The invention relates to novel 2-cyanosteroids of Formula I which are useful for the induction of menses and the termination of pregnancy.

BACKGROUND OF THE INVENTION 
The present invention relates to certain novel organic compounds. In 
particular the invention relates to certain 2-cyanosteroids useful for the 
induction of menses and the termination of pregnancy in mammals. 
Compounds which show activity for induction of menses and termination of 
pregnancy are well known. Estrogens have been used widely for induction of 
menses in the menopausal female, see e.g., U.S. Pat. No. 4,154,820. 
Progesterone and its derivatives have been shown to be useful for primary 
and secondary amenorrhea as described by Wiechert in U.S. Pat. No. 
3,812,166. 
INFORMATION DISCLOSURE 
Various steroids are known in the art for control of menses and induction 
of pregnancy as indicated above. In addition, U.S. Pat. No. 3,246,255 
describes a 2-cyanosteroid that shows activity as pituitary inhibitors, 
electrolyte modifying agents, hypotensive agents and coronary dilators. 
U.S. Pat. No. 4,160,027 describes certain 2-cyano-4,5-epoxy steroids 
useful as interceptive agents. Certain 3-oxo compounds are described in 
U.S. Pat. No. 3,296,255 granted to Sterling. The Sterling patent describes 
the activity of the compounds as adrenal and pituitary inhibitors, 
electrotyte modifying agents and as hypotensive and coronary dilating 
agents. U.S. Pat. No. 4,349,474 relates to certain 2-cyanosteroids and 
describes certain starting materials for the instant case. 
SUMMARY OF THE INVENTION 
The invention particularly provides a compound according to Formula I: 
##STR1## 
wherein R is: 
(a) hydroxy; or 
(b) --C(CH.sub.3).dbd.O; 
wherein R.sub.1 is: 
(a) hydrogen; or 
(b) alkyl of 1 to 6 carbon atoms, inclusive; 
wherein R.sub.2 is: 
(a) hydrogen; 
(b) alkyl of 1 to 6 carbon atoms, inclusive; 
(c) hydroxyphenyl; or 
(d) halogenated phenyl; or 
(e) phenyl 
wherein R.sub.3 is: 
(a) hydrogen; 
(b) alkyl of 1 to 6 carbon atoms, inclusive; 
(c) alkyl-C.dbd.O, wherein the alkyl portion is from 1 to 6 carbon atoms, 
inclusive; 
(d) aryl-C.dbd.O; optionally substituted by halogen or alkyl of 1 to 6 
carbon atoms, inclusive, wherein the aryl portion is from 6 to 10 carbon 
atoms inclusive; 
(e) alkyloxy-C.dbd.O, wherein the alkyl portion is from 1 to 6 carbon atoms 
inclusive; 
(f) aryloxy-C.dbd.O, optionally substituted by halogen or alkyl of 1 to 6 
carbon atoms, inclusive, wherein the aryl portion is from 6 to 10 carbon 
atoms, inclusive; or 
(g) arylalkylenoxy-C.dbd.O, wherein the alkylene portion is from 1 to 6 
carbon atoms, inclusive; wherein the aryl portion is from 6 to 10 carbon 
atoms, inclusive; 
wherein X is: 
(a) --O--; 
(b) --NH--; 
(c) --(CH.sub.2).sub.n -- wherein n is an integer of from 1 to 6; 
inclusive; or 
(d) --S--. 
Examples of alkyl of from one to six carbon atoms, inclusive, are methyl, 
ethyl, propyl, butyl, pentyl and hexyl and the isomeric forms thereof. 
Examples of aryl of 6 to 10 carbon atoms include phenyl, indenyl, and 
naphthyl, including isomeric forms thereof. 
Examples of halogen substitutions are chloro, bromo and fluoro. 
