U.S. patent application number 09/989074 was filed with the patent office on 2002-05-23 for anti-estrogen plus progestin containing oral contraceptives.
This patent application is currently assigned to American Home Products Corporation. Invention is credited to Gast, Michael J., Miller, Christopher P..
Application Number | 20020061875 09/989074 |
Document ID | / |
Family ID | 26786792 |
Filed Date | 2002-05-23 |
United States Patent
Application |
20020061875 |
Kind Code |
A1 |
Gast, Michael J. ; et
al. |
May 23, 2002 |
Anti-estrogen plus progestin containing oral contraceptives
Abstract
This invention provides a method of providing contraception
which comprises administering to a female of child bearing age a
combination of a non-uterotrophic anti-estrogen and a progestin for
28 days per 28-day menstrual cycle.
Inventors: |
Gast, Michael J.;
(Phoenixville, PA) ; Miller, Christopher P.;
(Wayne, PA) |
Correspondence
Address: |
AMERICAN HOME PRODUCTS CORPORATION
FIVE GIRALDA FARMS
PATENT LAW
MADISON
NJ
07940
US
|
Assignee: |
American Home Products
Corporation
Madison
NJ
|
Family ID: |
26786792 |
Appl. No.: |
09/989074 |
Filed: |
November 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09989074 |
Nov 21, 2001 |
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09185058 |
Nov 3, 1998 |
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60093051 |
Nov 6, 1997 |
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Current U.S.
Class: |
514/212.08 ;
514/217.08; 514/218; 514/228.2; 514/233.5; 514/252.06; 514/254.09;
514/256; 514/323; 514/365; 514/372; 514/385; 514/397; 514/414 |
Current CPC
Class: |
A61K 31/56 20130101;
A61K 31/405 20130101; A61K 2300/00 20130101; A61K 31/405 20130101;
A61K 31/56 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/212.08 ;
514/217.08; 514/218; 514/228.2; 514/233.5; 514/252.06; 514/254.09;
514/256; 514/323; 514/365; 514/372; 514/385; 514/397; 514/414 |
International
Class: |
A61K 031/55; A61K
031/551; A61K 031/5377; A61K 031/506; A61K 031/541; A61K 031/501;
A61K 031/496; A61K 031/454; A61K 031/427; A61K 031/425; A61K
031/422; A61K 031/42; A61K 031/4178; A61K 031/404 |
Claims
What is claimed is:
1. A method of providing contraception which comprises
administering to a female of childbearing age a contraceptive
effective amount of a combination of an anti-estrogen of formulas I
or II having the structure 65wherein: R.sub.1 is H, OH, carboalkoxy
of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen or mono-
or poly-fluoroalkoxy of 1-12 carbon atoms; R.sub.2 is H, OH,
carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms,
halogen, mono- or poly-fluoroalkoxy of 1-12 carbon atoms, cyano,
alkyl fo 1-6 carbon atoms, or trifluoromethyl, with the proviso
that, when R.sub.1 is H, R.sub.2 is not OH. R.sub.3 and R.sub.4 are
each, independently, H, OH, carboalkoxy of 2-12 carbon atoms,
alkoxy of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of
1-12 carbon atoms, or cyano, with the proviso that, when R.sub.1 is
H, R.sub.2 is not OH. X is H, alkyl of 1-6 carbon atoms, cyano,
nitro, triflouromethyl, or halogen, n is 2 or 3; Y is a saturated,
partially saturated or unsaturated 5-7 membered heterocycle
containing a nitrogen, which may optionally contain a second
heteroatom selected from the group consisting of --O--, --NH--,
alkylamine of 1-6 carbon atoms, --N.dbd., and S(O).sub.m; m is 0-2;
or a pharmaceutically acceptable salt thereof, and a progestin for
28 consequetive days per 28-day menstrual cycle.
2. The method according to claim 1, wherein Y is 66
3. The method according to claim 1, wherein the progestin is
selected from the group consisting of levonorgestrel, norgestrel,
desogestrel, 3-ketodesogestrel, norethindrone, gestodene,
norethisterone acetate, norgestimate, osaterone, cyproterone
acetate, trimegestone, dienogest, and drospirenone.
4. The method according to claim 3, wherein the progestin is
levonorgestrel.
