Note: Descriptions are shown in the official language in which they were submitted.
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07189.0054.PZUSOO
METHODS FOR IMPROVED
STABILITY OF STEROID DERIVATIVES
FIELD OF THE INVENTION
[0001] The present invention relates generally to compositions comprising
steroids
and, in particular, to compositions with potent antiprogestational activity,
minimal
antiglucocorticoid activity and improved stability, comprising a 19-
norprogesterone I
derivative. The present invention also relates to methods using the
compositions.
BACKGROUND OF THE INVENTION
[0002] There have been numerous attempts over the past few decades to prepare
steroids with antihormonal activity. It has been generally recognized for some
years,
that antiprogestational steroids would find wide applicability in population
control,
while antiglucocorticoids would be extremely valuable in the treatment of, for
example, Cushing's syndrome and other conditions characterized by excessive
endogenous production of cortisone.
[0003] For purposes of contraception, it would be advantageous to have
compounds
which possess antiprogestational activity without (or with minimal)
antiglucocorticoid
activity. Although there have been a number of attempts to modify the
mifepristone
structure in order to obtain separation of the antiprogestational activity
from the
antiglucocorticoid activity, this goal has not yet been fully achieved. As
such, there
remains a need in the art for the development of new formulations comprising
steroids
which possess antiprogestational activity with minimal antiglucocorticoid
activity.
[0004] U.S. Patents 6,861,415 and 6,900,193, both incorporated herein by
reference,
disclose new compounds which possess antiprogestational activity with minimal
antiglucorticoid activity. The compounds are steroid derivatives, and more
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specifically they are structural modifications of 19-norprogesterone I, such
as 17-a-
substituted-ll-0-substituted-4-aryl and 21-substituted 19-norpregnadienedione,
and
are poorly soluble in water. Therefore, a need remains in the art to develop
formulations comprising the steroid derivatives with increased stability and
improved
bioavailability.
SUMMARY OF THE INVENTION
100051 The present invention provides new formulations with potent
antiprogestational activity, minimal antiglucocorticoid activity and improved
stability.
[0006] More particularly, the present invention provides compositions
comprising a
pharmaceutically acceptable salt of a compound having the following general
formula
I:
R2
R' O
R4 ,o R3
X
[0007] Wherein: R' is a basic functional group upon which a salt may be
prepared,
preferably comprising a nitrogen, including, but not limited to, -N(CH3)2, -
NHCH3, -NC4H8, -NC5H,o, -NC4H8O, -O(CH2)2N(CH3)2, -O(CH2)2NC4H8
and -O(CHZ)2NC5H1 o; R2 is a functional group including, but not limited to,
hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy,
vinyloxy,
ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., formyloxy, acetoxy,
propionyloxy,
heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, -SCN, S-
acyl
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and -OC(O)R6, wherein R6 is a functional group including, but not limited to,
alkyl
(e.g., methyl, ethyl, etc.), alkoxyalkyl (e.g., --CH2OCH3) and alkoxy (-OCH3);
R3 is
a functional group including, but not limited to, alkyl (e.g., methyl,
methoxymethyl,
etc.), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, vinyloxy, etc.),
and
acyloxy; R4 is a functional group including, but not limited to, hydrogen and
alkyl;
and X is a functional group including, but not limited to, =0 and =N-ORS,
wherein
R5 is a member selected from the group consisting of hydrogen and alkyl and
with the
proviso that when R' is -N(CH3)2, RZ is methoxy, R3 is acetoxy, R4 is methyl
and X
is =0, the salt is not an HC1 or an HBr salt.
[0008] The compositions may possess potent antiprogestational activity with
minimal
antiglucocorticoid activity in combination with improved stability. Therefore,
the
compositions may be suitable for long term use in the treatment of human
endocrinological disorders or other conditions in steroid-sensitive tissues.
Specific
conditions for treatment include, but are not limited to, endometriosis,
dysmenorrhea,
uterine leiomyoma, uterine fibroid, meningioma and metastatic breast cancer.
Other
uses include, but are not limited to, contraception, including emergency post-
coital
contraception and inducement of cervical ripening.
[0009] Also provided is the use of any of the compositions of the present
invention in
the manufacture of a medicament for treatment of human endocrinological
disorders
or other conditions in steroid-sensitive tissues as described herein,
including but not
limited to, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroid,
meningioma and metastatic breast cancer.
