U.S. patent number 7,820,642 [Application Number 11/815,532] was granted by the patent office on 2010-10-26 for nandrolone 17.beta.-carbonates.
This patent grant is currently assigned to N/A, The United States of America as represented by the Department of Health and Human Services. Invention is credited to Richard P. Blye, Hyun K. Kim.
United States Patent |
7,820,642 |
Blye , et al. |
October 26, 2010 |
**Please see images for:
( Certificate of Correction ) ** |
Nandrolone 17.beta.-carbonates
Abstract
Disclosed are compounds of the formula (I) ##STR00001## wherein
R is C.sub.1-C.sub.30 alkyl, which may be optionally further
substituted with one or more of C.sub.5-C.sub.8 cycloalkyl groups,
or a C.sub.5-C.sub.12 cycloalkyl, which may be optionally
substituted with one or more C.sub.1-C.sub.30 alkyl groups, R' is
hydrogen or lower alkyl, R'' is a C.sub.1-C.sub.30 alkyl or halo,
and the bond between C14 and C15 can be a single bond or double
bond. Also disclosed are pharmaceutical compositions comprising
such compounds and methods of use thereof. These compounds can find
use in treating a number of diseases or conditions such as
hypogonadism, osteoporosis, and anemia, in providing hormonal
therapy and contraception, as an anabolic agent, and in suppressing
the release of hormones such as the luteinizing hormone.
Inventors: |
Blye; Richard P. (Highland,
MD), Kim; Hyun K. (Bethesda, MD) |
Assignee: |
The United States of America as
represented by the Department of Health and Human Services
(Washington, DC)
N/A (N/A)
|
Family
ID: |
36283873 |
Appl.
No.: |
11/815,532 |
Filed: |
January 24, 2006 |
PCT
Filed: |
January 24, 2006 |
PCT No.: |
PCT/US2006/002436 |
371(c)(1),(2),(4) Date: |
August 29, 2007 |
PCT
Pub. No.: |
WO2006/083618 |
PCT
Pub. Date: |
August 10, 2006 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20080167283 A1 |
Jul 10, 2008 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60650376 |
Feb 4, 2005 |
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Current U.S.
Class: |
514/179; 552/647;
552/646 |
Current CPC
Class: |
A61P
35/00 (20180101); A61P 19/10 (20180101); A61P
15/00 (20180101); A61P 7/06 (20180101); A61P
5/24 (20180101); A61P 43/00 (20180101); A61P
15/08 (20180101); A61P 15/16 (20180101); A61P
15/10 (20180101); A61P 21/00 (20180101); A61P
5/26 (20180101); A61P 21/04 (20180101); A61P
5/28 (20180101); A61P 5/36 (20180101); C07J
1/0074 (20130101); A61P 31/18 (20180101) |
Current International
Class: |
A61K
31/56 (20060101); C07J 1/00 (20060101) |
Field of
Search: |
;552/646,647
;514/179 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1291293 |
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May 1970 |
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GB |
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WO 01/74839 |
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Oct 2001 |
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WO |
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Other References
Muddana et al., "11beta-alkyl-Delta9-19-nortestosterone
derivatives: high-affinity ligands and potent partial agonists of
the androgen receptor," J. Med. Chem., 47, 4985-4988 (2004). cited
by other.
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Primary Examiner: Badio; Barbara P
Attorney, Agent or Firm: Leydig, Voit & Mayer, Ltd.
Claims
What is claimed is:
1. A compound of formula (I): ##STR00004## wherein R is a
C.sub.1-C.sub.30 alkyl which may be optionally further substituted
with one or more C.sub.5-C.sub.8 cycloalkyl groups or a
C.sub.5-C.sub.12 cycloalkyl which may be optionally substituted
with one or more C.sub.1-C.sub.30 alkyl groups; R' is hydrogen or
lower alkyl; R'' is a C.sub.1-C.sub.30 alkyl or halo; and the bond
between C14 and C15 can be a single bond or double bond.
2. The compound of claim 1, wherein R' is methyl or ethyl.
3. The compound of claim 1, wherein R'' is a C.sub.1-C.sub.30
alkyl.
4. The compound of claim 3, wherein R'' is C.sub.1-C.sub.6
alkyl.
5. The compound of claim 4, wherein R'' is methyl or ethyl.
6. The compound of claim 1, wherein R is C.sub.1-C.sub.30
alkyl.
7. The compound of claim 6, wherein R is C.sub.1-C.sub.18
alkyl.
8. The compound of claim 7, wherein R is C.sub.1-C.sub.12
alkyl.
9. The compound of claim 1, wherein the bond between C14 and C15 is
a single bond.
10. The compound of claim 9, wherein R' is hydrogen.
11. The compound of claim 10, which is selected from the group
consisting of 11.beta.-ethyl-19-nortestosterone-17-methylcarbonate,
11.beta.-ethyl-19-nortestosterone-17-decylcarbonate,
11.beta.-ethyl-19-nortestosterone-17-dodecylcarbonate,
11.beta.-methyl-19-nortestosterone-17-methylcarbonate,
11.beta.-methyl-19-nortestosterone-17-decylcarbonate, and
11.beta.-methyl-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate.
12. The compound of claim 9, wherein R'' is a halogen.
13. The compound of claim 12, which is selected from the group
consisting of 11.beta.-fluoro-19-nortestosterone-17-decylcarbonate,
11.beta.-fluoro-19-nortestosterone-17-dodecylcarbonate,
11.beta.-chloro-19-nortestosterone-17-decylcarbonate,
11.beta.-chloro-19-nortestosterone-17-dodecylcarbonate, and
11.beta.-fluoro-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate.
14. The compound of claim 9, which is selected from the group
consisting of 7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-methylcarbonate,
7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-decylcarbonate,
7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-dodecylcarbonate, 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-methylcarbonate, 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-hexylcarbonate, 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate, and
7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-dodecylcarbonate.
15. The compound of claim 9, which is selected from the group
consisting of 7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-methylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-hexylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-decylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-dodecylcarbonate, 7.alpha.,
11.beta.-diethyl-19-nortestosterone-17-methylcarbonate, 7.alpha.,
11.beta.-diethyl-19-nortestosterone-17-hexylcarbonate, 7.alpha.,
11.beta.-diethyl-19-nortestosterone-17-decylcarbonate, 7.alpha.,
11.beta.-diethyl-19-nortestosterone-17-dodecylcarbonate,
11.beta.-methyl-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate, and 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate.
16. The compound of claim 9, wherein R' is methyl or hydrogen and
R'' is halogen.
17. The compound of claim 16, which is selected from the group
consisting of 7.alpha.-methyl,
11.beta.-fluoro-19-nortestosterone-17-decylcarbonate,
7.alpha.-methyl,
11.beta.-fluoro-19-nortestosterone-17-dodecylcarbonate,
7.alpha.-methyl,
11.beta.-chloro-19-nortestosterone-17-decylcarbonate, and
7.alpha.-methyl,
11.beta.-chloro-19-nortestosterone-17-dodecylcarbonate, and
11.beta.-fluoro-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate.
18. The compound of claim 9, wherein R is decyl or dodecyl.
19. The compound of claim 9, wherein R'' is methyl or ethyl.
20. The compound of claim 9, wherein R'' is a halogen.
21. The compound of claim 9, wherein R'' is chloro or fluoro.
22. The compound of claim 1, wherein R is C.sub.5-C.sub.12
cycloalkyl.
23. The compound of claim 22, wherein the cycloalkyl is a
tricycloalkyl.
24. The compound of claim 23, wherein the tricycloalkyl is C.sub.10
tricycloalkyl.
25. The compound of claim 1, wherein the bond between C14 and C15
is a double bond.
26. The compound of claim 25, which is 7.alpha.,
11.beta.-dimethyl-14-dehydro-19-nortestosterone-17-adamantylcarbonate.
27. The compound of claim 25, wherein R is C.sub.1-C.sub.18
alkyl.
28. The compound of claim 27, wherein R is C.sub.1-C.sub.12
alkyl.
29. The compound of claim 28, wherein R is methyl.
30. The compound of claim 28, wherein R is decyl.
31. A pharmaceutical composition comprising a compound of claim 1,
and a pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 31, which is suitable
for oral administration.
33. The pharmaceutical composition of claim 31, which is suitable
for parenteral administration.
34. A pharmaceutical composition comprising a compound of claim 11
and a pharmaceutically acceptable carrier, wherein the composition
is suitable for oral administration.
35. The pharmaceutical composition of claim 34, wherein the
compound is 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate.
36. A pharmaceutical composition comprising the compound of claim
11 and a pharmaceutically acceptable carrier, wherein the
composition is suitable for subcutaneous injection.
37. The pharmaceutical composition of claim 36, wherein the
compound is 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-methylcarbonate or
7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-hexylcarbonate.
38. A pharmaceutical composition comprising an aqueous crystalline
suspension of a compound of claim 11, wherein the composition is
suitable for subcutaneous injection.
39. The pharmaceutical composition of claim 38, wherein the
compound is 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate.
40. A method for treating a male patient for hypogonadism
comprising administering an effective amount of a compound of claim
1.
41. The method of claim 40, wherein the hypogonadism is selected
from the group consisting of hypogonadotropic eunuchoidism, fertile
eunuch syndrome, prepubertal panhypopituitarism, and postpubertal
pituitary failure, and any combination thereof.
42. The method of claim 40, wherein the hypogonadism is selected
from the group consisting of Klinefelter's syndrome, Reifenstein's
syndrome, functional prepubertal castration syndrome, male
"Turner's syndrome", Sertoli cell-only syndrome, adult seminiferous
tubule failure, and adult Leydig cell failure, and any combination
thereof.
43. A method for providing hormonal therapy to a patient comprising
administering an effective amount of a compound of claim 1.
44. A method for providing a contraceptive to a male comprising
administering to the male an effective amount of a compound of
claim 1.
45. A method for treating a patient with osteoporosis comprising
administering an effective amount of a compound of claim 1.
46. A method for treating a patient with anemia comprising
administering an effective amount of a compound of claim 1.
47. A method for promoting and maintaining muscle growth in a
patient in need thereof comprising administering an effective
amount of a compound of claim 1.
48. The method of claim 47, wherein the patient is afflicted with a
muscle wasting disease.
49. The method of claim 48, wherein the muscle wasting disease is
AIDS.
50. The method of claim 47, wherein the patient is afflicted with
cancer.
51. A method of suppressing the release of luteinizing hormone in a
mammal comprising administering to the mammal an effective amount
of 7.alpha.,
11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate.
52. The compound of claim 1, wherein R' is hydrogen, R'' is methyl,
R is dodecyl, and the bond between C14 and C15 is a single
bond.
53. A pharmaceutical composition comprising the compound of claim
52 and a pharmaceutically acceptable carrier.
54. A method of treating a male patient for hypogonadism comprising
administering an effective amount of the compound of claim 52.
55. The method of claim 54, wherein the hypogonadism is selected
from the group consisting of hypogonadotropic eunuchoidism, fertile
eunuch syndrome, prepubertal panhypopituitarism, and postpubertal
pituitary failure, and any combination thereof.
56. The method of claim 54, wherein the hypogonadism is selected
from the group consisting of Klinefelter's syndrome, Reifenstein's
syndrome, functional prepubertal castration syndrome, male
"Turner's syndrome", Sertoli cell-only syndrome, adult seminiferous
tubule failure, and adult Leydig cell failure, and any combination
thereof.