5. The method according to claim 4, wherein the anti-estrogen is
selected from the group consisting of a)
5-benzyloxy-2-(4-ethoxy-phenyl)-3-methyl--
1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole or a
pharmaceutically acceptable salt thereof; b)
5-benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan--
1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable
salt thereof; c)
5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-
-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable
salt thereof; d)
5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1--
yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt
thereof; e)
5-benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl--
ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt
thereof; f)
5-benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy-
)-benzyl]-1H-indole or a pharmaceutically acceptable salt thereof;
g)
5-benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-b-
enzyl]-1H-indole or a pharmaceutically acceptable salt thereof; h)
5-benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-
-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt
thereof; i)
5-benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-et-
hoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt
thereof; j)
5-benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-b-
enzyl]-1H-indole or a pharmaceutically acceptable salt thereof; k)
5-benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy-
)-benzyl]-1H-indol or a pharmaceutically acceptable salt thereofe;
1)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3--
methyl-1H-indole or a pharmaceutically acceptable salt thereof; m)
5-benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1--
yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically acceptable salt
thereof; n)
5-benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2--
azepan-1-yl-ethoxy)-benzyl]-1H-indole or a pharmaceutically
acceptable salt thereof; o)
5-benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1-yl-e-
thoxy)-benzyl]-3-methyl-1H-indole or a pharmaceutically acceptable
salt thereof; p)
5-benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-
-(4-trifluoromethoxy-phenyl)-1H-indole or a pharmaceutically
acceptable salt thereof; q)
5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-methylp-
iperazin-1-yl)-ethoxy]-benzyl}-1H-indole or a pharmaceutically
acceptable salt thereof; r)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-met-
hoxyphenyl)-3-methyl-1H-indole or a pharmaceutically acceptable
salt thereof; s)
4-{3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole}-
hydrochloride; t)
4-{3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in-
dol-2-yl}-phenol hydrochloride; u)
3-methyl-2-phenyl-1-[4-(2-piperidine-1--
yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride; v)
4-{5-methoxy-3-methyl-1-
-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2-yl}-phenol or a
pharmaceutically acceptable salt thereof; w)
2-(4-methoxy-phenyl)-3-methy-
l-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol or a
pharmaceutically acceptable salt thereof; x)
5-methoxy-2-(4-methoxy-pheny-
l)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole
hydrochloride; y)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-meth-
oxy-phenyl) -3-methyl-1H-indole hydrochloride; z)
2-(4-ethoxy-phenyl)-3-me-
thyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a
pharmaceutically acceptable salt thereof; aa)
1-[4-(2-azepan-1-yl-ethoxy)-
-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol-5-ol or a
pharmaceutically acceptable salt thereof; ab)
4-{5-fluoro-3-methyl-1-[4-(2-piperidin-1-yl--
ethoxy)-benzyl]-1H-indol-2-yl }-phenol hydrochloride; ac)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol
-5-ol hydrochloride; ad)
2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl--
ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt
thereof; ae)
2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-
-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt
thereof; af)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol hydrochloride; ag)
2-(4-fluoro-phenyl)-3-methyl-1-[4-(2-piperidine--
1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride; ah)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indol-
-5-ol or a pharmaceutically acceptable salt thereof; ai)
2-(3-methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be-
nzyl]-1H-indol-5-ol hydrochloride; aj)
2-benzo[1,3]dioxol-5-yl-3-methyl-1--
[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride;
ak)
2-(4-isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1-
H-indol-5-ol hydrochloride; al)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-i-
sopropoxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride; am)
2-(4-cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl-
]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof; an)
2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in-
dol-5-ol hydrochloride; ao)
2-(2,4-dimethoxy-phenyl)-3-methyl-1-[4-(2-pipe-
ridin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically
acceptable salt thereof; ap)
2-(3-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-et-
hoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically acceptable salt
thereof; aq)
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H--
indole-5-ol or a pharmaceutically acceptable salt thereof; ar)
2-(3-fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-ben-
zyl]-1H-indol-5-ol or a pharmaceutically acceptable salt thereof;
as)
2-(3-fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy)-benzyl]--
1H-indol-5-ol or a pharmaceutically acceptable salt thereof; at)
2-(3-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i-
ndole-5-ol or a pharmaceutically acceptable salt thereof; au)
3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phe-
nyl)-1H-indole-5-ol or a pharmaceutically acceptable salt thereof;
av)
3-chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H--
indol-5-ol hydrochloride; aw)
3-chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperi-
din-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride; ax)
3-chloro-2-(4-hydroxy-phenyl)-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indo-
l-5-ol hydrochloride; ay)
3-chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-p-
iperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol or a pharmaceutically
acceptable salt thereof; az)
2-(4-hydroxy-phenyl)-3-ethyl-1-[4-(2-piperid-
in-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride; ba)
5-hydroxy-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H--
indole-3-carbonitrile hydrochloride; bb)
1-[4-(2-azepan-1-yl-ethoxy)-benzy-
l]-5-hydroxy-2-(4-hydroxy-phenyl) -1H-indole-3-cabonitrile
hydrochloride; bc) di-propionate of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phe-
nyl)-3-methyl-1H-indol-5-ol hydrochloride; bd) di-pivalate of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)
-3-methyl-1H-indol-5-ol hydrochloride; be) di-pivalate ester of
2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i-
ndol-5-ol or a pharmaceutically acceptable salt thereof;
6. The method according to claim 5, wherein the anti-estrogen is
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol or a pharmaceutically acceptable salt thereof.
7. The method according to claim 6, wherein the same dosage of the
antiestrogen and progestin combination is administered in each of
the 28 days.
8. The method according to claim 5, wherein the antiestrogen is
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol acetate.
9. The method according to claim 8, wherein the same dosage of the
anti-estrogen and progestin combination is administered in each of
the 28 days.
10. A method of providing contraception which comprises
administering to a female of child bearing age a combination of a
daily dosage of 0.5-25 mg
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol acetate and 30-150 .mu.g levonorgestrel for 28 consequetive
days per 28 day menstrual cycle.
11. The method according to claim 10, wherein the same dosage of
the combination is administered in each of the 28 days.
12. A method of providing contraception which comprises
administering to a female of child bearing age a combination of a
non-uterotrophic antiestrogen and a progestin for 28 days per
28-day menstrual cycle.
13. The method according to claim 12, wherein the progestin is
selected from the group consisting of levonorgestrel, norgestrel,
desogestrel, 3-ketodesogestrel, norethindrone, gestodene,
norethisterone acetate, norgestimate, osaterone, cyproterone
acetate, trimegestone, dienogest, and drospirenone.
14. The method according to claim 13, wherein the anti-estrogen is
selected from the group consisting of raloxifene, droloxifene,
idoxifine, nafoxidine, toremifene, TAT-59, levomeloxifene,
LY-353381, CP-336156, MDL-103323, EM-800, and ICI-182,780.
15. The method according to claim 14, wherein the same dosage of
the antiestrogen and progestin combination is administered in each
of the 28 days.
16. A contraceptive kit adapted for daily oral administration which
comprises 28 separate dosage units, each containing a combination
of a non-uterotrophic anti-estrogen and a progestin.
17. The kit according to claim 16, wherein the anti-estrogen is a
compound of formulas I or II having the structure 67wherein:
R.sub.1 is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12
carbon atoms, halogen or mono- or poly-fluoroalkoxy of 1-12 carbon
atoms; R.sub.2 is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy
of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of 1-12
carbon atoms, cyano, alkyl fo 1-6 carbon atoms, or trifluoromethyl,
with the proviso that, when R.sub.1 is H, R.sub.2 is not OH.
R.sub.3 and R.sub.4 are each, independently, H, OH, carboalkoxy of
2-12 carbon atoms, alkoxy of 1-12 carbon atoms, halogen, mono- or
poly-fluoroalkoxy of 1-12 carbon atoms, or cyano, with the proviso
that, when R.sub.1 is H, R.sub.2 is not OH. X is H, alkyl of 1-6
carbon atoms, cyano, nitro, triflouromethyl, or halogen; n is 2 or
3; Y is a saturated, partially saturated or unsaturated 5-7
membered heterocycle containing a nitrogen, which may optionally
contain a second heteroatom selected from the group consisting of
--O--, --NH--, alkylamine of 1-6 carbon atoms, --N.dbd., and
S(O).sub.m; m is 0-2; or a pharmaceutically acceptable salt
thereof, and the progestin is selected from the group consisting of
levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel,
norethindrone, gestodene, norethisterone acetate, norgestimate,
osaterone, cyproterone acetate, trimegestone, dienogest, and
drospirenone.
18. The kit according to claim 17, wherein the anti-estrogen is
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol acetate and the progestin is levonorgestrel.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/093,051, which was converted from U.S. patent
application Ser. No. 08/965,083, filed Nov. 6, 1997, pursuant to a
petition filed under 37 C.F.R. 1.53(c)(2)(i) on Apr. 15, 1998.