Successful implantation and the maintenance of the initial stages of 
pregnancy in humans are dependent upon the availability of adequate 
amounts of ovarian progesterone. An important step in the biosynthetic 
pathway for progesterone is the conversion of pregnenolone to 
progesterone. This reaction is catalyzed by the 
.DELTA..sup.5,3.beta.-hydroxysteroid dehydrogenase/.DELTA..sup.5-4, 
3-ketoisomerase (.DELTA..sup.5,3.beta.-HSD) enzyme system. Several known 
inhibitors of this enzyme system have already been shown to selectively or 
predominantly inhibit either gonadal/placental production of progesterone 
(see Creange et al. Fertility and Sterility 30: pps 86-90, 1978) or the 
adrenal production of progesterone (see Potts et al, Steroids 32: pps 
257-267, 1978). An in vitro technique for measuring the amount of 
progesterone produced by luteal microsomes incubated at 37.degree. C. with 
pregnenolone as substrate and NAD as cofactor has been developed and is 
described below. The progesterone produced can be measured 
spectrophotometrically in the ultraviolet range at 240 nm. Drugs which 
inhibit biosynthesis of progesterone are useful as contraceptive and 
contragestational agents. 
Luteal tissue is collected from immature pseudopregnant rats on day three 
or four and homogenized at 8 mg/ml in 0.25 M sucrose in Kreb's Ringer 
bicarbonate solution without calcium (pH 7.4) and centrifuged at 
750.times.g for ten minutes to remove nuclei and cell debris. The 
supernatant is then centrifuged at 7,000.times.g for twelve minutes to 
remove the mitochondria, leaving only the microsome-cytosol in the 
supernatant. Pregnenolone is used as substrate in a concentration of 157.2 
micromoles and 4.04 millimoles (6 mg/0.5 ml) NAD is used as cofactor. The 
order of addition of components of the incubate is 0.1 ml pregnenolone 
solution (100 micrograms/0.1 ml ethanol), 0.5 ml buffer, 0.02 ml ethanol 
or the inhibitor in 0.02 ml ethanol (when tested), 1 ml microsome-cytosol 
and 0.5 ml NAD solution thus making up a total volume of 2.12 ml. The 
reaction is initiated by the addition of the cofactor. The incubation is 
carried out for one hour at 37.degree. C. At the end of one hour 
incubation samples are immersed in a Dry Ice/ethanol bath to stop the 
reaction. Samples are stored at minus 20.degree. C. until extraction for 
progesterone with petroleum ether. 
Incubates are thawed in a warm water bath at 50.degree. C. and extracted 
twice with petroleum ether. The extract is dried under an air manifold and 
reconstituted in 2 ml of absolute ethanol. The progesterone concentration 
of the reconstitute is determined in a standard size quartz cell in a 
Gilford 240 spectrophotometer at 240 nm. A standard progesterone curve is 
prepared using progesterone diluted in absolute ethanol in doses of 1, 2, 
4, 8, 12, 16, 20, 40, 60, 80 and 100 micrograms/0.1 ml. These doses were 
added to 2.0 ml of deionized distilled water and extracted along with the 
samples from each incubation. 
By virtue of the above described activity the compounds of Formula I are 
useful in inducing menses and for the termination of pregnancy. A 
physician of ordinary skill could readily determine a subject who is in 
need of such treatment. Regardless of the route of administration 
selected, compounds of the present invention can be formulated into 
pharmaceutically acceptable dosage forms by conventional methods known to 
the pharmaceutical art. 
The compounds can be administered in such oral unit dosage forms as 
tablets, capsules, pills, powders or granules. They also may be 
administered parenterally for example rectally or vaginally in such forms 
as suppositories or bougies; subcutaneous, intramuscular, intraorbital, 
intranenous, etc. using forms known to the pharmaceutical art. In general, 
the preferred form of administration is oral. 