57. A method for providing a contraceptive to a male comprising
administering to the male an effective amount of a compound of
claim 52.
58. A method for treating a patient with osteoporosis comprising
administering an effective amount of a compound of claim 52.
59. A method for treating a patient with anemia comprising
administering an effective amount of a compound of claim 52.
60. A method for promoting and maintaining muscle growth in a
patient in need thereof comprising administering an effective
amount of a compound of claim 52.
61. The method of claim 60, wherein the patient is afflicted with a
muscle wasting disease.
62. The method of claim 61, wherein the muscle wasting disease is
AIDS.
Description
FIELD OF THE INVENTION
This invention pertains to androgenic compounds, particularly
17.beta.-carbonates of 19-nortestosterone, pharmaceutical
compositions, and methods of use thereof.
BACKGROUND OF THE INVENTION
Androgens are used in hormonal therapy. Androgens are administered
as part of any hormonally-based male contraceptive since
suppression of the hypophyseal-gonadal axis by progestational
steroids or analogs of GnRH (gonadotropin releasing hormone)
affects both the gametogenic and endocrine function of the testis.
Androgens are indicated in the treatment of hypogonadism
irrespective of the cause and have become the subject of intense
interest in hormone replacement therapy (HRT) for both men and
women.
The principal male hormone, testosterone, is responsible for the
development of the male body habitus, secondary sexual
characteristics, libido and potentia as well as the processes of
spermatogenesis. Testosterone is a steroid produced by the testis
and exhibits an extremely short half-life. It is only weakly active
by oral administration. Consequently, the natural hormone finds
limited use in therapeutic medicine where androgen supplementation
is desired.
A number of synthetic androgens have been prepared over the last
fifty years including esters of the free alcohol which exhibit
varying durations of activity following a single intramuscular
injection. Notable among these is testosterone enanthate, which is
used extensively for replacement therapy in hypogonadal men and as
the androgenic component of several experimental male
contraceptives. However, it must be administered at biweekly
intervals in order to maintain testosterone levels in the normal
range. Other 17-esters of testosterone are being developed as a
long-acting injectable androgen. Like testosterone enanthate, these
products are administered in an oily vehicle and have limited
duration of action.
The development of oral formulations of androgenic steroids has
been less successful. The most widely used commercial preparation
is methyltestosterone which unfortunately, is associated with
hepatotoxicity upon chronic administration. Therapeutic uses of
androgens for replacement therapy usually require long-term
treatment, thus precluding utilization of 17-alkylated steroids
with their associated toxicity. Testosterone undecanoate also has
been marketed as an oral androgen but, like testosterone, it is
rapidly metabolized by the liver and must be administered several
times a day, which may be inconvenient to the patient.
The foregoing shows that there exists a need for androgenic agents
with long-acting activity, particularly long-acting oral activity.
The advantages of the invention, as well as inventive features,
will be apparent from the description of the invention provided
herein.
BRIEF SUMMARY OF THE INVENTION
The invention provides androgenic compounds, particularly
nandrolone carbonates of the formula
##STR00002## wherein R is an alkyl group which may be optionally
further substituted with one or more cycloalkyl groups or a
cycloalkyl group which may be optionally substituted with one or
more alkyl groups; R' is hydrogen or a lower alkyl; R'' is an alkyl
group or halo; and the bond between C14 and C15 can be a single
bond or double bond.
The invention also provides pharmaceutical compositions comprising
such compounds, and methods of use thereof. The compounds of the
invention can find use in treating a number of diseases or
conditions such as hypogonadism, osteoporosis, and anemia, in
providing hormonal therapy and contraception, as an anabolic agent,
and in suppressing the release of hormones such as the luteinizing
hormone.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a reaction scheme to prepare dimethandrolone
carbonates 2a-2d in accordance with an embodiment of the invention.
Compound 1 is dimethandrolone.
FIG. 2 depicts a reaction scheme to prepare dimethandrolone
carbonates 4a-4-c in accordance with an embodiment of the
invention. Compound 3 is .DELTA..sup.14-dimethandrolone.
FIG. 3 depicts a reaction scheme to prepare nandrolone carbonates
8a-8b and 9a-9b in accordance with an embodiment of the
invention.
FIG. 4 depicts a reaction scheme to prepare nandrolone carbonates
11a-11e and 12a-12c in accordance with an embodiment of the
invention.
FIG. 5 depicts the androgenic activity; in a Hershberger test, of
compounds CDB-4730 (2d, open circles), CDB-4731 (2b, open squares),
CDB-4718 (2a, filled circles), and CDB-4719 (2c, filled squares)
following an oral administration to castrate Sprague-Dawley male
rats in 10% ethanol/sesame oil, in accordance with an embodiment of
the invention. CDB-110B (methyltestosterone standard): open
triangles, standard for CDB-4730 and CDB-4731 and filled triangles
standard for CDB-4718 and CDB-4719. `A` is vehicle control for
CDB-4730 and 4731. `B` is vehicle control for CDB-4718 and
4719.
FIG. 6 depicts the androgenic activity, in a Hershberger test, of
compounds CDB-4718 (2a, filled circles), CDB-4719 (2c, filled
squares), CDB-4730 (2d, open circles), and CDB-4731 (2b, open
squares) following a subcutaneous injection to castrate
Sprague-Dawley male rats of the compounds in an aqueous suspending
vehicle, in accordance with an embodiment of the invention.
CDB-1111C (testosterone standard): filled triangles standard for
CDB-4718, 4730, and 4731; and open triangles standard for CDB-4719.
`C` is mean vehicle control.
FIG. 7 depicts the duration of androgenic activity of CDB-4718 (2a,
open circles, 0.6 mg; filled circles, 1.2 mg) and CDB-4719 (2c,
open squares, 0.6 mg; filled squares, 1.2 mg) as a function time,
following a single subcutaneous injection of the compounds to
castrate Sprague-Dawley male rats. The AUC's (mgweek) were as
follows: open circles, 581; filled circles, 789; open squares,
1417; and filled squares, 2764. `D` is vehicle control, with an AUC
of 126 mgweek.
FIG. 8 depicts the duration of androgenic activity of CDB-4718 (2a,
filled diamonds), CDB-4719 (2c, filled circles) following a single
subcutaneous injection to castrate Sprague-Dawley male rats of 1.2
mg of the compounds in an aqueous suspending vehicle. CDB-3122E
(testosterone undecanoate, open circles) and CDB-112 (testosterone
enanthate in sesame oil, open triangles) were also tested at 1.2 mg
and are shown for comparison. The AUC's (mgweek) were as follows:
open circles, 494; open triangles, 760; filled diamonds, 789; and
filled circles, 2764. `E` is aqueous vehicle control, with an AUC
of 126 mgweek.
FIG. 9 depicts the serum concentration of dimethandrolone and
immunoreactive metabolites following a single subcutaneous
injection to castrate Sprague-Dawley male rats of 1.2 mg of
CDB-4718 (2a, open circles, 0.6 mg; filled circles, 1.2 mg),
CDB-4719 (2c, open squares, 0.6 mg; filled squares, 1.2 mg) in an
aqueous suspending vehicle (n=5). The AUC's (mgweek) were as
follows: open circles, 2848; filled circles, 3336; open squares,
4151; and filled squares, 6010. `F` is aqueous vehicle control,
with an AUC of 1590 mgweek.
FIG. 10A depicts the serum concentration of dimethandrolone and
immunoreactive metabolites and luteinizing hormone (rLH) during the
14-week period following a single subcutaneous injection of
CDB-4730 (2d) to castrate Sprague-Dawley rats as an aqueous
crystalline suspension. Open circles, dimethandrolone and
immunoreactive metabolites, facing the Y-axis on the left; open
triangles represent the serum level of rLH, facing the Y-axis on
the right. The dotted line `F` represents the vehicle control for
rLH. The limit of detection of rLH and dimethandrolone was 0.18
ng/ml; n=5. FIG. 10B depicts the androgenic activity during the
14-week period.
FIG. 11 depicts the androgenic activity of CDB-4757 (8a, open
triangles) following oral administration of the compound to
castrate Sprague-Dawley male rats in 10% ethanol/sesame oil. Open
circle represents dimethandrolone decanoate and open triangles
represent methyltestosterone standard. `G` is vehicle control.
FIG. 12 shows the duration of androgenic activity of CDB-4719 (2c)
and 4730 (2d) over a period of 8 weeks following a single dose (1.2
mg) administered by subcutaneous injection to castrate
Sprague-Dawley male rats in an aqueous suspending vehicle on week
0. The triangle represents vehicle control (aqueous suspending
vehicle).
FIG. 13 shows the duration of androgenic activity of CDB-4754 (8b)
and 4750A (4c),
.DELTA..sup.14-dimethandrolone-17.beta.-adamantylcarbonate) over a
period of 14 weeks following a single dose (0.6 mg or 1.2 mg)
administered by subcutaneous injection to castrate Sprague-Dawley
male rats in an aqueous suspending vehicle on week 0. Filled
circles represent CDB-4754, 1.2 mg. Filled squares represent
CDB-4750A, 1.2 mg. Open circles represent CDB-4754, 0.6 mg. Open
squares represent CDB-4750A, 0.6 mg. Open triangle represents
aqueous suspending vehicle control. The AUC's (mgweek) were as
follows: CDB-4754 0.6 mg, 564; CDB-4754 1.2 mg, 974; CDB-4750A, 0.6
mg 326; and CDB-4750A, 1.2 mg, 759.
FIG. 14 depicts the serum levels of rLH as a function of time for
groups 2 and 4 of the animals. Serum rLH were measured in the blood
from castrate male rats following fourteen daily 12 mg/kg oral
doses of CDB-4719A (dimethandrolone 17.beta.-decylcarbonate, filled
circles, group 2) or CDB-4521C (dimethandrolone
17.beta.-undecanoate, open triangles, group 4) in 10%
ethanol/sesame oil on days 0-13. Samples from weeks -1 to 6 or from
weeks 7 to 9 and repeats were assayed as described in the protocols
MEL-480AD using [.sup.125I]-rLH or MEL-480AE, AG using
[.sup.125I]-rLH. The limit of detection shown as dotted line, or
EC.sub.90, was the mean of 0.13, 0.14, or 0.16 in the first assay
and 0.17, 0.22, or 0.21 ng/ml in the second series of assays based
on 200 .mu.l of serum per tube.
FIG. 15 depicts the serum levels of rLH as a function of time for
groups 1 and 3 of the animals. Serum rLH were measured in the blood
from castrate male rats following a single 12 mg/kg subcutaneous
injection of CDB-4719A (dimethandrolone 17.beta.-decylcarbonate,
filled circles, group 1) or CDB-4521C (dimethandrolone
17.beta.-undecanoate, open triangles, group 3) in an aqueous
suspending vehicle on day 0. Samples from weeks -1 to 6 or from
weeks 7 to 22 and repeats were assayed as described in the
protocols MEL-480AD using [.sup.125I]-rLH or MEL-480AE, AG, AH
using [.sup.125I]-rLH. The limit of detection shown as dotted line,
or EC.sub.90, was the mean of 0.13, 0.14, or 0.16 in the first
assay and 0.17, 0.22, or 0.21 ng/ml in the second series of assays
based on 200 .mu.l of serum per tube.
FIG. 16 depicts the serum levels of dimethandrolone (CDB-1321) and
immunoreactive metabolites from castrate immature male rats given a
single subcutaneous dose of 0.6 (filled circles) or 1.2 mg (open
triangles) per rat of CDB-4730 (dimethandrolone
17.beta.-dodecylcarbonate) in an aqueous suspending vehicle. The
limit of detection, shown in dotted line, was 82.0 pg/ml (100 .mu.l
of serum per tube) calculated from the mean.+-.3 SD of the vehicle
control samples from weeks 1 and 14 (n=10).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides, in an embodiment, compounds of
formula (I):
##STR00003## wherein R is C.sub.1-C.sub.30 alkyl which may be
optionally further substituted with one or more C.sub.5-C.sub.8
cycloalkyl groups or C.sub.5-C.sub.12 cycloalkyl which may be
optionally substituted with one or more C.sub.1-C.sub.30 allyl
groups; R' is hydrogen or lower allyl; R'' is C.sub.1-C.sub.30
alkyl or halo; and the bond between C14 and C15 can be a single
bond or double bond. When R' is hydrogen, there is no
stereochemistry at C7.
Specifically, R can be C.sub.1-C.sub.18 alkyl, and more
specifically C.sub.1-C.sub.12 alkyl. In an embodiment, R'' is
C.sub.1-C.sub.30 alkyl, specifically C.sub.1-C.sub.6 alkyl, and
more specifically methyl or ethyl. In an embodiment, R' can be a
lower allyl, e.g., one having a C.sub.1-C.sub.4 alkyl group,
particularly, methyl or ethyl.
The alkyl group, in accordance with the present invention, can be
linear or branched. Examples of alkyl groups include methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl,
heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,
tetradecyl, pentadecyl, and the like.
The cycloalkyl group, in accordance with the present invention, can
be mono, bi, or tricyclic. Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, bornyl, norbornyl, bicyclooctyl, bicyclononyl,
adamantyl, tricyclodecanyl, and the like.
In a specific embodiment, the present invention provides compounds
wherein R' is methyl or ethyl, e.g., R' is methyl or ethyl and R''
is a C.sub.1-C.sub.30 alkyl.
In an embodiment of the invention, R is C.sub.1-C.sub.30 alkyl,
specifically C.sub.1-C.sub.18 alkyl, and more specifically,
C.sub.1-C.sub.12 alkyl. In another embodiment, R is a cycloalkyl
group, optionally substituted with an alkyl group, for example, a
cyclohexyl group substituted with a butyl group (e.g.,
trans-4-n-butylcyclohexyl).
In accordance with an embodiment of the invention, the bond between
C14 and C15 is a single bond. For example, the bond between C14 and
C15 is a single bond and R' is hydrogen. Examples of compounds of
the embodiment include
11.beta.-ethyl-19-nortestosterone-17-methylcarbonate,
11.beta.-ethyl-19-nortestosterone-17-decylcarbonate,
11.beta.-ethyl-19-nortestosterone-17-dodecylcarbonate,
11.beta.-methyl-19-nortestosterone-17-methylcarbonate, and
11.beta.-methyl-19-nortestosterone-17-decylcarbonate.
In another embodiment of the invention, R'' is a halogen, e.g.,
fluoro, chloro, bromo, or iodo. For example, the bond between C14
and C15 is a single bond and R'' is halogen, particularly where R
is a C.sub.1-C.sub.12 alkyl. Examples of compounds of the
embodiment include
11.beta.-fluoro-19-nortestosterone-17-decylcarbonate,
11.beta.-fluoro-19-nortestosterone-17-dodecylcarbonate,
11.beta.-chloro-19-nortestosterone-17-decylcarbonate, and
11.beta.-chloro-19-nortestosterone-17-dodecylcarbonate.
In accordance with another embodiment of the invention, R' is
methyl or ethyl and R'' is methyl or ethyl, and the bond between
C14 and C15 is a single bond, particularly where R is a
C.sub.1-C.sub.12 alkyl group or a C.sub.3-C.sub.8 cycloalkyl group
optionally substituted with an alkyl group. Examples of such
compounds include 7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-methylcarbonate,
7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-decylcarbonate,
7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-hexylcarbonate,
7.alpha.-methyl,
11.beta.-ethyl-19-nortestosterone-17-dodecylcarbonate,
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-methylcarbonate,
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-hexylcarbonate,
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate,
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-dodecylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-methylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-hexylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-decylcarbonate,
7.alpha.-ethyl,
11.beta.-methyl-19-nortestosterone-17-dodecylcarbonate,
7.alpha.,11.beta.-diethyl-19-nortestosterone-17-methylcarbonate,
7.alpha.,11.beta.-diethyl-19-nortestosterone-17-hexylcarbonate,
7.alpha.,11.beta.-diethyl-19-nortestosterone-17-decylcarbonate,
7.alpha.,11.beta.-diethyl-19-nortestosterone-17-dodecylcarbonate,
11.beta.-methyl-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate, and
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-(trans-4-n-butylcyclohex-
yl) carbonate.
In accordance with yet another embodiment of the invention, R' is
methyl and R'' is halogen, and the bond between C14 and C15 is a
single bond, particularly where R' is a C.sub.1-C.sub.12 alkyl.
Examples of such compounds include 7.alpha.-methyl,
11.beta.-fluoro-19-nortestosterone-17-decylcarbonate,
7.alpha.-methyl,
11.beta.-fluoro-19-nortestosterone-17-dodecylcarbonate,
7.alpha.-methyl,
11.beta.-chloro-19-nortestosterone-17-decylcarbonate, and
7.alpha.-methyl,
11.beta.-chloro-19-nortestosterone-17-dodecylcarbonate.
In accordance with another embodiment, R' is hydrogen and R'' is
halogen, and the bond between C14 and C15 is a single bond,
particularly where R is a cycloalkyl group substituted with an
alkyl; for example, the compound is
11.beta.-fluoro-19-nortestosterone-17-(trans-4-n-butylcyclohexyl)
carbonate.
In accordance with a further embodiment of the invention, the bond
between C14 and C15 is a single bond and R is decyl or dodecyl. In
accordance with another embodiment of the invention, the bond
between C14 and C15 is a single bond and R'' is methyl or ethyl. In
accordance with yet another embodiment of the invention, the bond
between C14 and C15 is a single bond and R'' is a halogen,
particularly chloro or fluoro.
In accordance with an embodiment, the present invention provides
compounds wherein R is a C.sub.5-C.sub.12 cycloalkyl, particularly
wherein the cycloalkyl is a tricycloalkyl, such as a C.sub.10
tricycloalkyl. In a specific embodiment of these compounds, the
bond between C14 and C15 is a double bond. An example of such a
compound is
7.alpha.,11.beta.-dimethyl-14-dehydro-19-nortestosterone-17-adamantylcarb-
onate.
In a specific embodiment of the invention, the bond between C14 and
C15 is a double bond and R is C.sub.1-C.sub.18 alkyl, particularly
C.sub.1-C.sub.12 alkyl, for example, methyl or decyl.
Examples of the alkyl group substituted with a cycloalkyl group, in
accordance with the present invention, can be cyclohexylmethyl,
cyclopentylmethyl, cyclohexylethyl, norbornylmethyl,
adamantylmethyl, norbornylethyl, adamantylethyl, and the like.
Examples of the cycloalkyl group substituted with an alkyl group,
in accordance with the present invention, can be methylcyclopentyl,
ethylcyclopentyl, propylcyclopentyl, butylcyclopentyl,
methylcyclohexyl, ethylcyclohexyl, propylcyclohexyl,
butylcyclohexyl, and the like.
The present invention further provides a pharmaceutical composition
comprising a compound of the invention and a pharmaceutically
acceptable carrier.
The pharmaceutically acceptable carriers described herein, for
example, vehicles, adjuvants, excipients, or diluents, are well
known to those who are skilled in the art and are available to the
public. It is preferred that the pharmaceutically acceptable
carrier be one which is chemically inert to the active compounds
and one which has no detrimental side effects or toxicity under the
conditions of use.
The choice of carrier will be determined in part by the particular
compound (active agent), as well as by the particular method used
to administer the composition. Accordingly, there is a wide variety
of suitable formulations of the pharmaceutical composition of the
present invention. The following formulations for oral, aerosol,
parenteral, subcutaneous, intravenous, intraarterial,
intramuscular, interperitoneal, intrathecal, rectal, and vaginal
administration are merely exemplary and are in no way limiting
A pharmaceutically acceptable carrier is advantageously combined
with each active to ease the administration of the compound to a
patient in need. Suitable carriers for oral and buccal dosage
forms, such as tablets, capsules, caplets and soft gelcaps (having
an oily carrier), are well known, and may be used in connection
with the compounds. Preferably, oral dosage formulations of the
actives include an oily carrier, and are provided in the form of a
soft gelcap, as this formulation was found to enhance the
beneficial properties of the actives upon oral administration.
Illustrative of oily substances that may be used to provide an oily
carrier include, but are not limited to, vegetable oils, e.g. olive
oil, safflower oil, corn oil, sunflower oil, cotton seed oil,
tsubaki oil, rice bran oil, soybean oil, sesame oil, wheat germ
oil, coconut oil, peanut oil, rape seed oil and the like, fish
oils, e.g., cuttlefish oil, cod oil, and the like, liver oils,
e.g., shark liver oil, cod liver oil and the like, blubber oils,
e.g., seal oil, blue whale oil, etc.), conchiferous oils, e.g.,
abalone oil, oyster oil, and the like, medicinal oily substances,
e.g., castor oil, fatty acid glycerides, vitamin E, vitamin A,
vitamin K, and the like, polyethylene glycol and the like, and
mixtures thereof.
Formulations suitable for oral administration can comprise (a)
liquid solutions, such as an effective amount of the compound
dissolved in diluents, such as water, saline, or orange juice; (b)
capsules, sachets, tablets, lozenges, and troches, each containing
a predetermined amount of the active ingredient, as solids or
granules; (c) powders; (d) suspensions in an appropriate liquid;
and (e) suitable emulsions. Liquid formulations can include
diluents, such as water and alcohols, for example, ethanol, benzyl
alcohol, and the polyethylene alcohols, either with or without the
addition of a pharmaceutically acceptable surfactant, suspending
agent, or emulsifying agent. Capsule forms can be of the ordinary
hard- or soft-shelled gelatin type containing, for example,
surfactants, lubricants, and inert fillers, such as lactose,
sucrose, calcium phosphate, and cornstarch. Tablet forms can
include one or more of lactose, sucrose, mannitol, corn starch,
potato starch, alginic acid, microcrystalline cellulose, acacia,
gelatin, guar gum, colloidal silicon dioxide, croscarmellose
sodium, talc, magnesium stearate, calcium stearate, zinc stearate,
stearic acid, and other excipients, colorants, diluents, buffering
agents, disintegrating agents, moistening agents, preservatives,
flavoring agents, and pharmacologically compatible carriers.
Lozenge forms can comprise the active ingredient in a flavor,
usually sucrose and acacia or tragacanth, as well as pastilles
comprising the active ingredient in an inert base, such as gelatin
and glycerin, or sucrose and acacia, emulsions, gels, and the like
containing, in addition to the active ingredient, such carriers as
are known in the art.
The compounds of the present invention, alone or in combination
with other suitable components, can be made into aerosol
formulations to be administered via inhalation. These aerosol
formulations can be placed into pressurized acceptable propellants,
such as dichlorodifluoromethane, propane, nitrogen, and the like.
They also can be formulated as pharmaceuticals for non-pressured
preparations, such as in a nebulizer or an atomizer.
For parenteral administration, any type of carrier that maintains
the benefits of the invention as described herein may be used.
Preferably, the compounds of the invention are suspended in an
aqueous carrier suitable for injection. The water component of the
aqueous carrier should constitute at least half thereof, on a
weight percent basis, preferably at least about 80 wt. %, and more
preferably at least about 90 wt. % of the aqueous carrier.
Illustrative of a preferred parenteral formulation is one that
includes up to 300 mg of the compound suspended in about 1 ml of an
aqueous carrier. An illustrative aqueous carrier may be prepared by
combining: 1 g benzyl alcohol, 0.5 g sodium carboxyethyl cellulose
50, 0.376 g disodium hydrogen phosphate dihydrate, 1.495 g sodium
dihydrogen phosphate dihydrate, with water for injection (WFI)
being added to bring volume of the aqueous carrier up to 100
ml.
Formulations suitable for parenteral administration include aqueous
and non-aqueous, isotonic sterile injection solutions, which can
contain anti-oxidants, buffers, bacteriostats, and solutes that
render the formulation isotonic with the blood of the intended
recipient, and aqueous and non-aqueous sterile suspensions that can
include suspending agents, solubilizers, thickening agents,
stabilizers, and preservatives. The compounds can be administered
in a physiologically acceptable diluent in a pharmaceutical
carrier, such as a sterile liquid or mixture of liquids, including
water, saline, aqueous dextrose and related sugar solutions, an
alcohol, such as ethanol, isopropanol, or hexadecyl alcohol,
glycols, such as propylene glycol or polyethylene glycol, glycerol
ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such
as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid
ester or glyceride, or an acetylated fatty acid glyceride with or
without the addition of a pharmaceutically acceptable surfactant,
such as a soap or a detergent, suspending agent, such as pectin,
carbomers, methylcellulose, hydroxypropylmethylcellulose, or
carboxymethylcellulose, or emulsifying agents and other
pharmaceutical adjuvants.
Oils, which can be used in parenteral formulations include
petroleum, animal, vegetable, or synthetic oils. Specific examples
of oils include peanut, soybean, sesame, cottonseed, corn, olive,
petrolatum, and mineral. Suitable fatty acids for use in parenteral
formulations include oleic acid, stearic acid, and isostearic acid.
Ethyl oleate and isopropyl myristate are examples of suitable fatty
acid esters. Suitable soaps for use in parenteral formulations
include fatty alkali metal, ammonium, and triethanolamine salts,
and suitable detergents include (a) cationic detergents such as,
for example, dimethyl diallyl ammonium halides, and allyl
pyridinium halides, (b) anionic detergents such as, for example,
alkyl, aryl, and olefin sulfonates, allyl, olefin, ether, and
monoglyceride sulfates, and sulfosuccinates, (c) nonionic
detergents such as, for example, fatty amine oxides, fatty acid
alkanolamides, and polyoxyethylenepolypropylene copolymers, (d)
amphoteric detergents such as, for example,
alkyl-.beta.-aminopropionates, and 2-alkyl-imidazoline quaternary
ammonium salts, and (e) mixtures thereof. Suitable preservatives
and buffers can be used in such formulations. In order to minimize
or eliminate irritation at the site of injection, such compositions
may contain one or more nonionic surfactants. The quantity of
surfactant in such formulations typically ranges from about 5 to
about 15% by weight. Suitable surfactants include polyethylene
sorbitan fatty acid esters, such as sorbitan monooleate and the
high molecular weight adducts of ethylene oxide with a hydrophobic
base, formed by the condensation of propylene oxide with propylene
glycol. The parenteral formulations can be presented in unit-dose
or multi-dose sealed containers, such as ampoules and vials, and
can be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example,
water, for injections, immediately prior to use. Extemporaneous
injection solutions and suspensions can be prepared from sterile
powders, granules, and tablets of the kind previously
described.
The compounds of the present invention may be made into injectable
formulations. The requirements for effective pharmaceutical
carriers for injectable compositions are well known to those of
ordinary skill in the art. See Pharmaceutics and Pharmacy Practice,
J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds.,
pages 238-250 (1982), and ASHP Handbook on Injectable Drugs,
Toissel, 4th ed., pages 622-630 (1986).
When formulated as an injectable, the compound may be provided in
any suitable form, e.g., lyophilizate, dry powder for
reconstitution, a ready-to-use liquid, and in any suitable
container, e.g., vial, pre-filled syringe, or the like. The
compounds may also be administered transdermally or subcutaneously.
Transdermal delivery devices are well known. Illustrative
transdermal devices are described in U.S. Pat. Nos. 5,635,203 and
6,024,976. When a transdermal delivery device is used, the amount
of the active included in the device for therapy should range from
about 5% to about 25% of the parenteral dose, and preferably from
about 10% to about 20% of that dose, as set forth herein
Additionally, the compounds of the present invention may be made
into suppositories by mixing with a variety of bases, such as
emulsifying bases or water-soluble bases. Formulations suitable for
vaginal administration may be presented as pessaries, tampons,
creams, gels, pastes, foams, or spray formulas containing, in
addition to the active ingredient, such carriers as are known in
the art to be appropriate.
In a specific embodiment, the pharmaceutical composition is
suitable for oral or administration. For example, the
pharmaceutical composition comprises
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate and
a pharmaceutically acceptable carrier, wherein the composition is
suitable for oral administration. In a further example, the
pharmaceutical composition
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-methylcarbonate or
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-hexylcarbonate and
a pharmaceutically acceptable carrier, wherein the composition is
suitable for subcutaneous injection. In another example, the
pharmaceutical composition comprises an aqueous crystalline
suspension of
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate,
wherein the composition is suitable for subcutaneous injection.
Suitable doses and dosage regimens can be determined by
conventional range-finding techniques known to those of ordinary
skill in the art. Generally, treatment is initiated with smaller
dosages, which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the
optimum effect under the circumstances is reached. For convenience,
the total daily dosage may be divided and administered in portions
during the day if desired. In proper doses and with suitable
administration of certain compounds, the present invention provides
for a wide range of responses. Typically the dosages range from
about 0.001 to about 1000 mg/kg body weight of the animal being
treated per day. Preferred dosages range from about 0.01 to about
10 mg/kg body weight/day, and further preferred dosages range from
about 0.01 to about 1 mg/kg body weight/day.
The present invention further provides a method for treating a male
patient for hypogonadism comprising administering an effective
amount of a compound of the invention. Any suitable hypogonadism
can be treated, for example, the hypogonadism is selected from the
group consisting of hypogonadotropic eunuchoidism, fertile eunuch
syndrome, prepubertal panhypopituitarism, and postpubertal
pituitary failure, and any combination thereof.
The present invention further provides a method for treating a male
patient for hypogonadism comprising administering an effective
amount of a compound of the invention. Any suitable hypogonadism
can be treated, for example, the hypogonadism can be selected from
the group consisting of Klinefelter's syndrome, Reifenstein's
syndrome, functional prepubertal castration syndrome, male
"Turner's syndrome", Sertoli cell-only syndrome, adult seminiferous
tubule failure, and adult Leydig cell failure, and any combination
thereof.
The present invention further provides a method for providing
hormonal therapy to a patient comprising administering an effective
amount of a compound of the invention. The present invention also
provides a method for providing a contraceptive to a male
comprising administering to the male an effective amount of a
compound of the invention. The present invention also provides a
method for treating a patient with osteoporosis comprising
administering an effective amount of a compound of the invention.
The present invention further provides a method for treating a
patient with anemia comprising administering an effective amount of
a compound of the invention. The present invention also provides a
method for treating a patient in need of an anabolic agent
comprising administering an effective amount of a compound of the
invention. The patient in need of anabolic agent may be one
afflicted with a muscle wasting disease, e.g., AIDS, or a patient
in need of anabolic agent may be one having low muscle mass, or the
patient is afflicted with cancer. The present invention also
provides a method for suppressing the release of luteinizing
hormone in a mammal comprising administering to the mammal an
effective amount of the compound of the invention, particularly
7.alpha.,11.beta.-dimethyl-19-nortestosterone-17-decylcarbonate.
The serum level of the hormone remains suppressed for both groups
of animals during the administration of the drug. When the
administration of the drug is discontinued, the hormone level, as
expected, bounces back and increases beyond the pretreatment level
(at week -1 or 0) for the ester drug. Thus, for example, the
hormone level can be suppressed up to several weeks, e.g., from
about 2 to about 20 weeks or more. This could have advantageous
clinical implications, for example, in obtaining sustained
suppression of the luteinizing hormone or hormone replacement
therapy. In addition, this could have an advantage by providing a
facile treatment using oral compositions such as tablets or
capsules of the carbonates of the invention in suppressing hormone
levels. Such treatment can be advantageous relative to a treatment
involving parenteral (e.g., subcutaneous) administration of a drug
such as the ester drug. Patient compliance can be better with oral
formulations than injections.
By way of example only, and without intending to limit the
therapeutic uses of the actives, the compounds may be used in the
treatment of hypogonadal males, e.g., hypogonadatrophic
eunuchoidism (complete, incomplete, delayed puberty), fertile
eunuch, prepubertal panhypopituitarism, postpubertal pituitary
failure (selective, panhypopituitarism). The compounds may also be
administered (either alone or, more effectively, in combination
with one or more steroidal progestins or estrogens) to induce and
maintain fertility suppression in male animals, or as an androgenic
component for feedback. Further, and due to their anabolic
properties, the compounds may be administered to promote and
maintain muscle growth and maintenance. These properties can be
particularly important in persons afflicted with muscle wasting
diseases such as AIDS, but are more generally applicable to the
elderly who typically have relatively low muscle mass. In addition,
the compounds may be used for the treatment of cancer, e.g., the
palliative treatment of breast cancer in men and women, the
treatment of osteoporosis, anemia, anabolism, hormonal replacement
therapy (in males and females) and hypogonadotrophic conditions
(e.g., Klinefelter's, Reifenstein's, functional prepubertal
castration syndrome, male Turner's syndrome, Sertoli cell-only
syndrome, adult seminiferous tubule failure (e.g., mumps orchitis,
irradiation, idiopathic, myotonia dystrophica), and adult Leydig
cell failure).
As a general statement, the effective oral dosage of any of the
compounds for any hormone replacement therapy which requires an
androgen, e.g., the treatment of hypogonadism, will be the inverse
of its potency ratio relative to the amount of the standard
required to provide the same effect, e.g., the amount of
methyltestosterone administered orally required to provide the same
effect. For example, in the case of hypogonadism, the compound may
be orally administered in therapeutically effective amounts. For
example, the oral dosage may range from about 1 mg/day to about 75
mg/day, such as from about 2 mg/day to about 50 mg/day, and
specifically from about 1 mg/day to about 25 mg/day. For the
treatment of cancer, e.g., breast cancer in women, the amount of
the compound administered can vary, but can range from at least
about 10 mg/day, specifically at least about 25 mg/day, and more
specifically, at least about 50 mg/day.
In the use of the compounds for male contraception, amounts
effective to provide such therapy may be administered. Generally,
the effective oral doses may vary, but can range from about 1 to
about 50 mg per day. Of course, the greater the relative potency,
the lesser the dose, for example, an effective oral dose may range
from about 1 mg/day to about 25 mg/day, advantageously from about 2
mg/day to about 20 mg/day, and up to about 15 mg/day.
In the case of conditions requiring chronic hormonal therapy, such
as hypogonadism, the compound may be dispersed in an aqueous
vehicle and may be administered as an aqueous formulation at lower
doses compared to both testosterone enanthate (in an oily carrier)
and testosterone bucyclate, and at relatively long intervals. More
specifically, and by further way of comparative example, doses of
the compound, when dispersed in an aqueous formulation, may
generally range from about one-third to about three-quarters the
dose of testosterone enanthate (provided in a sesame oil carrier)
required to provide substantially equivalent therapeutic results,
with between about one-half and about two-thirds of that latter
dose being preferred.
Because of its long-acting androgenic activity, particularly when
administered parenterally in an aqueous carrier in effective
amounts, the compound may be administered at intervals equal to, or
in excess of, about two weeks. More specifically, they may be
administered at intervals of about one month, preferably about two
months, more preferably once about every three months or about
every two to four months. This provides a significant advantage to
a patient relative to existing regimens that require therapeutic
injections on a more frequent basis.
For example, in treating hypogonadism, those compounds may be
formulated in an aqueous carrier and provide therapeutic benefits
over an extended time period may be administered in amounts ranging
from about 1 mg up to about 100 mg about every two weeks, and
advantageously from about 25 to about 75 mg during that period; up
to about 200 mg about every month, and advantageously from about 50
mg to about 150 mg during that time period; up to about 400 mg
about every 2 months, and advantageously from about 100 to about
300 mg during that time period; and up to about 600 mg about every
3 months, and advantageously from about 150 mg to about 450 mg
during that time period. These dosages, advantageously provided by
a single injection at the beginning of each time period, are less
than the dosages of testosterone enanthate and testosterone
bucyclate that may be used to provide similar therapeutic effects
over the same periods.
By way of further example, doses of the compounds of the invention
effective for male contraception via parenteral administration, if
used alone, may range from about 25 mg/week up to about 200
mg/week, advantageously up to about 150 mg/week, and preferably
from about 50 mg/week to about 100 mg/week. If used in a more
typical manner, i.e., combined with estrogen and/or progestins,
parenteral dosages of the foregoing actives may range from about 1
mg up to about 100 mg every about two weeks, advantageously from
about 2 mg up to about 75 mg, and preferably up to about 50 mg,
every two weeks. Of course, because of the long-acting activity of
these actives, these dosages may be administered on a substantially
linear basis if activity beyond the periods set forth above is
desired.
The enhanced potency of the compounds of the invention
advantageously permits a further advantage in that effective
amounts may be administered via a single injection, which is
desirable from a patient comfort and cost perspective. Equivalent
therapeutic results using testosterone enanthate would require
multiple injections. Of course, multiple injections of relatively
lower doses of the inventive actives may be administered if
required or desired. For example, actives formulated into an oily
carrier, despite relatively high potency, need to be administered
more frequently to obtain the desired therapy, with the dose being
adjusted based upon the particular active's potency in that
carrier.
The synthesis of dimethandrolone has been described in
International Patent Publication Number WO 01174839 A2.
The following examples further illustrate the invention but, of
course, should not be construed as in any way limiting its
scope.
EXAMPLE 1
This example illustrates a method for preparing compounds in
accordance with an embodiment of the invention.
The syntheses of the 17.beta.-methyl, hexyl, decyl and dodecyl
carbonates of dimethandrolone were carried out following the
procedure described below by treatment of dimethandrolone and the
corresponding alkyl chloroformates in the presence of pyridine in
dichloromethane, as described below.
17.beta.-Methoxycarbonyloxy-7.alpha.,11.beta.-dimethylestr-4-en-3-one
(2a, CDB-4718): A solution of the dimethandrolone (1 (FIG. 1), 1.0
g, 3.31 mmol) in dry CH.sub.2Cl.sub.2 (50 mL) under nitrogen, was
cooled to 0.degree. C. in an ice bath. Pyridine (1 mL, 12.4 mmol)
followed by methyl chloroformate (1 mL, 12.9 mmol) was added and
the mixture stirred at 0.degree. C. for about 15 min and allowed to
warm to room temperature. The reaction mixture was stirred at room
temperature for one hour after which time TLC (5% acetone in
CH.sub.2Cl.sub.2) indicated about 60% reaction. The reaction
mixture was cooled to 0.degree. C., and treated with additional
pyridine (1 mL) and methyl chloroformate (1 mL). Upon warming to
room temperature, evolution of gas was observed. After stirring at
room temperature overnight, TLC (5% acetone in CH.sub.2Cl.sub.2)
indicated about 80% reaction. Solvents were removed in vacuo under
a stream of dry nitrogen and the residue was dissolved in
CH.sub.2Cl.sub.2 and washed with H.sub.2O (3.times.). The organic
fractions were filtered through anhydrous Na.sub.2SO.sub.4,
combined and concentrated in vacuo to give 1.3 g of the residue as
yellow foam. This material was purified by Flash chromatography (3%
acetone in CH.sub.2Cl.sub.2) followed by crystallization from
methanol to give >0.74 g of the pure product 2a in 62% yield;
m.p.=153-154.degree. C. Analysis by HPLC on NovaPak C-18 column,
Waters Assoc eluted with CH.sub.3CN:H.sub.2O in a ratio of 7:3 at a
flow rate of 1 mL/min and at .lamda.=240 nm indicated compound 2a
to be >99% pure with a retention time of 4.62 min. FTIR (ATR),
.nu.max 2958, 2939, 2883, 1739, 1663 and 1620 cm.sup.-1.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.786 (d, 3H, J=6.97 Hz,
C7.alpha.-CH.sub.3), 0.953 (s, 3H, Cf18-CH.sub.3), 1.062 (d, 3H,
J=7.2 Hz, C11.beta.-CH.sub.3), 3.775 (s, 3H, --C(O)OCH.sub.3),
4.479 (dd, 1H, J=9 Hz, J=7.4 Hz, C17.alpha.-H) and 5.852 (s, 1H,
C4-CH.dbd.) ppm. .sup.13C NMR (300 MHz, CDCl.sub.3): .delta. 12.881
(C7-CH.sub.3), 15.117 (C18-CH.sub.3), 17.084 (C11.beta.-CH.sub.3),
22.642, 26.404, 27.175, 28.416, 30.726, 36.638, 36.781, 38.702,
42.669, 43.255, 44.571, 45.736, 47.635, 54.594 (OCH.sub.3), 87.352
(C17), 126.585 (C4), 155.773 (O--C.dbd.O), 165.533 (C5), and
199.421 (C3) ppm.
MS (El) m/z (relative intensity): 360 (M+, 53), 284(99), 175 (100),
and 147 (49).
Anal. Calcd. for C.sub.22H.sub.32O.sub.4: C, 73.30; H, 8.95. Found:
C, 73.21; H, 9.01.
17.beta.-Hexyloxycarbonyloxy-7.alpha.,11.beta.-dimethylestr-4-en-3-one
(2b, CDB-4731): Following the procedure in a manner similar to that
of the above for the preparation of 2a, dimethandrolone (1, 1.0 g,
3.31 mmol) in dry CH.sub.2Cl.sub.2 (50 mL) was reacted with hexyl
chloroformate (2 mL, 12.2 mmol) in the presence of pyridine (1 mL,
12.4 mmol) to give 1.6 g of the crude hexyl carbonate (2b).
Purification by flash chromatography using 2% acetone in
CH.sub.2Cl.sub.2 followed by crystallization from pentane gave 1.2
g of the pure product 2b in 84.3% yield; m.p.=60.4-61.1.degree. C.
Analysis by HPLC on NovaPak C-18 column, Waters Assoc, eluted with
100% CH.sub.3CN at a flow rate of 1 mL/min and at .lamda.=240 nm
indicated compound 2b to be >99% pure with a retention time of
3.1 min. FTIR (ATR), .nu.max 2948, 2914, 2880, 2854, 1740, 1666 and
1613 cm.sup.-1. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.785
(d, 3H, J=7.2 Hz, C7.alpha.-CH.sub.3), 0.895 (t, 3H, J=16.9 Hz,
hexyl-CH.sub.3), 0.956 (s, 3H, C18-CH.sub.3), 1.062 (d, 3H, J=7.8
Hz, C11.beta.-CH.sub.3), 4.114 (t, 2H, J=6.9 Hz,
hexyl-OCH.sub.2--), 4.476 (dd, 1H, J=9.3 Hz, J2=7.2 Hz,
C17.alpha.-CH) and 5.850 (s, 1H, C4-CH.dbd.) ppm. .sup.13C NMR (300
MHz, CDCl.sub.3): .delta. 12.884 (C7-CH.sub.3), 13.991
(hexyl-CH.sub.3), 15.215 (C18), 17.121 (C11-CH.sub.3), 22.537,
22.648, 25.382, 26.428, 27.201, 28.430, 28.663, 30.755, 31.434,
B6.649, 36.796, 38.734, 42.727, 43.284, 44.644, 45.763, 47.694,
68.065 (hexyl-OCH.sub.2--), 87.087 (C17), 126.585 (C4), 155.402
(OC(.dbd.O)--), 165.537 (C5) and 199.423 (C3) ppm: MS (El) m/z
(relative intensity): 430 (M+, 15), 302 (18), 284 (83), 173 (100),
159 (38), and 147 (44). Anal. Calcd. for C.sub.27H.sub.42O.sub.4:
C, 75.32; H, 9.83. Found: C, 75.47; H, 9.86.
17.beta.-Decyloxycarbonyloxy-7.alpha.,11.beta.-dimethylestr-4-en-3-one
(2c, CDB-4719); Following the same procedure used to synthesize
compound 2a, dimethandrolone (1, 1.0 g, 3.31 mmol) in dry
CH.sub.2Cl.sub.2 (50 mL) was reacted with decyl chloroformate (2
mL, 8.66 mmol) in the presence of pyridine (1 mL, 12.4 mmol).
Purification by flash chromatography using 1% acetone in
CH.sub.2Cl.sub.2 followed by crystallization from hot hexanes gave
1.2 g of the pure product 2c in 74.6% yield; m.p. 66-68.degree. C.
Analysis by HPLC on NovaPak C-18 column, Waters Assoc., eluted with
100% CH.sub.3CN at a flow rate of 1 mL/min and at .lamda.=240 nm
indicated compound 2c to be >99% pure with a retention time of
6.62 min. FTIR (ATR), .nu.max 2954, 2918, 2849, 1743, 1666 and 1613
cm.sup.-1. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.784<d,
3H, J=6.6 Hz, C7.alpha.-CH.sub.3), 0.880 (t, J=6.6 Hz, 3H,
decyl-CH.sub.3), 0.955 (s, 3H, C18-CH.sub.3), 1.062 (d, 3H, J=7.5
Hz, C11.beta.-CH.sub.3), 4.110 (t, 2H, J=6.9 Hz,
decyl-OCH.sub.2--), 4.473 (dd, J=9 Hz, J2=7.2 Hz, C17.alpha.-CH),
and 5.848 (s, 11H, C4-CH.dbd.) ppm. .sup.13C NMR (300 MHz,
CDCl.sub.3) .delta. 12.904 (C7-CH.sub.3), 14.130 (decyl-CH.sub.3),
15.237 (C18), 17.116 (C11-CH.sub.3), 22.654, 22.689, 25.710,
26.434, 27.204, 28.443, 28.695, 29.252, 29.312, 29.500, 30.759,
31.906, 36.653, 36.814, 38.725, 42.708, 43.270, 44.640, 45.768,
47.704, 68.090 (decyl-OCH.sub.2--), 87.107 (C17), 126.569 (C4),
155.410 (OC.dbd.O), 165.589 (C5) and 199.475 (C3) ppm. MS (El) m/z
(relative intensity): 486 (M+, 34), 284 (87), 175 (100), and 147
(52). Anal. Calcd. for C.sub.31H.sub.50O.sub.4.1/4C.sub.6H.sub.14:
C, 76.80; H, 10.61. Found: C, 77.02; H, 10.42.
17.beta.-Dodecyloxycarbonyloxy-7.alpha.,11.beta.-dimethylestr-4-en-3-one
(2d, CDB-4730): Following the same procedure used in the synthesis
of compound 2a, dimethandrolone (1, 1.0 g, 3.31 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was reacted with dodecyl chloroformate (2
mL, 7.4 mmol) in the presence of pyridine (1 mL, 12.4 mmol) to give
2.1 g of the crude product 2d. Purification by Flash chromatography
(1% acetone in CH.sub.2Cl.sub.2) followed by crystallization from
hot hexanes gave 1.3 g of the pure product 2d in 76% yield:
m.p.=52.7-53.7.degree. C. Analysis by HPLC on NovaPak C-18 column,
Waters Assoc. eluted with 100% CH.sub.3CN at a flow rate of 1
mL/min and at .lamda.=240 nm indicated compound 2d to be >99%
pure with a retention time of 8.65 min. FTIR (ATR), .nu.max 2953,
2920, 2851, 1743, 1668 and 1615 cm.sup.-1.
.sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 0.785 (d, 3H, J=7.2 Hz,
C7.alpha.-CH.sub.3), 0.882 (t, J=6.8 Hz, 3H, dodecyl-CH.sub.3),
0.956 (s, 3H, C18-CH.sub.3), 1.062 (d, 3H, J=7.5 Hz,
C11.beta.-CH.sub.3), 4.110 (t, 2H, J=7.1 Hz, decyl-OCH.sub.2--),
4.473 (dd, J=9 Hz, J2=7.4 Hz, C17.alpha.-CH), and 5.848 (s, 1H,
C4-CH.dbd.) ppm. .sup.13C NMR (300 MHz, CDCl.sub.3): .delta. 12.870
(C7-CH.sub.3), 14.122 (decyl-CH.sub.3), 15.204 (C18), 17.104
(C11-CH.sub.3), 22.657, 22.694, 25.726, 26.438, 27.212, 28.471,
28.713, 29.246, 29.356, 29.498, 29.549, 29.627, 30.766, 31.932,
36.671, 36.837, 38.757, 42.745, 43.276, 44.662, 45.767, 47.729,
68.078 (dodecyl-OCH.sub.2--), 87.111 (C17), 126.602 (C4), 155.411
(OC--O), 165.477 (C5), and 199.477 (C3) ppm. MS (El) m/z (relative
intensity): 514 (M.sup.+, 50), 284.2 (81), 175.1 (100), and 57.0
(75). Anal. Calcd. for C.sub.33H.sub.54O.sub.4: C, 77.04; H, 10.51.
Found: C, 77.15; H, 10.54.
The synthesis of .DELTA..sup.14-dimethandrolone (3 or
7.alpha.,11.beta.-dimethylestra-4,14-dien-3-one) has been described
in U.S. Patent Publication No. 20030130243 A1. The syntheses of
17.beta.-methyl, 17.beta.-decyl and 17.beta.-adamantyl carbonates
of .DELTA..sup.14-Dimethandrolone were carried out following the
procedure in a manner similar to those of dimethandrolone
17-carbonates as described above. See also FIG. 2.
17.beta.-Methoxycarbonyloxy-7.alpha.,11.beta.-dimethylestra-4,14-dien-3-o-
ne (4a, CDB-4748): A solution of .DELTA..sup.14-dimethandrolone (3,
150 mg, 0.50 mmol) in CH.sub.2Cl.sub.2 (7 mL) and pyridine (0.2 mL)
was cooled to 0.degree. C. in an ice bath and treated with methyl
chloroformate (0.096 mL, 1.25 mmol). The solution was allowed to
warm to room temperature and stirred for 5 hr. The reaction mixture
was poured into cold water and extracted with dichloromethane. The
dichloromethane extracts were washed with water, combined, and
dried over Na.sub.2SO.sub.4. Evaporation of the solvent gave 182 mg
of an oil. The material was chromatographed using 5% acetone in
CH.sub.2Cl.sub.2 to yield 138 mg of 4a in 77% yield as a stable
foam. The starting material 3 (35 mg) was recovered in 23% yield.
Attempts for recrystallization of 4a from a variety of solvent
systems were failed to give a solid. FTIR (ATR), .nu.max 2954,
1742, 1667, 1618, and 1261 cm.sup.-1. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 0.849 (d, 3H, J=7.2 Hz, C7.alpha.-CH.sub.3),
1.113 (s, 3H, C18-CH.sub.3), 1.119 (d, J=7.2 Hz,
C11.alpha.-CH.sub.3), 3.793 (s, 3H, --OCH.sub.3), 4.780 (t, 1H,
J=7.8 Hz, C17.alpha.-H), 5.166 (br s 1H, C15-H), and 5.876 (s, 1H,
C4-CH.dbd.) ppm. MS (EI) m/z (relative intensity): 358 (M.sup.+,
3.1), 282 (100), 190 (22.1), 173 (41.3), 157 (28.1) and 147
(48.8).
17.beta.-Decyloxycarbonyloxy-7.alpha.,11.beta.-dimethylestra-4,14-dien-3--
one (4b, CDB-4749): Following the same procedure used to synthesize
4a, A4-Dimethandrolone (3, 150 mg, 0.50 mmol) in CH.sub.2Cl.sub.2
(7 mL) was reacted with decyl chloroformate (0.290 mL, 1.25 mmol)
in the presence of pyridine (0.20 mL). Following work up and
chromatography using 2% acetone in CH.sub.2Cl.sub.2, 246.3 mg of 4b
was obtained as a clear oil which resisted efforts at
recrystallization from a variety of solvents. FTIR (ATR), .nu.max
2922, 2853, 1740, 1671, 1618, 1254 and 977 cm-1. H.sup.1 NMR (300
MHz, CDCl.sub.3) .delta. 0.849 (d, 3H, J=7.2 Hz, C7.alpha.-CH3),
0.882 (t, 3H, J=8.0 Hz, --O(CH.sub.2).sub.9CH.sub.3), 1.115 (s, 3H,
C18-CH.sub.3), 1.117 (d, J=7.2 Hz, C11.beta.-CH.sub.3), 4.129 (t,
J=8.0 Hz, --OCH.sub.2(CH.sub.2).sub.8CH.sub.3) 4.780 (t, 1H, J=7.8
Hz, C17.alpha.-H), 5.166 (br s 1H, C15-H), and 5.876 (s, 1H,
C4-CH.dbd.) ppm. MS (EI) m/z (relative intensity): 484 (M+, 2.5),
282 (100), 190 (12.5), 172 (31.9), 147 (46.9), and 145 (21.9).
17.beta.-Adamantyloxycarbonyloxy-7.alpha.,11-dimethylestra-4,14-dien-3-on-
e (4c, CDB-4650): A pyridine (35 mL) solution of 3 (280 mg, 0.93
mmol) was treated with adamantyl fluoroformate (740 mg, 3.73 mmol)
and the solution was heated at reflux for 18 hours. The solution
was chilled in an ice bath and diluted with cold water. The aqueous
mixture was extracted with ethyl acetate (3.times.). The ethyl
acetate extracts were washed with water and brine, combined, and
dried over sodium sulfate. Evaporation of the solvent gave 970 mg
of a semi-solid. The material was chromatographed using 2%
acetone/dichloromethane) to yield 330 mg of 4c as a stable foam.
The material was dissolved in ethanol (ca. 4 mL) and added dropwise
to cold water (ca. 40 mL) while stirring vigorously. The resulting
solid was filtered, washed with water, and dried in vacuo to yield
303 mg of 4c as a white powder: m.p.=97-100.degree. C. NMR
(CDCl.sub.3) .delta. 0.847 (d, 3H, J=7 Hz, C7.alpha.-Me), 1.100 (s,
3H, C18-Me), 1.116 (d, 3H, J=7 Hz, C11.beta.-Me), 4.730 (t, 11H,
J=8 Hz, C17.alpha.-H), 5.150 (br. s, 11H, C15-C H.dbd.), 5.827 (s,
1H, C4-CH.dbd.) ppm. FTIR (ATR): 2908, 2851, 1723, 1670, 1610,
1238, 1041 cm.sup.-1. MS (EI) m/z (relative intensity): 478
(M.sup.+), 300, 282 (base), 190, 172, 147, 135.
Many of the 11.beta.-substituted 19-nortestosterone such as methyl,
ethyl, chloro and fluoro are known in U.S. Pat. Nos. 3,983,144;
3,325,520; 3,652,606; 4,292,251 and Steroids, 30, 481-510
(1977).
11.beta.-Methyl-17.beta.-dodecyloxycarbonyloxyestr-4-en-3-one (8b),
CDB-4754) (FIG. 3): 11.beta.-Methyl 17.beta.-hydroxyestra-4,9-diene
(5a) was prepared in a manner similar to the procedure described in
Muddana et al., J. Med. Chem., 47, 4985-4988 (2004) for the
preparation of the 11.beta.-ethyl 17.beta.-hydroxyestra-4,9-diene
(5b).
11.beta.-Alkyl-.DELTA..sup.9-19-Nor-testerone derivatives:
High-Affinity ligands and potent partial agonists of the androgen
receptor. (1) 11.beta.-Methyl-17.beta.-hydroxyestr-4-en-3-one
(7.alpha., CDB-4746, FIG. 3).
3,3-Ethylenedioxy-5.alpha.,10.alpha.-epoxy-17.beta.-hydroxyestr-9(11)-ene
(4'): 30% hydrogen peroxide (6.7 mL, 65.1 mmol) was added to an
ice-cold CH.sub.2Cl.sub.2 (70 mL) solution of hexafluoro-acetone
trihydrate (13.15 g, 65.1 mmol). Disodium hydrogen phosphate (3.9
g, 27.47 mmol) was added and the mixture was stirred at 0.degree.
C. for 2 hr. A CH.sub.2Cl.sub.2 (70 mL) of
3,3-Ethylenedioxy-17.beta.-hydroxyestra-5(10), 9(11)-diene (3',
6.85 g, 21.69 mmol) was added and the mixture was stirred at
0-4.degree. C. overnight. The reaction was quenched through the
addition of 10% sodium sulfate solution (100 mL). The aqueous
mixture was extracted with CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2
extracts were washed with H.sub.2O and brine, combined, and dried
over Na.sub.2SO.sub.4. Evaporation of the solvent gave 7.75 g of
the epoxides as a stable foam in quantitative yield. NMR analysis
of the material showed it to be approximately a 5:1 mixture of
5.alpha.,10.alpha.-/5.beta.,10.beta.-epoxides. The material was
used without further purification in the following reaction. NMR
(300 MHz, CDCl.sub.3) .delta. 0.744 (s, 3H, C18-Me), 3.747 (t, 1H,
J=7 Hz, C17.alpha.-H), 3.928 (m, 4H, 3-ketal), 5.836 (m,
C11.beta.-H of 5.beta.,10.alpha.-epoxide) and 6.038 (m,
C11.alpha.-H of 5.alpha.,10.alpha.-epoxide).
11.beta.-Methyl-17.beta.-hydroxyestra-4,9-diene (5a): A solution of
methyl-magnesium bromide (1.4 M THF/toluene) was added to 95 mL of
THF and 1.9 g of copper (I) chloride was added. After stirring at
room temperature for 2 hr a THF solution of the
5.alpha.,10.alpha.-epoxide
(=3,3-ethylenedioxy-5.alpha.,10.alpha.-epoxy-17.beta.-hydroxyestra-9(11)--
ene (10 g, 0.035 mol) was added dropwise over 5 min. The mixture
was stirred at room temperature for 3 hr. The mixture was diluted
with saturated ammonium chloride solution and air bubbled through
the mixture for 2 hr to oxidize Cu (I) to Cu (II). The aqueous
mixture was extracted with ether (3.times.). The ether extracts
were washed with H.sub.2O and brine, combined, and dried over
Na.sub.2SO.sub.4. Evaporation of the solvent gave 9.83 g of yellow
solid.
This solid was dissolved in methanol (400 mL) and 10% HCl solution
(40 mL) was added. The solution was heated to reflux for 3 hr. The
solvent was evaporated in vacuo and the residue was diluted with
water, extracted with ether (3.times.). The ether extracts were
washed with H.sub.2O and brine, combined, and dried over
Na.sub.2SO.sub.4. Evaporation of solvent gave 9.83 g of yellow
solid.
The solid was dissolved in methanol (400 mL) and 40 mL of 10% of
HCl was added. The solution was heated to reflux for 3 hr. The
solvent was evaporated in vacuo and the residue was treated with
saturated sodium bicarbonate solution. The aqueous mixture was
extracted with CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extracts were
washed with H.sub.2O and brine, combined, and dried over
Na.sub.2SO.sub.4. Evaporation of the solvent gave 8.3 g of the
crude 5a as a stable foam in 82% yield. The crude material was
chromatographed by eluting with 11% acetone/CH.sub.2Cl.sub.2 to
afford 6.1 g of 5a. Recrystallization of the solid 5a from
acetone/hexane gave 4.03 g of a yellow crystalline solid in three
crops in 47% yield: m.p.=194-195.degree. C. IR (ATR): .nu.max 3394,
2939, 1641 and 1576 cm.sup.-1. NMR (300 MHz, CDCl.sub.3): .delta.
0.979 (s, 3H, C18-CH.sub.3), 1.170 (d, 3H, C11-CH.sub.3), 3.642 (t,
1H, C17.beta.-H) ppm.
11.beta.-Methyl 17.beta.-hydroxyestr-5(10)-en-3-one (6a): Under an
argon atmosphere, lithium wire (270 mg, 38.9 mmol), cut into small
pieces, was added to anhydrous ammonia (200 mL) and stirred at
reflux for 2 hr. The lithium/ammonia mixture was chilled to
-78.degree. C. and a THF solution of the dienone (5a, 4.03 g, 14.07
mmol) containing t-butanol (1.24 mL), was added over 15 min. The
mixture was stirred at -78.degree. C. for 15 min before excess of
lithium was destroyed with isoprene (1.5 mL). The reaction was
quenched by means of the addition of solid ammonium chloride (16 g,
296.3 mmol). Ammonia was allowed to evaporate under a constant
stream of nitrogen. The THF layer was washed with H.sub.2O and
brine. The aqueous washes were extracted with ether (2.times.200
mL). the combined organic extracts were dried over Na.sub.2SO.sub.4
and evaporation of the solvent gave 4.25 g of 6a as a white solid
in 100% yield. NMR (300 MHz, CDCl.sub.3): .delta. 0.889 (s, 3H,
C18-7CH.sub.3), 0.916 (d, 3H, C11.beta.-CH.sub.3), and 3.655 (t,
1H, C17.beta.-H) ppm.
11.beta.-Methyl 17.beta.-hydroxyestr-4-en-3-one (7.alpha.,
CDB-4746)): The white solid (6a, 4.25 g, 14.73 mmol) was dissolved
in methanol (400 mL) and 40% of 10% HCl was added. The solution was
heated to reflux for 3 hr. The solvent was evaporated in vacuo and
the residue was diluted with saturated sodium bicarbonate solution
and extracted with CH.sub.2Cl.sub.2 (3.times.500 mL). The methylene
chloride extracts were washed with H.sub.2O and brine, combined,
and dried over Na.sub.2SO.sub.4. Evaporation of solvent gave 4.20 g
of a yellow crystalline solid in 99% yield. The crude material was
recrystallized from acetone/hexane to give 1.49 g of solid
(7.alpha., CDB-4746) in two crops in 35% yield.
m.p.=160-161.degree. C. Analysis by a reverse phase HPLC on a
Waters Associate NovaPak C.sub.18 column eluted with 50% aqueous
CH.sub.3CN, at a flow rate of 1 mL/min and at .lamda.=240 nm
indicated 100% purity of 7a with retention time, t.sub.R=3.2 min.
FTIR (ATR): .nu.max 3404, 2939, 2898, 1637, and 1435 cm.sup.-1. NMR
(300 MHz, CDCl.sub.3) .delta. 0.887 (s, 3H, C18-CH.sub.3), 1.008
(d, 3H, C11.beta.-CH.sub.3), 3.615 (t, 1H, C17_-H), and 5.851 (s,
1H, C4-CH.dbd.) ppm. MS (EI) m/z (relative intensity): 288
(M.sup.+, 100), 270 (28), 246 (25), 229 (25), 179 (22), 161 (28),
133 (29), 109 (50) and 90 (22). Anal. Calcd. for
C.sub.19H.sub.28O.sub.2: C, 79.05, H, 9.70. Found: C, 79.05, H,
9.78.
11.beta.-Methyl-17-dodecyloxycarbonyloxy estr-4-en-3-one (8b,
CDB-4754). Dodecyl chloroformate (1.23 g, 4.94 mmol) was added
dropwise to a solution of 7a (950 mg, 3.39 mmol) in
CH.sub.2Cl.sub.2 (50 mL) and pyridine (1.30 g, 5 eq) chilled at
0.degree. C. After addition, and removal of ice bath it was allowed
to stir at room temperature for 4 hr. The reaction was monitored by
Thin Layer Chromatography (TLC) (2% acetone/CH.sub.2Cl.sub.2). The
organic layer was washed with H.sub.2O and brine, combined, and
dried over Na.sub.2SO.sub.4. Evaporation of the solvent gave 2.67 g
of solid. This material was chromatographed over silica (2%
acetone/CH.sub.2Cl.sub.2) and recrystallized twice from pentane,
recovering 1.11 g of a fine white crystalline powder (8b, CDB-4754)
in 43% yield. m.p.=54.7-55.4.degree. C. Analysis by a reverse phase
HPLC on a Waters Associate NovaPak C.sub.18 column eluted with 50%
H.sub.2O in CH.sub.3CN, at a flow rate of 1 mL/min and at
.lamda.=240 nm indicated 100% purity of 8b with retention time,
t.sub.R=12.13 min. FTIR (ATR): .nu.max 2899, 2848, 1727, 1616, and
1253 cm.sup.-1. NMR (300 MHz, CDCl.sub.3) .delta. 0.881 (s, 3H,
C18-CH.sub.3), 1.052 (d, 3H, C11.beta.-CH.sub.3), 4.109 (t, 1H,
C17.beta.-H), and 5.848 (s, 1H, C4-C H.dbd.) ppm. MS (EI) m/z
(relative intensity): 500.52 (M.sup.+, 57), 271 (44), 270 (48),
161(100), 160 (70), 147 (41), 119 (34), and 110 (65). Anal. Calcd.
for C.sub.32H.sub.52O.sub.4: C, 76.68, H, 10.38. Found: C, 76.44,
H, 10.37.
11.beta.-Methyl-17.beta.-decyloxycarbonyloxyestr-4-en-3-one (8a,
CDB-4757): Decyl chloroformate (7.6 mL, 2 eq) was added dropwise
with a syringe to a solution of 7a (5.0 g, 17.33 mmol) in
CH.sub.2Cl.sub.2 (250 mL) and pyridine (6.9 g, 5 eq) chilled at
-4.degree. C. After completion of addition of decyl chloroformate,
the ice bath was removed and the reaction mixture was stirred for 5
hr at room temperature. The reaction was monitored by TLC (3%
acetone/CH.sub.2Cl.sub.2). The reaction mixture was poured into
cold distilled H.sub.2O; and the lower organic phase was washed
with H.sub.2O and brine. All aqueous washes were extracted twice
with CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2 were dried
over anhydrous Na.sub.2SO.sub.4. Evaporation of the solvent gave
8.9 g of a white solid. The crude white solid was recrystallized
from pentane to afford 3.9 g of a white crystalline powder in 47.6%
yield. m.p.=48.9 -49.3.degree. C. Analysis by a reverse phase HPLC
on a Waters Associate NovaPak C.sub.18 column eluted with 100%
CH.sub.3CN, at a flow rate of 1 mL/min and at .lamda.=240 nm
indicated 100% purity of (8a, CDB-4757) with retention time,
t.sub.R=6.99 min. FTIR (ATR): .nu.max 2919, 2848, 1727, 1621, 1379,
1253 and 960 cm.sup.-1. NMR (300 MHz, CDCl.sub.3): .delta.0.880 (s,
3H, C18-CH.sub.3), 1.052 (d, 3H, C11.beta.-CH.sub.3), 4.108 (t, 1H,
C17.beta.-H), and 5.847 (s, 1H, C4-C H.dbd.) ppm. MS (EI) m/z
(relative intensity): 472 (M.sup.+, 27), 270 (41), 161 (100), 145
(36), 119 (31), and 110 (21). Anal. Calcd for
C.sub.30H.sub.48O.sub.4: C, 76.16, H, 10.15. Found: C, 76.05, H,
10.29.
11.beta.-Ethyl-17.beta.-dodecyloxycarbonyloxyestr-4-en-3-one (9b,
CDB-4722) was prepared from 7b. (1)
11.beta.-Ethyl-17.beta.-hydroxyestr-4-en-3-one (7b, CDB-4758, FIG.
3) was prepared from 5b as follows:
3,3-Ethylenedioxy-5.alpha.,10.alpha.-epoxy-17.beta.-hydroxyestr-9(11)-ene-
: 30% hydrogen peroxide (6.7 mL, 65.1 mmol) was added to an
ice-cold CH.sub.2Cl.sub.2 (70 mL) solution of hexafluoro-acetone
trihydrate (13.15 g, 65.1 mmol). Disodium hydrogen phosphate (2.8
g, 19.74 mmol) was added and the mixture was stirred at 0.degree.
C. for 2 hr. A CH.sub.2Cl.sub.2 (70 mL) of
3,3-ethylenedioxy-17.beta.-hydroxyestra-5(10), 9(11)-diene (6.85 g,
21.69 mmol) was added and the mixture was stirred at 0-4.degree. C.
overnight. The reaction was quenched through the addition of 10%
sodium sulfate solution (100 mL). The aqueous mixture was extracted
with CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extracts were washed
with H.sub.2O and brine, combined, and dried over Na.sub.2SO.sub.4.