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DETAILED DESCRIPTION OF THE INVENTION
[0010] A composition is provided comprising a steroid derivative with the
following
general formula I:
R2
R' O
R4 3
X
[0011] In Formula I, R' is a basic functional group upon which a salt may be
prepared, preferably comprising a nitrogen, including, but not limited to, -
N(CH3)2.
-NHCH3, -NC4H8, NC5H1o, -NC4H8O, -O(CH2)2N(CH3)2, -O(CH2)2NC4H8
and -O(CH2)2NC5Hj0; R2 is a functional group including, but not limited to,
hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy,
vinyloxy,
ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., formyloxy, acetoxy,
propionyloxy,
heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, -SCN, S-
acyl
and -OC(O)R6, wherein R6 is a functional group including, but not limited to,
alkyl
(e.g., methyl, ethyl, etc.), alkoxyalkyl (e.g., -CH2OCH3) and alkoxy (-OCH3);
R3 is
a functional group including, but not limited to, alkyl, hydroxy, alkoxy and
acyloxy;
R4 is a functional group including, but not limited to, hydrogen and alkyl;
and X is a
functional group including, but not limited to, =0 and =N-OR5, wherein R5 is a
member selected from the group consisting of hydrogen and alkyl, with the
proviso
that when R] is N(CH3)2, R2 is methoxy, R3 is acetoxy, R4 is methyl and X is
=0,
the salt is not an HC1 or an HBr salt.
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[00121 Thus, compositions of the present invention comprise a compound of
general
formula I which is capable of forming a salt when the compound is reacted with
a
suitable acid. Preferably, a compound of general formula I comprises a basic
functional group attached at the 4 position of the phenyl group located at the
11(3
position of the compound (i.e., the R' position); however, compounds of
general
formula I comprising a basic functional group attached at any position are
within the
scope of the invention so long as a salt of the compound may be prepared. In
addition
to the basic functional groups listed above, other suitable basic functional
groups for
R' upon which a salt may be prepared include, without limitation, methylamine,
dimethylamine, ethylamine, diethylamine, ethylmethylamine, isopropylamine,
diisopropylamine, n-butylamine, ethanolamine, diethanolamine,
methylethanolamine,
isopropanolamine, diisopropanolamine, ethyleneimine, ethylenediamine, pyridine
and
morpholine functional groups.
100131 The term "alkyl" refers to a branched, unbranched, monovalent
hydrocarbon
radical having from 1-12 carbons. When the alkyl group has from 1-6 carbon
atoms,
it may be referred to as a "lower alkyl." Representative alkyl radicals
include, for
example, methyl, ethyl, n-propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-
butyl, i-
butyl (or 2-methylpropyl), etc. As used herein, the term alkyl encompasses
"substituted alkyls." A substituted alkyl refers to alkyl further containing
one or more
functional groups such as lower alkyl, aryl, aralkyl, acyl, halogen (i.e.,
alkylhalos,
e.g., CF3), hydroxy (e.g., hydroxymethyl), amino, alkylamino, acylamino,
acyloxy,
alkoxy (e.g., methoxymethyl), mercapto and the like. These groups may be
attached
to any carbon atom of the lower alkyl moiety.
[00141 The term "alkoxy" may refer to a -OR group, where R is a lower alkyl,
substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted
aralkyl. Suitable
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alkoxy radicals include, for example, methoxy, ethoxy, phenoxy, t-butoxy
(e.g.,
methoxyethoxy, methoxymethoxy, etc.), etc.
[0015] The term "acyloxy" may refer to an organic radical derived from an
organic
acid by the removal of a hydrogen. The organic radical can be further
substituted
with one or more functional groups such as alkyl, aryl, aralkyl, acyl,
halogen, amino,
thiol, hydroxy, alkoxy, etc. An example of such a substituted organic radical
is
glycinate (e.g., --OC(O)CHzNHz). Suitable acyloxy groups include, for example,
acetoxy, i.e., CH3COO-, which may be derived from acetic acid, formyloxy,
i.e.,
H(CO)O-, which may be derived from formic acid and cypionyloxy, which may be
derived from 3-cyclopentylpropionic acid.