BACKGROUND OF THE INVENTION
[0002] This invention relates to oral contraceptive regimens
containing a nonuterotrophic antiestrogen (i.e., a tissue selective
estrogen) and a progestin.
[0003] The vast majority of oral contraceptives consist of a
combination of a progestin and estrogen that are administered
concurrently for 21 days followed either by a 7 day pill free
interval or by the administration of a placebo for 7 days in each
28 day cycle. The most important aspects of a successful oral
contraceptive product are effective contraception, good cycle
control (absence of spotting and breakthrough bleeding and
occurrence of withdrawal bleeding), and minimal side effects.
Combination oral contraceptives have traditionally acted by
suppression of gonadotropins. In addition, it appears that the
progestin component is primarily responsible for contraceptive
efficacy through inhibition of ovulation, and other peripheral
effects which include changes in the cervical mucus (which increase
the difficulty-of sperm entry into the uterus) and the endometrium
(which reduce the likelihood of implantation). The estrogenic
component intensifies the anovulatory effect of the progestin, and
is also important for maintaining cycle control.
[0004] Several examples of progestin only contraceptives are known.
For example products containing norethindrone (350 .mu.g) or
levonorgestrel (75 .mu.g) are available, but raise several issues
which limit their ultimate acceptablilty. The first is that
currently available oral progestin only contraceptives are
administered at doses that fail to completely inhibit ovulation
thus pregnancy rates are marginally higher than currently available
combined oral contraceptive preparations. Nonetheless, the
pregnancy rates (generally less than 3 per 100 women per year) are
excellent and are based primarily on cervical mucous changes and
modest changes in endometrium. The second difficulty with these
preparations is the extraordinarily high rate of abnormal or
unexpected vaginal bleeding in women who utilize them. The absence
of predictable vaginal bleeding which results from irregular
development and shedding of the uterine lining (endometrium) is a
phenomenon that is common to injectable, implantable and oral
progestin only contraceptives. This side-effect is reported by up
to 80% of women using any of these forms of progestin only
contraception.
[0005] GB Patent Specification 1326528 discloses estrogen
antagonizing agents (preferrably cis-clomiphene) in combination
with a progestin for use as a contraceptive. The estrogen
antagonists disclosed in GB 1326528 are uterotrophic (see Kumar, A.
India. J. Biosc. 20(5): 665 (1995)) whereas the anti-estrogens of
this invention are not.
DESCRIPTION OF THE INVENTION
[0006] This invention provides a contraceptive regimen for females
of child-bearing age which comprises administering a combination of
a non-uterotrophic anti-estrogen and a progestin continuously
during the 28-day menstrual cycle. Non-uterotrophic antiestrogens
are defined as those which typically will not produce clinically
significant endometrial proliferation. More particularly, this
invention provides a method providing contraception to a female of
child bearing age which comprises administering a contraceptive
effective amount of a combination of a non-uterotrophic
anti-estrtogen of formulas I or II having the structures 1
[0007] wherein:
[0008] R.sub.1 is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy
of 1-12 carbon atoms, halogen or mono- or poly-fluoroalkoxy of 1-12
carbon atoms;
[0009] R.sub.2 is H, OH, carboalkoxy of 2-12 carbon atoms, alkoxy
of 1-12 carbon atoms, halogen, mono- or poly-fluoroalkoxy of 1-12
carbon atoms, cyano, alkyl fo 1-6 carbon atoms, or trifluoromethyl,
with the proviso that, when R.sub.1 is H, R.sub.2 is not OH.
[0010] R.sub.3 and R.sub.4 are each, independently, H, OH,
carboalkoxy of 2-12 carbon atoms, alkoxy of 1-12 carbon atoms,
halogen, mono- or poly-fluoroalkoxy of 1-12 carbon atoms, or cyano,
with the proviso that, when R.sub.1 is H, R.sub.2 is not OH.
[0011] X is H, alkyl of 1-6 carbon atoms, cyano, nitro,
triflouromethyl, or halogen;
[0012] n is 2 or 3;
[0013] Y is a saturated, partially saturated or unsaturated 5-7
membered heterocycle containing a nitrogen, which may optionally
contain a second heteroatom selected from the group consisting of
--O--, --NH--, alkylamine of 1-6 carbon atoms, --N.dbd., and
S(O).sub.m;
[0014] m is 0-2;
[0015] or a pharmaceutically acceptable salt thereof,
[0016] and a progestin for 28 consequetive days per 28-day
menstrual cycle.