An effective but non-toxic quantity of the compound is employed in 
treatment. The dosage regimen of the compounds of this invention is 
selected in accordance with a variety of factors including the type, age, 
weight and medical condition of the mammal, the route of administration 
and the particular compound employed. An ordinary skilled physician or 
veterinarian will readily determine and prescribe the effective amount of 
the compound of the instant invention. 
Dosages of the compound of the invention are ordinarily in the area of 1 
milligram per kilogram up to at most 20 milligrams per kilogram orally. 
When other forms of administration are employed equivalent doses are 
administered. 
The compounds of this invention are prepared from a mixture of 
2.alpha.-cyano-17.beta.-hydroxy-4,4,17.alpha.-trimethylandrost-5-en-3-one, 
2.beta.-cyano-17.beta.-hydroxy-4,4,17.alpha.-trimethylandrost-5-en-3-one, 
and 2-cyano-4,4,17.alpha.-trimethylandrosta-2,5-diene-3,17.beta.-diol by 
reaction with appropriate acylating reagents known to those skilled in the 
art. The preferred solvent for the acylations is pyridine. The preferred 
acylating reagents include the following: (1) appropriate carboxylic acids 
activated by a condensing reagent, preferably dicyclohexycarbodiimide; or 
(2) appropriate carboxylic acyl halides or anhydrides, preferably an acyl 
chloride. The reaction mixtures are typically purified by column 
chromatography on silica gel followed by crystallization. Certain starting 
materials and procedures are described in U.S. application Ser. No. 
00/375,619, which is incorporated herein by reference, and will teach one 
skilled in the art additional methods which can be applied to obtain 
compounds of the invention. 
The invention will appear more fully from the Examples which follow. These 
Examples are given by way of illustration only and are not to be construed 
as limiting the invention either in spirit or in scope, as many 
modifications both in materials and methods will be apparent from this 
disclosure to those skilled in the art. In these examples temperatures are 
given in degrees Celcius (.degree.C.) and quantities of materials in grams 
and milliliters unless otherwise noted.

EXAMPLE 1 
N-[(phenylmethoxy)carbonyl]glycine,2-cyano-17.beta.-hydroxy-4,4,17.alpha.-t 
rimethylandrosta-2,5-dien-3-yl ester 
To a solution of 3.7 g (0.01 mole) of a mixture of 2- and 
2.beta.-cyano-17.beta.-hydroxy-4,4,17.alpha.-trimethylandrost-5-en-3-one 
and 2-cyano-4,4,17.alpha.-trimethylandrosta-2,5-diene-3,17.beta.-diol (see 
U.S. Ser. No. 06/375,619) and 2.46 g (11.5 m mole) of carbobenzoxyglycine 
in 60 ml of dry pyridine was added 0.15 g of p-toluenesulfonic acid. After 
stirring for 15 minutes, 2.90 g (14 m mole) of dicyclohexylcarbodiimide 
was added. After stirring an additional 24 hours at room temperature, 
acetic acid (1 ml) was added and the mixture was kept overnight at 
5.degree.. It was then filtered and the crystalline sold was washed with a 
small amount of cold pyridine. The filtrate was extracted with methylene 
chloride and the organic extracts were washed successively with water, 
cold 5% hydrochloric acid, and water, then dried over anhydrous sodium 
sulfate, filtered, and concentrated to dryness. Chromatography of the 
residue on silica gel using 15% ethyl acetate/toluene as eluent gave 1.1 g 
of an amorphous solid. Recrystallization of a portion of this material 
afforded the title compound, mp. 152.degree.-168.degree.. Structure 
assignment was confirmed by nmr and infrared spectra and by elemental 
analysis. 
Calcd. for C.sub.33 H.sub.40 N.sub.2 O.sub.5 : C, 72.77; H, 7.40; N, 5.14. 
Found: C, 72.60; H, 7.76; N, 5.02. 