[0016] The term "halogen" may refer to fluorine, bromine, chlorine and iodine
atoms.
The term "hydroxyl" may refer to the group -OH. The term "acyl" may denote
groups -C(O)R, where R is alkyl or substituted alkyl, aryl or substituted aryl
as
defined herein. The term "aryl" may refer to an aromatic substituent which may
be a
single ring or multiple rings which are fused together, linked covalently, or
linked to a
common group such as an ethylene or methylene moiety. The aromatic ring(s) may
include phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-l-ethyl, and
may
contain a heteroatom, such as thienyl, pyridyl and quinoxalyl. The aryl group
may
also be substituted with halogen atoms, or other groups such as nitro,
carboxyl,
alkoxy, phenoxy, and the like. Additionally, the aryl group may be attached to
other
moieties at any position on the aryl radical which would otherwise be occupied
by a
hydrogen atom (such as 2-pyridyl, 3-pyridyl and 4-pyridyl).
[0017] The term "alkyl carbonate" may refer to the group -OC(O)OR, where R is
alkyl, substituted alkyl, aryl, or substituted aryl as defined herein.
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[0018] The term "S-alkyl" may refer to the group -SR, where R is lower alkyl
or
substituted lower alkyl. The term "S-acyl" may refer to a thioester derived
from the
reaction of a thiol group with an acylating agent. Suitable S-acyls include,
for
example, S-acetyl, S-propionyl and S-pivaloyl. S-acyl may refer to such
thioesters
regardless of their method of preparation. The terms "N-oxime" and "N-
alkyloxime"
may refer to the group =N-OR5, wherein R5 is, for example, hydrogen (N-oxime)
or
alkyl (N-alkyloxime). The oximes can consist of the syn-isomer, the anti-
isomer or a
mixture of both the syn- and anti-isomers.
100191 Representative compounds within Formula I, include those in which R' is
--N(CH3)2; those in which R2 is hydrogen, halogen or alkoxy; those in which R3
is
acyloxy; those in which R4 is alkyl (e.g., methyl and ethyl); and those in
which X is
=0 and =N-OR5, wherein R5 is hydrogen or alkyl. Additional compounds include
those in which R' is --N(CH3)2; R2 is halogen; R3 is acyloxy; and R4 is alkyl,
such
where R2 is F, Br or Cl; and R4 is methyl. Also included are compounds in
which R'
is -N(CH3)2; R2 is alkyl; R3 is acyloxy; R4 is alkyl; and X is =0. Also
included are
compounds in which R' is --N(CH3)2; R2 is alkoxy; R3 is acyloxy; R4 is alkyl;
and X
is =0. Additional compounds are those in which R 2 is methoxy or ethoxy; and
R3 is
acetoxy or methoxy. Also included are compounds in which R' is -N(CH3); R 2 is
hydroxy; R3 is acyloxy; R4 is alkyl; and X is =0. Also included are compounds
in
which R' is -N(CH3)2; R2 and R3 are both acyloxy; R4 is alkyl; and X is =0.
Additional compounds are those in which R2 and R3 are both acetoxy. Also
included
are compounds in which R' is -N(CH3)2; R 2 is S-acyl; R3 is hydroxy or
acyloxy; R4
is alkyl; and X is =0. Also included are compounds in which R' is -N(CH3)2; R
2 is
cypionyloxy; R3 is acetoxy; R4 is alkyl; and X is =0. Also included are
compounds
in which R' is -N(CH3)2; R 2 is methoxy; R3 is acetoxy; R4 is alkyl; and X is
=0 and
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=N-ORS, wherein R5 is, for example, hydrogen or alkyl (e.g., methyl, ethyl,
etc.).
Also included are compounds in which R' is -N(CH3)2; R2 and R3 are both
acetoxy;
R4 is alkyl; and X is =0 and =N-ORS, wherein RS is, for example, hydrogen or
alkyl
(e.g., methyl, ethyl, etc.).
[0020] Exemplar compounds include, but are not limited to, 17a-acetoxy-11(3-[4-
(N,N-dimethylamino)phenyl]-21-methoxy-l9-norpregna-4,9(10)-diene-3,20-dione
(CDB-4124) with the following structural formula:
i H3 OMe
HC~N
3 OAc
O
with the proviso that salts of CDB-4124 are not HC1 or HBr acid salts.