[0017] Preferred compounds are those in which
[0018] R.sub.1 is selected from H, OH or the C.sub.1-C.sub.12
esters or alkyl ethers thereof, halogen;
[0019] R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
independently selected from H, OH or the C.sub.1-C.sub.12 esters or
alkyl ethers thereof, halogen, cyano, C.sub.1-C.sub.6 alkyl, or
trihalomethyl, preferably trifluoromethyl, with the proviso that,
when R.sub.1 is H, R.sub.2 is not OH;
[0020] X is selected from H, C.sub.1-C.sub.6 alkyl, cyano, nitro,
triflouromethyl, halogen;
[0021] and Y is 2
[0022] The preparation of the anti-estrogens of Formulas I and II
is disclosed in U.S. patent application Ser. No. 08/833,271, filed
Apr. 4, 1997, which is hereby incorporated by reference.
[0023] Specifically preferred anti-estrogens of formulas I and II
are shown in the Tables below.
1TABLE 1 3 Example No. X Q Z No. 1 OBn 4'-OEt 4 No. 2 OBn H 5 No. 3
OBn 4'-OBn 6 No. 4 OBn 4'-OBn 7 No. 5 OBn 4'-F 8 No. 6 OBn 4'-F 9
No. 7 OBn 4'-Cl 10 No. 8 OBn 3',4'-OCH.sub.2O-- 11 No. 9 OBn
4'-O--iPr 12 No. 10 OBn 4'-CH.sub.3 13 No. 11 OBn 3'-OBn 14 No. 12
OBn 3'-OBn 15 No. 13 OBn 4'-OBn, 3'-F 16 No. 14 OBn 4'-OBn, 3'-F 17
No. 15 OBn 3'-OMe 18 No. 16 OBn 4'-OCF.sub.3 19 No. 17 OBn 4'-OBn
20 No. 18 OBn 3'-OMe 21
[0024]
2TABLE 2 22 Example No. X Q Z No. 19 H H 23 No. 20 H 4'-OH 24 No.
21 OH H 25 No. 22 OMe 4'-OH 26 No. 23 OH 4'-OMe 27 No. 24 OMe
4'-OMe 28 No. 25 OMe 4'-OMe 29 No. 26 OH 4'-OEt 30 No. 27 OH 4'-OEt
31 No. 28 F 4'-OH 32 No. 29 OH H 33 No. 30 OH 4'-OH 34 No. 31 OH
4'-OH 35 No. 32 OH 4'-OH 36 No. 33 OH 4'-OH 37 No. 34 OH 4'-F 38
No. 35 OH 4'-F 39 No. 36 OH 3'-OMe, 4'-OH 40 No. 37 OH
3',4'-OCH.sub.2O-- 41 No. 38 OH 4'-O--iPr 42 No. 39 OH 4'-O--iPr 43
No. 40 OH 4'-O-Cp 44 No. 41 OH 4'-Cl 45 No. 42 OH 2',4'-Dimethoxy
46 No. 43 OH 3'-OH 47 No. 44 OH 3'-OH 48 No. 45 OH 4'-OH, 3'-F 49
No. 46 OH 4'-OH, 3'-F 50 No. 47 OH 3'-OMe 51 No. 48 OH 4'-OCF.sub.3
52
[0025]
3TABLE 3 53 Example No. X Q Z No. 49 Cl H 54 No. 50 Cl H 55 No. 51
Cl H 56 No. 52 Cl CH.sub.3 57 No. 53 Et H 58 No. 54 CN H 59 No. 55
CN H 60
[0026]
4TABLE 4 61 Example No. R Z No. 56 Et 62 No. 57 t-Bu 63 No. 58 t-Bu
64
[0027] Particularly preferred anti-estrogens of Formulas I or II
are those of Examples 31 and 32 in the tables above. It is
preferred that the anti-estrogen of Formulas I or II is
administered at a daily dosage equivalent to 0.1-150 mg of the
compound of Example 32.
[0028] Preferred progestins include, but are not limited to
levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel,
norethindrone, gestodene, norethisterone acetate, norgestimate,
osaterone, cyproterone acetate, trimegestone, dienogest, and
drospirenone. It is more preferred that the progestin is
levonorgestrel. When levonorgestrel is used as the progestin, it is
preferred that the daily dosage of levonorgestrel is 30-150 .mu.g,
with 50-110 .mu.g being more preferred, and 75-100 .mu.g being most
preferred. The following table shows the preferred dosages of
representative progestins of this invention.