EXAMPLE 2 
N-[(phenylmethoxy)carbonyl]-L-alanine, 
2-cyano-17.beta.-hydroxy-4,4,17.alpha.-trimethylandrosta-2,5-dien-3-yl 
ester 
The title compound was prepared by the method of Example 1 using 1.8 g 
(8.05 mmole) of carbobenzoxy-L-alanine. Structure assignment was confirmed 
by nmr and infrared spectra and by elemental analysis. 
Calcd. for C.sub.34 H.sub.44 N.sub.2 O.sub.5 : C, 72.85; H, 7.91; N, 5.00 
Found: C, 72.80; H, 7.93; N, 4.90 
EXAMPLE 3 
N-[(phenylmethoxy)carbonyl]-D-alanine, 
2-cyano-17.beta.-hydroxy-4,4,17.alpha.-trimethylandrosta-2,5-dien-3-yl 
ester 
The title compound was prepared by the method of Example 1 using 1.8 g 
(8.05 mmole) of carbobenzoxy-D-alanine. Structure assignment was confirmed 
by nmr and infrared spectra and by elemental analysis. 
Calcd. for C.sub.34 H.sub.44 H.sub.2 O.sub.5 : C, 72.85; H, 7.91; N, 5.00. 
Found: C, 72.98; H, 8.01; N, 4.85. 
EXAMPLE 4 
3-(1,4-dioxopentoxy)-17.beta.-hydroxy-4,4,17.alpha.-trimethylandrosta-2,5-d 
iene-2-carbonitrile 
The title compound, mp. 153.5.degree.-154.degree. C., was prepared by the 
method of Example 1 using 0.73 g (6.3 mmole) of levulinic acid. Structure 
assignment was confirmed by nmr and infrared spectra and by elemental 
analysis. 
Calcd. for C.sub.28 H.sub.39 NO.sub.4 : C, 74.14; H, 8.67; N, 3.09 Found: 
C, 73.99; H, 8.66; N, 2.94. 
EXAMPLE 5 
3-[2-(acetyloxy)-1-oxopropoxy]-17.beta.-hydroxy-4,4,17.alpha.-trimethylandr 
osta-2,5-diene-2-carbonitrile (Isomer A) 
3-[2-(acetyloxy)-1-oxopropoxy]-17.beta.-hydroxy-4,4,17.alpha.-trimethylandr 
osta-2,5-diene-2-carbonitrile (Isomer B) 
A solution of 2 ml of d,l-2-acetoxypropionyl chloride in 10 ml of pyridine 
was added to a mixture of 4 g of 2.alpha.- and 
2.beta.-cyano-17.beta.-hydroxy-4,4,17-trimethylandrost-5-en-3-one and 
2-cyano-4,4,17.alpha.-trimethylandrosta-2,5-diene-3,17.beta.-diol in 80 ml 
of cold dry pyridine. After stirring for 1 hour at 0.degree., the reaction 
mixture was diluted with cold water and extracted with methylene chloride. 
The combined extracts were washed with water, dried over anhydrous sodium 
sulfate, filtered, and concentrated to dryness. Chromatography of the 
residue in silica gel using 30% ethyl acetate/hexane as eluent afforded a 
solid which was recrystallized from ether/Skillysolve B to give 0.7 g of 
isomer "A", mp. 190.degree.-193.degree.. 
The mother liquors were rechromatographed on Porasil silica gel using 50% 
ethyl acetate/methylene chloride as eluent to yield a solid. It was 
recrystallized from methylene chloride/Skellysolve B to afford isomer "B", 
mp. 147.degree.-148.degree.. Structure assignments for isomers "A" and "B" 
were confirmed by nmr and infrared spectra and by elemental analysis. 
Calcd. for C.sub.28 H.sub.39 NO.sub.5 : C, 71.61; H, 8.37; N, 2.98. Isomer 
"A" Found: C, 71.31; H, 8.29; N, 2.95. Isomer "B" Found: C, 71.43; H, 
8.28; N, 2.86.