100211 Another exemplar compound is 17a-acetoxy-11(3-[4-(N,N-
dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione (CDB-2914) with the
following structural formula:
CH3
H C~N
3 OAc
O
[0022] Other exemplar compounds include, but are not limited to, 17a-acetoxy-
21-
chloro-11(3-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione;
17a-acetoxy-2l-bromoro-11 [3-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-
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diene-3,20-dione; 17-,21-diacetoxy-11(3-(4-N,N-dimethylaminophenyl) 19-
norpregna-
4,9-diene-3,20-dione; 17a-hydroxy-21-acetylthio-11(3-(4-N,N-
dimethylaminophenyl)-
19-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-21 -acetylthio-11(3-(4-N,N-
dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-21-ethoxy-
11(3-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-
21-methyl-11(3-(4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione;
17a-acetoxy-21-methoxy-11(3-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-
3,20-dione; 17a-acetoxy-21 -ethoxy-11(3-(4-N,N-dimethylaminophenyl)-19-
norpregna-4,9-diene-3,20-dione; 17a-acetoxy-21-(3'-cyclopentylpropionyloxy)
11(3-
(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-21-
hydroxy-11(3-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione;
17a,21-diacetoxy-11 [3-(4-N,N-dimethylaminophenyl) 9-norpregna-4,9-diene-3,20-
dione 3-oxime; 17a-acetoxy-21-methoxy-11(3-(4-N,N-dimethylaminophenyl)-19-
norpregna-4,9-diene-3,2-dione 3-oxime; 17a-acetoxy-11(3-[4-(N-
methylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione; and 17a,21-diacetoxy-11
[3-
[4-(N-methylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione.
[0023] Also included are those compounds in which R' is -N(CH3)2, -NC4H8,
--NC4H1 o, -NC4HgO, -O(CH2)2N(CH3)2, -O(CH2)2NC4H8, --O(CH2)2NC3H1 o, and
-O(CH2)2NCSHjo; those in which R 2 is hydrogen, alkyloxy, alkoxy, -SAc, -SCN,
-OC(O)CH2N(CH3)2, and -OC(O)R6, wherein R6 is a functional group including,
but not limited to, alkyls (e.g., -CH2CH3), alkoxy esters (e.g., -CHzOMe) and
alkoxys (e.g., -OCH3); those in which R3 is alkyl, alkoxy, acyloxy and
hydroxy;
those in which R4 is alkyl (e.g., methyl and ethyl); and those is which X is
=0 or
=N-OR5, wherein R5 is hydrogen or alkyl. Also preferred are compounds in which
R' is -N(CH3)2; R2 is hydrogen; R3 is methoxymethyl; R4 is methyl; and X is
=0.
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Also included are compounds in which R' is -N(CH3)2; R 2 is hydrogen; R3 is -
OC(O)H, -OC(O)CH2CH3 or -OC(O)C6H13; R4 is methyl; and X is =0. Also
included are compounds in which R' is -NC4Hs, -NC5H~o, or -NC4HgO; R2 is
hydrogen; R3 is acetoxy; R4 is methyl; and X is =0. Also included are
compounds in
which R' is -N(CH3)2 or NC5Hio; R2 is hydrogen; R3 is methoxy; R4 is methyl;
and X is =0. Also included are compounds in which R' is --NC5Hio; R2 and R3
are
both acetoxy; R4 is methyl; and X is =0. Also included are compounds in which
R' is
-NC5HI o or --O(CH2)2N(CH3)2; R 2 is methoxy; R3 is acetoxy; R4 is methyl; and
X is
=0. Also included are compounds in which R' is -N(CH3)2; R2 is -OC(O)CH2CH3,
--OC(O)OCH3, -OC(O)OCH2OCH3, -OCH=CH2, -OC(O)CH2N(CH3)2 or -
SCN; R3 is acetoxy; R4 is methyl; and X is =0. Also included are compounds in
which Ri is --N(CH3)2; R2 is -OC(O)H; R3 is -OC(O)H; R4 is methyl; and X is
=0. Also included are compounds in which R' is -N(CH3)2; R2 is -OC(O)H; R3 is
hydroxy; R4 is methyl; and X is =0. Also included are compounds in which R' is
-
NC5Hlo; R2 is hydrogen; R3 is acetoxy; R4 is methyl; and X is =N-ORS, wherein
R5
is hydrogen. Also included are compounds in which R' is -N(CH3)2 or -NC5Hio;
R 2 is hydrogen or methoxy; R3 is methoxy or ethoxy; R4 is methyl; and X is =N-
----
ORS, wherein RS is hydrogen.
