Novel 17-esters of 17.alpha.-hydroxy gestogens, compositions containing such compounds, processes for their preparation and methods of treatment therewith

This invention relates to novel 17.alpha.-esters of gestogens having an antitumour activity and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and method of treatment therewith.

This invention relates to novel 17.alpha.-esters of gestogens having an 
antitumour activity, and to the preparation thereof. The invention is also 
concerned with pharmaceutical compositions containing the said compounds, 
and methods of treatment therewith. 
BACKGROUND OF THE INVENTION 
It is known that esters of certain steroids with alkanoic acids containing 
a phenyl group substituted with a bis(2-chloroethyl)amino group have 
antitumour activities in animals and human beings. The acid part of such 
known esters has in the main been 
4-/N,N-bis(2-chloroethyl)amino/phenylacetic acid and 
4-/4-(N,N-bis(2-chloroethyl)amino)phenyl/butanoic acid. 
The types of steroids which have been investigated are estrogens, 
androgens, corticoids, and one sterol, cholesterol. The hydroxy group or 
groups in these steroids which have been esterified have been situated in 
one or two of the positions 3-(estrogens), 3.beta.-(androgens, 
pregnenolone, and cholesterol), 17.beta.-(estrogens and androgens) and 
21-(corticosteroids). 
Such esters are described in e.g. J. Med. Chem. 11 (1968) 1106, ibid 12 
(1969) 810, ibid 15 (1972) 1158, and U.S. Pat. No. 3,732,260. 
No esters of gestogens are known which in their acid part contain an 
alkylating group such as the bis(2-chloroethyl)amino group, although 
numerous gestogens are known which contain esterifiable hydroxy groups in 
various positions of the steroid molecules, e.g., at the 3, 11, 16, and 
17-positions, much less are any such gestogen esters known in which the 
esterification is at the position of particular interest to the present 
invention, namely in the 17.alpha.-position. 
It has now, surprisingly, been found that the esters of the present 
invention being 17.alpha.-esters of gestogens are active against animal 
tumours, and that they also show a very low toxicity resulting in very 
favouralbe therapeutic indexes. 
The esters of this invention are of value in the treatment of tumours, for 
instance, in uro-genital organs, such as the ovaries, the endometrium, the 
prostate, the bladder, and the kidneys. The compounds are particularly 
useful in the treatment of tumours situated in organs which are targets 
for gestogens, such as the endometrium and the mammary glands. The 
compounds of the invention are also valuable in the treatment of 
haematological disorders. 
SUMMARY OF THE INVENTION 
The new 17.alpha.-esters of gestogens of the invention correspond to the 
general formula I as defined below. 
The compounds of the invention have shown effect in inhibiting the growth 
of tumours, e.g. Ehrlich ascites, Melanoma Harding-Passey, Hepatoma AH 
130, Lymphocytic leukemia (L 1210), and Walker carcinoma 256, according to 
the procedures set by Cancer Chemotherapy National Service Center (see: 
Cancer Chemotherapy Reports, January 1959 and December 1962). 
The compounds of the invention have also been found to possess a high 
affinity to specific gestogen binders, i.e. receptors, in the cell 
cytoplasm. 
The compounds of the invention can be employed in disorders responsive to 
treatment with antitumour agents and with immunosuppressive agents, as 
such or combined with either solid or liquid carriers or diluents and made 
available in varying amounts in such pharmaceutical forms, as, e.g., 
tablets, pills, capsules, pellets, powders, ointments, suppositories, 
aqueous or non-aqueous suspensions, and non-aqueous solutions. 
Accordingly, one object of the invention is to provide new compounds, 
having the general formula I, having the aforesaid activity, preferably 
also with a relatively low degree of toxicity. 
A second object is to provide such type of compounds, which can be employed 
in disorders responsive to treatment with anti-tumour agents and with 
immunosuppressive agents, for the amelioration or palliation thereof. 
A further object of the invention is to provide a method of treating a 
living animal body suffering from disorders responsive to treatment with 
anti-tumour agents and with immunosuppressive agents, for the amelioration 
or palliation thereof, which comprises the step of administering to said 
living animal body a compound having the general formula I, said compound 
being administered in an amount sufficient to at least mitigate said 
disorders. 
Yet another object of the invention is to provide compositions containing 
as an active ingredient one or more of the compounds, having the general 
formula I, preferably together with a pharmaceutically acceptable carrier 
and, if desired, other pharmacologically acitve agents. 
Accordingly what we believe and claim to be our invention comprises novel 
compounds having the general formula: 
EQU St--R I 
wherein R is 
##STR1## 
where R.sup.1 is a .beta.- or .gamma.-halogensubstituted alkyl group 
having 2 to 4 carbon atoms, the halogen being chlorine or bromine; where 
R.sup.2 is selected from the group consisting of hydrogen, lower alkyl, 
lower alkoxy, and halogen; 
where A is a straight hydrocarbon chain having at most 4 carbon atoms and 
being saturated or containing one double bond. At most 2 hydrogen atoms of 
A may be replaced by lower alkyl and at most one of the hydrogen atoms 
situated at the carbon atom adjacent to a 
##STR2## 
group may be replaced by a group selected from the group consisting of 
amino and lower alkanoylamino; 
where B is a straight saturated hydrocarbon chain having at most 4 carbon 
atoms. At most 2 hydrogen atoms of B may be replaced by lower alkyl; 
where X and Y are independently selected from the group consisting of 
--O--, --NH--, and --S--; 
where k, and n are independently selected from the group consisting of zero 
and one; n always being zero when k is zero; 
wherein St is a residue of a steroid having a cyclopentanophenanthrene 
carbon-carbon skeleton containing up to a maximum of 40 carbon atoms, 
inclusive of substituents, said carbon-carbon skeleton including a 
carbon-carbon skeleton of a steroid nucleus selected from the group 
consisting of pregnane and 19-norpregnane nuclei, having from zero up to a 
maximum of 4 double bonds, said steroid residue being attached in its 
17-position to R, said position being identified according to steroid 
nomenclature. 
This invention also comprises novel compounds being useful as intermediates 
for preparing the anti-tumour compounds I and having the general formula: 
##STR3## 
wherein St and B have the meaning given above, and where St is attached in 
its 17-position to the group 
##STR4## 
wherein R.sup.10 is selected from the group consisting of hydroxy, 
mercapto, hydroxy and mercapto esterified with a carboxylic acid or a 
sulfonic acid having at most 15 carbon atoms, amino, acylamino having at 
most 15 carbon atoms, and azido. When R.sup.10 is amino, those 
heterocyclic compounds are included which are formed by cyclisation 
reaction of said group and the keto group in the 20-position of the 
steroid molecule. 
In this disclosure the expression "lower" means that the group referred to 
contains one to four carbon atoms, inclusive. Thus, lower alkyl, lower 
alkoxy, and lower alkanoyl include: methyl, ethyl, propyl, iso-propyl, 
butyl, secondary butyl, iso-butyl, tertiary butyl, methoxy, ethoxy, 
propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, 
acetyl, propionyl, butyryl, and isobutyryl. 
The nomenclature used in this disclosure is in accordance with the 
I.U.P.A.C. 1957 Rules for Nomenclature of Steroids. Whenever used herein 
the general formula I and XV and the symbols A, B, X, Y, R.sup.1, R.sup.2, 
R.sup.10, St, k, m, and n have the meaning given above. 
Among those compounds covered by the above general formula I those are 
preferred wherein the halogen atom of R.sup.1 is in .beta.-position and 
the alkyl group of R.sup.1 is ethyl, n-propyl, or n-butyl. 
Compounds, wherein R.sup.1 is --CH.sub.2 --CH.sub.2 --Cl are particularly 
preferred. 
The group --NR.sub.2.sup.1 is preferably in m- or p-position, particularly 
when k and n are zero and in p-position when at least one of k and n is 
one. 
It is preferred that R.sup.2 is hydrogen or lower alkyl. 
When the group --NR.sub.2.sup.1 is in m-position, it is preferred that 
R.sup.2 is in p-position and different from hydrogen, especially when k 
and n are zero. 
When A is substituted with an amino or a lower alkanoylamino group, it is 
preferred that n is zero and that A is a saturated hydrocarbon chain 
containing 2 carbon atoms. 
It is preferred that n is zero. 
X, when present, is preferably --O-- or --NH--, and especially --O--, when 
k is one. 
When n is one and k is zero, compounds with highly active metabolites are 
obtained. 
It is preferred that Y is --O-- or --NH--. 
When k is one, it is particularly preferred that Y is --O--. 
Among those compounds covered by the above general formula XV those are 
preferred as intermediates wherein R.sup.10 is hydroxy, hydroxy esterified 
with a carboxylic acid having at most 10 carbon atoms, amino, and azido. 
The residue of a steroid, St, as defined above, has a carbon-carbon 
skeleton preferably selected from the group consisting of: the 
carbon-carbon skeleton of pregn-4-ene, pregna-4,6-diene, and of 
19-norpregn-4-ene. 
Preferred nuclei of said steroid residue having the aforementioned 
skeletons are as follows: 17.alpha.-pregn-4-ene-3,20-dione, 
17.alpha.-pregna-4,6-diene-3,20-dione, and 
17.alpha.-(19-norpregn-4-ene-3,20-dione) nuclei, having the radical, R, 
attached to the said 17-position. 
Preferably, any further substitution that is present in the carbon-carbon 
skeletons of said steroid nuclei, being at most a tetrasubstitution 
wherein the positions of the steroid carbon-carbon skeleton which are 
substituted are selected from the positions consisting of the 1-, 2-, 6-, 
and 16-positions, comprises at least one substituent preferably selected 
from the group consisting of methyl, methylene, fluoro, and chloro. It is 
particularly preferred that said substitution is at most a disubstitution, 
comprising one or two substituents selected from the group consisting of 
6-methyl, 6-chloro, 6-fluoro, 1,2-methylene, and 16-methylene. 
The steroid residue (St) is preferably derived from following steroids: 
17.alpha.-hydroxypregn-4-ene-3,20-dione (17.alpha.-hydroxyprogesterone), 
17.alpha.-hydroxy-19-norpregn-4-ene-3,20-dione, 
6.alpha.-fluoro-17.alpha.-hydroxypregn-4-ene-3,20-dione, 
6.alpha.-chloro-17.alpha.-hydroxypregn-4-ene-3,20-dione, 
17.alpha.-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione 
(medroxyprogesterone), 
17.alpha.-hydroxy-6.alpha.,16.alpha.-dimethylpregn-4-ene-3,20-dione, 
17.alpha.-hydroxypregna-4,6-diene-3,20-dione, 
6-fluoro-17.alpha.-hydroxypregna-4,6-diene-3,20-dione, 
6-chloro-17.alpha.-hydroxypregna-4,6-diene-3,20-dione (chlormadinone), 
17.alpha.-hydroxy-6-methylpregna-4,6-diene-3,20-dione (megestrol), 
6-chloro-17.alpha.-hydroxy-1.alpha.,2.alpha.-methylenepregna-4,6-diene-3,20 
-dione (cyproterone), 
6-chloro-17.alpha.-hydroxy-16.alpha.-methylpregna-4,6-diene-3,20-dione, 
6-chloro-17.alpha.-hydroxy-16-methylenepregna-4,6-diene-3,20-dione, 
17.alpha.-hydroxy-6,16.alpha.-dimethylpregna-4,6-diene-3,20-dione, 
6-fluoro-17.alpha.-hydroxy-16-methylene-9.beta.,10.alpha.-pregna-4,6-diene- 
3,20-dione, 
6-fluoro-17.alpha.-hydroxy-1.beta.,2.beta.-methylene-9.beta.,10.alpha.-preg 
na-4,6-diene-3,20-dione. 
Among the steroids mentioned above 17.alpha.-hydroxyprogesterone, 
medroxyprogesterone, chlormadinone, cyproterone, and megestrol are 
particularly preferred. 
In the following, references to the literature are given by elevated, 
underlined, numbers, e.g. "this method.sup.18 is". The numbers refer to 
literature sources listed after the examples. 
METHODS OF PREATION 
The compounds having structures I and XV may be prepared by conventional 
methods. 
A general process (method 1 below) for preparing compounds having structure 
I is as follows: 
METHOD 1 
Compound I is prepared by reacting a 17-hydroxysteroid having structure 
III, or a reactive derivative thereof, and an acid IV, or a reactive 
derivative thereof. (See for instance references 1 and 2 for the 
esterification of 17-hydroxysteroids.) 
##STR5## 
Among other methods for preparing compounds having structure I the 
following may be mentioned. 
METHOD 2 
Reacting a 17-hydroxyester of a steroid having structure II and an acid V, 
or a reactive derivative thereof, provides compound I. 
##STR6## 
R.sup.3 is a group, which, together with a --COOH group, in one or more 
steps, can form the group 
##STR7## 
METHOD 3 
Reacting a halide VI and a compound VII, or a reactive derivative thereof, 
produces compound I, wherein n is one. 
##STR8## 
Whenever used herein Hal means a halogen atom selected from chlorine and 
bromine. 
METHOD 4 
A 17-hydroxysteroid having structure III and having one hydrogen atom in 
21-position replaced by a hydroxyl group and a suitable derivative of acid 
IV are reacted to form a 17,21-ortho ester. (See reference 3 for the 
preparation of ortho esters.) 
The 17,21-ortho ester is then by known methods converted into compound I. 
(See reference 4 for the transformation of 17,21-ortho esters into 
17-monoesters.) 
A general process for preparing compounds having structure XV is as 
follows: 
METHOD 5 
Reaction of compound III, or a reactive derivative thereof, and an acid 
XVI, or a reactive derivative thereof, produces compound XV or a compound 
which, in one or more steps, can be transformed into said compound. 
EQU HOOC--B--R.sup.11 XVI 
R.sup.11 is the group R.sup.10 or a group, such as a halogen, which, in one 
or more steps, can be transformed into R.sup.10. 
In synthetizing compounds having structures I and XV by any of the methods 
mentioned above each group of the starting materials involved must be 
compatible with the process in question or, if necessary, protected during 
one or more reaction steps and then converted to the desired 
group..sup.5,6 Pertinent examples of groups that may be protected are the 
carbonyl groups in the steroid and an amino group of A. 
Examples of protective groups for carbonyl groups in the steroids are 
ketals, e.g. 1,3-dioxolans, hemithioketals, e.g. 1,3-oxathiolans, and 
dithioketals, e.g. 1,3-dithiolans. 1,3-Dioxlan derivatives may be prepared 
by treatment of carbonyl compounds with ethylene glycol in the presence of 
an acid catalyst,.sup.19 and the carbonyl groups may be regenerated upon 
treatment with acids, such as hydrochloric acid in acetone..sup.20 
1,3-Oxathiolans may be formed by acid-catalyzed reaction between 
2-mercaptoethanol and carbonyl compounds.sup.21 and they may be 
reconverted into ketones by treatment with acids, such as hydrochloric 
acid in dioxan,.sup.22 or by the action of Raney nickel..sup.20 
1,3-Dithiolans may be prepared by acid-catalyzed reaction of carbonyl 
compounds with ethanedithiol,.sup.21 and the carbonyl functions may 
subsequently be regenerated by the action of mercuric salts..sup.23 
Examples of protective groups for an amino group of A are substituted or 
unsubstituted benzyloxycarbonyl and benzyl groups. Such 
N-benzyloxycarbonyl derivatives may be prepared by reaction of amino 
compounds with benzyl chloroformate in the presence of an alkaline 
catalyst,.sup.24 and the amino group may subsequently be regenerated by 
treatment with acidic reagents, such as hydrogen chloride.sup.25 or by 
catalytic hydrogenation..sup.26 Mono-N-benzyl derivatives may be 
synthesized by treatment of amines with benzyl chloride in the presence of 
base and subsequent partial hydrogenation of the dibenzyl compounds 
formed;.sup.27 debenzylation may be achieved by catalytic hydrogenation. 
It is understood that one or more of the steps described in the methods 1-4 
above may be carried out with one or both of the halogen atoms of R.sup.1 
replaced by groups, e.g. hydroxyl or sulfonic esters thereof, which 
subsequently can be substituted by Hal, thus providing the desired 
compound. 
Methods 1-5 above are illustrated by the following processes (a-e): 
(a) A process according to method 1, characterized by reacting, in one or 
more steps, compound III, or a reactive derivative thereof, and acid IV, 
or a reactive derivative thereof, preferably in the presence of an 
anhydride or a catalyst. 
Examples of reactive derivatives of acid IV are its anhydride or acyl 
halide, e.g. acyl chloride. A suitable anhydride is trifluoroacetic 
anhydride, and suitable catalysts are, for instance, strong organic or 
inorganic acids, such as arylsulfonic acids or perchloric acid. 
Acid IV may be prepared by reacting acid V, or a reactive derivative 
thereof, and a compound VIII, wherein R.sup.4 is a suitable carboxyl 
protecting group,.sup.15 e.g. a benzyl group, and subsequent removal of 
the protective group by a suitable method,.sup.15 e.g. catalytic 
hydrogenation. 
##STR9## 
When the group 
##STR10## 
the group R.sup.3 may be a halogen atom, a hydroxyl group, or a reactive 
organic ester thereof. If R.sup.3 is a halogen atom, acid V is suitable 
either in the form of an ion pair, e.g., by using an equivalent or a 
catalytic amount of a quaternary ammonium cation as counter-ion,.sup.7 or 
in the form of a metal salt, e.g., of an alkali metal or silver..sup.8 If 
R.sup.3 is a hydroxyl group, acid V is either free or in the form of its 
anhydride or acyl halide, e.g., acyl chloride, and the reaction is 
preferably performed in the presence of a carbodiimide, such as 
dicyclohexylcarbodiimide, an anhydride, such as trifluoroacetic anhydride, 
or a catalyst, e.g., a strong organic or inorganic acid, such as an 
arylsulfonic acid or perchloric acid, or a base, such as pyridine, 
N,N-dimethylaniline, or triethylamine..sup.9 If R.sup.3 is hydroxyl 
esterified with an organic acid, e.g., a sulfonic acid, such as 
4-toluenesulfonic acid, or a lower alkanoic acid, optionally substituted 
with a member of the group consisting of chlorine and fluorine, such as 
trifluoroacetic acid, acid V is suitably either free or in the form of an 
ion pair, e.g., with a quaternary ammonium ion as counter-ion, and the 
reaction may be performed in the presence of a catalyst, e.g. a strong 
acid, such as sulfuric acid or 4-toluenesulfonic acid, a base, such as an 
aluminium alkoxide, or a quaternary ammonium salt, such as 
tetrabutylammonium salt..sup.28 
When the group 
##STR11## 
the group R.sup.3 may be an amino group. Acid V is suitably in the form of 
its anhydride, mixed anhydride, ester with lower alkanols or alkenols, or 
acyl halide, e.g. acyl chloride. The reaction may be performed with or 
without a basic catalyst such as pyridine, N,N-dimethylaniline, or 
triethylamine..sup.11 
When the group 
##STR12## 
the group R.sup.3 may be a hydrogen sulfide group. Acid V is either free 
or in the form of its anhydride, mixed anhydride, or acyl halide, e.g. 
acyl chloride. The reaction may be performed with or without a catalyst 
such as a strong acid, e.g., 4-toluenesulfonic acid, or a base, e.g., 
pyridine..sup.13 
(b) A process according to method 2, characterized by reacting, in one or 
more steps, compound II and acid V, or a reactive derivative thereof, 
preferably in the presence of a catalyst. 
The same principles as described in process a regarding the formation of 
the group 
##STR13## 
are also valid for the condensation of the groups --R.sup.3 of compound II 
and --COOH of acid V to give the group 
##STR14## 
of compound I. 
Compound II, wherein R.sup.3 is --Hal, may be prepared by reacting a 
17.alpha.-hydroxysteroid having structure III and a haloacid IX, or a 
reactive derivative thereof, in the presence of an anhydride, such as 
trifluoroacetic anhydride, or a catalyst, e.g., a strong organic or 
inorganic acid, such as an arylsulfonic acid or perchloric acid..sup.1,2 
##STR15## 
Compound II, wherein R.sup.3 is --OH, may be prepared from the 
corresponding halogen compound (II, R.sup.3 =Hal) by known methods, for 
instance as described in reference 10 or in the following way: The above 
halogen compound is reacted with a suitable acid, such as 4-nitrobenzoic 
acid, in the form of its ion pair.sup.7 or metal salt.sup.8, to form a 
compound X having a labile ester bond, which is then hydrolyzed with a 
suitable base, e.g. potassium t-butoxide. 
##STR16## 
R.sup.5 means a group, such as 4-nitrophenyl, which renders the adjacent 
ester bond of compound X labile. 
Compound II, wherein R.sup.3 is --NH.sub.2, may be prepared by converting 
the corresponding halogen compound (II, R.sup.3 =Hal) to the corresponding 
azide (II, R.sup.3 =N.sub.3) by a suitable method, e.g., by reaction of 
the halogen compound with sodium azide,.sup.12 and subsequent reduction of 
the azide to the desired amine. The reduction may be performed by reacting 
the azide with a suitable trivalent phosphorus compound, such as 
triphenylphosphine or trimethylphosphite, to give a compound XI, which, 
when reacted with water, provides compound II, wherein R.sup.3 is 
--NH.sub.2. 
##STR17## 
R.sup.6 means an aryl or lower alkoxy group. 
Compound II, wherein R.sup.3 is --NH.sub.2, may spontaneously undergo a 
cyclization, by way of reaction of the amino group with the keto group in 
the 20-position of the steroid, to give the cyclic amine XVIII, which may 
be isolated. The formation of XVIII from II, wherein R.sup.3 is 
--NH.sub.2, is reversible in solution, and in the next reaction step imine 
XVIII is transformed into compound II, wherein R.sup.3 is --NH.sub.2, when 
the latter compound is consumed by reaction with acid V. 
##STR18## 
Compound II, wherein R.sup.3 is --SH, may be prepared from the 
corresponding halogen compound (II, R.sup.3 =Hal) by known methods, e.g. 
by reacting the above halide with thiourea to form a compound XII, which 
is then hydrolyzed..sup.14 
##STR19## 
(c) A process according to method 3, characterized by reacting, in one or 
more steps, halide VI and compound VII, or a reactive derivative hereof, 
with or without a catalyst. 
Examples of reactive derivatices of VII, when the group --X-- is --O--, are 
ion pairs, e.g. with a quaternary ammonium cation as counterion,.sup.16 
and metal salts of for instance silver or an alkali metal..sup.17 A 
suitable catalyst is, e.g., a quaternary ammonium salt, such as a 
tetrabutylammonium salt. 
##STR20## 
Halide VI, wherein m and k are one, may be prepared by known methods, e.g. 
by reaction of compound II, prepared as described under (b) above, and 
acid XIII, wherein k is one, or a reactive derivative thereof. The same 
principles as described under (a) regarding the formation of the group 
##STR21## 
also apply to the formation of the group 
##STR22## 
of halide VI. 
##STR23## 
Reacting compound II, wherein R.sup.3 is --OH, NH.sub.2, or --SH, prepared 
as described under (b) above, and phosgene or its bromine analogue, 
provides halide VI, wherein k is zero, and Y is --O--, --NH--, and --S--, 
respectively. 
##STR24## 
(d) A process according to method 4, where compound III, or a reactive 
derivative thereof, contains a 21-hydroxyl group, characterized by 
reacting this 17.alpha.,21-dihydroxy compound and such a derivative of 
acid IV that a 17,21-ortho ester is formed,.sup.4 the reaction preferably 
being performed in the presence of an acid catalyst, such as sulfuric 
acid. This cyclic ortho ester is then hydrolyzed, e.g., by the action of 
an acid, such as oxalic acid, to give the corresponding 
17-acyloxy-21-hydroxy compound, which is transformed into compound I by 
reductive elimination of the 21-hydroxyl group, e.g. via the corresponding 
21-iodo and 21-p-toluenesulfonate compounds..sup.4 
Acid IV may be prepared as described under (a) above. Suitable derivatives 
of IV are, e.g., its ortho esters with lower alkanols..sup.18 
(e) A process according to method 5, characterized by reacting, in one or 
more steps, compound III, or a reactive derivative thereof, and acid XVI, 
or a reactive derivative thereof, and, in those cases where R.sup.11 is 
different from R.sup.10, subsequent transformation of the product formed 
into compound XV. The reactions are preferably performed in the presence 
of an anhydride or a catalyst. 
Examples of reactive derivatives of acid XVI are its anhydride and acyl 
halide, e.g., acyl chloride. A suitable anhydride is trifluoroacetic 
anhydride and suitable catalysts are, e.g., strong organic or inorganic 
acids, such as arylsulfonic acids or perchloric acid. 
The group R.sup.11 of acid XVI may be the group R.sup.10 or --Hal. If 
R.sup.11 is --Hal, reaction of compound III and acid XVI, or a reactive 
derivative thereof, produces a compound XVII which is subsequently 
converted to compound XV. 
##STR25## 
Compound XV, wherein R.sup.10 is --OH, --SH, --N.sub.3, or --NH.sub.2 may 
be obtained from compound XVII by the methods given under (b) above for 
the preparation of compound II, wherein R.sup.3 is --OH, --SH, --N.sub.3, 
and --NH.sub.2, respectively, from compound II, wherein R.sup.3 is --Hal. 
Compound XV, wherein R.sup.10 is --OH esterified with a carboxylic or a 
sulfonic acid having at most 15 carbon atoms, may be prepared from 
compound XV, wherein R.sup.10 is --OH, or from compound XVII by reaction 
with the appropriate acid, or a reactive derivative thereof. Suitable 
derivatives of the acid for reaction with compound XV, wherein R.sup.10 is 
--OH, are its anhydride and acyl halide, e.g. acyl chloride, and the 
reaction is performed in the presence of an anhydride, such as 
trifluoroacetic anhydride, or a catalyst, e.g., a strong organic or 
inorganic acid, such as an arylsulfonic acid or perchloric acid, or a 
base, such as pyridine, N,N-dimethylaniline, or triethylamine. If the acid 
is reacted with compound XVII, it is suitably either in the form of an ion 
pair, e.g. with a quaternary ammonium cation as counterion,.sup.7 or in 
the form of a metal salt, e.g. of an alkali metal or silver..sup.8 
Compound XV, wherein R.sup.10 is acylamino having at most 15 carbon atoms 
or --SH esterified with a carboxylic acid or a sulfonic acid having at 
most 15 carbon atoms, may be prepared by reaction of the appropriate acid, 
or a reactive derivative thereof, and compound XV, wherein R.sup.10 is 
--NH.sub.2 and --SH, respectively. Suitable derivatives of the acid are 
its anhydride, mixed anhydride, or acyl halide, e.g. acyl chloride. The 
reaction may be performed with or without a catalyst such as a strong 
acid, e.g. 4-toluenesulfonic acid, or a base, e.g. pyridine. 
The compounds of the invention are generally characterized by the 
pharmacological activity hereinbefore stated, making them useful in 
counteracting certain physiological abnormalities in a living animal body. 
Effective quantities of the pharmacologically active compounds of the 
invention may be administered to a living animal body in anyone of various 
ways, for example orally as in capsules or tablets, parenterally in the 
form of sterile solutions, suspensions. and by pellet implantation. Among 
routes of parenteral administration are intravenously, subcutaneously, 
intramuscularly, intraperitoneally, intraarticularly, and intradermally. 
Other modes of administration are vaginally, rectally, and topically as 
e.g. in the form of ointments, suppositories, and powders. 
As representative of living animal bodies, which may be treated with the 
compounds and compositions of the invention, and according to the method 
of treatment of the invention, for alleviation of the same and/or similar 
conditions as those described, in addition the following may be mentioned: 
domestic animals such as dogs and cats and farm animals such as horses, 
cows, sheep, and goats. 
Pharmaceutical formulations are usually prepared from a predetermined 
quantity of one or more of the compounds of the invention. Such 
formulations may take the form of powder, syrups, suppositories, 
ointments, solutions, pills, capsules, pellets or tablets, suspensions, 
emulsions, oil solutions etc., with or without, but preferably with, any 
one of a large variety of pharmaceutically acceptable vehicles or 
carriers. When in a mixture with a pharmaceutical vehicle or carrier, the 
active ingredient usually comprises from about 0.01 to about 75 percent, 
normally from about 0.05 to about 15 percent, by weights of the 
composition. Carriers such as starch, sugar, talc, commonly used synthetic 
and natural gums, water, and the like, may be used in such formulations. 
Binders such as polyvinylpyrrolidone and lubricants such as sodium 
stearate, may be used to form tablets. Disintegrating agents such as 
sodium bicarbonate may also be included in tablets. 
Although relatively small quantities of the active materials of the 
invention, even as low as 5.0 milligrams, may be used in cases of 
administration to subjects having a relatively low body weight, unit 
dosages are preferably five milligrams or above and preferably 
twenty-five, fifty, or one hundred milligrams, or even higher, depending 
of course upon the subject treated and the particular result desired, as 
will be apparent to one skilled in the art. Broader ranges appear to be 1 
to 1000 milligrams per unit dose. 
The active agents of the invention may be combined for administration with 
other pharmacologically active agents such as analgesics, steroids or 
hormones, or the like, or with buffers, antacids or the like, and the 
proportion of the active agent or agents in the compositions may be varied 
widely. It is only necessary that the active ingredient of the invention 
constitutes an effective amount, i.e. such that a suitable effective 
dosage will be obtained consistent with the dosage form employed. 
Obviously, several unit dosage forms may be administered at about the same 
time. The exact individual dosages as well as daily dosages in a 
particular case will of course be determined according to well established 
medical and/or veterinary principles under the supervision of the 
physician or veterinarian in charge. As a rule, however, when used 
therapeutically, the present compounds may be administered in a quantity 
of 1 to 1000 milligrams, preferred ranges being 1-100 milligrams per day 
and subject or patient, divided in 1 to 4 or more doses, over a suitable 
period and depending upon the subject and the type of subject being 
treated.

The following examples are intended to illustrate but not to limit the 
scope of the invention, although the compounds named are of particular 
interest for our intended purposes. These compounds have been designated 
by underlined numbers which are used in the biological examples below. The 
NMR data given in the examples are obtained from solutions in deuterated 
chloroform using a 60 MHz instrument (Perkin-Elmer R 12). 
EXAMPLE 1 
A mixture of 17.alpha.-hydroxypregn-4-ene-3,20-dione (20.0 g) and 
chloroacetic anhydride (145 g) is heated at 85.degree. C. for 22 h. After 
cooling chloroform (200 ml) is added, and the solution is washed with 
H.sub.2 O and aq. NaHCO.sub.3, dried, and evaporated to give an oil, to 
which ether (50 ml) is added. The precipitate is filtered off and the 
filtrate evaporated to dryness. The residue is dissolved in a mixture of 
conc. H.sub.2 SO.sub.4 (2 ml), methanol (100 ml), and toluene (100 ml). 
After 3 h at 50.degree. C., the solution is evaporated and the residue 
dissolved in chloroform (200 ml). After washing with aq. NaHCO.sub.3 and 
H.sub.2 O, drying, and evaporation an oil is obtained, from which on 
treatment with ether (25 ml) crystals of 
17.alpha.-chloroacetoxy-pregn-4-ene-3,20-dione (1, 13.1 g) deposit. M.P. 
216.degree.-7.degree. C. after recrystallization from acetone/H.sub.2 O. 
The structure is confirmed by NMR, IR, and analysis for Cl. The significant 
signals of the NMR spectrum are the following: .delta. (ppm) 0.70 (s, 3H, 
H-18), 1.20 (s, 3H, H-19), 2.09 (s, 3H, --COCH.sub.3), 4.12 (s, 2H, 
--CH.sub.2 Cl), 5.80 (broad s, 1H, H-4). 
In substantially the same manner the following compounds are obtained from 
the corresponding starting materials. The structures of the compounds are 
confirmed as above. 
2. 17.alpha.-bromoacetoxypregn-4-ene-3,20-dione, 
3. 17.alpha.-chloroacetoxy-6.alpha.-methylpregn-4-ene-3,20-dione, 
4. 6-chloro-17.alpha.-(2-chloropropanoyloxy)pregna-4,6-diene-3,20-dione, 
5. 17.alpha.-(2-bromopropanoyloxy)-6-methylpregna-4,6-diene-3,20-dione, 
6. 17.alpha.-bromoacetoxy-6.alpha.-fluoropregn-4-ene-3,20-dione, 
7. 
6-chloro-17.alpha.-chloroacetoxy-16-methylenepregna-4,6-diene-3,20-dione, 
8. 
17.alpha.-bromoacetoxy-6-chloro-16.alpha.-methylpregna-4,6-diene-3,20-dion 
e, and 
9. 
6-chloro-17.alpha.-chloroacetoxy-1.alpha.,2.alpha.-methylenepregna-4,6-die 
ne-3,20-dione. 
EXAMPLE 2 
To a mixture of 4-bromobutyric acid (80.8 g) and trifluoroacetic anhydride 
(68.0 ml) 17.alpha.-hydroxypregn-4-ene-3,20-dione (80.0 g) is added. After 
48 h at 4.degree. C. the reaction mixture is poured into an 
ice-dichloromethane mixture. The organic phase is washed with H.sub.2 O 
and aq. NaHCO.sub.3, dried, and evaporated to give an oil, which is 
dissolved in a mixture of conc. H.sub.2 SO.sub.4 (4 ml), methanol (200 
ml), and toluene (200 ml). After 3 h at 50.degree. C. the solution is 
worked up as described in Example 1 to give 
17.alpha.-(4-bromobutanoyloxy)pregn-4-ene-3,20-dione (1, 99.0 g) M.P. 
134.degree.-5.degree. C. (acetone/H.sub.2 O). 
The structure is confirmed by NMR, IR, and analysis for Br. The significant 
signals of the NMR spectrum are the following: .delta. (ppm) 0.70 (s, 3H, 
H-18), 1.20 (s, 3H, H-19), 2.06 (s, 3H, --COCH.sub.3), 3.48 (t, 2H, 
--CH.sub.2 Br, J=6 Hz), 5.78 (broad s, 1H, H-4). 
In substantially the same manner the following compounds are obtained from 
the corresponding starting materials. The structures of the compounds are 
confirmed as above. 
2. 17.alpha.-(4-chlorobutanoyloxy)-19-norpregn-4-ene-3,20-dione, 
3. 17.alpha.-(5-bromopentanoyloxy)-6.alpha.-fluoropregn-4-ene-3,20-dione, 
4. 17.alpha.-(4-bromobutanoyloxy)-6.alpha.-methylpregn-4-ene-3,20-dione, 
5. 17.alpha.-(4-bromobutanoyloxy)-6-chloropregna-4,6-diene-3,20-dione, 
6. 17.alpha.-(4-bromobutanoyloxy)-6-methylpregna-4,6-diene-3,20-dione, and 
7. 
17.alpha.-(4-bromobutanoyloxy)-6-chloro-1.alpha.,2.alpha.-methylenepregna- 
4,6-diene-3,20-dione. 
EXAMPLE 3 
4-/N,N-bis(2-chloroethyl)amino/phenylacetic acid (22.1 g) is added to a 
solution of tetrabutylammonium hydrogen sulfate (27.2 g) in 2 M NaOH (80.0 
ml). The mixture is vigorously stirred for 3 min and then extracted with 
chloroform (3.times.150 ml). To the dried extract 
17.alpha.-chloroacetoxypregn-4-ene-3,20-dione (24.4 g), prepared according 
to Example 1, is added, and the mixture is refluxed for 16 h. The residue, 
obtained after evaporation of the solvent, is chromatographed on a silica 
gel column using toluene/ethyl acetate (2:1) as eluent. The eluate 
fraction having R.sub.f =0.40 gives 
17.alpha.-/4-(N,N-bis(2-chloroethyl)amino)phenylacetoxyacetoxy/pregn-4-ene 
-3,20-dione (1, 33.4 g), m.p. 72.degree.-73.degree. C. after 
recrystallization from methanol. 
The structure is confirmed by NMR, IR, and analysis for Cl and N. The 
significant signals of the NMR spectrum are the following: .delta. (ppm) 
0.70 (s, 3H, H-18), 1.20 (s, 3H, H-19), 2.05 (s, 3H, --COCH.sub.3), 3.65 
(s, 10H,22--CH.sub.2 CH.sub.2 Cl and --OCOCH.sub.2 .phi.-), 4.63 (s, 2H, 
--OCOCH.sub.2 OCO--), 5.75 (broad s, 1H, H-4), 6.65 (d, 2H, aromatic H, 
J=8 Hz), 7.13 (d, 2H, aromatic H, J=8 Hz). 
In substantially the same manner the following compounds are obtained from 
the corresponding haloesters of 17.alpha.-hydroxysteroids, prepared 
according to Examples 1 and 2, and the corresponding acids. The structures 
of the compounds are confirmed as above. 
2. 
17.alpha.-/4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxyacetoxy/pre 
gn-4-ene-3,20-dione, 
3. 
17.alpha.-/4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxy)butanoylox 
y/pregn-4-ene-3,20-dione, 
4. 
17.alpha.-/4-(4-(N,N-bis(2-chloroethyl)amino)phenylacetoxyy)butanoyloxy/pr 
egn-4-ene-3,20-dione, 
5. 
17.alpha.-/4-(N,N-bis(2-chloroethyl)amino)phenylthioacetoxyacetoxy/pregn-4 
-ene-3,20-dione, 
6. 
17.alpha.-/3-(N,N-bis(2-chloroethyl)amino)benzoyloxyacetoxy/pregn-4-ene-3, 
20-dione, 
7. 
17.alpha.-/3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxyacetoxy/pregn 
-4-ene-3,20-dione, 
8. 
6-chloro-17.alpha.-/2-(5-(4-(N,N-bis(2-chloroethyl)amino)phenyl)pentanoylo 
xy)propanoyloxy/pregna-4,6-diene-3,20-dione, 
9. 
17.alpha.-/2-((2E)-3-(2-(N,N-bis(2-chloroethyl)amino)phenyl)propenoyloxy)p 
ropanoyloxy/-6-methylpregna-4,6-diene-3,20-dione, 
10. 
17.alpha.-/5-(2-amino-3-(4-(N,N-bis(2-chloroethyl)amino)phenyl)propanoylox 
y)pentanoyloxy/-6.alpha.-fluoropregn-4-ene-3,20-dione, 
11. 
6-chloro-17.alpha.-[4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxyac 
etoxy]-1.alpha.,2.alpha.-methylenepregna-4,6-diene-3,20-dione, 
12. 
17-[(2S)-2-amino-3-(4-(N,N-bis(2-chloroethyl)amino)phenyl)propanoyloxyacet 
oxy]pregn-4-ene-3,20-dione (prepared from the corresponding N-benzyl 
derivative) 
12a. and its hydrochloride (12a, prepared by treatment of the free amine 
with HCl), 
13. 
17-[4-((2S)-2-amino-3-(4-(N,N-bis(2-chloroethyl)amino)phenyl)propanoyloxy) 
butanoyloxy]pregn-4-ene-3,20-dione (prepared from the corresponding 
N-carbonyloxybenzyl 
13a. derivative) and its hydrochloride (13a, prepared by treatment of the 
free amine with HCl), 
14. 
17-[(2S)-2-acetamido-3-(4-(N,N-bis(2-chloroethyl)amino)phenyl)propanoyloxy 
acetoxy]pregn-4-ene-3,20-dione, 
15. 
17-[4-((2S)-2-acetamido-3-(4-(N,N-bis(2-chloroethyl)amino)phenyl)propanoyl 
oxy)butanoyloxy]pregn-4-ene-3,20-dione, 
16. 
17.alpha.-[4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxyacetoxy]-6. 
alpha.-methylpregn-4-ene-3,20-dione, 
17. 
17.alpha.-[4-(N,N-bis(2-chloroethyl)amino)phenylacetoxyacetoxy]-6-methylpr 
egna-4,6-diene-3,20-dione, 
18. 
6-chloro-17.alpha.-[3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxyacet 
oxy]pregna-4,6-diene-3,20-dione, 
19. 
17-[(2S)-2-amino-3-(3-(N,N-bis(2-chloroethyl)amino)phenyl)propanoyloxyacet 
oxy]pregn-4-ene-3,20-dione (prepared from the corresponding 
N-carbonyloxybenzyl 
19a. derivative) and its hydrochloride (19a, prepared by treatment of the 
free amine with HCl), 
20. 
17-[(2S)-2-amino-3-(2-(N,N-bis(2-chloroethyl)amino)phenyl)propanoyloxyacet 
oxy]pregn-4-ene-3,20-dione (prepared from the corresponding 
N-carbonyloxybenzyl 
20a. derivative) and its hydrochloride (20a, prepared by treatment of the 
free amine with HCl), 
21. 
17.alpha.-[4-(4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxy)butanoy 
loxy]-6.alpha.-methylpregn-4-ene-3,20-dione, 
22. 
6-chloro-17.alpha.-[4-(4-(N,N-bis(2-chloroethyl)amino)phenylacetoxy)butano 
yloxy]pregn-2,4-diene-3,20-dione, 
23. 
17.alpha.-[4-(3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxy)butanoylo 
xy]-6-methylpregna-4,6-diene-3,20-dione, 
24. 
6-chloro-17.alpha.-[4-(4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoylox 
y)butanoyloxy]-1.alpha.,2.alpha.-methylenepregna-4,6-diene-3,20-dione, 
25. 
17.alpha.-[4-chloro-3-(N,N-bis(2-chloroethyl)amino)benzoyloxyacetoxy]-6.al 
pha.-fluoropregn-4-ene-3,20-dione, and 
26. 
17.alpha.-[3-(4-(N,N-bis(2-chloroethyl)amino)phenoxy)propionyloxyacetoxy]p 
regn-4-ene-3,20-dione. 
EXAMPLE 4 
A mixture of 17.alpha.-chloroacetoxypregn-4-ene-3,20-dione (40.7 g), 
prepared according to Example 1, and NaN.sub.3 (32.6 g) in 60% acetone 
(500 ml) is refluxed for 16 h. The acetone is removed by evaporation, and 
the aqueous solution is extracted with a 1:1 mixture of ether and ethyl 
acetate (3.times.100 ml). The combined extracts are washed with H.sub.2 O, 
dried, and evaporated to give an oil, from which, on treatment with ether, 
crystals of 17.alpha.-azidoacetoxypregn-4-ene-3,20-dione (32.0 g) deposit. 
A solution of triphenylphosphine (25.2 g) in benzene (100 ml) is added 
dropwise to a solution of the above azide (32.0 g) in benzene (200 ml). 
After 4 h reflux the solution is cooled to room temperature, and HCl is 
bubbled through the solution until precipitation begins. Ether is added to 
complete the precipitation, and the crystals formed are collected. The 
product is dissolved in dichloromethane, and the solution, after washing 
with aq. NaHCO.sub.3 and H.sub.2 O, drying, and evaporation, gives the 
1-oxa-4-azacyclohex-3-en-6-one A (9.40 g), formed by a spontaneous 
intramolecular condensation of 
17.alpha.-aminoacetoxypregn-4-ene-3,20-dione. The structure of compound A 
is verified by its NMR spectrum: .delta. (ppm) 0.97 (s, 3H, H-18), 1.19 
(s, 3H, H-19), 2.27 (s, 3H, CH.sub.3 --C.dbd.N--), 4.14 and 4.48 
(doublets, 1H each, AB system with J=22 Hz, --N--CH.sub.2 --CO--), 5.75 
(broad s, 1H, H-4). 
##STR26## 
Compound A (9.40 g) is dissolved in a mixture of acetone (240 ml) and 0.15 
M aq. KCl (120 ml). The pH is kept constant at 4.2 by a continuous 
addition of 5 M HCl. When the consumption of HCl has ceased, a solution of 
4-/4-(N,N-bis(2-chloroethyl)amino)phenyl/butanoic anhydride (22.0 g) in 
acetone (200 ml) is added and the pH is kept at 4.2 by a continuous 
addition of 5 M NaOH. When the consumption of NaOH has ceased the acetone 
is removed by evaporation, and the aqueous solution is extracted with 
ether/ethyl acetate (1:1, 3.times.100 ml). The extract is washed with 1 M 
aq. NaCO.sub.3 and H.sub.2 O, dried, and evaporated. The residue is 
triturated in refluxing isopropyl ether and then recrystallized from ethyl 
acetate/isopropylether to give 
17.alpha.-/4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoylaminoacetoxy/p 
regn-4-ene-3,20-dione (1, 8.85 g, decomposes on heating). 
The structure is confirmed by NMR, IR, and analysis for Cl and N. The 
significant signals of the NMR spectrum are the following: .delta. (ppm) 
0.68 (s, 3H, H-18), 1.18 (s, 3H, H-19), 2.05 (s, 3H, --COCH.sub.3), 3.65 
(s, 8H, 2 --CH.sub.2 CH.sub.2 Cl), 4.03 (d, 2H, --COCH.sub.2 N&lt;, J=6 Hz), 
5.74 (broad s, 1H, H-4), 6.16 (t, 1H, &gt;NH, J=6 Hz), 6.64 (d, 2H, aromatic 
H, J=7 Hz), 7.05 (d, 2H, aromatic H, J-7 Hz). 
In substantially the same manner the following compound is obtained from 
the corresponding haloester of a 17.alpha.-hydroxysteroid, prepared 
according to Example 1, and the corresponding acid. The structure of the 
compound is confirmed as above. 
2. 
17.alpha.-/3-(N,N-bis(2-chloropropyl)amino)-4-methylbenzoylaminoacetoxy/-6 
.alpha.-methylpregn-4-ene-3,20-dione. 
EXAMPLE 5 
To a solution of tetrabutylammonium hydrogen sulfate (27.2 g) in 2 M NaOH 
(80.0 ml) 4-nitrobenzoic acid (13.4 g) is added. The mixture is vigorously 
stirred for 15 min and is then extracted with chloroform (3.times.150 ml). 
To the dried extract 17.alpha.-bromoacetoxypregn-4-ene-3,20-dione (27.2 
g), prepared according to Example 1, is added. After 24 h reflux the 
solution is washed with H.sub.2 O, 2.5 M H.sub.2 SO.sub.4, H.sub.2 O, aq. 
NaHCO.sub.3, and H.sub.2 O, dried, and evaporated. On the addition of a 
1:1 mixture of toluene/ethyl acetate (100 ml) to the residue crystals of 
17.alpha.-(4-nitrobenzoyloxyacetoxy)pregn-4-ene-3,20-dione (29.1 g) 
precipitate. 
The above 4-nitrobenzoic ester (29.1 g) is suspended in a mixture of tert. 
butanol (4300 ml) and H.sub.2 O (700 ml), and 1 M KOH (58 ml) is added 
dropwise under stirring. After 16 h at room temperature H.sub.2 O is added 
and the solution is extracted with chloroform (5.times.1000 ml). The 
combined extracts are dried and evaporated, and to the residue a 1:1 
mixture of toluene/ethyl acetate (120 ml) is added. After 16 h at room 
temperature crystals of 17.alpha.-hydroxyacetoxypregn-4-ene-3,20-dione 
(11.0 g, m.p. 220.degree.-1.degree. C.) are filtered off. The compound 
exhibits the following significant NMR signals: .delta. (ppm) 0.70 (s, 3H, 
H-18), 1.19 (s, 3H, H-19), 2.06 (s, 3H, --COCH.sub.3), 
##STR27## 
5.31 (s, 1H, OH), 5.75 (broad s, 1H, H-4). 
Additional 17.alpha.-hydroxyacetoxypregn-4-ene-3,20-dione (2.6 g) is 
obtained from the filtrate by chromatography on a silica gel column using 
toluene/ethyl acetate 1:2 as eluent (R.sub.f =0.25). 
The above alcohol is acetylated with acetic anhydride in pyridine to give 
17.alpha.-acetoxyacetoxypregn-4-ene-3,20-dione, which shows the following 
significant NMR signals: .delta.(ppm) 0.69 (s, 3H, H-18), 1.19 (s, 3H, 
H-19), 2.07 and 2.17 (singlets, 3H each, 2-COCH.sub.3), 
##STR28## 
5.76 (broad s, 1H, H-4). 
A solution of the above alcohol (13.6 g) in abs. benzene (200 ml) is 
treated with phosgene at 5.degree. C. After 16 h at room temperature the 
solution is evaporated to yield a crystalline residue, from which, on 
treatment with ether, 
17.alpha.-chlorocarbonyloxyacetoxypregn-4-ene-3,20-dione (14.2 g) is 
obtained. 
A solution of the above chloroformate (14. 2 g) in dry chloroform (100 ml) 
is added dropwise with stirring at 0.degree. C. to a mixture of 
N,N-bis-(2-chloroethyl)-4-phenylenediamine hydrochloride (11.4 g) and 
triethylamine (7.95 g) in dry chloroform (100 ml). After 16h at room 
temperature the solution is washed with H.sub.2 O, 2 M HCl, and H.sub.2 O. 
Drying and evaporation give an oil, which is chromatographed on a silica 
gel column using toluene/ethyl acetate (2:1) as eluent. The fraction 
having a R.sub.f -value of 0.28 yields 
17.alpha.-/4-(N,N-bis(2-chloroethyl)amino)phenylcarbamoyloxyacetoxy/pregn- 
4-ene-3,20-dione (1, 7.35 m.p. 104.degree.-5.degree. C.). 
The structure is confirmed by NMR, IR, and analysis for Cl and N. The 
significant signals of the NMR spectrum are the following: .delta. (ppm) 
0.66 (s, 3H, H-18), 1.13 (s, 3H, H-19), 2.08 (s, 3H, --COCH.sub.3), 3.66 
(s, 8H, 2 --CH.sub.2 CH.sub.2 Cl), 4.68 (s, 2H, --OCOCH.sub.2 OCO--), 5.69 
(broad s, 1H, H-4), 6.64 (d, 2H, aromatic H, J=9 Hz), 7.27 (d, 2H, 
aromatic H, J=9 Hz). 
In substantially the same manner the following compounds are obtained from 
the corresponding haloesters of 17.alpha.-hydroxysteroids, prepared 
according to Example 1, and the corresponding 4-phenylenediamine and 
4-aminophenol, respectively. The structures of the compounds are confirmed 
as above. 
2. 
6-chloro-17.alpha.-/4-(N,N-bis(2-chloroethyl)amino)-2-methoxyphenylcarbamo 
yloxyacetoxy/-16-methylenepregna-4,6-diene-3,20-dione, 
3. 
6-chloro-17.alpha.-/4-(N,N-bis(2-chloroethyl)amino)phenoxycarbonyloxyaceto 
xy/-16.alpha.-methylpregna-4,6-diene-3,20-dione, and 
4. 
17.alpha.-[4-(N,N-bis(2-chloroethyl)amino)phenoxycarbonyloxyacetoxy]pregn- 
4-ene-3,20-dione. 
EXAMPLE 6 
To a solution of tetrabutylammonium hydrogen sulfate (17.0 g) in 5 M NaOH 
(10.0 ml) NaN.sub.3 (3.25 g) is added. The solution is extracted with 
dichloromethane (100 ml), and to the dried extract toluene (100 ml) is 
added. The dichloromethane is removed by evaporation, and to the toluene 
solution 17.alpha.-(4-bromobutanoyloxy)pregn-4-ene-3,20-dione (17.2 g), 
prepared according to Example 2, is added. After 20 H at room temperature 
the solution is washed with H.sub.2 O, dried, and evaporated. The residue, 
on treatment with ether, yields 
17.alpha.-(4-azidobutanoyloxy)pregn-4-ene-3,20-dione (14.2 g). 
A mixture of trimethyl phosphite (5.8 g), the above azide (14.2 g), and 
toluene (130 ml) is heated at 85.degree. C. for 3 h. The solution is 
evaporated, and to the residue methanol (250 ml) and 1 M HCl (250 ml) are 
added. After 3 h at 45.degree. C. the methanol is evaporated, the aqueous 
solution is washed with ethyl acetate, and the aqueous phase is extracted 
with dichloromethane. After drying and evaporation of the extract 
17.alpha.-(4-aminobutanoyloxy)pregn-4-ene-3,20-dione hydrochloride (29.1 
g) is obtained. 
The above amine hydrochloride is acetylated with acetyl chloride to give 
17.alpha.-(4-acetylaminobutyanoyloxy)pregn-4-ene-3,20-dione, which shows 
the following significant NMR signals: .delta. (ppm) 0.65 (s, 3H, H-18), 
1.19 (s, 3H, H-19), 2.00 and 2.10 (singlets, 3H each, 2-COCH.sub.3), 5.70 
(broad s, 1H, H-4), 7.42 (broad t, 1H, NH). 
To a mixture of acetone (1200 ml) and 0.15 M KCl (400 ml) 
4-/N,N-bis(2-chloroethyl)amino/phenylacetic anhydride (42.8 g) is added. 
pH of the solution is adjusted to 6.0, and a solution of the above amine 
hydrochloride (29.1 g) in a mixture of acetone (1200 ml) and 0.15 M KCl 
(400 ml) is added. The pH is maintained at 6.0-6.5 by a continuous 
addition of 5 M NaOH. When the comsumption of NaOH has ceased, the acetone 
is removed by evaporation and the aqueous solution extracted with ethyl 
acetate (2400 ml). The organic phase is washed with 1 M Na.sub.2 CO.sub.3 
and H.sub.2 O, dried, and evaporated to give 
17.alpha.-/4-(4-(N,N-bis(2-chloroethyl)amino)phenylacetylamino)butanoyloxy 
/pregn-4-ene-3,20-dione (1, 41.0 g, decomposes on heating). 
The structure is confirmed by NMR, IR, and analysis for Cl and N. The 
significant signals of the NMR spectrum are the following: .delta. (ppm) 
0.65 (s, 3H, H-18), 1.19 (s, 3H, H-19), 1.99 (s, 3H, --COCH.sub.3), 3.37 
(s, 2H, --COCH.sub.2 .phi.-), 3.69 (s, 8H, 2-CH.sub.2 CH.sub.2 Cl), 5.70 
(broad s, 1H, H-4), 6.68 (d, 2H, aromatic H, J=9 Hz), 7.17 (d, 2H, 
aromatic H, J=9 Hz). 
In substantially the same manner the following compounds are obtained from 
the corresponding haloesters of 17.alpha.-hydroxysteroids, prepared 
according to Example 2, and the corresponding acids. The structures of the 
compounds are confirmed as above. 
2. 
17.alpha.-/4-(2-(4-(N,N-bis(2-chloroethyl)amino)phenyl)-2-methylpropanoyla 
mino)butyanoyloxy/-19-norpregn-4-ene-3,20-dione 
3. 
17.alpha.-/5-(3-(N,N-bis(2-bromoethyl)amino)-4-methylbenzoylamino)pentanoy 
loxy/-6.alpha.-fluoropregn-4-ene-3,20-dione, and 
4. 
17.alpha.-[4-(3-(N,N-bis(2-chloroethyl)amino-4-methylbenzoylamino)butanoyl 
oxy]pregn-4-ene-3,20-dione. 
EXAMPLE 7 
A mixture of 3-/N,N-bis(2-chloroethyl)amino/-4-methylbenzoic acid (27.6 g) 
and trifluoroacetic anhydride (21.0 g) is heated under stirring at 
60.degree. C. for 15 min. To the mixture 
17.alpha.-hydroxypregn-4-ene-3,20-dione (16.5 g) is added and the mixture 
is heated under stirring at 80.degree. C. for 5 h. Toluene (150 ml) is 
added, the solution is filtered, and to the filtrate chloroform (200 ml) 
is added. After washing with H.sub.2 O and aq. NaHCO.sub.3, drying, and 
evaporation an oil is obtained, to which a mixture of methanol (300 ml) 
and conc. HCl (3 ml) is added. After 16 h at room temperature the solution 
is evaporated and the residue chromatographed on a silica gel column using 
toluene/ethyl acetate (2:1) as eluent. The eluate fraction having R.sub.f 
=0.40 gives 
17.alpha.-/3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxy/pregn-4-ene- 
3,20-dione (1, 6.8 g, m.p. 170.degree.-1.degree. C.). 
The structure is confirmed by NMR, IR, and analysis for Cl and N. The 
significant signals of the NMR spectrum are the following: .delta. (ppm) 
0.75 (s, 3H, H-18), 1.23 (s, 3H, H-19), 2.00 (s, 3H, --COCH.sub.3), 2.40 
(s, 3H, aromatic CH.sub.3), 3.45 (s, 8H, 2-CH.sub.2 CH.sub.2 Cl), 5.76 
(broad, s, 1H, H-4), 7.34 (d, 1H, aromatic H, J=8 Hz), 7.71 (dd, 1H, 
aromatic H, J.sup.1 =8 Hz and J.sup.2 =2 Hz), 7.86 (d, 1H, aromatic H, J=2 
Hz). 
In substantially the same manner the following compounds are obtained from 
the corresponding starting materials. The structures of the compounds are 
confirmed as above. 
2. 
17.alpha.-/4-(N,N-bis(2-chloroethyl)amino)phenylacetoxy/pregn-4-ene-3,20-d 
ione, 
3. 
17.alpha.-/4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxy/pregn-4-en 
e-3,20-dione, 
4. 
17.alpha.-/4-(3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxy)butanoylo 
xy/pregn-4-ene-3,20-dione, and 
EXAMPLE 8 
To a mixture of 1,2-dimethoxyethane (125 ml) and 70% HClO.sub.4 (6.5 g) HgO 
(10.8 g) is added. The mixture is heated under stirring at 
45.degree.-55.degree. C. for 25 min and is then cooled to room 
temperature. 17.alpha.-(4-bromobutanoyloxy)pregn-4-ene-3,20-dione (24.0 
g), prepared according to Example 2, and H.sub.2 O (10 ml) are added, and 
the reaction mixture is stirred at room temperature for 5 h. Chloroform 
(100 ml) is added, the mixture is filtered, and the filtrate is washed 
with H.sub.2 O, aq. NaHCO.sub.3, and H.sub.2 O. The residue, obtained 
after drying and evaporation, is chromatographed on a silica gel column 
using toluene/ethyl acetate (1:4) as eluent. 
17.alpha.-(4-hydroxybutanoyloxy)pregn-4-ene-3,20-dione (13.6 g, m.p. 
161.degree.-2.degree. C.) is obtained from an eluate fraction having 
R.sub.f =0.20. The structure is confirmed by NMR and IR. The following NMR 
signals are significant: .delta. (ppm) 0.68 (s, 3H, H-18), 1.20 (s, 3H, 
H-19), 1.99 (s, 3H, --COCH.sub.3), 4.19 (t, 1H, OH, disappears on addition 
of HCOOH), 5.70 (broad s, 1H, H-4). 
The alcohol is acetylated with acetic anhydride in pyridine to give 
17.alpha.-(4-acetoxybutanoyloxy)pregn-4-ene-3,20-dione, which exhibits the 
following significant NMR signals: .delta. (ppm) 0.69 (s, 3H, H-18), 1.19 
(s, 3H, H-19), 2.02 and 2.06 (singlets, 3H each, 2-COCH.sub.3), 
##STR29## 
5.75 (broad s, 1H, H-4). 
EXAMPLE 9 
This example illustrates the effect of the compounds of the general formula 
I in inhibiting the growth of tumours. 
LD50 is the dose that causes a 50 percent lethality of the animals, and 
ED50 is the dose that causes a 50 percent reduction of tumour size. 
From the data below it is obvious that the compounds have a very low 
toxicity, and that the therapeutic indexes (T.I.), i.e. the ratios 
LD50/ED50, are very high. 
The experimental design and the interpretation of the results are in 
accordance with the standards set by the CCNSC (Cancer Chemotherpy 
Reports, January 1959 and December 1962). 
Some of the results obtained are given in the tables below. The compounds 
are named by number code, a:b, where a means the example, wherein the 
preparation of the compound in question is described, and b refers to the 
order of the compounds prepared according to that example. Thus, compound 
4:2 means the second compound prepared according to Example 4. The 
systematic names of the compounds are given in the examples. 
This example shows that the new compounds are useful to interfere with and 
suppress the growth of tumours and in some cases even cause complete 
remission of tumours and therefore can be employed in treating a living 
animal body suffering from disorders responsive to treatment with 
anticancer agents and with immunosuppressive agents. 
Table 1. 
______________________________________ 
Walker carcinosarcoma 256. 
Experimental animals: Sprague-Dawley rats. 
Tumour implant: Tumour pieces with 2-4 mm diameter, sub- 
cutaneously. 
Therapy: Daily p.o. administration for 5 days starting on 
the day following implantation. 
Termination: The animals are killed on the 9th day. 
Evaluation: Weights of tumours of test animals are compared 
with those of control animals. 
Results: 
Compound LD50 ED50 T.I. 
______________________________________ 
3:1 &gt;250 8 &gt;31 
3:2 &gt;250 3 &gt;83 
3:3 40 2 20 
3:4 80 4 20 
3:7 &gt;250 16 &gt;15 
______________________________________ 
The following additional compounds exhibit antitumour activity in the 
foregoing test: 3:5, 3:6, 3:11, 3:12, 3:14, 3:16, 3:18, 3:21, 4:1, 5:1, 
6:1, and 7:4. 
Table 2. 
______________________________________ 
Hepatome AH 130. 
Experimental animals: Sprague-Dawley rats. 
Tumour implant: 5 .times. 10.sup.6 tumour cells i.p. 
Therapy: One injection i.p. on the day following implanta- 
tion. 
Termination: The animals are killed on the 8th day. 
Evaluation: Weights of tumours of test animals are compared 
with those of control animals. 
Results: 
Compound ED50 T.I. 
______________________________________ 
3:1 &gt;250 3 &gt;83 
3:2 &gt;1000 100 &gt;10 
3:3 180 6 30 
3:4 50 2 25 
3:5 &gt;250 50 &gt;5 
3:7 &gt;250 2 &gt;125 
4:1 &gt;250 125 &gt;2 
5:1 &gt;250 30 &gt;8 
7:4 &gt;250 16 &gt;15 
______________________________________ 
The following additional compounds exhibit antitumour activity in the 
foregoing test: 3:6, 3:8, 3:9, 3:10, 3:13, 3:15, 3:17, 3:19, 3:20, 3:22, 
3:23, 3:24, 3:25, 3:26, 4:2, 5:2, 5:3, 5:4, 6:2, 6:3, and 6:4. 
Table 3. 
______________________________________ 
Ehrlich ascites tumour, ELD hyperdiploid 
(46 chromosomes). 
Experimental animals: SPF NMRI mice. 
Tumour implant: 2 .times. 10.sup.6 tumour cells i.p. 
Therapy: One injection i.p. on the day following implanta- 
tion. 
Termination: The animals are killed on the 8th day. 
Evaluation: Weight of tumours of test animals compared with 
those of control animals. 
Results: 
Tumour weight 
Dose Treated/Control 
Compound (mg/kg) Mortality (%) 
______________________________________ 
3:1 50 1/12 3 
3:2 50 0/12 1 
3:7 100 0/12 2 
5:1 1000 0/12 1 
______________________________________ 
The following additional compounds exhibit antitumour activity in the 
foregoing test: 3:3, 3:4, 3:5, 3:6, 3:8, 3:9, 3:11, 3:12, 3:14, 3:16, 4:1 
5:1, 5:4, 6:1, 6:4, and 7:4. 
Table 4. 
______________________________________ 
Lymphatic leukemia L 1210. 
Experimental animals: CDF.sub.1 (C3H.times.DBA/2)F.sub.1 mice 
Tumour implant: 10.sup.5 tumour cells i.p. 
Therapy: One injection i.p. on the day following implanta- 
tion. 
Evaluation: (a) The survival time of the test animals (t) 
expressed as the percentage of that of control animals (c). 
##STR30## 
(b) Weight change in the test animals (T) compared with that 
of the control animals (C) up to the 5th day. 
.DELTA..sub.v = T - C 
(c) The mortality rate must not exceed 35% in the test 
animals on the 5th day of therapy. 
Results: 
Dose Weight change 
Effect 
Compound (mg/kg) Mortality .DELTA..sub.v (g) 
(%) 
______________________________________ 
3:7 500 0/19 -5.2 172 
3:7 250 0/20 -4.0 130 
______________________________________ 
EXAMPLE 10 
This example illustrates the compound's relative affinity to rabbit uterus 
cytosol progesterone receptor compared with progesterone. The method used 
for this purpose is a modification of methods already described by 
Kontula, K. et al. (Acta Endocrinol. 78 (1975) 574) and Terenius, L. 
(Steroids 23 (1974) 909) among others. 
Cytosol preparation 
Female rabbits (3-4 pounds) from Knut Larsen, Uddevalla, Sweden, were 
injected i.m. with 1 mg Estradurin (polyestradiol phosphate, 1 mg/ml 
saline, AB Leo, Sweden). After one week, the animals were killed and the 
uteri were immediately removed, chilled and cut free from connective 
tissues. All the following operations were performed at 
0.degree.-4.degree. C. The uteri were cut into small pieces and washed 
several times with 3 vol. of buffer at pH 7.4 containing 50 MM TRIS-HCl, 
1.5 mM EDTA, 3 mM NaN.sub.3, 2 mM dithiothreitol, and 25% glycerol (by 
vol.). The tissue was homogenized in the same buffer (3 vol.) with four 
15-s bursts at rheostat setting 36-37 of an Ultra Turrax (Janke and Kunkel 
KG, Staufen, The Federal Republic of Germany). The homogenate was 
centifuged in a Sorvall GLC-2 centrifuge for 15 min at 600.times.g. The 
supernatanate was recentrifuged at 105,000.times.g for 60 min in a Beckman 
ultracentrifuge model LB-65-B with rotor SW 56. 
One ml portions of the supernatant (rabbit uterus cytosol) were pipetted 
into small centrifuge tubes of glass and were kept at -70.degree. C. until 
used. The protein content was determined by the method of Lowry (J. Biol. 
Chem. 193 (1951) 265). 
Dissolving the compounds 
10.0 mg of each compound was dissolved in 10.0 ml 99.5% ethanol. 100 .mu.l 
of this standard solution was diluted to 5.0 ml ethanol/glycerol 1:1 
(v/v). The ethanol was evaporated by blowing air at 40.degree. C. on the 
solution. The volume was then adjusted to 5.0 ml by adding buffer without 
glycerol. 
Incubation of the compounds 
The compounds were diluted with glycerol/buffer 1:1 to final concentrations 
between 10.sup.-8 -10.sup.-5 M in total 300 .mu.l incubation media. 100 
.mu.l of each compound and of each dilution were incubated in small 
centrifuge tubes (2 ml) together with 100 .mu.l (10 pg) .sup.3 
H-progesterone (1,2,6,7-3H-progesterone, 47.8 Ci/mMol, The Radiochemical 
Centre, Amersham, England) and 100 .mu.l cytosol adjusted with buffer to a 
final concentration of about 0.7 g/ml. The incubations were carried out 
for 16-18 hours at 4.degree. C. 
The separation of bound from free radioactivity was carried out at 
0.degree. C. using the dextran coated charcoal technique (DCC). To each 
incubation tube was added 0.5 ml DCC-suspension (0.05% dextran-70, 
Pharmacia, Uppsala, Sweden and 0.5% Norit A, Sigma, Saint Louis, Missouri, 
U.S.A.) The tubes were agitated 2-3 times during 10 minutes whereupon they 
were centrifuged at 100.times.g for five minutes. The supernatantes were 
decanted directly into Scintillation vials (polyethene, Packard) 
containing 10 ml InstaGel (Packard). The radioactivity was counted in a 
Philip's liquid scintillation spectrometer Model PW 4510/00 with external 
standard and automatic quenching correction. 
Standard curve for progesterone 
To incubation tubes were added 100 .mu.l cytosol, 100 .mu.l .sup.3 
H-progesterone (10 pg) and 100 .mu.l of different dilutions of 
non-radioactive progesterone in glycerol/buffer 1:1 ranging from 
0-10.sup.4 pg/100 .mu.l. The tubes were incubated parallel with the 
compounds described above. The radioactivity was calculated by 
substracting the counted radioactivity in the incubation tubes with the 
radioactivity counted in incubations tubes in which the cytosol was 
replaced with buffer (100 .mu.l). 
Calculations 
The concentration of non-radioactive progesterone [P].sub.i which competes 
for 50% of bound radioactive progesterone was calculated from the standard 
curve constructed [B] i/[B] o=0.5 where [B].sub.i is the bound 
radioactivity at different concentrations of non-radioactive progesterone 
and [B].sub.o is the bound radioactivity at progesterone concentration 
zero. 
In the same manner, curves were constructed for each compound X and the 
concentration for each compound which competes for 50% with bound .sup.3 
H-progesterone ([X].sub.50) was calculated. 
The relative binding affinity (RBA) in percent for each substance compared 
to progesterone was calculated and is summarized in the table below. 
Table 
______________________________________ 
Compound RBA 
______________________________________ 
3:3 0.6 
3:2 0.7 
7:4 0.9 
4:1 1.1 
3:7 1.8 
3:1 6.6 
5:1 15.8 
______________________________________ 
From this example it is evident that the compounds have the ability to 
specifically concentrate in tumour cells rich in progesterone receptors, 
frequently found in mammary and endometrical tumours. 
EXAMPLE 11 
______________________________________ 
Manufacturing Process for tablets a 10 mg 
Model batch of 1000 tablets. 
Compound 3:7, mesh* 70 
10.0 g 
I Lactosum, Ph. Nord. 210 g 
Amylum maidis, Ph. Nord. 
75 g 
Kollidon 25, B.A.S.F. 
3.5 g 
II 
Aqua purificata q.s. 
Talcum, Ph. Nord. 15 g 
III 
Magnesii stearas, Ph. Nord. 
1.5 g 
Weight of 1000 tablets: 
315 g 
Weight of 1 tablet: 315 mg 
______________________________________ 
*The mesh standard is according to the international system of code DIN 
4189/1968. 
Punch: 10.5 mm round, flat, scored, beveledged. 
Mix the screened substances I thoroughly and then moisten with II, 
whereupon it is granulated through a stainless sieve No. 10 (mesh 25). Dry 
the granulate in an oven at a maximum temperature of 40.degree. C., then 
repeat sieving through sieve No. 10. 
Add the substances under III and mix thoroughly. Punch tablets with a gross 
weight of about 315 mg. 
EXAMPLE 12 
______________________________________ 
Injectable solution 10 mg/ml 
______________________________________ 
Compound 3:2, mesh 70 10 mg 
Benzyl alcohol 80 mg 
Peanut oil to make 1 ml 
______________________________________ 
The substance is dissolved in the benzyl alcohol and peanut oil is added. 
EXAMPLE 13 
______________________________________ 
Vagitoria a 25 mg 
______________________________________ 
Compound 4:1 25 mg 
Cacao butter q.s. 
______________________________________ 
EXAMPLE 14 
______________________________________ 
Ointment 2% 
______________________________________ 
Compound 5:1 2 g 
Triethanolamine 1 g 
Glycerol 7 g 
Cetanol 2.5 g 
Lanoline 2.5 g 
Stearic acid 20 g 
Sorbitan monooleate 0.5 g 
Sodium hydroxide 0.2 g 
Methyl paraben 0.3 g 
Propyl paraben 0.1 g 
Ethanol 0.9 g 
Water to make 100 g 
______________________________________ 
EXAMPLE 14a 
Similar to Example 14 above, but compound 5:1 replaced by compound 7:4 
EXAMPLE 15 
______________________________________ 
Capsules a 10 mg 
______________________________________ 
Compound 3:2 10 mg 
Magnesium stearate 2 mg 
Talcum 188 mg 
______________________________________ 
The substances are mixed and filled in capsules. 
EXAMPLE 16 
______________________________________ 
Injectable solution 15 mg/ml 
______________________________________ 
Compound 3:3 15 mg 
Benzyl benzoate 120 mg 
Castor oil to make 1 ml 
______________________________________ 
The compound is dissolved in the benzyl benzoate and castor oil is added. 
In the above Examples 11-16 to compositions the compounds are named 
according to the number code defined in Example 9. The Examples 11-16 are 
merely representative with regard to active ingredients exemplified. It is 
to be understood that other compounds disclosed in the foregoing Examples 
3-7 may also be substituted for the active ingredients illustrated in the 
above examples. 
Also, it is to be noted that two or more compounds of the invention may be 
used in combination in the compositions illustrated, and also, if desired, 
in combination with other pharmacologically active agents. 
Various modifications and equivalents will be apparent to one skilled in 
the art and may be made in the compounds, compositions and methods of the 
present invention without departing from the spirit or scope thereof, and 
it is therefore to be understood that the invention is not to be limited 
to the specific examples and embodiments disclosed herein. 
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