5 PREFERRED PROGESTIN DAILY DOSAGE RANGES Progestin Dosage
Levonorgestrel 30-150 .mu.g Norgestrel 60-300 .mu.g Desogestrel
45-225 .mu.g 3-Ketodesogestrel 45-225 .mu.g Norethindrone 100
.mu.g-1 mg Norethisterone Acetate 100 .mu.g-1 mg Gestodene 20-115
.mu.g Norgestimate 75-500 .mu.g Osaterone 100 .mu.g-2.5 mg
Trimegestone 30-1500 .mu.g Dienogest 500 .mu.g-3.75 mg Drospirenone
500 .mu.g-3.75 mg Cyproterone Acetate 450 .mu.g-25 mg
[0029] This invention also covers the administration of a
combination of other non-uterotrophic anti-estrogens (and preferred
daily dosages), such as raloxifene (1-600 mg), droloxifene (1-600
mg), idoxifine (1-600 mg), nafoxidine (0.5-600 mg), toremifene,
TAT-59 (0.1-600 mg), levomeloxifene (0.5-600 mg), LY-353381 (1-600
mg), CP-336156, MDL-103323, EM-800, and ICI-182,780 (0.1-150 mg)
with a progestin for 28 consequetive days per 28 day menstrual
cycle to provide contraception.
[0030] This invention also covers other progestins and
non-uterotrophic antiestrogens, which will be apparent to one
skilled in the art.
[0031] It is preferred that the the anti-estrogen plus progestin
regimen be administered according to a monophasic type regimen
continuously during the 28-day menstrual cycle. In a monophasic
regimen, the same dose of each of the anti-estrogen and progestin
are administered each day during the administration period. The
continuous 28-day administration of the anti-estrogen plus
progestin combination will eliminate the withdrawl bleed that is
associated with other non-continuous oral contraceptive regimens,
and will eliminate the irregular bleeding (breakthrough and
spotting) that is associated with progestin only oral contraceptive
regimens.
[0032] When the compound of Example 32 and levonorgestrel are
administered according to a 28-day monophasic regimen, the
following dosages are preferred, with regimen A being most
preferred.
6 Regimen Example 32 Levonorgestrel A 2 mg 90 .mu.g B 3 mg 75 .mu.g
C 5 mg 100 .mu.g
[0033] The anti-estrogen plus progestin contraceptives of this
invention can also be administered for 28 days each menstrual cycle
according to phased regimens (i.e., biphasic, triphasic,
quadraphasic, and the like). In such regimen, the same dosage of
the combination is administered each day of the particular phase,
with each phase having a different dosage than the preceding or
subsequent phase. In a typical quadraphasic regimen, each phase may
be 7 days in length. The regimens may be quadraphasic rising
regimens in which the dosage of antiestrogen and progestin is
increased from phase I to phase II and from phase II to phase III;
the dosage during the fourth phase is then typically lower than in
the first phase. One skilled in the art will appreciate that this
invention also covers regimens in which the dosages of the first or
second phase will be highest. Other variations include maintaining
a constant dosage of progestin during all four phases, while
varying the dosage of antiestrogen of the four phases, with the
phase III dosage typically being the highest, and phase IV dosage
being the lowest. Alternatively, the dosage of antiestrogen can be
held constant during all four phases, while the dosage of progestin
is being varied from phase to phase.
[0034] For administration, it is preferred that the combination
anti-estrogen plus progestin contraceptive be administered in unit
dosage form i.e., tablet or pill, with each unit providing the
entire daily dosage. It is preferred that the progestin and
antiestrogen are admixed together in the same dosage unit. Such
dosage units can be prepared by conventional methodology that is
well known to one skilled in the art. In each dosage unit, the
contraceptively active progestin and estrogen are combined with
excipients, vehicles, pharmaceutically acceptable carriers, and
colorants.
[0035] This invention also provides a contraceptive kit adapted for
daily oral administration which comprises a total of 28 separate
dosage units. In this kit, each dosage units each consisting of a
combination of progestin at a daily dosage equivalent in
progestational activity to 30-150 .mu.g levonorgestrel and an
anti-estrogen at a daily dosage equivalent to 0.5-25 mg of the
compound of Example 32. The daily dosage arrangements are
preferably arranged in a blister pack or in a dial pack type tablet
dispenser. Specific referred progestins and anti-estrogens and the
specifically preferred dosages of each combination dosage unit are
described above.
* * * * *