[0024] Exemplar compounds also include, but are not limited to, 17a-acetoxy-
11(3-[4-
(N,N-dimethylamino)phenyl]-21-methoxy-l9-norpregna-4,9(10)-diene-3,20-dione;
17a-formyloxy-11(3-[4-(N,N-diethylamino)phenyl]-19-norpregna-4,9-diene-3,20-
dione; 17a-propionoxy-11(3-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-
diene-
3,20-dione; 17a-heptanoyloxy-11 R-[4-(N,N-dimethylamino)phenyl]-19-norpregna-
4,9-diene-3,20-dione; 17a-methoxymethyl-11(3-[4-N,N-dimethylamino)phenyl]-19-
norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-(4-N-pyrrolidinophenyl)-19-
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norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-(4-N-piperidinophenyl)-19-
norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-(4-N-morpholinophenyl)-19-
norpregna-4,9-diene-3,20-dione; 17a-methoxy-11(3-[4-(N,N-dimethylamino)phenyl]-
19-norpregna-4,9-diene-3,20-dione; 17a-methoxy-11 P-(4-N-piperidinophenyl)-19-
norpregna-4,9-diene-3,20-dione; 17a,21-diacetoxy-11(3-(4-N-piperidinophenyl)-
19-
norpregna-4,9-diene-3,20-dione; 17a,21-dimethoxy-11(3-[4-(N,N-
dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione; 17a,21-dimethoxy-11(3-
(4-N-pyrrolidinophenyl)-19-norpregna-4,9-diene-3,20-dione; 17a,21-dimethoxy-
11(3-
(4-N-piperidinophenyl) 19-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-{4-
[2'-
(N,N-dimethylamino)ethoxy]phenyl } -21-methoxy-l9-norpregna-4,9-diene-3,20-
dione; 17a,21-diformyloxy-11(3-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-
diene-3,20-dione; 17a-acetoxy-11(3-[4-(N,N-dimethylamino)phenyl]-21-
propionyloxy-19-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-[4-(N,N-
dimethylamino)phenyl]-21-(2'-methoxyacetyl)oxy-l9-norpregna-4,9-diene-3,20-
dione; 17a-acetoxy-21-hydroxy-11(3-[4-(N,N-dimethylamino)phenyl]-19-norpregna-
4,9-diene-3,20-dione-2l-methyl carbonate; 17a-acetoxy-110-[4-(N,N-
dimethylamino)phenyl]-21-(1'-ethenyloxy)-19-norpregna-4,9-diene-3,20-dione;
17a-
acetoxy-11(3-[4-(N,N-dimethylamino)phenyl]-21-(2'-N,N-dimethylamino)acetoxy-19-
norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-[4-(N,N-dimethylamino)phenyl]-
21-thiocyanato-l9-norpregna-4,9-diene-3,20-dione; 17a-acetoxy-11(3-(4-N-
piperidinophenyl)-19-norpregna-4,9-diene-3,20-dione 3-oxime; 17a-methoxy-11(3-
[4-
(N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione 3-oxime; 17a-
methoxy-11 [1-(4-N-piperidinophenyl)-19-norpregna-4,9-diene-3,20-dione 3 -
oxime;
and 17a,21-dimethoxy-11(3-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene-
3,20-dione 3-oxime.
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100251 The stability of a compound having general formula I may be
significantly
increased when the compound is in the form of a salt. A composition is
provided
comprising a pharmaceutically acceptable salt of a compound of formula I and
optionally a pharmaceutically acceptable carrier.
100261 In practice, the use of the salt form inherently amounts to use of the
free base
form. Accordingly, acids which are suitable to prepare the salts include
preferably
those which produce, when combined with the free base, pharmaceutically
acceptable
salts, that is, salts whose anions are non-toxic to the patient in
pharmaceutical doses of
the salts, so that the beneficial pharmaceutical effects of these compounds in
the free
base are not vitiated by side effects ascribable to the anions. The compounds
of
general formula I may be regenerated from the salts by the application or
adaptation
of known methods. For example, the compounds can be regenerated from their
acid
addition salts by treatment with an alkali, e.g., sodium bicarbonate solution.
[0027] The salts can be prepared in situ during the final isolation and
purification of a
compound of general formula I or by separately reacting the purified compound
in its
free base form with a suitable organic or inorganic acid and isolating the
salt thus
formed. Representative salts include the hydrobromide, halide, hydrochloride,
sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,
palmitate,
stearate, laurate, borate, benzoate, lactate, tosylate, citrate, maleate,
fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate, lactiobionate,
laurylsulphonate salts and the like (See, for example, S. M. Berge, et al.,
"Pharmaceutical Salts," J. Pharm. Sci., 66:1-19, 1977, the contents of which
are
hereby incorporated herein by reference). For example, the salts may be
prepared
either by dissolving the free base in aqueous or aqueous-alcohol solution or
other
suitable solvents containing the appropriate acid and isolating the salt by
evaporating
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the solution, or by reacting the free base and acid in an organic solvent, in
which case
the salt separates directly or can be obtained by concentration of the
solution.
[0028] The term "pharmaceutically acceptable salt" refers to a relatively non-
toxic,
inorganic or organic acid addition salt of a compound of general formula I.
[0029] Compositions are provided comprising a pharmaceutically acceptable salt
of a
compound of general formula I. It is expected that salts of a compound of
general
formula I will have increased stability relative to an equivalent amount of
the free
base form of the compound under equivalent conditions. Thus, it is expected
that
compositions of the instant invention will have increased resistance to
chemical
modification. The stability of a pharmaceutically acceptable salt of a
compound of
general formula I may be enhanced by at least 1, 5, 10, 15, 20, 25, 30, 35,
40, 45, 50,
60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, or 1000
percent or
more relative to an equivalent amount of the free base form of the same
compound
under equivalent conditions.
[0030] A typical parameter of stability is shelf life, which is defined as the
time
period during which a drug product is expected to remain within the approved
shelf
life specification. Accelerated testing may be performed for a 6-month period
at 40
degrees C and 75% relative humidity. Under these conditions, a change in drug
concentration of about 5% from the initial assay values is considered
significant. It is
expected that compositions comprising pharmaceutically acceptable salts of
compounds of general formula I will exhibit an increased shelf life relative
to
equivalent compositions comprising the free base form of the same compounds
under
equivalent conditions.
[0031] Stability, as used herein, refers to the ability to detect the active
ingredient
(i.e., a compound of general formula I), in a composition, typically by HPLC,
after
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storage interval under predetermined conditions of temperature and humidity.
Although HPLC is preferred, any method for detecting the active ingredient
capable
of identifying chemical modification and/or change in concentration of the
active
ingredient may be used.
[0032] Also provided is a method for increasing the stability of a compound of
general formula I by reacting the compound with a suitable acid to form a
pharmaceutically acceptable salt.
[0033] The compositions may possess potent antiprogestational activity and
minimal
antiglucocorticoid activity, combined with improved stability, which may
render these
compositions suitable for oral administration.
100341 The compositions can be advantageously used, inter alia, to antagonize
endogenous progesterone; to induce menses; to treat endometriosis; to treat
dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat
meningioma; to
treat uterine leiomyonas, to treat uterine fibroids; to inhibit uterine
endometrial
proliferation; to induce labor; to induce cervical ripening, for hormone
therapy; and
for contraception.
[0035] The compositions having antiprogestational activity may also be
characterized
by antagonizing the effects of progesterone. As such, the compositions may be
of
particular value in the control of hormonal irregularities in the menstrual
cycle, for
controlling endometriosis and dysmenorrhea, and for inducing menses. In
addition,
the compositions can be used as a method of providing hormone therapy either
alone
or in combination with estrogenic substances in postmenopausal women, or in
women
whose ovarian hormone production is otherwise compromised.
[0036] Moreover, the compositions can be used for control of fertility during
the
whole of the reproductive cycle. For long-term contraception, the compositions
can
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be administered either continuously or periodically depending on the dose. In
addition, the compositions may be of particular value as post-coital
contraceptives, for
rendering the uterus inimical to implantation, and as "once a month"
contraceptive
agents.
100371 A further important utility for the compositions lies in their ability
to slow
down growth of hormone-dependent tumors and/or tumors present in hormone-
responsive tissues. Such tumors include, but are not limited to, kidney,
breast,
endometrial, ovarian, and prostate tumors, e.g., cancers, which may be
characterized
by possessing progesterone receptors. In addition, such tumors include
meningiomas.
Other utilities of the compositions include the treatment of fibrocystic
disease of the
breast and uterine.
100381 The compositions can be administered to any warm-blooded mammal such as
humans, domestic pets, and farm animals. Domestic pets include dogs, cats,
etc. Farm
animals include cows, horses, pigs, sheep goats, etc.
[0039] The amount of active ingredient that can be combined with an optimal
carrier
material to produce a single dosage form will vary depending upon the disease
treated, the mammalian species, and the particular mode of administration. For
example, a unit dose may comprise between 0.1 milligram and 1 gram of the
active
ingredient or between 0.001 and 0.5 grams. However, the specific dose level
for any
particular patient will depend on a variety of factors including the activity
of the
specific compound employed; the age, body weight, general health, sex and diet
of the
individual being treated; the time and route of administration; the rate of
excretion;
other drugs which have previously been administered; and the severity of the
particular disease undergoing therapy.
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[0040] The compositions can be administered by a variety of methods. For
example,
the compositions can be administered via the oral route in a form of
solutions,
suspensions, emulsions, tablets, including sublingual and intrabuccal tablets,
soft
gelatin capsules, including solutions used in soft gelatin capsules, aqueous
or oil
suspensions, emulsions, pills, lozenges, troches, tablets, syrups or elixirs
and the like.
[0041] The compositions can be also administered as an implant including
SILASTIC
and biodegradable implants or via intramuscular and intravenous injections.
[0042] The compositions can contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents and
preserving
agents. Tablets containing the active ingredient in admixture with nontoxic
pharmaceutically acceptable excipients, which are suitable for manufacture of
tablets
are acceptable. These excipients can be, for example, inert diluents, such as
calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate,
granulating and disintegrating agents, such as maize starch, or alginic acid;
binding
agents, such as starch, gelatin or acacia; and lubricating agents, such as
magnesium
stearate, stearic acid and talc. Tablets can be uncoated or, alternatively,
they can be
coated by known methods to delay disintegration and adsorption in the
gastrointestinal tract and thereby provide a sustained action over a longer
period. For
example, a time delay such as glyceryl monostearate or glyceryl distearate
alone or
with a wax can be employed.
[0043] Formulations for oral use can also be presented as hard gelatin
capsules
wherein the active ingredient is mixed with an inert solid diluent, for
example calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein
the active
ingredient is mixed with water or an oil medium, such as peanut oil, liquid
paraffin or
olive oil.
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100441 Aqueous suspensions may contain the active materials in admixture with
excipients suitable for the manufacture of aqueous suspensions. Such
excipients
include a suspending agent, such as sodium carboxymethylcellulose,
methylcellulose,
hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as a
naturally
occurring phosphatide (e.g., lecithin), a condensation product of an alkylene
oxide
with a fatty acid (erg., polyoxyethylene stearate), a condensation product of
ethylene
oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene
oxycetanol), a
condensation product of ethylene oxide with a partial ester derived from a
fatty acid
and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product
of ethylene oxide with a partial ester derived from fatty acid and a hexitol
anhydride
(e.g. polyoxyethylene sorbitan monooleate). The aqueous suspension can also
contain
one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more
coloring agents, one or more flavoring agents and one or more sweetening
agents,
such as sucrose, aspartame or saccharin.
[0045] Oil suspensions can be formulated by suspending the active ingredient
in a
vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or
in a mineral
oil such as liquid paraffin. The oil suspensions can contain a thickening
agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to
provide a palatable oral preparation. These compositions can be preserved by
the
addition of an antioxidant such as ascorbic acid.
[0046] Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water can be formulated from the active
ingredients in
admixture with a dispersing, suspending and/or wetting agent, and one or more
preservatives. Suitable dispersing or wetting agents and suspending agents are
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exemplified by those disclosed above. Additional excipients, for example
sweetening, flavoring and coloring agents, can also be present.
[0047] The pharmaceutical composition can also be in the form of oil-in-water
emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis
oil, a
mineral oil, such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents
include naturally-occurring gums, such as gum acacia and gum tragacanth,
naturally
occurring phosphatides, such as soybean lecithin, esters or partial esters
derived from
fatty acids and hexitol anhydrides, such as sorbitan monooleate, and
condensation
products of these partial esters with ethylene oxide, such as polyoxyethylene
sorbitan
monooleate. The emulsion can also contain sweetening and flavoring agents.
[0048] Syrups and elixirs can be formulated with sweetening agents, such as
glycerol,
sorbitol or sucrose. Such formulations can also contain a demulcent, a
preservative, a
flavoring or a coloring agent.
100491 The pharmaceutical composition can be in the form of a sterile
injectable
preparation, such as a sterile injectable aqueous or oleaginous suspension.
This
suspension can be formulated using those suitable dispersing or wetting agents
and
suspending agents which have been mentioned above. The sterile injectable
preparation can also be a sterile injectable solution or suspension in a
nontoxic
parenterally-acceptable diluent or solvent, such as a solution of 1,3-
butanediol.
Among the acceptable vehicles and solvents that can be employed are water and
Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed
oils can be
employed as a solvent or suspending medium. For this purpose any bland fixed
oil
can be employed including synthetic mono- or diglycerides. In addition, fatty
acids
such as oleic acid can likewise be used in the preparation of injectables.
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[0050] The compound can also be administered in the form of suppositories for
rectal
administration of the drug. These compositions can be prepared by mixing the
drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but
liquid at the rectal temperatures and will therefore melt in the rectum to
release the
drug. Such materials are cocoa butter and polyethylene glycols.
100511 They can also be administered by in intranasal, intraocular,
intravaginal, and
intrarectal routes including suppositories, insufflation, powders and aerosol
formulations.
[0052] Compounds administered by the topical route can be administered as
applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments,
pastes,
jellies, paints, powders, and aerosols.
[0053] The invention will be described in greater detail by way of the
following
specific, but not limiting, example.
Example 1. Formulations of the Instant Invention Can Be Prepared As Tablets.
[0054] To obtain tablets for practicing the instant invention, the following
ingredients
can be pressed together in a tablet press:
10.0 mg of a pharmaceutically acceptable salt of CDB-4124
140.5 mg of lactose
69.5 mg of corn starch
2.5 mg of poly-N-vinylpyrrolidone
2.0 mg of aerosil
0.5 mg of magnesium stearate
[0055] To obtain oily preparations for practicing the instant invention, the
following
ingredients can be mixed together and loaded into ampoules:
100.0 mg of a pharmaceutically acceptable salt of CDB-4124
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343.3 mg of castor oil
608.6 mg of benzyl benzoate
Example 2. Formation of the perchloric, methanesulfonic and phosphoric
acid salts of CDB-4124
[0056] CDB-4124 was dissolved in one-part acetone and five-parts ethyl acetate
and
the resulting solution was split into five fractions. To each fraction, either
citric acid,
mandelic acid, perchloric acid, methanesulfonic acid or phosphoric acid was
added in
sufficient molar quantity to create the corresponding acid salt of CDB-4124.
The
reaction mixtures were stirred for about 2 hours at about 20 C followed by 2
hours
below 0 C. The resulting solids were then filtered and washed with cold ethyl
acetate
and dried.
[0057] The citric and mandelic acid salts were not formed under these
conditions.
The perchloric, methanesulfonic and phosphoric acid steroid salts were all
prepared in
good recovery yields (-90%). It was immediately determined that these acid
steroid
salts were hygroscopic and required handling in a glove bag with a nitrogen
atmosphere. Recrystallizations using various solvent systems (e.g.
ethanol/ethyl
ether) were attempted with no success. It was believed that the starting
steroid used
(90% peak area purity) was not high enough in purity and perhaps was
contributing to
the difficulty in recrystallization of the acid salts.
[0058] Accordingly, a higher purity yield of CDB-4124 was used for the
formation of
the methanesulfonic acid salt, by the procedure described above. The
methanesulfonic acid salt was successfully recrystallized using an
acetone/water
solvent system.
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