-propionyloxy-1 ,3 ,5 10) estratrieno[3,4-e}-1',3 oxazine,

Example 4 A trace of potassium hydroxide and 0.3 g. of trioxymethylene are dissolved in 2 ml. of methanol, the solution is cooled in ice and 0.15 g. of methylamine in 10 ml. of methanol is added, followed by 1.3 g. of equilenin and 75 ml. of methanol. The reaction mixture is allowed to stand at 20 and then refluxed for two hours under an atmosphere of nitrogen; after cooling, the crystalline material is filtered off and recrystallized from a mixture of methylene chloride and ethanol to yield 1.2 g. of 2',4'- dihydro-3-methyl-17-oxo-1,3,5(10),6,8 estrapenteno[3, 4-e]-1,3'-oxazine of the formula:

which melts at 190-192".

0.5 g. of 2,4'-dihydro-3-methyl-17-oXo-1,3,5(10),6,8- estrapenteno[3,4,-e]-1',3'-oxazine is dissolved in an excess of methyl iodide, and the reaction mixture is allowed to stand at room temperature for several days. The methyl iodide is evaporated off to yield the methiodide of 2,4'- dihydro-3-methyl-17-oxo-1,3,5 10) ,6,8 estrapenteno[3,4-

e] -1,3-oxazine.

0.3 g. of 2',4-dihydro-3'methyl-17-oXo-1,3,5(10),6,8 estrapenteno[3,4-e]-1',3-oxazine is dissolved in benzene and hydrogen chloride gas is passed through the solution; the resulting 2,4'-dihydro-3'-methyl-17-oxo-1,3,5(10),6,8- estrapenteno[3,4-e]-1',3'-oxazine hydrochloride precipitates and is filtered off.

By selecting the appropriate starting materials and reacting them according to the previously shown procedure, the 3-benzyl-2',4'-dihydro-17 oxo 1,3,5 (10),6,8 estrapentaeno[3,4-e]-1,3-oxazine, M.P. 188-189", yield: 77 percent, the 3-cyclohexyl-2',4' dihydro 17 oxo- 1,3,5(10),6,8-estrapentaeno[3,4-e] 1,3' oxazine, M.P. 192193, yield: 84 percent, and the 2,4'-dihydro-3'-(2- phenylet-hy1)-17-oxo-1,3,5 (10),6,8-estrapentaeno[3,4 e]- 1',3'-oxazine, M.P. 148-149, yield: 84 percent, can be obtained.

14 What is claimed is: v t 1. A member of the group consisting of compounds of the formulae:

in which R' represents a member of the group consisting of lower alkyl, lower alkyl substituted by carbo-lower alkoxy, lower alkyl substituted by carbamyl, cycloalkyl, monocyclic carbocyclic aryl-lower alkyl and monocyclic monoheterocyclic aryl-lower alkyl, R represents a member of the group consisting ofgroups of the formulae ,6-OH(a-H), B-OAC'(a-H), B-OH(-R ;8-OAc'(a-R and =0, in which formulae Ac represents the acyl radical of a therapeutically acceptable carboxylic acid containing from one to twelve carbon atoms, and R represents a member of the group consisting of lower alkyl, lower alkenyl and lower alkynyl, and R stands for a member of the group consisting of hydrogen and hydroxy, and therapeutically acceptable acid addition salts thereof and lower alkyl quaternary ammonium compounds thereof.

2. 3'-R"-2,4'-dihydro-17ot ethynyl 17p hydroxy- 1,3,5 (10)-estratrieno[2,3-e]-1,3'-oxazine, in which R" represents phenyl-lower alkyl.

3. 3-benzyl-2',4-dihydro-17u-ethynyl 17 3 hydroxy- 1,3,5 10)'-estratrieno [2,3-e]-1',3'oxazine.

4. 2',4'-dihydro-17a-ethynyl-17fi-hydroxy-3'-(2 phenylethyl)-1,3,5(10)-estratrieno[2,3-e]-1,3'-oxazine.

5. 3'-R-2',4'-dihydro-17a ethynyl 17,8 hydroxy- 1,3,5(10)-estratrieno[3,4-e]-1',3'oxazine, in which R represents phenyl-lower alkyl.

6. 3-benzyl-2,4'-dihydro-17u-ethynyl 17,8 hydroxy- 1,3,5 10) -estratrieno [3,4-e] -1',3-oxazine.

Claims (1)

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE: