U.S. patent number 5,372,996 [Application Number 07/963,278] was granted by the patent office on 1994-12-13 for method of treatment of androgen-related diseases.
This patent grant is currently assigned to Endorecherche, Inc.. Invention is credited to Fernand Labrie.
United States Patent |
5,372,996 |
Labrie |
December 13, 1994 |
Method of treatment of androgen-related diseases
Abstract
A method of treatment of androgen-related diseases such as
prostate cancer in susceptible male animals, including humans,
comprises administering novel antiandrogens and/or novel sex
steroid biosynthesis inhibitors as part of a combination therapy.
Sex steroid biosynthesis inhibitors, especially those capable of
inhibiting conversion of dehydroepiandrosterone (DHEA) or
4-androstenedione (.DELTA..sup.4 -dione) to natural sex steroida
(and testosterone into dihydrotestosterone) in peripheral tissues,
are used in combination with antiandrogens usually after blockade
of testicular hormonal secretions. Antiestrogens can also be part
of the combination therapy. Pharmaceutical compositions and two,
three, four and five component kits are useful for such combination
treatment.
Inventors: |
Labrie; Fernand (Ste-Foy,
CA) |
Assignee: |
Endorecherche, Inc.
(CA)
|
Family
ID: |
26983290 |
Appl.
No.: |
07/963,278 |
Filed: |
October 19, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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376710 |
Jul 7, 1989 |
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322154 |
Mar 10, 1989 |
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Current U.S.
Class: |
514/10.1;
514/10.2; 514/114; 514/177; 514/19.5; 514/800; 540/22; 540/23;
540/4; 540/5; 552/304; 552/515; 552/522; 552/540 |
Current CPC
Class: |
A61K
31/565 (20130101); A61K 31/57 (20130101); A61K
31/575 (20130101); A61K 31/58 (20130101); A61K
31/585 (20130101); C07C 235/34 (20130101); C07D
235/18 (20130101); C07J 1/0011 (20130101); C07J
1/0022 (20130101); C07J 1/0025 (20130101); C07J
1/0044 (20130101); C07J 1/0048 (20130101); C07J
1/0055 (20130101); C07J 1/0059 (20130101); C07J
1/007 (20130101); C07J 1/0074 (20130101); C07J
1/0081 (20130101); C07J 1/0096 (20130101); C07J
17/00 (20130101); C07J 21/006 (20130101); C07J
21/008 (20130101); C07J 41/0038 (20130101); C07J
41/0072 (20130101); C07J 41/0088 (20130101); C07J
41/0094 (20130101); C07J 51/00 (20130101); C07J
53/008 (20130101); C07J 71/001 (20130101); C07J
71/0021 (20130101); A61K 31/57 (20130101); A61K
31/575 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); Y10S 514/80 (20130101) |
Current International
Class: |
A61K
31/585 (20060101); A61K 31/57 (20060101); A61K
31/58 (20060101); A61K 31/575 (20060101); A61K
31/565 (20060101); C07C 235/00 (20060101); C07C
235/34 (20060101); C07D 235/00 (20060101); C07D
235/18 (20060101); C07J 17/00 (20060101); C07J
41/00 (20060101); C07J 53/00 (20060101); C07J
51/00 (20060101); C07J 1/00 (20060101); C07J
71/00 (20060101); C07J 21/00 (20060101); A61K
037/02 (); A61K 037/43 (); C07J 041/00 () |
Field of
Search: |
;514/15,16,171.63,114,176,177,182,17,80,18,800 ;540/4.5,22,23
;552/505,506,515,522,540,304 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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10669/88 |
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Jul 1988 |
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AU |
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10778/88 |
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Aug 1988 |
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AU |
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31569/89 |
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Sep 1989 |
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AU |
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0285383 |
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Oct 1988 |
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EP |
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2529969 |
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May 1984 |
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DE |
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3339295 |
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May 1984 |
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DE |
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83545 |
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Mar 1986 |
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LU |
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123341 |
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Sep 1970 |
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NZ |
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181107 |
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Nov 1978 |
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NZ |
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182661 |
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Jul 1979 |
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NZ |
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201536 |
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Aug 1982 |
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NZ |
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206745 |
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Jan 1984 |
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NZ |
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207413 |
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Jun 1984 |
|
NZ |
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208441 |
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Jun 1984 |
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NZ |
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213652 |
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Sep 1985 |
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NZ |
|
214798 |
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Jan 1986 |
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NZ |
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214998 |
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Jan 1986 |
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NZ |
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222103 |
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Oct 1987 |
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NZ |
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222883 |
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Dec 1987 |
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NZ |
|
223262 |
|
Jan 1988 |
|
NZ |
|
8601105 |
|
Feb 1986 |
|
WO |
|
WO/8705216 |
|
Oct 1988 |
|
WO |
|
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Primary Examiner: Shah; Mukund J.
Assistant Examiner: Sripada; P. K.
Attorney, Agent or Firm: Ostrolenk, Faber, Gerb &
Soffen
Parent Case Text
RELATED APPLICATION
This application is a continuation of U.S. application Ser. No.
07/376,710 filed Jul. 7, 1989 now abandoned, which is a
continuation-in-part of U.S. patent patent application Ser. No.
07/322,154, filed Mar. 10, 1989 entitled: "INHIBITORS OF SEX
STEROID BIOSYNTHESIS AND METHODS FOR THEIR PRODUCTION AND USE", now
abandoned the entire disclosure of which is hereby incorporated by
reference as though fully set forth herein.
Claims
I claim:
1. A method of treating prostate cancer in humans or other
warm-blooded animals in need of such treatment, said method
comprising the steps of blocking androgen receptors by
administering a therapeutically effective amount of an antiandrogen
having, as part of its molecular structure, a substituted or
unsubstituted androgenic nucleus of the formula: ##STR14## having a
non-aromatic A ring and having as another part of its molecular
structure, at least one side chain represented by the formula:
--R.sup.1 (--B--R.sup.2 --).sub.x L--G said chain being substituted
onto said androgenic nucleus at a position selected from the group
consisting of 6, 7, 14, 15, 16 and 17, wherein:
x is an integer from 0 to 6, wherein at least one of L and G is a
polar moiety distanced from said ring carbon by at least three
intervening atoms, and wherein:
R.sup.1 and R.sup.2 are independently either absent or selected
from the group consisting of straight- or branched-chain alkylene,
straight- or branched-chain alkynlene, straight- or branched-chain
alkenylene, phenylene and fluoro-substituted analogs of the
foregoing;
B is either absent or selected from the group consisting of --O--,
--S--, --Se--, --SO.sub.3 --, --SO.sub.2 --, NR.sup.3 --,
SiR.sub.2.sup.3 --, CR.sup.3 OR.sup.3 --, NR.sup.3 CO--, --NR.sup.3
CS--, --CONR.sup.3 --, CSNR.sup.3 --, --COO--, --COS--, --SCO--,
--CSS--, --SCS--, --OCO-- and phenylene (R.sup.3 being hydrogen or
lower alkyl);
L is selected from the group consisting of lower alkyl,
--CONR.sup.4 --, --CSNR.sup.4 --, --NR.sup.5 CO--, NR.sup.5 CS--,
--NR.sup.5 CONR.sup.4 -- ##STR15## --SO.sub.2 --NR.sup.4 --,
--CSS--, --SCS--, --(NO)R.sup.4 --, --(PO)R.sup.4 --, --NR.sup.5
COO--, --NR.sup.5 SO.sub.2 --, --O--, --NR.sup.4 --, --S--, --SO--
and --SO.sub.2 -- (R.sup.4 and R.sup.5 being independently selected
from the group consisting of hydrogen and lower alkyl; and R.sup.6
being selected from the group consisting of hydrogen, nitrile and
nitro); and
G is selected from the group consisting of hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, (C.sub.3 -C.sub.7)cycloalkyl,
bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,
cyano(lower)alkyl, carboxy(lower)alkyl,
(lower)alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl,
(C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl, and
fluoro-substituted analogs of the foregoing;
said method of treatment further comprising the step of inhibiting
sex steroid formation by administering a therapeutically effective
amount of at least one additional compound that is a sex steroid
formation inhibitor whose mechanism of inhibition is other than
suppression of adrenal activity.
2. The method of claim 1 wherein said inhibition of sex steroid
synthesis includes administering a therapeutically effective amount
of an inhibitor of 5.alpha.-reductase.
3. The method of claim 1 wherein said inhibition of sex steroid
synthesis includes administering a therapeutically effective amount
of an inhibitor of 17.beta.-hydroxysteroid dehydrogenase.
4. The method of claim 1 wherein said inhibition of sex steroid
synthesis includes administering a therapeutically effective amount
of an inhibitor of 5.alpha.-reductase and an inhibitor of
17.beta.-hydroxysteroid dehydrogenase.
5. The method according to claim 1 further comprising the step of
administering a therapeutically effective amount of an
antiestrogen.
6. The method according to claim 2 further comprising the step of
administering a therapeutically effective amount of an
antiestrogen.
7. The method according to claim 3 further comprising the step of
administering a therapeutically effective amount of an
antiestrogen.
8. The method according to claim 4 further comprising the step of
administering a therapeutically effective amount of an
antiestrogen.
9. The method of claim 1 wherein said inhibition includes the step
of administering a mixture of sex steroid inhibitors which together
are capable of inhibiting the function of 5.alpha.-reductase and
the function of 17.beta.-hydroxysteroid dehydrogenase and the
function of 3.beta.-hydroxysteroid dehydrogenase.
10. The method according to claim 9 further comprising the step of
administering a therapeutically effective amount of an
antiestrogen.
11. The method of claim 1 further comprising the step of inhibiting
testicular hormonal secretion of said warm-blooded animal.
12. The method of claim 11 wherein said testicular hormonal
secretion is inhibited by at least one technique selected from the
group consisting of surgical castration, administration of an
antagonist of luteinizing hormone releasing hormone, and
administration of an agonist of luteinizing hormone releasing
hormone.
13. The method of claim 1 wherein said inhibition of sex steroid
synthesis includes the step of administering an inhibitor of
5.alpha.-reductase activity, and wherein said method further
includes inhibiting the testicular hormonal secretion of said
warm-blooded animal.
14. A method of treating prostate cancer in humans or other
warm-blooded animals in need of such treatment, said method
comprising the steps of blocking androgen receptors by
administering a therapeutically effective amount of an antiandrogen
having, as part of its molecular structure, a substituted or
unsubstituted androgenic nucleus of the formula: ##STR16## having a
non-aromatic A ring and having as another part of its molecular
structure, at least one side chain represented by the formula:
--R.sup.1.sub.x L--G said chain being substituted onto said
androgenic nucleus at a position selected from the group consisting
of 6, 7, 14, 15, 16 and 17, wherein:
x is an integer from 0 to 6, wherein at least one of L and G is a
polar moiety distanced from said ring carbon by at least three
intervening atoms, and wherein:
R.sup.1 and R.sup.2 are independently either absent or selected
from the group consisting of straight- or branched-chain alkylene,
straight- or branched-chain alkynylene, straight- or branched-chain
alkenylene, phenylene and fluoro-substituted analogs of the
foregoing;
B is either absent or selected from the group consisting of --O--,
--S--, --Se--, --SO--, --SO.sub.2 --, --NR.sup.3 --,
--SiR.sub.2.sup.3 --, --CR.sup.3 OR.sup.3 --, --NR.sup.3 CO--,
NR.sup.3 CS--, --CONR.sup.3 --, --CSNR.sup.3 --, --COO--, --COS--,
--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R.sup.3 being
hydrogen or lower alkyl);
L is selected from the group consisting of lower alkyl --CONR.sup.4
--, --CSNR.sup.4 --, --NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5
CONR.sup.4 --, ##STR17## --SO.sub.2 NR.sup.4 --, --CSS--, --SCS--,
--(NO)R.sup.4 --, --(PO)R.sup.4 --, --NR.sup.5 COO--, --NR.sup.5
SO.sub.2 --, --O--, --NR.sup.4 --, --S--, --SO-- and --SO.sub.2 --
(R.sup.4 and R.sup.5 being independently selected from the group
consisting of hydrogen and lower alkyl; and R.sup.6 being selected
from the group consisting of hydrogen, nitrile and nitro); and
G is selected from the group consisting of hydrogen, lower alkyl,
lower alkenyl, lower alkynl, (C.sub.3 -C.sub.7) cycloalkyl,
bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,
cyano(lower)alkyl, carboxy(lower)alkyl,
(lower)alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl,
(C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl, and
fluoro-substituted analogs of the foregoing;
said method of treatment further comprising the step of inhibiting
sex steroid activity formation by administering a therapeutically
effective amount of at least one sex steroid formation inhibitor
selected from the group consisting of: N-butyl,
N-methyl-11-(16'.alpha.-chloro-3', 17'.beta.-dihydroxy estra-1',
3', 5'(10') -trien-7'.alpha.-yl) undecanamide ("EM 139"): ##STR18##
##STR19## N-n-butyl-N-methyl-11-(16'.alpha.-bromo-3',
17'.alpha.-dihydroxy-estra-1',3',5'(10')-trien-7'.alpha.-yl)
undecanamide ("EM 171"): ##STR20## wherein R is either hydrogen or
ethynl.
15. The method of claim 14, said method further including
inhibiting testicular hormone secretion of said warm-blooded
animal.
16. A method for treating prostrate cancer in humans or other warm
blooded animals in need of such treatment said method comprising
the step of blocking androgen receptors by administering a
therapeutically amount of an antiandrogen represented by the
formula: ##STR21## wherein the dotted line represents an optional
double bond; x is 0, R.sup.1 is (--CH.sub.2 --).sub.2 (with y being
an integer from 4 to 20), R.sup.17(.alpha.) is hydrogen, lower
alkyl or a moiety which together with R.sup.17(.beta.) forms:
##STR22## wherein R.sup.17(.beta.) is selected from the group
consisting of hydrogen, hydroxyl, lower alkyl, acyloxy, and a
moiety which, together with R.sup.17(.alpha.) forms: ##STR23##
wherein said treatment further comprises the step of inhibiting sex
steroid formation by administering a therapeutically effective
amount of at least one additional compound that is a sex steroid
formation inhibitor.
17. The method of claim wherein said antiandrogen is represented by
the formula: ##STR24## wherein the dotted lines represent optional
double bonds; wherein R.sup.10 is hydrogen or lower alkyl, R.sup.13
is absent, hydrogen or methyl in .beta. position,
R.sup.17(.alpha.) is selected from the group consisting of
hydrogen, hydroxyl, lower alkanoyloxy, lower alkyl, lower alkenyl,
lower alkynyl, halo(lower)alkyl, halo(lower)alkenyl,
halo(lower)alkynyl and fluoro-substituted aromatic ring, and a
moiety which, together with R.sup.17(.beta.) forms ##STR25##
R.sup.17(.beta.) is selected from the group consisting of hydroxyl,
(C.sub.1 -C.sub.20) alkanoyloxy, (C.sub.3 -C.sub.7)alkenoyloxy,
(C.sub.3 -C.sub.7) alkynoyloxy, aroyloxy, alkenoyloxy,
cycloalkenyloxy, 1alkyloxy-alkyloxy, 1-alkyloxycycloalkyloxy,
alkyl-, ##STR26## silyloxy, carboxyl, alkanoyl and a moiety which
together with R.sup.17 forms ##STR27##
18. The method of claim 1 wherein said antiandrogen is represented
by the formula: ##STR28## wherein the AB-ring junction is trans,
the dotted lines represent optional pi bonds; wherein y is an
integer from 4 to 20, wherein L is selected from the group
consisting of --CONR.sup.4 --, --CSNR.sup.4 --, --NR.sup.5 CO--,
--NR.sup.5 CS-- and --CH.sup.2 -- (R.sup.4 and R.sup.5 being
hydrogen or methyl) and G is selected from the group consisting of
n-propyl, n-butyl, n-pentyl and haloalkyl.
19. A method of treating prostate cancer in humans or other
warm-blooded animals in need of such treatment, said method
comprising the step of blocking androgen receptors by administering
a therapeutically effective amount of an antiandrogen having, as
part of its molecular structure, a substituted or unsubstituted
androgenic nucleus of the formula: ##STR29## having a non-aromatic
A ring and having as another part of its molecular structure, at
least one side chain represented by the formula:
--R.sup.1 (--B--R.sup.2 --).sub.x L-G said chain being substituted
onto said androgenic nucleus at a position selected from the group
consisting of 6, 7, 14, 15, 16 and 17, wherein:
x is an integer from 0 to 6, wherein at least one of L and G is a
polar moiety distanced from said ring carbon by at least three
intervening atoms, and wherein:
R.sup.1 and R.sup.2 are independently either absent or selected
from the group consisting of straight- or branched-chain alkylene,
straight- or branched-chain alkynylene, straight- or branched-chain
alkenylene, phenylene and fluoro-substituted analogs of the
foregoing;
B is either absent or selected from the group consisting of --O--,
--S--, --Se--, --SO--, --SO.sub.2 --, --NR.sup.3 --,
--SiR.sup.3.sub.2 --, --CR.sup.3 OR.sup.3 --, --NR.sup.3 CO--,
NR.sup.3 CS--, --CONR.sup.3 --, --CSNR.sup.3 --, --COO--, --COS--,
--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R.sup.3 being
hydrogen or lower alkyl);
L is selected from the group consisting of lower alkyl --CONR.sup.4
--, --CSNR.sup.4 --, --NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5
CONR.sup.4 --, ##STR30## --SO.sub.2 NR.sup.4 --, --CSS--, --SCS--,
--(NO)R.sup.4 --, --(PO)R.sup.4 --, --NR.sup.5 COO--, --NR.sup.5
SO.sub.2 --, --O--, --NR.sup.4 --, --S--, --SO-- and --SO.sub.2 --
(R.sup.4 and R.sup.5 being independently selected from the group
consisting of hydrogen and lower alkyl; and R.sup.6 being selected
from the group consisting of hydrogen, nitrile and nitro); and
G is selected from the group consisting of hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, (C.sub.3 -C.sub.7) cycloalkyl,
bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,
cyano(lower)alkyl, carboxy(lower)alkyl,
(lower)alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl,
(C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl, and
fluoro-substituted analogs of the foregoing;
said method of treatment further comprising the step of inhibiting
sex steroid activity formation by administering a therapeutically
effective amount of at least one non-adrenal sex steroid formation
inhibitor;
wherein said sex steroid formation inhibitor is selected from a
group consisting of an inhibitor of 3.beta.-hydrogenase, an
inhibitor of 17.beta.-hydroxysteroid dehydrogenase, an inhibitor of
5.alpha.-reductase and an inhibitor of aromatase.
20. The method of claim 19, wherein said sex steroid formation
inhibitor is an inhibitor of 3.beta.-hydroxysteroid
dehydrogenase.
21. The method of claim 19, wherein said sex steroid formation
inhibitor is an inhibitor of aromatase.
22. A method of treating prostate cancer in humans or other
warm-blooded animals in need of such treatment, said method
comprising the steps of blocking androgen receptors by
administering a therapeutically effective amount of an antiandrogen
having, as part of its molecular structure, a substituted or
unsubstituted androgenic nucleus of the formula: ##STR31## having a
non-aromatic A ring and having as another part of its molecular
structure, at least one side chain represented by the formula:
--R.sup.1 (--B--R.sup.2 --).sub.x L-G said chain being substituted
onto said androgenic nucleus at a position selected from the group
consisting of 6, 7, 14, 15, 16 and 17, wherein:
x is an integer from 0 to 6, wherein at least one of L and G is a
polar moiety distanced from said ring carbon by at least three
intervening atoms, and wherein:
R.sup.1 and R.sup.2 are independently either absent or selected
from the group consisting of straight- or branched-chain alkylene,
straight- or branched-chain alkynylene, straight- or branched-chain
alkenylene, phenylene and fluoro-substituted analogs of the
foregoing;
B is either absent or selected from the group consisting of --O--,
--S--, --Se--, --SO--, --SO.sub.2 --, --NR.sup.3 --,
--SiR.sup.3.sub.2 --, --CR.sup.3 OR.sup.3 --, --NR.sup.3 CO--,
NR.sup.3 CS--, --CONR.sup.3 --, --CSNR.sup.3 --, --COO--, --COS--,
--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R.sup.3 being
hydrogen or lower alkyl);
L is selected from the group consisting of lower alkyl --CONR.sup.4
--, --CSNR.sup.4 --, --NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5
CONR.sup.4 --, ##STR32## --SO.sub.2 NR.sup.4 --, --CSS--, --SCS--,
--(NO)R.sup.4 --, --(PO)R.sup.4 --, --NR.sup.5 COO--, --NR.sup.5
SO.sub.2 --, --O--, --NR.sup.4 --, --S--, --SO-- and --SO.sub.2 --
(R.sup.4 and R.sup.5 being independently selected from the group
consisting of hydrogen and lower alkyl; and R.sup.6 being selected
from the group consisting of hydrogen, nitrile and nitro); and
G is selected from the group consisting of hydrogen, lower alkyl,
lower alkenyl, lower alkynyl, (C.sub.3 -C.sub.7) cycloalkyl,
bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,
cyano(lower)alkyl, carboxy(lower)alkyl,
(lower)alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl,
(C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl, and
fluoro-substituted analogs of the foregoing;
said method of treatment further comprising the step of inhibiting
sex steroid activity formation by administering a therapeutically
effective amount of at least one non-adrenal sex steroid formation
inhibitor;
wherein said inhibitor of sex steroid formation is: ##STR33##
wherein R is either hydrogen or ethynyl.
23. The method of claim 1, wherein said sex steroid formation
inhibitor is an aromatase inhibitor.
24. The method of claim 2, wherein said inhibitor of
5.alpha.-reductase is Proscar.
25. The method of claim 1, wherein L is selected from the group
consisting of --CONR.sup.4 --, --O--, --NR.sup.4 --, --S--, --SO--
and --SO.sub.2 --(R.sup.4 being hydrogen or lower alkyl); and
wherein G is selected from the group consisting of hydrogen, lower
alkyl, lower alkenyl, lower alkynyl, (C.sub.3 -C.sub.7)cycloalkyl,
bromo(lower)alkyl, chloro(lower)alkyl, fluoro(lower)alkyl,
cyano(lower)alkyl, carboxy(lower)alkyl,
(lower)alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl,
(C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl.
26. The method of claim 25, wherein L is --CONR.sup.4 --.
27. The method of claim 25, wherein G is selected from the group
consisting of lower alkyl, bromo(lower)alkyl, chloro(lower)alkyl
and fluoro(lower)alkyl.
28. The method of claim 27, where L is --CONR.sup.4 --.
29. The method of claim 13, wherein testicular hormonal secretion
is inhibited by administering an LHRH agonist or antagonist.
Description
BACKGROUND OF THE INVENTION
This invention relates to a method of treatment of androgen-related
diseases such as prostate cancer in warm-blooded male animals
(including humans) in need of such treatment, and in particular, to
a combination therapy comprising administering an antiandrogen in
association with an inhibitor of sex steroid biosynthesis to such
animals. The invention also includes pharmaceutical compositions
and kits useful for such treatment. Androgen-dependent diseases
include diseases whose onset, maintenance or progress is, at least
in part, dependent upon biological activities induced by androgens
(e.q. testosterone and dihydrotestosterone). In one embodiment, the
invention provides a treatment of hormone-dependent prostate cancer
in warm-blooded male animals which comprises administering both an
antiandrogen and at least one inhibitor of sex steroid biosynthesis
capable of inhibiting conversion of dehydroepiandrosterone or
4-androstenedione to natural sex steroids in extra-testicular and
extra-adrenal tissues.
While various investigators have been studying hormone-dependent
prostate cancer, none have proposed the combination therapy of this
invention.
A. V. Schally et al., Cancer Treatment Reports, 68 (No. 1) 281-289
(1984), summarize the results of animal and clinical studies on
growth inhibition of hormone-dependent mammary and prostate tumors
by use of analogues of luteinizing hormone-releasing hormones, the
so-called LHRH agonists and suggest that LHRH analogs and/or
antagonists may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Proc. Natl Acad. Sci. UA 80,
1459-1462 (1983), relates to inhibition of prostate tumor growth in
rats by chronic use of an LHRH agonist, [D-Trp.sup.6 ]LHRH.
U.S. Pat. No. 4,329,364 relates to use of the antiandrogen,
4'-nitro-3'trifluoromethyl isobutyranilide for treatment of
prostatic cancer.
U.S. Pat. No. 4,472,382 relates to treatment of prostate
adenocarcinoma, benign prostate hypertrophy and hormone-dependent
mammary tumors may with various LHRH agonists and treatment of
prostate adenocarcinoma and benign hypertrophy by use of various
LHRH agonists and an antiandrogen.
U.S. Pat. No. 4,659,695 (Labrie) relates to treatment of prostate
cancer in animals whose testicular hormonal secretions are blocked.
The method of treatment includes administering an antiandrogen such
as flutamide as an inhibitor of sex steroid biosynthesis such as
aminoglutethimide and/or ketoconazole.
Some clinical improvement in men with prostate cancer by use of the
two LHRH agonists, Buserelin and Leuprolide, is also reported by N.
Faure et al. at pages 337-350 and by R. J. Santen et al. at pages
351-364, respectively, LHRH and its Analogues--A new Class of
Contraceptive and therapeutic Agents (B. H. Vickery and J. J.
Nestor, Jr., and E. S. E. Hafez, eds), Lancaster, MTP Press,
(1984).
R. Santen et al., The Journal of Steroid Biochemistry, volume 20,
no. 6B, at page 1375 (1984), relates that the use of ketoconazole
in combination with chronic administration of Leuprolide in rodents
decreased basal and Leuprolide-stimulated testosterone levels.
One of Applicant's Co-pending U.S. patent application Ser. No.
07/321,926 filed Mar. 10, 1989, relates to a combination therapy
for treatment of estrogen-related diseases by inhibiting ovarian
hormonal secretions and administering an antiestrogen in
combination with at least one of several enumerated activity
blockers, sex steroid formation inhibitors and the like.
D. Kerle et al., The Journal of Steroid Biochemistry, volume 20,
no. 6B, at page 1395 (1984) relates to the combined use of a LHRH
analogue and ketoconazole producing objective responses in some
prostate cancer patients who have relapsed or failed to respond to
treatment with a LHRH analogue alone.
F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that
use of a combination therapy of an LHRH agonist (Buserelin) and an
antiandrogen (Anandron) to treat advanced prostate cancer in
previously untreated patients effects simultaneous elimination of
androgens of both testicular and adrenal origin.
F. Labrie et al., J. Steroid Biochem., 19, 999-1007 (1983),
disclose the treatment of prostate cancer by the combined
administration of an LHRH agonist and an antiandrogen. Labrie et
al. disclose animal and clinical data in support of the proposition
that the combined LHRH/antiandrogen treatment neutralizes the
stimulatory influence of all androgens on the development and
growth of androgen-dependent prostatic cancer.
F. Labrie et al., Abstracts of the 7th International Congress of
Endocrinology, Excerpta Medica (1984) at page 98 disclose that
treatment of prostate cancer patients with LHRH agonists alone
causes a transient increase in serum androgen levels lasting for 5
to 15 days before castration levels are reached. While F. Labrie et
al. recommend that orchiectomy, estrogen and LHRH agonists alone
should not be further used for treatment of prostate cancer in the
absence of a pure antiandrogen, there still is a need for a method
of treatment of prostate cancer that effects more complete androgen
blockage at the start as well as during the full period of
treatment.
There are many data indicating that estrogens have a stimulatory
effect on prostatic growth (Lee et al., 1981; J. Androl. 2:293-299;
Belis et al., 1983; J. Androl. 4: 144-149; Walsh and Wilson, 1976;
J. Clin. Invest. 57: 1093-1097; De Klerk et al., 1985; Prostate 7,
1-12; Habesucht et al., 1987; Prostate 11: 313-326). Estrogens have
also been found to enhance the growth-promoting effect of androgens
(Farnsworth, 1969; Invest. Urol. 6: 423-427; Groom et al., 1971;
Biochem. J. 122: 125-126; Lee et al., 1973; Steroids 22:
677-683).
Estrogen receptors have been demonstrated in human normal,
hyperplastic and cancer prostatic tissue (Mobbs et al., 1989; Proc.
84th Endocrine Soc., Meeting, abst. No. 1410; Mobbs et al., 1983;
J. Steroid Biochem. 19, 1279-1290; Wagner et al., 1975; Acta
Endocrinol. (Kbh), suppl. 193, 52; and also in laboratory animal
prostatic tissue (Swaneck et al., 1982; Biochem. Biophys. Res.
Commun. 106: 1441-1447).
Moreover, androgen receptor levels were found to be elevated in
prostatic tissue of patients treated with estrogen, thus indicating
a stimulatory effect of estrogen on the level of androgen receptors
in prostatic tissue (Mobbs et al., 1983; J. Ster. Biochem. 19,
1279-1290). A similar stimulatory effect of estrogen has been
observed in the dog prostate (Moore et al., 1979; J. Clin. Invest.
63, 351-357).
In the prostate as well as in many other tissues, testosterone is
irreversibly converted by 5.alpha.-reductase into the more potent
androgen dihydrotestosterone (Bruchovsky and Wilson, J. Biol. Chem.
243: 2012-2021, 1968; Wilson, Handbook of Physiology 5 (section 7),
pp. 491-508, 1975). Inhibitors of 5.alpha.-reductase have been
found to inhibit prostatic growth (Brooks et al., Endocrinology
109: 830, 1981; Brooks et al., Proc. Soc. Exp. Biol. Med. 169: 67,
1982; Brooks et al., Prostate 3: 35, 1982; Wenderoth et al.,
Endocrinology 113, 569-573, 1983; McConnell et al., J. Urol. 141:
239A, 1989); Stoner, E., Lecture on the role of 5.alpha.-reductase
inhibitor in benign prostatic hypertrophy, 84th AUA Annual Meeting,
Dallas, May 8th, 1989.
The inhibitory effect of the 5.alpha.-reductase inhibitor Merck L.
652,931 on prostatic and seminal vesicle development in the
prepubertal rat was described in Proc. 71st Annual Meeting of
Endocrine Society, abst. #1165, p. 314, 1989. The inhibitory effect
of MK-906 on dihydrotestosterone formation in men has been
described in men by Gormley et al., in Proc. 71st Annual Meeting of
Endocrine Society, abst. #1225, p. 329, 1989; Imperato-McGinley et
al., in Proc. 71st Annual Meeting of Endocrine Society, abst.
#1639, p. 432, 1989; Geller and Franson, in Proc. 71st Annual
Meeting of Endocr. Soc., abst. #1640p. 432, 1989, and Tenover et
al., in Proc. 71st Annual Meeting of Endocr. Soc., abst. #583, p.
169, 1989. The activity of the 5.alpha.-reductase inhibitors
N,N-diethyl-4-methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxamide
(4-MA) and 6-methylene-4-pregnene-3,20-dione (LY207320) has been
described by Toomey et al., Proc. 71st Annual Meeting of Endocr.
Soc., abst. #1226, p. 329, 1989.
BRIEF DESCRIPTION OF THE DRAWING
There is shown in FIG. 1 a schematic representation of the site(s)
of action of various drugs, enzymes and hormones. The following
abbreviations are used: ER: estrogen receptor; AR: androgen
receptor; DHEA: dehydroepiandrosterone.; .DELTA..sup.5 -diol:
adrost-5-ene-3.beta., 17.beta.-diol; .DELTA..sup.4 -dione;
androstenedione; DHT: dihydrotestosterone; Anti-A: antiandrogen;
Anti-E: antiestrogen; ARO: aromatase; 3.beta.-HSD:
3.beta.-hydroxysteroid dehydrogenase, .DELTA..sup.5 -.DELTA..sup.4
isomerase; 17.beta.-HSD: 17.beta.-hydroxysteroid dehydrogenase; 1:
antiandrogen; 2: inhibitor of 5.alpha.-reductase activity; 3:
inhibitor of 17.beta.-hydroxysteroid dehydrogenase activity; 4:
antiestrogen; 5: inhibitor of aromatase activity; 6: inhibitor of
3.beta. activity.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide combination
therapy for the treatment of prostate cancer wherein the treatment
selectively inhibits the formation and/or action of hormones which
would otherwise contribute to tumor growth.
It is another object of the invention to provide combination
therapy having increased effectiveness in slowing or reversing
tumor growth.
It is another object of the invention to provide therapy for
treating prostate cancer having significantly reduced frequency of
unwanted side effects.
It is a further object of the invention to provide kits having a
plurality of active ingredients (with or without diluent or
carrier) which, together, may be effectively utilized for carrying
out the novel combination therapies of the invention.
It is another object of the invention to provide a novel
pharmaceutical composition which is effective, in and of itself,
for utilization in a beneficial combination therapy because it
includes a plurality of active ingredients which may be utilized in
accordance with the invention.
In one aspect, the present invention provides a method for treating
prostate cancer in humans or other warm-blooded animals in need of
such treatment, said method comprising the steps of blocking
androgen receptors by administering a therapeutically effective
amount of an antiandrogen having as part of its molecular structure
a substituted or unsubstituted androgenic nucleus of the formula:
##STR1## said antiandrogen having as another part of its molecular
structure at least one side chain represented by the formula:
--R.sup.1 [--B--R.sup.2 --].sub.x L--G wherein said side chain is
substituted onto said androgenic nucleus at a position selected
from the group consisting of 6.alpha., 7.alpha., 14.alpha.,
15.alpha., 16.alpha., 17.alpha. and 17.beta., and wherein:
x is an integer from 0 to 6, wherein at least one of L and G is a
polar moiety distanced from said ring carbon by at least three
intervening atoms, and wherein:
R.sup.1 and R.sup.2 are independently either absent or selected
from the group consisting of straight- or branched-chain alkylene,
straight- or branched-chain alkynylene, straight- or branched-chain
alkenylene, phenylene and fluoro-substituted analogs of the
foregoing;
B is either absent or selected from the group consisting of --O--,
--S--, --Se--, --SO--, --SO.sub.2 --, --NR.sup.3 --,
--SiR.sup.3.sub.2 --, --CR.sup.3 OR.sup.3 --, --NR.sup.3 CO--,
--NR.sup.3 CS--, --CONR.sup.3 --, --CSNR.sup.3 --, --COO--,
--COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R.sup.3
being hydrogen or lower alkyl);
L is either a moiety which together with G, forms a heterocyclic
ring having at least one nitrogen atom or is selected from the
group consisting of lower alkyl, --CONR.sup.4 --, --CSNR.sup.4 --,
--NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5 CONR.sup.4 -- NR.sup.6
--NR.sup.5 C--NR.sup.4 --, --SO.sub.2 NR.sup.4 --, --CSS--,
--SCS--, --(NO)R.sup.4 --, --(PO)R.sup.4 --, --NR.sup.5 COO--,
--NR.sup.5 SO.sub.2 --, --O--, --NR.sup.4 --, --S--, --SO-- and
--SO.sub.2 -- (R.sup.4 and R.sup.5 being independently selected
from the group consisting of hydrogen and lower alkyl; and R.sup.6
being selected from the group consisting of hydrogen, nitrile and
nitro); and
G is either a moiety which together with L forms a heterocyclic
ring having at least one nitrogen atom or is selected from the
group consisting of hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, (C.sub.3 -C.sub.7)cycloalkyl, bromo(lower)alkyl,
chloro(lower)alkyl, fluoro(lower)alkyl, cyano(lower)alkyl,
carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C.sub.6
-C.sub.10)aryl, (C.sub.7 -C.sub.11)arylalkyl,
di(lower)alkylamino(lower)alkyl, fluoro-substituted analogs of the
foregoing,
said method of treatment further comprising the step of inhibiting
sex steroid formation by administering a therapeutically effective
amount of at least one sex steroid formation inhibitor.
In another aspect, the present invention provides a method for
treatment of prostate cancer in a human or other warm-blooded
animal in need of such treatment, said method comprising the steps
of inhibiting sex steroid formation by administering a
therapeutically effect of amount of an inhibitor of sex steroid
formation capable of blocking formation of natural sex steroids
from dehydroepiandrosterone and from 4-androstenedione in
peripheral tissues (extra-adrenal and extra-testicular), or an
inhibitor of sex steroid formation having as part of its molecular
structure a substituted or unsubstituted sex-steroid nucleus, and,
as another part of its molecular structure at least one side chain
of the formula
--R.sup.1 [--B--R.sup.2 --].sub.x L--G substituted onto a ring atom
of said sex steroid nucleur wherein:
x is an integer from 0 to 6, wherein at least one of L and G is a
polar moiety distanced from said ring carbon by at least three
intervening atoms, and wherein:
R.sup.1 and R.sup.2 are independently either absent or selected
from the group consisting of straight- or branched-chain alkylene,
straight- or branched-chain alkynylene, straight- or branched-chain
alkenylene, phenylene and fluoro-substituted analogs of the
foregoing;
B is either absent or selected from the group consisting of --O--,
--S--, --Se--, --SO--, --SO.sub.2 --, --NR.sup.3 --,
--SiR.sup.3.sub.2 --, --CR.sup.3 OR.sup.3 --, --NR.sup.3 CO--,
--NR.sup.3 CS--, --CONR.sup.3 --, --CSNR.sup.3 --, --COO--,
--COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R.sup.3
being hydrogen or lower alkyl);
L is either a moiety which together with G, forms a heterocyclic
ring having at least one nitrogen atom or is selected from the
group consisting of lower alkyl, --CONR.sup.4 --, --CSNR.sup.4 --,
--NR.sup.5 CO--, --NR.sup.5 CS--, --NR.sup.5 CONR.sup.4 -- ##STR2##
--SO.sub.2 NR.sup.4 --, --CSS--, --SCS--, --(NO)R.sup.4 --,
--(PO)R.sup.4 --, --NR.sup.5 COO--, --NR.sup.5 SO.sub.2 --, --O--,
--NR.sup.4 --, --S--, --SO-- and --SO.sub.2 -- (R.sup.4 and R.sup.5
being independently selected from the group consisting of hydrogen
and lower alkyl; and R.sup.6 being selected from the group
consisting of hydrogen, nitrile and nitro); and
G is either a moiety which together with L forms a heterocyclic
ring having at least one nitrogen atom or is selected from the
group consisting of hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, (C.sub.3 -C.sub.7)cycloalkyl, bromo(lower)alkyl,
chloro(lower)alkyl, fluoro(lower)alkyl, cyano(lower)alkyl,
carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C.sub.6
-C.sub.10)aryl, (C.sub.7 -C.sub.11)arylalkyl,
di(lower)alkylamino(lower)alkyl, fluoro-substituted analogs of the
foregoing;
said method of treatment further comprising administering a
therapeutically effective amount of an antiandrogen.
In another aspect, the present invention provides a method for
treating prostate cancer in a human or other warm-blooded animal in
need of such treatment, said method including the steps of
administering a therapeutically effective amount of an inhibitor of
5.alpha.-reductase activity and administering a therapeutically
effective amount of an antiandrogen.
In another aspect, the present invention provides a method for
treating prostate cancer in a human or other warm-blooded animal in
need of such treatment, said method including the steps of
administering a therapeutically effective amount of an inhibitor of
17.beta.-hydroxysteroid dehydrogenase and administering a
therapeutically effective amount of an antiandrogen.
In another aspect, the present invention provides a method for
treating prostate cancer in a human or other warm-blooded animal in
need of such treatment, said method including the steps of
administering an effective amount of an antiandrogen and at least
one sex steroid formation inhibitor from the groups consisting of
inhibitors of extragonadal and inhibitors of extraadrenal sex
steroid formation.
The invention also provides kits or single packages combining two
or more active ingredients useful in treating prostate cancer. A
kit may provide (alone or in combination with a pharmaceutically
acceptable diluent or carrier), an antiandrogen and at least one
additional active ingredient (alone or in combination with diluent
or carrier) selected from the group consisting of an LHRH agonist
or LHRH antagonist, a sex steroid formation inhibitor (preferably
an inhibitor of 5.alpha.-reductase activity, an inhibitor of
17.beta.-hydroxysteroid dehydrogenase activity or an inhibitor of
3.beta.-hydroxysteroid dehydrogenase activity) and an
antiestrogen.
The foregoing active ingredients may also be mixed in any of the
foregoing combinations to form pharmaceutical compositions (with or
without diluent or carrier) which, when administered, provide
simultaneous administration of a combination of active ingredients
resulting in the combination therapy of the invention. Preferably,
when LHRH antagonist or agonist is used, it is administered
parenterally. For this reason, it may be administered separately in
instances where the other active ingredients are formulated for
oral ingestion.
The term "sex steroid nucleus" includes estrogenic and androgenic
nuclei.
As used herein, the term "androgenic nucleus" includes any compound
which, in the absence of the side chain substituent specified
herein (R.sup.1 [--B--R.sup.2 --].sub.x L--G), is capable of acting
as an androgen as determined by a weight increase of at least 35
percent over a seven-day period of the ventral prostate of
castrated rats treated with the compound in question (15 milligrams
twice daily per 100 grams of body weight) versus a control group of
castrated rats. Treatment should start on the day of castration.
The precise test, other than any parameters set forth in this
paragraph, is that reported in Labrie et al., J. Ster. Biochem. 28,
379-384, 1987.
As used herein, the term "estrogenic nucleus" includes any compound
which, in the absence of the side chain substituent specified
herein (R.sup.1 [--B--R.sup.2 --].sub.x L--G), is capable of acting
as an estrogen as determined by a weight increase of at least 100
percent over a seven-day period of the uterus of ovariectomized
rats treated with the compound in question (0.5 mg twice daily per
100 grams of body weight) versus a control group of ovariectomized
rats. Treatment should start on the day of castration. The precise
test, other than any parameters set forth in this paragraph, is
that reported in Simard et al., Mol. Endocrinol. 2: 775-784
(1988).
The following conventions apply to structural formulae set forth
herein. Unless specifically designated to the contrary,
substituents may have either .alpha. or .beta. stereochemistry or,
where valence permits, may represent one substituent in .alpha.
position and another in .beta. position. Presence of optional
double bonds are independent of each other. All structures include
salts thereof. Atoms of any sex steroid nucleus for which no
substituent is shown or described may optionally be substituted or
unsubstituted so long as such substitution does not prevent the
nucleus from functioning as a "sex steroid nucleus" as defined
herein. Those atoms having a defined substituent may optionally be
further substituted by other substituents where their valence
permits such further substitution. As used herein, the term
"lower", when describing a chemical moiety means a moiety having 8
or fewer atoms. For instance, a "lower alkyl" means a C.sub.1 to
C.sub.8 alkyl. Any moiety of more than two atoms may be straight-
or branched-chain unless otherwise specified.
The term "sex steroid formation inhibitor" includes both androgen
and estrogen formation inhibitors and encompasses any compound
which inhibits the biosynthesis of active sex steroids or their
precursors. One mechanism by which sex steroid formation inhibitors
act is by blocking enzymes which catalyze production of natural sex
steroids (e.g. dihydrotestosterone), 17.beta.-estradiol and
androst-5-ene-3.beta.-17.beta.-diol or precursors to such sex
steroids (e.g. androstenedione). Examples of such sex steroid
formation inhibitors are compounds capable of blocking the
enzymatic activity of, for example, 5.alpha.-reductase,
3.beta.-hydroxysteroid dehydrogenase, 17.beta.-hydroxysteroid
dehydrogenase or aromatase.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In a preferred aspect, a combination therapy for prostate cancer
includes administering active ingredients effective to inhibit a
variety of different mechanisms which may, directly or indirectly,
lead to prostatic cancer growth. Desirably, the inhibition of
biological activity which leads to prostatic cancer growth proceeds
selectively, without substantially inhibiting other desirable
biological activity. Side effects of the treatment are therefore
minimized.
Activation of prostatic androgen receptors stimulates growth of
prostatic cancer cells. Growth may be inhibited by blocking these
receptors with antiandrogens as explained herein. Growth may also
be inhibited by reducing the concentration of androgens available
to activate the receptors by administering at least one sex steroid
synthesis inhibitor. An inhibitor of 5.alpha.-reductase catalyzes
conversion of testosterone to dihydrotestosterone (DHT). This is a
particularly preferred sex steroid synthesis inhibitor because it
selectively reduces DHT levels without reducing testosterone
levels. DHT stimulates prostatic cancer growth to a much greater
extent than does testosterone. Also absence of DHT forecloses fewer
desirable biological functions than does absence of testosterone.
For many patients, blocking of testosterone production is also
appropriate.
It is believed that estrogens may also increase prostatic cancer
growth. Without intending to be bound by theory, estrogens appear
to at least be involved in increasing the number of androgen
receptors, and may stimulate prostatic cancer growth directly by
binding estrogen receptors. Regardless of the mechanism by which
estrogens contribute to prostatic cancer growth, it has now been
found that a combination therapy which includes inhibition of
estrogen activity can enhance effectiveness of treatment without
inhibiting desirable biological functions which, in males, are
largely independent of estrogen.
There is shown in FIG. 1 a schematic representation of the site(s)
of action of various drugs, enzymes and hormones. The following
abbreviations are used: ER: estrogen receptor; AR: androgen
receptor; DHEA: dehydroepiandrosterone; .DELTA..sup.5 -diol:
androst-5-ene-3.beta.,17.beta.-diol; .DELTA..sup.4 -dione:
androstenedione; DHT: dihydrotestosterone; Anti-A: antiandrogen;
Anti-E: antiestrogen; ARO: aromatase; 3.beta.-HSD:
3.beta.-hydroxysteroid dehydrogenase, .DELTA..sup.5 -.DELTA..sup.4
isomerase; 17.beta.-HSD: 17.beta.-hydroxysteroid dehydrogenase; 1:
antiandrogen; 2: inhibitor of 5.alpha.-reductase activity; 3:
inhibitor of 17.alpha.-hydroxysteroid dehydrogenase activity; 4:
antiestrogen; 5: inhibitor of aromatase activity; 6: inhibitor of
3.beta.-HSD activity.
Referring to FIG. 1, + means increase in androgen receptor levels.
As may be seen from FIG. 1, stimulation of the androgen receptor is
shown to stimulate prostatic cancer growth, and is therefore to be
prevented. In addition, stimulation of the estrogen receptor leads
to increased levels of androgen receptors and thus may, in
addition, exert direct stimulatory effects on prostatic cancer
growth. The action of estrogens is therefore to be prevented.
Blockers of sex steroid formation from DHEA and .DELTA..sup.4
-dione in peripheral tissues does not cause inhibition of adrenal
glucocorticoid formation. For example, cortisol and aldosterone
production is not inhibited and significant complications which
could result from their inhibition are avoided. The desired
inhibition of sex steroid formation is thus aimed selectively at
androgens and estrogens.
A method of inhibiting activation of the androgen receptor is
treatment with an effective antiandrogen compound having an
affinity for the receptor site such that it binds to the receptor
site and prevents androgens from binding and activating the site.
It is important to select antiandrogens which tend to be pure
antagonists and which have no agonistic activity. Otherwise, the
antiandrogen which blocks the receptor site from androgens, may
itself activate the site. Preferred antiandrogens are discussed in
detail below. Because it is extremely difficult to block all
receptor sites, it is desirable to simultaneously decrease the
concentration of androgens available to activate androgen receptors
in the prostatic cancer tissue. Hence, it is desirable to inhibit
secretion of androgens by the testis. This may be accomplished by a
variety of known techniques including but not limited to surgical
orchiectomy or by administering LHRH agonists or antagonists. For
example, LHRH analogues act in a manner effective to stop the
production of bioactive luteinizing hormone, the hormone necessary
to cause the testis to produce and secrete androgens and other
hormones which may be converted to androgens in peripheral tissues.
For some patients, it may be unnecessary to inhibit testicular
hormonal secretions where sufficiently potent antiandrogens and sex
steroid biosynthesis inhibitors are administered.
As may be seen from the scheme of FIG. 1, a number of hormones
(especially DHEA and .DELTA..sup.4 -dione) released by the adrenals
may be converted by a variety of biological pathways into androgens
and estrogens in peripheral tissues. The most potent androgen
produced is DHT. It is therefore highly desirable to include an
inhibitor of 5.beta.-reductase which prevents the conversion of
testosterone into the more potent androgen DHT.
In peripheral tissues, in addition to DHT, the precursors DHEA and
.DELTA..sup.4 -dione can be converted into the estrogens
.DELTA..sup.5 -diol and estradiol. It is desirable to have an
inhibitor of 17.beta.-hydroxysteroid dehydrogenase which prevents
the formation of testosterone as well as of .DELTA..sup.5 -diol and
estradiol. In addition, since .DELTA..sup.4 -androstenedione can be
converted into estrone and then to estradiol, it may be useful to
block the activity of aromatase, the enzyme responsible for such
conversion. Other sex steroid formation inhibitors, such as
inhibitors of 3.beta.-HSD can also be used. However, as mentioned
earlier, when 3.beta.-HSD is blocked in peripheral tissues, it is
also likely that a similar inhibition will take place in the
adrenals, thus leading to low secretion of glucocorticoids and
mineralocorticoids. When such compounds are used, essential
glucocorticoids and sometimes mineralocorticoids should be added
back as part of the therapy.
Estrogens, at physiological concentrations, are known to stimulate
the growth of the human prostatic cancer cell line LNCaP. This
effect of estrogen may be inhibited, however, by antiestrogenic
compounds described herein.
In one embodiment, the present invention provides a method of
treating prostate cancer comprising the step of administering a
therapeutically effective amount of an antiandrogen, and of
administering a therapeutically effective amount of an inhibitor of
sex steroid formation which has, as part of its molecular
structure, a substituted or unsubstituted estrogen nucleus of
general structure I: ##STR3## wherein the dotted lines represent
optional pi bonds; and wherein said compound includes as another
part of its molecular structure a side chain substitution onto a
ring carbon of said general structure I in at least one position
selected from the group consisting of 7, 14, 15, 16, 17 (preferably
7.alpha., 15.alpha., or 17.alpha.), said side chain being of the
formula --R.sup.1 [--B--R.sup.2 --] L-G, as defined above, wherein
general structure I further includes at least one substitution
selected from the group consisting of 15-halo, 16-halo, a 15,16
bridge atom (preferably carbon), a 14,15 bridge atom (preferably
oxygen), and a 16-pi-bonded lower alkyl.
In certain embodiments, the antiandrogen utilized in the present
invention may be represented by the general formula: ##STR4##
wherein the dotted lines represent optical double bonds; wherein
R.sup.10 is hydrogen or lower alkyl, R.sup.13 is absent, hydrogen
or methyl in .beta. position,
R.sup.17.spsp.(.alpha.) is selected from the group consisting of
hydrogen, hydroxyl, lower alkanoyloxy, lower alkyl, lower alkenyl,
lower alkynyl, halo(lower)alkyl, halo(lower)alkenyl,
halo(lower)alkynyl and fluro-substituted aromatic ring, and a
moiety which, together with R.sup.17.spsp.(.beta.) forms ##STR5##
R.sup.17.spsp.(.beta.) is selected from the group consisting of
hydroxyl, (C.sub.1 -C.sub.20) alkanoyloxy, (C.sub.3
-C.sub.7)alkenoyloxy, (C.sub.3 -C.sub.7) alkynoyloxy, aroyloxy,
alkenoyloxy, cycloalkenyloxy, 1-alkyloxy-alkyloxy,
1-alkyloxycycloalkyloxy, alkylsilyloxy, carboxyl, alkanoyl and a
moiety which together with R.sup.17.spsp.(.alpha.) forms
##STR6##
Antiandrogens useful in the combination therapy of the invention
also include but are not limited to flutamide (available from
Schering-Plough Corp., Kenilworth, N.J., under trade name EULEXIN),
Nilutamide (available from Roussel of Paris, France, under trade
name ANANDRON), cyproterone acetate (available from Schering AG,
Berlin under trade name ANDROCUR), Casodex available from ICI
Pharmaceuticals, Macclesfield, England. Preferably, the
antiandrogen has, as part of its molecular structure, a substituted
or unsubstituted androgenic nucleus, and as another part of its
molecular structure, the side-chain --R'[--B--R.sup.2 --].sub.x L-G
as defined above. Numerous syntheses of the preferred compounds set
forth in the U.S. patent application of Labrie and Merand entitled
"Androgen Derivatives for use in the inhibition of sex steroid
activity" which is being executed on even date herewith, the entire
disclosure of which is hereby incorporated by reference as though
fully set forth herein. A preferred antiandrogen is ##STR7## which
may be synthesized as set forth below.
EXAMPLE 1
Synthesis of N-butyl,
N-methyl-11-(17'.beta.-hydroxy-4'-androsten-3'-on-7'.beta.-yl)
undecanamide (EM 101) (5, .times.=10) (Scheme 1)
17.beta.-acetoxy-7.alpha.-(11'-hydroxy undecanyl)-4-androsten-3-one
(2)
Under argon atmosphere, in a flame dried apparatus with magnetic
stirrer, a solution of 11-bromo undecanol tetrahydropyranyl ether
(25 g, 74 mmol) in anhydrous THF (150 ml) was added dropwise to
iodine-activated magnesium (1.9 g). The mixture was kept at room
temperature overnight and then was cooled to -30.degree. C. and
anhydrous cuprous chloride (0.3 g) was added quickly. After 45 min
of stirring at this temperature, commercial
4,6-androstadien-17.beta.-ol-3-one acetate (1) (10 g, 30.5 mmol) in
anhydrous THF (100 ml) was added dropwise during 4 h. After 35 min,
acetic acid (6 ml) and water (100 ml) was added. The mixture was
allowed to reach room temperature and was stirred overnight.
Afterwards, the organic compound was extracted with ether (3X). The
organic layers were washed with water, dried on magnesium sulfate
and evaporated. The residue was dissolved in acetic acid (35 ml)
and water (100 ml) and kept 48 h at room temperature. And then, the
organic compounds were extracted with ether (3X). The organic
layers were washed with saturated sodium bicarbonate solution and
water, dried on magnesium sulfate and evaporated. The product was
purified by Silica gel dry column chromatography (Kieselgel,
60F254, Merk, 0.063-0.200 mm, 150 g). Elution with a mixture of
methylene chloride and ethyl acetate (20:1 v/v) gave
17.beta.-acetoxy-7.alpha.-(11'-hydroxy-undecanyl)-4-androsten-3-one
(2a, 1.46 g, 2.8 mmol, 9.2%) as a colorless oil; IR .nu..sub.max
neat 3450, 1740, 1685, 1620 and 1245 cm.sup.-1 ; NMR 0.84 (s, 3H,
18'--CH.sub.3), 1.21 (s, 3H, 19'--CH.sub.3) 2.05 (s,3H,
OCOCH.sub.3), 3.61 (t, 2H, J=6.59 Hz, H-C.1'), 4.61 (t, 1H, J=7.69
Hz, H-C.17) and 5.73 (s, 1H, H-C.4) and
17.beta.-acetoxy-7.beta.-(11'-hydroxy undecanyl)-4-androsten-3-one
(2b, 0.9 g, 1.7 mmol, 5.6%) as a colorless oil.
11-(17'.beta.-acetoxy-4'-androsten-3'-androsten-3'-on-7'.alpha.-yl)
undecanoic acid (3)
To 17.beta.-acetoxy-7.alpha.-(11'-hydroxy
undecanyl)-4-androsten-3-one (2a, 800 mg, 1.6 mmol) dissolved in
acetone (50 ml) and cooled to 0.degree. C. was added under stirring
during 5 min, a solution of Jones' reagent (8N chromic acid
solution) (0.283 ml). After 15 min, isopropanol (0.5 ml) was added
followed by water and the mixture was extracted with ethyl acetate
(3X). The organic layers were washed with brine, dried on magnesium
sulfate and evaporated to dryness under reduced pressure. The crude
11-(17'.beta.-acetoxy-4'-androsten-3'-on-7'.alpha.-yl) undecanoic
acid (3) (740 mg) was used in the next step without
purification.
N-butyl,
N-methyl-11-(17'.beta.-acetoxy-4'-androsten-3'-on-7'.alpha.-yl)
undecanamide (4)
To a solution of the above undecanoic acid derivative 3 (390 mg,
0.78 mmol) in anhydrous methylene chloride (8 ml) cooled at
-10.degree. C. was added, under stirring, triisobutylamine (240
.mu.l) and isobutylchloroformate (140 .mu.l). After 30 min,
N-methylbutylamine (1.8 ml was was added and the mixture was
stirred at room temperature for 1 h. Methylene chloride was added.
The organic solution was washed with 1N hydrochloric acid, water,
saturated sodium bicarbonate solution and finally with water, dried
on magnesium sulfate and evaporated to dryness. The residue was
chromatographed on silica gel (Kieselgel, 60F254, Merck,
0.063-0.200 mm, 20 g). Elution with a mixture of diethyl ether and
methylene chloride (1:20, v/v) gave N-butyl,
N-methyl-11-(17'.beta.-acetoxy-4'-androsten-3'-on-7'.alpha.-yl)
undecanamide 4 (230 mg, 0.39 mmol, 46% for the alcohol (2a)) as a
colorless oil; IR .nu..sub.max neat 1740, 1680, 1640 and 1240
cm.sup.-1 ; NMR 0.84 (s, 3H, 18'--CH.sub.3), 0.95 (t, 3H, J=6.93
Hz, N--(CH.sub.2).sub.3 CH.sub.3), 1.21 (s, 3H, 19'--CH.sub.3),
2.04 (s, 3H, OCOCH.sub.3), 2.91 and 2.97 (2s, 3H, N--CH.sub.3),
3.26 and 3.36 (2t, 2H, J=7.86 Hz, N--CH.sub.2 C.sub.3 H.sub. 7),
4.61 (t, 1H, J=8.42 Hz, H--C.17') and 5.72 (s, 1H, H--C.4').
N-butyl,
N-methyl-11-(17'.beta.-hydroxy-4'-androsten-3'-on-7'.alpha.-yl)
undecanamide (5) (EM 101)
The above acetoxy amide 4 (170 mg, 0.29 mmol) was dissolved in
methanol (20 ml) and 6% potassium carbonate (2 ml) and heated at
65.degree. C. for 200 min. After cooling, acetic acid (1 ml) and
water (150 ml) were added and the mixture was extracted with ethyl
acetate (3.times.). The organic layers were washed with water,
dried on magnesium sulfate and evaporated to dryness. The residue
was purified by Silica gel dry column chromatography (Kieselgel,
60F254, Merk, 0.063-0.200 mm, 20 g). Elution with a mixture of
diethyl ether and methylene chloride (1:9, v/v) gave
N-butyl-N-methyl-11-(17'.beta.-hydroxy-4'-androsten-3'-on-7'.alpha.-yl)
undecanamide (EM 101, 94 mg, 0.17 mmol, 58%) as a colorless oil; IR
.nu..sub.max (neat) 3400, 1670 and 1640 cm.sup.-1 ; NMR 0.80 (s,
3H, 18'--CH.sub.3), 0.95 (t,3H, J=6.75 Hz, N--(CH.sub.2).sub.3
CH.sub.3), 1.21 (s, 3H, 19'--CH.sub.3), 2.91 and 2.97 (2s, 3H,
N--CH.sub.3), 3.25 and 3.35 (2t, 2H, J=7.3 Hz, N--CH.sub.2 C.sub.3
H.sub.7), 3.67 (t, 1H, J=8.18, H--C.17') and 5.72 (s, 1H, H--C.4').
##STR8##
Sex steroid formation inhibitors useful in the combination therapy
of the invention include but are not limited to inhibitors of
5.alpha.-reductase activity, inhibitors of 17.beta.-hydroxysteroid
dehydrogenase activity, inhibitors of 3.beta.-hydroxysteriod
dehydrogenase activity and inhibitors of aromatase activity.
A typically suitable 5.alpha.-reductase inhibitor is MK-906, a
product of Merck, Sharp & Dohme (Mc Connell et al., J. Urol.
141: 239A, 1989). Another inhibitor of 5.alpha.-reductase is
17.beta.-N,N-diethylcarbamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one
(4-MA) (Brooks et al., Endocrinology 109: 830, 1981; Liang et al.,
Endocrinology 112: 1460, 1983). Other 4-azasteroids acting as
5.alpha.-reductase inhibitors can be formed in Liang et al., J.
Biol. chem. 259: 734-739, 1984; and in Brooks et al., Steroids 47:
1-19, 1986, 6-methylene-4-pregnene-3,20-dione has also been
described as 5.alpha.-reductase inhibitor (Petrow et al., J.
Endocrinol. 95: 311-313, 1982). Similar properties have been
described for 4-methyl-3-oxo-4-aza-5.alpha.-pregnane-30(s)
carboxylate (Kadohama et al., J. Natl. Cancer Inst. 74: 475-486,
1985).
Trilostane and epostane have been described as inhibitors of
3.beta.-hydroxysteroid dehydrogenase activity (Ernshaw et al.,
Clin. Endocrinol. 21, 13-21, 1984; Robinson et al., J. Steroid
Biochem. 21, 601-605, 1984; Lambert et al., Ann. Clin. Biochem. 23,
225-229, 1986; Potts et al., Steroids 32, 257-267, 1978) and have
been successfully used for the treatment of breast cancer in
combination with corticosteroids (Beardwell et al., Cancer
Chemother. Pharmacol. 10: 158-160, 1983; Williams et al., Cancer
Treat. Rep. 71, 1197-1201, 1987).
4-MA,
(17.beta.-N,N-diethylcarbamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one)
has been found to inhibit 3.beta.-hydroxysteroid dehydrogenase
activity in granulosa cells (Chan et al., Biochem. Biophys. Res.
Commun. 144, 166-171, 1987). Epostane has been shown to inhibit
3.beta.-hydroxysteroid dehydrogenase activity in pregnant goats
(Taylor, J. Endocrinol. 113, 489-493, 1987).
Preferred inhibitors of 17.beta.-hydroxysteroid dehydrogenase
activity include but are not limited to:
N-butyl, N-methyl-11-(16'.alpha.-chloro-3',17'.beta.-dihydroxy
estra-1',3',5'(10')-trien-7'.alpha.-yl) undecanamide ("EM 139").
##STR9##
N-n-butyl-N-methyl-11-(16'.alpha.-chloro-3',17'.alpha.-dihydroxy-estra-1',3
',5'(10')-trien-7'.alpha.-yl) undecanamide ("EM 170") ##STR10##
N-n-butyl-N-methyl-11-(16'.alpha.-bromo-3',17'.alpha.-dihydroxy-estra-1',3'
,5'(10')-trien-7'.alpha.-yl) undecanamide ("EM 171") ##STR11##
Examples of certain synthesis schemes for EM 139, EM 170 and EM 171
are set forth below (see example 2 and schemes 2 and 3). Those of
skill in the art will recognize analogous schemes for synthesizing
analogous compounds.
EXAMPLE 2
Synthesis of Preferred Sex Steroid Activity Inhibitors
Synthesis of a starting compound, N-n-butyl,
N-methyl-11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')
-trien-7'.alpha.-yl)undecanamide (14a) (SCHEME 2)
19-nor-testosterone acetate 3-enolacetate (7)
In an apparatus supplied with a drierite drying tube, a solution of
19-nor-testosterone (6) (100 g; 0.365 mole) in acetic anhydride
(200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated
at reflux under magnetic stirring, for 3 h and then concentrated to
dryness under vacuum. The dry residue was triturated in absolute
ethanol, filtered and washed with little portions of absolute
ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate
was obtained as a white powder (121.4 g, yield 93%) mp.
176.degree.-177.degree. C. The structure was confirmed by
spectroscopic means.
17.beta.-acetoxy-estra-4,6-dien-3-one (8)
To a cooled suspension of enolacetate (121 g; 0.337 mole) in a
mixture of DMF (330 ml) and water (7.2 ml) at 0.degree. C. was
added, under nitrogen, over a period of 1 h, N-bromosuccinimide (63
g). The resulting solution was stirred for an additional 0.5 h at
0.degree. C. Then lithium carbonate (60.8 g) and lithium bromide
(30.4 g) were added. The mixture was heated at 95.degree. C. for 3
h and then poured into 1.7 of ice-cold water containing 165 ml of
glacial acetic acid. After stirring during 15 hours, the crude
17.beta.-acetoxy-estra-4,6-dien-3-one (8) was filtered, washed with
water, dried in a desiccating apparatus and recrystallized twice
from isopropyl ether (72 g, yield 68%, mp 110.degree. C.). The
structure was confirmed by spectroscopic means.
7.alpha.-(11'-acetoxy-undecyl) 17.beta.-acetoxy estra-4-en-3-one
(9)
A. Preparation of reagents and solvents
11-bromo undecanol tetrahydro pyranyl ether
11-bromo-undecanol (100 g, 398 mmol) was dissolved in dry ether
(768 ml) and the solution was cooled to 0.degree. C. using an
ice/H.sub.2 O bath. To this solution was added HCl gas (2.13 g,
58.4 mmol, 26 ml of HCl/ether).
To this mixture, a solution of 3,4-dihydro-2H-pyran (39.9 g, 43.3
ml) freshly distilled in dry ether (218 ml) was added over a period
of 90 min. The solution was then stirred over a period of 16 hours
at room temperature. Afterwards, sodium bicarbonate was added to
the mixture. The residue was filtered and the solvent was
evaporated under vacuum.
The product was then filtered through basic alumina (250 g, Woelm,
grade II) using petroleum ether (30-60) as solvent (112 g,
81%).
B. Grignard reagent
In a dry three-neck flask (1000 ml) under dry argon, magnesium
(12.0 g, 494 mmol) was placed and activated with iodine. Magnesium
was heated with the flame to remove iodine and to dry the
apparatus. The system was then cooled to -20.degree. C., and a
solution of 11-bromo-undecanol tetrahydro pyranyl ether (73.8 g,
211 mmol) in dry THF (420 ml) was added dropwise. The mixture was
stirred under dry argon during one day at -20.degree. C.
The mixture was cooled to -35.degree. C. (.+-.2.degree. C.) using a
dry ice/CCL.sub.4 /acetone bath. The anhydrous cuprous chloride
(1.18 g, 12 mmol) was added and the mixture was stirred over a
period of 0.5 h.
C. Addition of Grignard reagent
After 0.5 h, using the same apparatus mentioned above (Ar,
-35.degree. C.), a solution of 17 .beta.-acetoxy
estra-4,6-diene-3-one (8) (32.0 g, 102 mmol) in dry THF (300 ml)
was added dropwise over a period of 6 h to the Grignard reagent
(red coloration appeared and disappeared). The mixture was stirred
for an additional 1 h and, after removal the cooling bath,
acidified (about 0.degree. C.) with acetic acid (40 ml), diluted
with water and extracted with ether (3.times.). The ether solution
was washed with a saturate sodium bicarbonate solution and water.
The organic layer was dried over anhydrous magnesium sulfate and
evaporated under reduced pressure to dryness.
The residue was dissolved in MeOH (660 ml) and 5N HCl (180 ml),
refluxed for 1 h and 45 min, then concentrated under reduced
pressure and cooled in an ice bath. The mixture was then filtered
to remove the white precipitate. After the solution had been
diluted with water and extracted with methylene chloride
(3.times.), the organic layer was dried over anhydrous MgSO.sub.4
and evaporated under reduced pressure to dryness. Finally, the
product (55.9 g, brown oil) was chromatographed on silica gel
(Kieselgel 60F254, Merck, 0.063-0.200 mm, 1500 g). Elution with
mixtures of methylene chloride and ethyl acetate (4:1 to 1:2 v/v)
and then pure ethyl acetate gave crude
7.alpha.-(11'-hydroxy-undecyl)-17.beta.-hydroxy estra-4-en-3-one
(34.8 g) which was dissolved in dry pyridine (200 ml) and dry
acetic anhydride (200 ml), stirred 17 h at room temperature and
then poured in ice-water. The product was extracted with methylene
chloride (3.times. ), washed with 1N hydrochloric acid, water,
saturated sodium bicarbonate and water (3.times.), dried on
anhydrous magnesium sulfate and filtered. After evaporation of
solvent, the mixture (35 g) of 7.alpha.- and
7.beta.-diacetoxyenones and degradation products of Grignard
reagent were separated by flash chromatography on silica gel
(Kieselgel 60, Merck, 230 mesh ASTM, 2.0 ) developed with a mixture
of hexane and diethyl ether (2:3 v/v). The first product eluted was
pure amorphous 7.alpha.-(11'-acetoxy undecyl)
17.beta.-acetoxy-estra-4-en-3-one, (9) (20.8 g, 39.4 mmol, yield
from dienone was 39.0%). Further elution gave the 7.beta.-isomer
(10) (5.4 g, 10.3 mmol, 10%). All structures were determined by
spectroscopic means.
7.alpha.-(11'-hydroxy-undecyl)
estra-1,3,5(10)-trien-3,17.beta.-diol (11a)
Under dry argon, a solution of 7.alpha.-(11'-acetoxy undecyl)
17.beta.-acetoxy-estra-4-en-3-one (9) (17.0 g, 32.4 mmol) in dry
acetonitrile (150 ml) was added rapidly to a suspension of cupric
bromide (14.8 g, 66.2 mmol) and mmol) and lithium bromide (2.89 g,
33.6 mmol) in warm acetonitrile (75 ml). The mixture was heated to
reflux over a period of 30 min and stirred vigorously, and then
cooled to room temperature. A saturated aqueous solution of sodium
bicarbonate (50 ml) was added, and then the organic compound was
extracted with ethyl acetate (3.times.150 ml). The organic layers
were washed with water, dried over anhydrous magnesium sulfate,
filtered and evaporated under vacuum to dryness. The residue was
chromatographed on silica gel (Kieselgel 60F254 Merck 0.063-0.200
mm; 1000 g). Elution with hexane-ethyl acetate (1:1 v/v) gave the
7.alpha.-(11'-acetoxy-undecyl)
estra-1',3',5'(10')-trien-3,17.beta.-diol, 17.beta.-acetate (11b)
(8.51 g; 50.3%) and the starting product (1.33 g; 15%).
The above diacetate phenol (8.51 g, 16.2 mmol) was dissolved in
methanol (90 ml) and sodium hydroxyde 30% (w/v) (9 ml). The mixture
was refluxed for 90 min under dry nitrogen. The solution was then
concentrated under vacuum and diluted with hydrochloric acid (10%
v/v). The mixture was extracted using ethyl acetate (4.times.150
ml) and the ethyl acetate extract was washed with water, dried over
anhydrous magnesium sulfate, filtered and evaporated under vacuum.
The evaporation gave 7.beta.-(11'-hydroxy undecyl)
estra-1,3,5(10)-trien-3,17.beta.-diol (11a) (6.99 g, 98% brut) as a
yellow foam, the structure of which was confirmed by spectroscopic
means.
3-benzoyloxy 7.alpha.-(11'-hydroxy undecyl)
estra-1,3,5(10)-trien-17.beta.-ol (12)
The above triol (6.99 g; 15.8 mmol) was dissolved in acetone (25
ml) and an aqueous solution of sodium hydroxyde (1N, 19.1 ml). The
mixture was cooled to 0.degree. C. using an ice/water bath. Benzoyl
chloride (2.22 ml, 19.1 mmol) was then added dropwise. The mixture
was stirred for 40 min at 0.degree. C. and then diluted with water.
The solution was extracted using ethyl acetate (3X) and the organic
layers were washed with a saturated aqueous solution of sodium
bicarbonate and finally with water. The ethyl acetate solution was
dried over anhydrous magnesium sulfate, filtered and evaporated
under vacuum to dryness. Then, the residue was immediately
chromatographed on silica gel (Kieselgel, 60F254, 0.063-0.200 mm;
500 g). The chromatography was carried out, first, using methylene
chloride as solvent (about 1 liter) and secondly the pure
3-benzoyloxy 7.alpha.-(11'-hydroxy undecyl)
estra-1,3,5(10)-trien-17.beta.-ol (12), colorless oil (6.50 g, 75%)
was eluted with methylene chloride-ethyl acetate (5:1 about 1 liter
and 4:1; v/v). The structure was confirmed by spectroscopic
means.
11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)
undecanoic acid (13)
To a cooled solution of 3-benzoyloxy-7.alpha.-(11'-hydroxy
undecyl)estra-1,3,5(10)-trien-17.beta.-ol (12) (4.3 g) in acetone
(100 ml) was added dropwise Jone's reagent (8N-chromic acid
solution, 6.7 ml). After 30 min, isopropanol (40 ml) was added and
the mixture was concentrated under vacuo. Water was added and the
mixture was extracted four times with ethyl acetate. The organic
layers were washed twice with brine, dried over magnesium sulfate
and evaporated to dryness. The crude
11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)
undecanoic acid (13) (3.94 g) was used in the next step without
purification. ##STR12##
N-n-butyl,
n-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)
undecanamide (14b)
To
11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)
undecanoic acid (13) (3.94 g, 7.22 mmol), dissolved in anhydrous
CH.sub.2 Cl.sub.2 (100 ml) and cooled at -10.degree. C. was added
tributylamine (2.18 ml, 9.15 mmol) and isobutylchloroformate (1.30
ml, 10.0 mmol). The solution was stirred during 35 min. and
N-methylbutylamine (13 ml, 109.7 mmol) was added. The mixture was
warmed to room temperature and stirred during 1 h. Afterward,
CH.sub.2 Cl.sub.2 was added and the organic phase was washed with
1N HCl water, saturated sodium bicarbonate solution and finally
with water, dried with anhydrous MgSO.sub.4 and the solvent was
removed under reduced pressure. The residue was purified by
chromatography on silica gel. Elution with mixture of EtOAc/hexane
(1.5:8.5 v/v) yielded N-butyl,
N-methyl-11-(3'-benzoyloxy-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)
undecanamide (14a) (4.25 g, 96%) as colorless oil; IR .nu.(neat)
1750, 1725 and 1640 cm.sup.-1. The above described benzoyloxy amide
(341 mg, 0.54 mmol) was dissolved in methanol (10 ml) and cooled at
0.degree. C. Following this 2N NaOH (5 ml) was added and the
mixture was stirred during 60 min. at 0.degree. C. The solution was
neutralized with 1N HCl and extracted with CH.sub.2 Cl.sub.2. The
organic phase was dried with anhydrous MgSO.sub.4 and the solvent
was removed under reduced pressure. The residue was purified by
chromatography on silica gel. Elution with mixture of EtOAc/hexane
(3:7 v/v) yielded N-butyl,
N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',
4'(10')-trien-7'.alpha.-yl) undecanamide (14b) (284 mg, 97%) as
colorless oil; .sup.1 H-NMR .delta.(CDCl.sub.3) 0.91
(s,3H,18'--CH.sub.3), 2.76 app(d,1HJ=16,3 Hz, part of ABX system,
6'-H) 2.96 and 2.98 (2s,3H N--CH.sub.3), 3.27 and 3.38
(2t.sub.app,2H,J=7.5 Hz,N--CH.sub.2 --), 6.63 (broad s,1H,4'-H),
6.70 (broad d,1H,J=8.5 Hz, 2'-H), 7.12 (d,1H,J=8.4 Hz,1'-H); IR
.nu..sub.max (neat) 3270, 1730, 1615 cm.sup.-1 ; MS m/e 523
(M.sup.+,100%), 508 (M.sup.+ --CH.sub.3,32%), 142 (C.sub.2 H.sub.4
CON(CH.sub.3)C.sub.4 H.sub.9.sup.+, 47%).
16-Halo-Estradiol Undecanamide (Scheme 3)
N-n-butyl,
N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10'),16'-tetraen-7'.alpha.-yl
) undecanamide (15)
The ketone amide 14 b (163 mg, 0.50 mmol) was dissolved in
isoprenyl acetate (10 ml). p-toluenesulfonic acid (44 mg) was then
added and the solution was distilled to about two-thirds of the
original volume in 7 h and was then stirred at reflux for 12 h.
Afterwards, the solution was cooled with an ice-water bath and
extracted with 50 ml of cooled ether. The ether was washed with a
cooled satured sodium bicarbonate and water. The organic phase was
dried with anhydrous MgSO.sub.4 and the solvent was removed under
reduced pressure. The residue was filtered through alumina (15
mm.times.50 mm alumina Woehlm neutral, activity II) using a mixture
of benzene-diethyl ether (3:7 v/v) as eluant. The solvent was
removed under reduced pressure and, the residue was purified by
flash chromatography on silica gel. Elution with mixture of
EtOAc/hexane (1:4 v/v) yielded the N-butyl,
N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10'),
16'-tetraen-7'.alpha.-yl) undecanamide (15) (244 mg, 80%) as
colorless oil; .sup.1 H-NMR .delta..sub.m (CDCl.sub.3) 0.92
(s,3H,18'-CH.sub.3), 0.92 and 0.95 (2t,3H,J=7.0
Hz,N(CH.sub.2).sub.3 CH.sub.3), 2.18 (s,3H,17'-OCOCH.sub.3),
2.28(s,3H,3'OCOCH.sub.3), 2.76 app (d,1H,J=16.1 Hz, part of ABX
system,6'-H), 2.90 and 2.96 (2s,3H,N-CH.sub.3), 3.26 and 3.35
(2t.sub.app,2H,J=7.6 Hz,N-CH.sub.2 -), 5.52 (m,1H,16'-H), 6.80
(broad s,1H,4'-H), 6.85 (dd,1H,J.sub.1 =9.1 Hz and J.sub.2 =3.0
Hz,2'-H), 7.27 (d,1H,J=9.1 Hz,1'-H); IR.nu..sub.max (neat) 1750,
1635, 1200 cm-.sup.1 ; MS m/e 607 (M.sup.+,2 %), 5(M.sup.+
--COCH.sub.2,100%), 550 (M.sup.+ --COCH.sub.2 --CH.sub.3,13%), 523
(M.sup.+ --2COCH.sub.2,45%), 142 (C.sub.2 H.sub.4
CON(CH.sub.3)C.sub.4 H.sub.9.sup.+,55%), 129 (C.sub.4 H.sub.9
(CH.sub.3)NCOCH.sub.3.sup.+,38%), 114 (C.sub.4 H.sub.9
(CH.sub.3)NCO.sup.+, 60%), 86 (C.sub.4 H.sub.9 (CH.sub.3)N.sup.+,
25%); EXACT MASS calcd for C.sub.38 H.sub.57 O.sub.5 N 607.4239,
found 607.4234.
N-butyl,
N-methyl-11-(16'.alpha.-chloro-3'acetoxy-17'-oxo-estra-1',3',4'(10')-trien
-7'.alpha.-yl) undecanamide (16, X.dbd.Cl)
To diacetate amide 15, dissolved in 5 ml of acetone, was added a
solution of sodium acetate (2.6 equivalents) in acetic acid and
water (1:11.3 v/v) and then, was treated with tertbutyl
hypochlorite (1 eq.) prepared from t-butanol (4 ml) and Javel water
(Javex 6.1%, 50 ml). The clear solution was warmed to 55.degree. C.
and stirred for 1 h. Afterwards, the solvent was evaporated to
dryness. The residue was dissolved in ether (100 ml) and water was
added (20 ml). The organic phase was washed with water, dried with
anhydrous MgSO.sub.4 and evaporated to dryness. The residue was
purified by chromatography on silica gel carried out with mixture
of EtOAc/hexane (3:7 v/v) to give the N-butyl,
N-methyl-11-(16'.alpha.-chloro-3'-acetoxy-17'-oxo-estra-1',3',4'(10')-trie
n-7'.alpha.-yl) undecanamide 16, X.dbd.Cl) (115 mg, 89%) as
colorless oil; .sup.1 H-NMR .nu. (CDCl.sub.3) 0.92 and 0.95
(2t,3H,J=7.0 Hz,N(CH.sub.2).sub.3 CH.sub.3), 0.96
(s,3H,18'--CH.sub.3), 2.28 (s,3H,3'--OCOCH.sub.3), 2.80 app
(d,1H,J=16,6 Hz, part of ABX system, 6'-H) 2.90 and 2.96 (2s,3H,
N--CH.sub.3), 3.24 and 3.35 (2t.sub.app,2H,J=7.4 Hz, --N--CH.sub.2
--), 4.46 (d,1H,J=6.6 Hz,16'.beta.-H), 6.82 (broad s,1H, 4'-H),
6.86 (dd,1H,J=9.1 Hz and J.sub.2 =,2.6 Hz,2'-H), 7.29 (d,1H,J=9.1
Hz,1'-H); IR .nu..sub.max (neat) 1750, 1640, 1205 cm.sup.-1 ; MS
m/e 601, 599 (M.sup.+,24%, 68%), 142 (C.sub.2 H.sub.4
CON(CH.sub.3)C.sub.4 H.sub. 9.sup.+, 100%), 114 (C.sub.4 H.sub.9
(CH.sub.3)NCO.sup.+,93%).
N-butyl,
N-methyl-11-(16.alpha.-chloro-3',17'-dihdroxy-estra-1',3',5'(10')-trien-7'
.alpha.-yl) undecanamide ("EM 139") and ("EM 170")
A stirred solution of haloketone amide (16, X.dbd.Cl) in anhydrous
tetrahydrofuran (THF) (10 ml) under argon was chilled to
-70.degree. C. with 2-propanol/dry ice bath. A solution of 1.0M of
lithium aluminium hybride (2 eq.) was then added dropwise. After 30
min, the reaction was allowed to return slowly at 0.degree. C. for
5 min, then was quenched by the dropwise addition of a mixture of
THF-EtOAc (5 ml) (1:1 v/v) and acidified at pH.about.4 with (10%)
HCl. The mixture was stirring for 5 min at room temperature and
then extracted with EtOAc. The organic phase was washed with water,
dried on anhydrous Na.sub.2 SO.sub.4 and evaporated under reduced
pressure. The residue was chromatographed on silica gel with a
mixture of EtoOAc/hexane (4:6 v/v) as eluant:
N-butyl,
N-methyl-11-(16'.alpha.-chloro-3'17'.alpha.-dihydroxy-estra-1',3',5'(10')-
trien-7'.alpha.-yl) undecanamide ("EM 170")
(15 mg, 29%) as colorless oil; analytical sample was obtained by
HPLC purification; .sup.1 H-NMR .delta.(CDCl.sub.3, 400 MHz) 0.79
(s,3H,18'--CH.sub.3), 0.93 and 0.96 (2t, 3H,J=7.3
Hz,N(CH.sub.2).sub.3 CH.sub.3), 2.80 (2H,J.sub.6,6 =17.1 Hz and
J.sub.6,7 =4.5 Hz, .DELTA..delta.=24.34 Hz, system ABX, 6'-H), 2.94
and 2.99 (2s, 3H,N--CH.sub.3), 3.26 (dd,J.sub.1 =7.6 Hz and J.sub.2
=7.4 Hz) and 3.32-3.43 (m)--[2H,--N--CH.sub.2 --], 3.71 (d,1H,J=4.5
Hz,17'.beta.-H), 4.63 (ddd, 1H, J.sub.16,15 =10.2 Hz, J.sub.16,17
=4.5 Hz and J.sub.16,15 3.9 Hz, 16'.beta.-H), 6.50 (d, 1H, j=24 Hz,
3' -OH), 6.60 (d, 1H,J=2.5 Hz, 4'-H), 6.66 (dd,1H,J.sub.1 =8.4 Hz
and J.sub.2 =2.5 Hz, 2'-H), 7.14 (d,1H,J=8.5 Hz, 1'-H); IR
.nu..sub.max (neat) 3300, 1615, 1495 cm.sup.-1 ; MS m/e 561,559
(M.sup.+, 40%, 100%), 523 (M.sup.+ -HCl, 20%), 142 (C.sub.2 H.sub.4
CON(CH.sub.3)C.sub.4 H.sub.9.sup.+, 44%), 114 (C.sub.4 H.sub.9
(CH.sub.3)CNO.sup.+, 37%); Exact mass calculated for C.sub.34
H.sub.54 O.sub.3 N.sup.35 Cl 559.3785, found 559.3821; and
-N-butyl,
N-methyl-11-(16'.alpha.-chloro-3',17'.beta.-dihydroxy-estra-1'3',5'(10')-t
rien-7'.alpha.-yl) undecanamide ("EM 139")
(25 mg, 55%) as a colorless oil; analytical sample was obtained by
HPLC purification; 1H-NMR .delta.(CDCl.sub.3, 400 MHz), 0.81 (s,3H,
18'---CH.sub.3), 0.93 and 0.96 (2t, 3H,J=7.3 Hz, (CH.sub.2).sub.3
CH.sub.3), 2.78 (2H, J.sub.6,6 =16.2 Hz and J.sub.6,7 =4.5 Hz,
.DELTA..sup.5 =24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2s,
3H,N-CH.sub.3), 3.27 (dd, J.sub.1 =7.6 Hz and J.sub.2 =7.5 Hz) and
3.31-3.45 (M)[2H, --N--CH.sub.2 --], 3.86 (dd, 1H, J.sub.17,17
-.sub.OH =3.4 Hz and J.sub.17,16 =5.9 Hz, 17'.alpha.-H), 4.11 (ddd,
1H, J.sub.16,15 =10.8 Hz, J.sub.16,17 =5.9 Hz and 4.11 (ddd, 1H,
J.sub. 16,15 =10.8 Hz, J.sub.16,17 =5.9 Hz and J.sub.16,15 =2.5 Hz,
16'.beta.-H), 6.56 (d, 1H, J=19.7 Hz, 3'--OH), 6.61 (d, 1H, J=2.5
Hz, 4'-H), 6.66 (dd, 1H, J.sub.1 =8.4 Hz and J.sub.2 =2.6 Hz,
2'-H), 7.13 (d, 1H, J=8.4 Hz, 1'-H); IR .nu..sub.max (neat) 3320,
1615, 1490 cm.sup.-1 ; MS m/e 561,559 (M.sup.+, 38%, 100%), 523
(M.sup.+ -HCl, 16%), 142 (C.sub.2 H.sub.4 CON(CH.sub.3)C.sub.4
H.sub.9.sup.+, 80%), 114 (C.sub.4 H.sub.9 (CH.sub.3)NCO.sup.+,76%);
exact mass calculated for C.sub.34 H.sub.54 O.sub.3 N.sup.35 Cl
559.3785, found 559.3825. ##STR13##
N-n-butyl,
N-methyl-11-(16'.alpha.-bromo-3'-acetoxy-17'-oxo-estra-1',3',5'-(10'),trie
n-7'.alpha.-yl) undecanamide (16, X.dbd.Br)
To the above diacetate 15 (244 mg, 0.40 mmol) dissolved in 10 ml of
acetic acid was added dropwise with stirring within 10 minutes and
at room temperature, a brominating solution composed of 50 mg (0.6
mmol) of sodium acetate, 1.6 ml of acetic acid, 0.04 ml of water
and 63.9 mg (0.02 ml, 0.40 mmol) of bromine. During the course of
this reaction, a red coloration appeared and disappeared. To the
solution, 50 ml of ether was added and the organic phase was washed
with water (4.times.50 ml) followed by a saturated sodium
bicarbonate solution (2.times.50 ml) and finally with water
(3.times.50 ml). The combined phase was dried over anhydrous
magnesium sulfate and the solvent was removed in vacuo. The residue
was chromatographed on silica gel (Kieselgel, 60F254, Merck,
0.063-0.200 mm). Elution with a mixture of hexane-ethyl acetate
(4:1 v/v) yielded N-butyl,
N-methyl-11-(16.alpha.-bromo-3'-acetoxy-17'-oxo-estra-
1',3',5'(10'),trien-7'-.alpha.-yl) undecanamide (16, X.dbd.Br) (201
mg, 78%) as colorless oil (201 mg, 78%), as colorless oil; .sup.1
H-NMR o (CDCl.sub.3), 0.94 (s, 3H,18'--CH.sub.3), 2.28 (s, 3H,
3'--OCOCH.sub.3), 2.82 app (d,1H,J=16.4 Hz, part of ABX system,
6'-H), 2.90 and 2.96 (2s, 3H,N--CH.sub.3), 3.24 and 3.35
(2t.sub.app, 2H, J=7.7 Hz, --N--CH.sub.2 --), 4.58 (t,1H,J=3.6 Hz,
16.beta.-H), 6.82 (broad s,1H,4'-H), 6.88 (dd,1H, J=8.0 Hz and
J.sub.2 =4.0 Hz,2'-H), 7.29 (d,1H,J=8.0 Hz, 1'-H); MS m/e 644
(M.sup.+,7 %), 565 (M.sup.+ --Br, 77%), 522 (M.sup.+
--Br--COCH.sub.2, 55%), 142 (C.sub.2 H.sub.4 CON(CH.sub.3)C.sub.4
H.sub.9.sup.+, 67%), 114 (C.sub.4 H.sub.9 (CH.sub.3)NCO.sup.+,
66%), 88 (100%).
N-butyl,
N-methyl-11-(16'.alpha.-bromo-3',17'-dihydroxy-estra-1',3,4'(10')-trien-7'
.alpha.-yl) undecanamide ("EM 105") and ("EM 171")
A solution of bromoketone amide 16 (X.dbd.Br) (295 mg, 0.46 mmol)
in anhydrous tetrahydrofuran (10 ml) under argon was chilled to
-70.degree. C. and a solution of 1.0M of lithium aluminium hybride
in ether (0.92 ml, 0.92 mmol) was added dropwise with rapid
magnetic stirring. After 30 min, the reaction was quenched by the
dropwise addition of a mixture of THF-ethyl acetate (1:1 v/v) and
acidified by 10% hydrochloric acid. The mixture was stirring for 5
min at room temperature and then extracted with ethyl acetate. The
organic phase was washed with water, dried on anhydrous sodium
sulfate and evaporated to dryness under reduced pressure. The
residue was purified by chromatography on silica gel. Elution with
a mixture of hexane-ethyl acetate (7:3 v/v) gave:
N-n-butyl,
N-methyl-11-(16'.alpha.-bromo-3',17'.alpha.-dihydroxy-estra-1',3',5'(10')-
trien-7'.alpha.-yl) undecanamide ("EM 171")
(63 mg, 21%) as colorless oil; .sup.1 H-NMR .delta.(CDCl.sub.3, 400
MHz) 0.81 (s, 3H, 18'--CH.sub.3), 0.93 and 0.96 (2t, 3H,J=7.3
Hz,N(CH.sub.2).sub.3 CH.sub.3), 2.79 (2H,J.sub.6,6 =16.6 Hz,
J.sub.6,7 =4.7 Hz, =.DELTA..delta.=24.34 Hz, system ABX, 6'-H),
2.94 and 2.99 (2s,3H,N--CH.sub.3), 3.27 (dd,2H,J.sub.1 =7.7 Hz and
J.sub.2 =7.5 Hz, --N--CH.sub.2 --), 3.31-3.44 (m,2H,--N--CH.sub.2
--), 3.66 (dd,1H,J.sub.17,17 =1.4 Hz, J.sub.17,16 =4,3 Hz,
17'.beta.-H), 4.68 (dt,1H,J.sub.16,17 =4,3 Hz, m, J.sub.16,15 =9.7
Hz, 16'.beta.-H), 6.60 (d,1H,J=2.4 Hz, 4'-H), 6.65 (dd, 1H,J=8.5 Hz
and J.sub.2 2.5 Hz, 2'-H), 7.14 (d,1H,J=8.5 Hz, 1'-H); IR
.nu..sub.max (neat) 3300, 1615, 1495 cm.sup.-1 ; MS m/e 605,603
(M.sup.+, 17%), 523 (M.sup.+ -HBr, 81%), 142 (C.sub.2 H.sub.4
CON(CH.sub.3)C.sub.4 H.sub.9.sup.+, 100%), 114 (C.sub.4 H.sub.9
(CH.sub.3)NCO.sup.+, 97%); Exact mass calculated for C.sub.34
H.sub.54 O.sub.3 N.sup.79 Br 603.8289, found 603.3304. N-n-butyl,
N-methyl-11-(16'.alpha.-bromo-3',17'.beta.-dihydroxy-estra-1',3',-5'(10')-
trien-7.alpha.-yl) undecanamide ("EM 105")
(170 mg, 50%) as a colorless oil; analytical sample was obtained by
HPLC purification; .sup.1 H-NMR .delta.(CDCl.sub.3, 400 MHz), 0.80
(s,3H,18,--CH.sub.3), 0.93 and 0.96 (2 t,3H,J=7.3
Hz,N(CH.sub.2).sub.3 CH.sub.3), 2.80 (2H,J.sub.6,6 =16.4,J.sub.6,7
=4.6 Hz, .DELTA..delta.=24.34 Hz, system ABX, 6'-H), 2.94 and 2.99
(2s,3H,N--CH.sub.3), 3.27 (dd, 2H,J.sub.1 =7.7 Hz and J.sub.2 =7.5
Hz, --N--CH.sub.2 --), 3.31-3.45 (m,2H,--N--CH.sub.2 --), 4.02
(dd,1H,J.sub.17,17 =3.7 Hz, and J.sub.17,16 =6.1 Hz, 17'.alpha.-H),
4.15 (ddd,1H,J.sub.16,15 =10.2 Hz, J.sub.16,17 =6.1 Hz and
J.sub.16,15 =2.9 Hz, 16'.beta.-H), 6.61 (d, 1H,J=2.5 Hz, 4'-H),
6.66 (dd,1H,J=8.4 Hz and J.sub.2 2.5 Hz, 2'-H), 7.12 (d,1H,J=8.4
Hz, 1'-H); IR .nu..sub.max (neat) 3320, 1610, 1490 cm.sup.-1 ; MS
m/e 605, 603 (M.sup.+, 29%), 523 (M.sup.+ -HBr, 100%), 142 (C.sub.2
H.sub.4 CON(CH.sub.3)C.sub.4 H.sub.9.sup.+, 70%), 114 (C.sub.4
H.sub.9 (CH.sub.3)NCO.sup.+, 60%); Exact mass calculated for
C.sub.34 H.sub.54 O.sub.3 N.sup.79 Br 603.3289, found 603.3289.
Antiestrogens useful in the combination therapy of the invention
include but are not limited to Tamoxifen, commercially available
from Imperial Chemical Industries, and EM 139, EM 170 and EM 171
whose synthesis are set forth above. Some steroidal antagonists
also function as inhibitors of sex steroid formation. The
antiestrogens EM 139, EM 170 and EM 171, for example, exhibit the
dual function of acting as sex steroid formation inhibitors. For
this reason, a combination therapy requiring both an inhibitor of
sex steroid formation and a steroidal antagonist may be produced by
administering a single active compound (alone or together with
diluent) capable of performing both functions. Another example of a
dual function active ingredient is the antiandrogen EM 101 which
has also shown an inhibitory effect on sex steroid formation.
The inhibitor of sex steroid biosynthesis is preferably capable of
acting at least in peripheral tissue (extra-testicular and
extra-adrenal). In preferred embodiments, it is used in association
with an antiandrogen, and with an LHRH agonist or LHRH antagonist.
The use of an LHRH agonist is the more preferred method of chemical
castration. Surgical castration may alternatively be used as a
means of inhibiting testicular hormonal secretions, but chemical
castration is preferred.
By the term "LHRH agonist" is meant synthetic analogues of the
natural luteinizing hormone-releasing hormone (LHRH), a decapeptide
of the structure:
L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-a
rginyl-L-prolylglycyl-NH.sub.2.
Typical suitable LHRH agonists include nonapeptides and
decapeptides represented by the formula:
L-pyroglutamyl-L-histidyl-L-trypyophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-p
rolyl-Z wherein X is D-tryptophyl, D-leucyl, D-alanyl,
iminobenzyl-D-histidyl, 3-(2-naphthyl)-D-alanyl,
O-terbutyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyl or
N-methyl-D-alanyl and Y is L-leucyl, D-leucyl, N.sup..alpha.
-methyl-D-leucyl, N.sup..alpha. -methyl-L-leucyl or D-alanyl and
wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein R.sub.1 is H,
lower alkyl or lower haloalkyl. Lower alkyl includes, for example,
methyl, ethyl, propyl, pentyl, hexyls, iso-butyl, neopentyl and the
like. Haloloweralkyl includes, for example, --CF--.sub.3,
--CH.sub.2 CF.sub.3, --CF.sub.2 CH.sub.3, and the like. Fluorine is
a preferred halogen.
Preferred nonapeptides wherein Y is L-leucyl and X is an optically
active D-form of selected amino acids and Z is NHC.sub.2 H.sub.5
are [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide
(X=D-Trp.sup.6); [D-Ser-t-BuO).sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH
ethylamide [X-D-Ser(t-BuO.sup.6)]; [D-Leu.sup.6,
des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide (X=D-Leu.sup.6,
[D-His(Bzl).sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide
(X=iminobenzyl-D-His.sup.6) and [D-Ala.sup.6,
des-Gly-NH.sub.2.sup.10 ]-LHRH ethylamide (X=D-Ala.sup.6).
Preferred decapeptides include [D-Trp.sup.6 ]LHRH wherein X=D-Trp,
Y=L-leucyl, Z=glycyl-NH.sub.2, [D-Phe.sup.6 ]-LHRH wherein
X=D-phenylalanyl, Y=L-leucyl and Z=glycyl-HN.sub.2) or
[D-Nal(2).sup.6 LHRH which is [.sup.93 -3-(2-naphthyl)-D-Ala.sup.6
]-LHRH wherein X=3(2-naphthyl)-D-alanyl, Y=L-leucyl and
Z=glycyl-NH.sub.2.
Other LHRH agonists useful within the scope of this invention are
the .alpha.-aza analogues of the natural LHRH, especially,
[D-Phe.sup.6, Azgly.sup.10 ]LHRH, [D-Tyr(--Me).sup.6, Azgly.sup.10
]LHRH, and [D-Ser-(t-BuO).sup.6, Azgly.sup.10 ]LHRH disclosed by A.
S. Dutta et al. in J. Med. Chem., 21, 1018 (1978) and U.S. Pat. No.
4,100,274 as well as those disclosed in U.S. Pat. Nos. 4,024,248
and 4,118,483.
Typical suitable LHRH antagonists include
[N-Ac-D-p-Cl-Phe.sup.1,.sup.2, D-Phe.sup.3, D-Arg.sup.6,
D-Ala.sup.10 ]-LHRH disclosed by J. Ercheggi et al., Biochem.
Biophys. Res. Commun. 100, 915-920 (1981);
[N-Ac-D-p-Cl-Phe.sup.1,.sup.2, D-Trp.sup.3, D-Arg.sup.6,
D-Ala.sup.10 ]LHRH disclosed by D. H. Coy et al., Endocrinology,
110: 1445-1447 (1982); [N-Ac-D-(3-(2-naphthyl)-OAla).sup.1,
D-p-Cl-Phe.sup.2, D-Trp.sup.3, D-hArg(Et.sub.2).sup.6, D-Ala.sup.10
]LHRH and [N-Ac-Pro.sup.1 .BECAUSE. D-pF-Phe.sup.2,
D-(3-(2-naphthyl)-Ala.sup.3,.sup.6 ]-LHRH disclosed by J. J. Nestor
et al. J. Steroid Biochem., 20 9no. 6B), 1366 (1984); the nona- and
decapeptide analogs of LHRH useful as LHRH antagonists disclosed in
U.S. Pat. No. 4,481,190 (J. J. Nestor et al.); analogs of the
highly constrained cyclic antagonist, cycle [.DELTA..sup.3
Pro.sup.1, D-p-Cl-Phe.sup.2, D-Trp.sup.3,.sup.6, N-Me-Leu.sup.7,
.beta.-Ala.sup.10 ]-LHRH disclosed by J. Rivier, J. Steroid
Biochem., 20 (no. 6B), 1365 (1984); and
[N-Ac-D-(3-(2-naphthpyl)-Ala.sup.1, D-p-F-Phe.sup.2, D-Trp.sup.3,
D-Arg.sup.6 ]LHRH disclosed by A. Corbin et al., J. Steroid
Biochem. 20 (no. 6B) 1369 (1984).
Preferred nonapeptides wherein Y is L-leucyl and X is an optionally
active D-form of selected amino acids and Z is NHC.sub.2 H.sub.5
are [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide
(X=D-Trp.sup.6); [D-Ser-t-BuO).sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH
ethylamide [X-D-Ser(t-BuO.sup.6)]; [D-Leu.sup.6,
des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide (X=D-Leu.sup.6,
[D-His(Bzl).sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide
(X=iminobenzyl-D-His.sup.6) and [D-Ala.sup.6,
des-Gly-NH.sub.2.sup.10 ]-LHRH ethylamide (X=D-Ala.sup.6).
Preferred decapeptides include [D-Trp.sup.6 ]LHRH wherein X=D-Trp,
Y=L-leucyl, Z=glycyl-NH.sub.2, [D-Phe.sup.6 ]-LHRH wherein
X=D-phenylalanyl, Y=L-leucyl and Z=glycyl-HN.sub.2) or
[D-Nal(2).sup.6 LHRH which is [.sup.93 -3-(2-naphthyl)-D-Ala.sup.6
]LHRH wherein X=3(2-naphthyl)-D-alanyl, Y=L-leucyl and
Z=glycyl-NH.sub.2.
Other LHRH agonists useful within the scope of this invention are
the .alpha.-aza analogues of the natural LHRH, especially,
[D-Phe.sup.6, Azgly.sup.10 ]LHRH, [D-Tyr(--Me).sup.6, Azgly.sup.10
]LHRH, and [D-Ser-(t-BuO).sup.6, Azgly.sup.10 ]LHRH disclosed by A.
S. Dutta et al. in J. Med. Chem., 21, 1081 (1978) and U.S. Pat. No.
4,100,274 as well as those disclosed in U.S. Pat. Nos. 4,024,248
and 4,118,483.
Typical suitable LHRH antagonists include
[N-Ac-D-p-Cl-Phe.sup.1,.sup.2, D-Phe.sup.3, D-Arg.sup.6,
D-Ala.sup.10 ]-LHRH disclosed by J. Ercheggi et al., Biochem.
Biophys. Res. Commun. 100, 915-920 (1981);
[N-Ac-D-p-Cl-Phe.sup.1,.sup.2, D-Trp.sup.3, D-Arg.sup.6,
D-Ala.sup.10 ]LHRH disclosed by D. H. Coy et al., Endocrinology,
110: 1445-1447 (1982); [N-Ac-D-(3-(2-naphthyl)-OAla).sup.1,
D-p-Cl-Phe.sup.2, D-Trp.sup.3, D-hArg(Et.sub.2).sup.6, D-Ala.sup.10
]LHRH and [N-Ac-Pro.sup.1, D-pF-Phe.sup.2,
D-(3-(2-naphthyl)-Ala.sup.3,.sup.6 ]-LHRH disclosed by J. J. Nestor
et al. J. Steroid Biochem., 20 9no. 6B), 1366 (1984); the nona- and
decapeptide analogs of LHRH useful as LHRH antagonists disclosed in
U.S. Pat. No. 4,481,190 (J. J. Nestor et al.); analogs of the
highly constrained cyclic antagonist, cycle [.DELTA..sup.3
Pro.sup.1, D-p-Cl-Phe.sup.2, D-Trp.sup.3,.sup.6, N-Me-Leu.sup.7,
.beta.-Ala.sup.10 ]-LHRH disclosed by J. Rivier, J. Steroid
Biochem., 20 (no. 6B), 1365 (1984); and
[N-Ac-D-(3-(2-naphthyl)-Ala.sup.1, D-p-F-Phe.sup.2, D-Trp.sup.3,
D-Arg.sup.6 ]LHRH disclosed by A. Corbin et al., J. Steroid
Biochem. 20 (no. 6B) 1369 (1984).
Other LHRH agonist and antagonist analogs are disclosed in LHRH and
its analogs (B. H. Vickery et al. eds, at pages 3-10 (J. J.
Nestor), 11-22 (J. Rivier et al.) and 22-33 (J. J. Nestor et al.)
as well as in The Case for LHRH agonists (Clinical Oncology, Furr
and Denis, eds), Bailliere Tindall, vol. 2, no. 3, pp. 559-570,
1988).
The LHRH agonists and antagonists useful in this invention may
conveniently be prepared by the method described by Stewart et al.
in "Solid Phase Peptide Synthesis" (published in 1969 by Freeman
& Co., San Francisco, page 1) but solution phase synthesis may
also be used.
The nona- and decapeptides used in this invention are conveniently
assembled on a solid resin support, such as 1% cross-linked
Pro-merrifield resin by use of an automatic peptide synthesizer.
Typically, side-chain protecting groups, well known to those in the
peptide arts, are used during the dicyclohexylcarbodiimidecatalyzed
coupling of a tert-butyloxycarbonylamino acid to the growing
peptide attached to a benzhydrylamide resin. The
tert-butyloxycarbonyl protecting groups are removed at each stage
with trifluoroacetic acid. The nona- or decapeptide is cleaved from
the resin and deprotected by use of HF. The crude peptide is
purified by the usual techniques, e.g., gel filtration and
partition chromatography and optionally lyophilization. See also D.
H. Coy et al., J. Med. Chem. 19, pages 423-425 (1976).
In this invention, the LHRH agonist or antagonist, the
5.alpha.-reductase inhibitor, the antiandrogen, the antiestrogen,
and, where applicable, the inhibitor of 3.beta.- and
17.beta.-hydroxysteroid dehydrogenase activities are administered
as pharmaceutical compositions via topical, parenteral or oral
means. The LHRH agonist or antagonist is administered parenterally,
i.e., intramuscularly, subcutaneously or intravenously by injection
or infusion by nasal drops or by suppository. The LHRH agonist or
antagonist may also be microencapsulated in or attached to a
biocompatable, biodegradable polymer, e.g.,
poly(d,l-lactide-co-glycolide) and subcutaneously or
intramuscularly injected by a technique called subcutaneous or
intra-muscular depot to provide continuous, slow release of the
LHRH agonist or antagonist over a period of 30 days or longer. The
most preferred route of administration of the LHRH agonist or
antagonist is subcutaneous or intramuscular depot injection.
Preferably the antiestrogen will be administered orally.
Preferably, the 5.alpha.-reductase inhibitor, the antiandrogen, the
antiestrogen, the inhibitor of 3.beta.-HSD and the inhibitor of
17.beta.-HSD can also be administered orally. The antiestrogen, an
inhibitor of 3.beta.-HSD and inhibitor of 17.beta.-HSD can also be
administered in a slow release formulation, e.g.
poly(d,l-lactide-coglycolide) or as implants.
The amount of each component administered is determined by the
attending clinicians taking into consideration the etiology and
severity of the disease, the patient's condition and age, the
potency of each component and other factors. According to this
invention, the following dosage ranges are suitable.
The LHRH agonist or antagonist is generally administered at from
about 10 to 5000 .mu.g per day with contemplated dosage ranges of
about 10 to 1500 .mu.g per day and about 250 (preferably 50 .mu.g
to 500 .mu.g per day) for the LHRH agonist and to about 100 to 2000
.mu.g per day for the LHRH antogonist being preferred.
In the most preferred embodiment of this invention, the LHRH
agonist or antagonist is administered subcutaneously in a daily
dose of 500 .mu.g for the first 30 days and thereafter
subcutaneously in a daily dose of 250 .mu.g regardless of the
patients' body weight. When the LHRH agonist or antagonist is
administered, once every 30-day period is used, with a dose of 750
to 15,000 .mu.g per 30-day period being preferred. Similar daily
delivery doses are used for longer-term controlled release
formulations.
The inhibitors of 3.beta.-HSD and 17.beta.-HSD are preferably
administered in dosages ranging from about 0.1 to 25 mg/kg per day
with 200 mg per day in two equally divided doses being
preferred.
The antiestrogen compositions are administered in a dosage range of
about 0.05 to 25 mg/kg body weight per day, with 20 mg, especially
40 mg, in two equally divided doses being preferred.
The 5.alpha.-reductase inhibitor compositions are administered in a
dosage ranging from 0.1 to 25 mg/kg per day with 50 mg per day in
two equivalent doses being preferred.
The antiandrogen and aromatase inhibitor compositions are
administered in a dosage range of 0.5 to 25 mg/kg body weight per
day with 750 mg per day in three equally divided doses being
preferred.
The LHRH agonist or antagonist, antiestrogen, antiandrogen, an
inhibitor of aromatase, 17.beta.-HSD and 3.beta.-HSD each may be
administered separately or when the modes of administration are the
same, all or at least two of them may be administered in the same
composition, but in any case the preferred ratio of LHRH agonist to
antiestrogen, to antiandrogen to inhibitor of 17.beta.-HSD and
administered daily will be about 250 .mu.g of LHRH agonist to about
750 mg of antiandrogen, about 40 mg of antiestrogen, to about 40 mg
of inhibitor of 17.beta.-HSD and about 40 mg of inhibitor of
3.beta.-HSD.
In the therapy of prostate cancer, combining the administration of
an LHRH agonist or antagonist, an antiestrogen, an antiandrogen and
an inhibitor of 17.beta.-HSD, the dosages preferable are as
follows: the LHRH agonist or antagonist is generally administered
at from about 10 to 2000 .mu.g per day, with contemplated dosage
ranges of 10 to 500 .mu.g per day, 50-250 .mu.g per day and 250 to
500 .mu.g per day being preferred. In the most preferred embodiment
of this aspect of this invention, the LHRH agonist or antagonist is
administered subcutaneously in a daily dose of 500 .mu.g for the
first 30 days and thereafter subcutaneously in a daily dose of 250
.mu.g regardless of the patients' body weight. When the LHRH
agonist or antagonist is administered, once every 30-day period, by
intramuscular or subcutaneous depot injection, a dose from about
300 to 60000 (occasionally 10000) .mu.g per 30-day period is used,
with a dose of 750 to 2000 .mu.g per 30-day period being preferred.
The antiandrogen composition is generally administered in a dosage
range of about 0.5 to 25 mg/kg (body weight) per day with 400
especially 750 mg per day in three equally divided doses being
preferred. The antiestrogen and inhibitor of 17.beta.-HSD and
3.beta.-HSD activities are administered in a dosage range of about
0.1 to 25 mg/kg body weight per day, with 100 mg in two, preferably
with 50 mg in two, equally divided doses being preferred.
The LHRH agonist or antagonist, antiandrogen, antiestrogen,
5.alpha.-reductase inhibitor, inhibitor of 17.beta.-HSD, inhibitor
of 3.beta.-HSD, inhibitor of aromatase, each may be administered
separately or when the modes of administration are the same, all or
two or three of them may be administered in the same composition,
but in any case the preferred ratio of LHRH agonist to antiandrogen
to antiestrogen administered daily will be about 750 .mu.g of LHRH
agonist to about 250 mg of antiandrogen to preferably 40 mg of
antiestrogen.
In the therapy of prostate cancer, according to this invention, it
is preferred that the LHRH agonist is [D-Trp.sup.6,
des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide be administered
subcutaneously in single daily dose of 500 .mu.g for the first
thirty (30) days of treatment and thereafter in a single daily dose
of 250 .mu.g.
In the combination therapy of prostate cancer according to this
invention, the administration of the antiandrogen, antiestrogen,
inhibitor of 17.beta.-HSD, inhibitor of 5.alpha.-reductase,
inhibitor of aromatase, and inhibitor of 3.beta.-HSD, LHRH agonist
or LHRH antagonist can be started in any order of sequence.
Preferably, the administration of the antiandrogen and
5.alpha.-reductase inhibitor, are started before (preferably two to
four hours before) the administration of the LHRH agonist or LHRH
antagonist is started. Orchiectomy can replace LHRH agonist or
antagonist. Preferably, the administration of the inhibitor of
17.beta.-HSD and inhibitor of 3.beta.-HSD is started on the same
day as the administration of the LHRH agonist or LHRH antagonist.
However, the attending clinician may elect to start administration
of the LHRH agonist or antagonist simultaneously with the
antiandrogen, antiestrogen inhibitor of 17.beta.-HSD and inhibitor
of 3.beta.-HSD.
When patients whose testes have already been surgically removed are
treated according to this invention, the administration and dosage
of the antiandrogen and the other components of the therapy (except
the LHRH agonist or antagonist which is not used) are the same as
indicated for the therapy in which the LHRH agonist or antagonist
is used.
The LHRH agonists or antagonists useful in the present invention
are typically amorphous solids which are freely soluble in water or
dilute acids, e.g., HCl, H.sub.2 SO.sub.4, citric, acetic, mandelic
or fumaric. The LHRH agonist or antagonist for subcutaneous
injection is supplied in vials containing 5 ml of sterile solution
with the LHRH agonist or antagonist at a concentration of about 1.0
mg/ml.
A typical pharmaceutical composition of the LHRH agonist or
antagonist includes the LHRH agonist or antagonist or a
pharmaceutically acceptable acid salt thereof, benzyl alcohol, a
phosphate buffer (pH 6.0-6.5) and sterile water.
The LHRH agonist or antagonist for intramuscular or subcutaneous
depot injection may be microencapsulated in a biocompatible,
biodegradable polymer, e.g., poly (d,l-lactide-co-glycolide) by a
phase separation process or formed into a pellet. The microspheres
may then be suspended in a carrier to provide an injectable
preparation or the depot may be injected in the form of a pellet.
See also European patent application EPA No. 58,481 published Aug.
25, 1982 for solid compositions for subdermal injection or
implantation or liquid formulations for intramuscular or
subcutaneous injections containing biocompatible, biodegradable
polymers such as lactide-glycolide copolymer and an LHRH agonist,
e.g. D-Ser-t-BuO.sup.6, Azgly.sup.10 -LHRH. These formulations
permit controlled release of the peptide.
The inhibitors of 17.beta.-HSD, 3.beta.-HSD, aromatase and
5.alpha.-reductase are typically compounded in customary ways for
oral administration, e.g., in tablets, capsules and the like. These
compounds useful in the present invention are typically formulated
with conventional pharmaceutical excipients, e.g., spray dried
lactose and magnesium stearate into tablets or capsules for oral
administration. The antiestrogens, when used with the invention,
are typically compounded in customary ways for oral administration,
e.g., in capsules, tablets, as dragees or even in liquid form,
e.g., suspensions or syrups. One or more of the active substances,
with or without additional types of active agents, can be worked
into tablets or dragee cores by being mixed with solid, pulverulent
carrier substances, such as sodium citrate, calcium carbonate or
dicalcium phosphate, and binders such as polyvinyl pyrrolidone,
gelatin or cellulose derivatives, possibly by adding also
lubricants such as magnesium stearate, sodium lauryl sulfate,
"Carbowax" or polyethylene glycols. Of course, taste-improving
substances can be added in the case of oral administration
forms.
The therapeutically active antiestrogen compound should be present
in a concentration of about 0.5-90% by weight of the total mixture,
i.e., in amounts that are sufficient for maintaining the
above-mentioned dosage range.
As further forms, one can use plug capsules, e.g., of hard gelatin,
as well as closed soft-gelatin capsules comprising a softener or
plasticizer, e.g. glycerine. The plug capsules contain the active
substance preferably in the form of granulate, e.g., in mixture
with fillers, such as lactose, saccharose, mannitol, starches, such
as potato starch or amylopectin, cellulose derivatives or
highly-dispersed silicic acids. In soft-gelatin capsules, the
active substance is preferably dissolved or suspended in suitable
liquids, such as vegetable oils or liquid polyethylene glycols.
In place of oral administration, the active compounds may be
administered parenterally. In such case, one can use a solution of
the active substance, e.g., in sesame oil or olive oil. One or more
of the active substances (antiestrogen or inhibitor of 17.beta.-HSD
and 3.beta.-HSD can be microencapsulated in or attached to a
biocompatible, biodegradable polymer, e.g.
poly(d,l-lactide-co-glycolide) and subcutaneously or
intra-muscularly injected by a technique called subcutaneous or
intramuscular depot to provide continuous slow release of the
compound(s) for a period of 2 weeks or longer.
In the most preferred aspect of this invention, the LHRH agonist is
[D-Trp.sup.6,des-Gly-NH.sub.2.sup.10 ] LHRH ethylamide which is
administered subcutaneously in single daily dose of 500 .mu.g for
the first thirty (30) days of treatment and thereafter in a single
daily dose of 250 .mu.g: the antiandrogen is EM 101 which is
administered orally in three equally divided daily doses of 250 mg;
and the inhibitor of sex steroid biosynthesis is EM 139 and/or MK
906 administered orally in two equally divided doses of 50 mg every
12 hours.
The inhibitor(s) of sex steroid biosynthesis and the antiandrogen
are preferably administered to a male in need of the prostate
cancer treatment of this invention two to four hours before the
LHRH agonist or antagonist is administered, but the at tending
clinician may elect to start administration of the LHRH agonist or
antagonist, the antiandrogen and the inhibitor of steroid
biosynthesis simultaneously. When the antiandrogen and sex steroid
inhibitor are particularly effective, both chemical (LHRH agonist
or antagonist) and surgical castration may be avoided. Especially,
when patients whose testes have already been surgically removed are
treated according to this invention, no LHRH agonist or antagonist
need to be used but other dosages remain the same.
The terms and descriptions used herein are preferred embodiments
set forth by way of illustration only, and are not intended as
limitations on the many variations which those of skill in the art
will recognize to be possible in practicing the present invention
as defined by the following claims.
* * * * *