Evaporation of the solvent gave 7.75 g of the epoxides as a stable
foam in quantitative yield. NMR analysis of the material showed it
to be approximately a 5:1 mixture of
5.alpha.,10.alpha.-/5.beta.,10.beta.-epoxides. The material was
used without further purification in the following reaction. NMR
(300 MHz, CDCl.sub.3) .delta. 0.744 (s, 3H, C18-Me), 3.747 (t, 1H,
J=7 Hz, C17.alpha.-H), 3.928 (m, 4H, 3-ketal), 5.836 (m,
C11.beta.-H of 5.beta.,10.beta.-epoxide) and 6.038 (m, C11.alpha.-H
of 5.alpha.,10.beta.-epoxide).
11.beta.-Ethyl-17.beta.-hydroxyestra-4,9-dien-3-one (5b): Ethyl
magnesium bromide (1.0 M/THF, 19.5 mL, 19.5 mmol) was chilled to
0.degree. C. and diluted dry ether (19.5 mL). With stirring, copper
chloride (193.6 mg. 1.95 mmol) was added over 2 hr and the mixture
was allowed to stir for 45 min. A THF (50 mL) of the epoxide (1.0
g, 3.01 mmol) prepared according to the procedure described above
was added over 2 hr to the mixture. The reaction mixture was
stirred for 3 hr at 0.degree. C. and then carefully quenched
through the addition of a saturated ammonium chloride solution (100
mL). While stirring, air was drawn through the mixture to oxidize
Cu(I) to Cu(II). The mixture was extracted with ether. The ether
extracts were washed with H.sub.2O and brine, combined, and dried
over Na.sub.2SO.sub.4. Evaporation of the solvent gave 1.24 g of a
stable foam. The above product from two identical reactions (2.58
g) was dissolved in methanol (200 mL) and 10% HCl solution (20 mL)
was added. The solution was stirred overnight at room temperature.
The methanol was evaporated in vacuo and the residue was diluted
with water. The aqueous mixture was extracted with
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extracts were washed with
H.sub.2O and brine, combined, and dried over Na.sub.2SO.sub.4.
Evaporation of the solvent gave 1.73 g. The crude material was
chromatographed eluting with 12% acetone/to afford 660 mg of the
dien-one 5b as a stable foam in 71% yield. Repeated efforts at
crystallization of this material from a variety of solvents were
unsuccessful. The material was homogeneous by TLC and NMR analysis
showed it to be only one epimer. NMR (300 MHz, CDCl.sub.3): .delta.
0.931 (t, 3H, J=7.2 Hz, --CH.sub.2-CH.sub.3), 0.963 (s, 3H,
C18-CH.sub.3), 3.645 (t, 1H, J=7 Hz, C17.alpha.-H), and 5.683 (s,
1H, C4-CH.dbd.) ppm.
11.beta.-Ethyl-17.beta.-hydroxyestr-4-en-3-one (7b, CDB-4758) (2):
Lithium wire (45.74 mg, 6.59 mmol), cut into small pieces, was
added to anhydrous ammonia (ca. 20 mL). The mixture was stirred at
-35.degree. C. for 20 min. After chilling, the reaction mixture to
-78.degree. C., a THF (20 mL/t-butanol (0.21 mL, 2.22 mmol)
solution of the dien-one (5b, 660 mg, 2.22 mmol) was added dropwise
over 10 min. After stirring for 15 min, excess lithium was
destroyed through the addition of isoprene (1.0 mL), followed by
the addition of ammonium chloride (2.64 g). The ammonia was
evaporated under as stream of nitrogen. The residue was diluted
with phosphate buffer (0.1 M, pH=7.0, 50 mL). The aqueous mixture
was extracted with ether. The ether extracts were washed with
H.sub.2O and brine, combined, and dried over Na.sub.2SO.sub.4.
Evaporation of the solvent gave 850 mg. The crude material above
was dissolved in methanol (125 mL) and 10% HCl solution (12.5 mL)
was added. The solution was heated at reflux for 4 hr. The solvent
was evaporated in vacuo and the residue was diluted with H.sub.2O.
The aqueous mixture was extracted with CH.sub.2Cl.sub.2. The
CH.sub.2Cl.sub.2 extracts were washed with H.sub.2O and brine,
combined, and dried over Na.sub.2SO.sub.4. Evaporation of the
solvent gave 720 mg of a stable foam. The material was
chromatographed using 3% MeOH/CH.sub.2Cl.sub.2 to give 400 mg in
60% yield. This material was recrystallized from acetone/hexanes to
give 182 mg of pure 7b as a white crystalline powder in 27% yield.
m.p.=147-148.degree. C. Analysis by a reverse phase HPLC on a
Waters Associate NovaPak C.sub.18 column eluted with 50% aq.
CH.sub.3CN, at a flow rate of 1.0 mL/min and at .lamda.=240 nm
indicated 98% purity of 8a (CDB-4757) with retention time,
t.sub.R=4.62 min. FTIR (ATR): .nu.max 3433, 2958, 2858, 1651, 1613,
1447, 1262, 1212, 1070, 974 and 889 cm.sup.-1. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 0.888 (s, 3H, C18-CH.sub.3), 0.992 (t, 3H,
J=7.2 Hz, C11.beta.-CH.sub.2CH.sub.3), 3.627 (t, 1H, J=7 Hz,
C17.beta.-H), and 5.846 (s, 1H, C4-CH.dbd.) ppm. .sup.13C NMR
(CDCl.sub.3) .delta. 12.741, 13.359, 20.645, 23.086, 25.947,
30.131, 35.265, 35.912, 37.415, 38.036, 42.849, 52.022, 53.595,
82.750, 124.200, 168.043, and 199.928 ppm. MS (EI) m/z (relative
intensity): 302.6 (M.sup.+), 284.6 (M.sup.+ -18, 9), 193 (26), 175
(11), 147 (18), 133 (24), 123 (38), and 110 (100). Anal. Calcd. for
C.sub.20H.sub.30O.sub.2C, 79.46, H, 9.81. Found: C, 79.42, H,
10.00.
11.beta.-Ethyl-17.beta.-dodecyloxycarbonyloxyestr-4-en-3-one (9b,
CDB-4722) was prepared as follows: Under nitrogen, a solution of
11.beta.-ethylestr-4-en-17.beta.-ol (7b, 0.1 g, 0.33 mmol) in dry
CH.sub.2Cl.sub.2 (5 mL) was cooled to 0.degree. C. in an ice bath.
Pyridine (0.1 mL, 97.8 mg, 1.24 mmol) followed by dodecyl
chloroformate (0.2 mL, 1.84 mg, 0.74 mmol) were added and the
mixture stirred at 0.degree. C. for 15 min and then allowed to warm
to room temperature. The reaction was stirred at room temperature
overnight, after which time, TLC (2% acetone in CH.sub.2Cl.sub.2)
indicated a complete reaction. The mixture was diluted with
additional CH.sub.2Cl.sub.2 (50 mL) and washed with water
(1.times.), saturated sodium bicarbonate solution (1.times.), and
water (1.times.). The organic fractions were filtered through
anhydrous Na.sub.2SO.sub.4, combined and concentrated in vacuo to
give 0.3 g residue as a clear oil. This crude material was purified
by Flash chromatography (2% acetone in CH.sub.2Cl.sub.2) to give
0.16 g of a clear oil in 94% yield, which resisted
crystallization.
Analysis by HPLC on Waters Assoc. NovaPak C-18 eluted with 100%
CH.sub.3CN at a flow rate of 1 mL/min and at .lamda.=240 nm)
indicated compound 9b to be 99% pure with a retention time
(t.sub.R) of 12.37 min. FTIR (ATR) .nu.max 2923, 2853, 1740, 1674
and 1526 cm.sup.-.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.882 (t, 3H, J=6.8 Hz,
dodecyl CH.sub.3), 0.956 (s, 3H, C18-CH.sub.3), 0.981 (t, 3H, J=7.4
Hz, C11.beta.-CH.sub.2CH.sub.3), 4.119 (t, 2H, J=6.8 Hz,
dodecyl-OCH.sub.2--), 4.468 (dd, 1H, J1=9 Hz, J2=7.2 Hz,
C17.alpha.-CH), and 5.858 (s, 1H, C4-CH.dbd.).
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 12.818
(C11.beta.-CH.sub.2CH.sub.3), 14.124 (dodecyl-CH.sub.3), 14.344
(C18), 20.743, 22.681, 23.117, 25.693, 26.0690, 27.288, 28.680,
29.239, 29.339, 29.492, 29.555, 29.621, 31.410, 31.913, 35.019,
35.225, 36.243, 37.624, 37.959, 38.024, 42.675, 51.756, 53.446,
68.022 (dodecyl-OCH.sub.2--), 87.134 (C17), 124.426 (C4), 155.361
(carbonate C.dbd.O), 167.444 (C5) and 199.652 (C3) ppm. Anal.
Calc'd for C.sub.33H.sub.54O.sub.4: C, 77.04, H, 10.51.
EXAMPLE 2
This example demonstrates some of the biological activity of
compounds in accordance with an embodiment of the invention. The
androgenic activity was tested as follows (see, Hershberger et al.,
Proc. Soc. Exptl. Biol. Med., 83: 175-180 (1953)). Immature
(approximately 21 day old) male rats of the Sprague-Dawley strain
were orchidectomized under METOFANE.RTM. anesthesia and randomly
assigned to groups of ten animals for each dose level of test
material and vehicle controls. Animals were maintained under
standard conditions of housing and had free access to food and
water. Illumination was controlled for 14-hour periods of light and
10 hours of darkness. Test compounds were dissolved in 10%
ethanol/sesame oil and administered by gavage (oral) or
subcutaneous injection daily for seven consecutive days starting on
the day of surgery. Animals were sacrificed 24 hours after the last
dose and the ventral prostate and seminal vesicles excised, cleaned
of fat and connective tissue, blotted on moist filter paper and
weighed to the nearest 0.1 mg. Ventral prostate weight was used as
the endpoint because ventral prostate is the more sensitive organ
to androgenic stimulation.
Statistical analysis was performed by conventional methods using a
PROPHET data management system operating on SUN Microsystems OS
4.1.1 (see e.g., Bliss, Cl (1952) The Statistics of Bioassay, New
York, Academic Press; Hollister, C (1988), Nucleic Acids Research,
16:1873-1875.
Duration of androgenic activity was determined as follows. Immature
(22 days of age) male rats of the Sprague-Dawley CD strain were
orchidectomized under METOFANE anesthesia and randomly assigned to
groups of forty or more animals. Animals were maintained under
standard conditions of housing and had free access to food and
water. Illumination was controlled for 14-hour periods of light and
10 hours of darkness. Animals received a single subcutaneous
injection of 0.6 mg of test material in aqueous suspending vehicle
(ASV) and/or an oily vehicle (10% ethanol/sesame oil, sesame oil
containing 5 mg/ml chlorobutanol as a preservative or ethyl oleate)
on the day of surgery. Controls received vehicle alone.
Testosterone enanthate in sesame oil was used as a standard. In
cases where the test material was not solid at room temperature,
i.e., a wax or oil, 10% ethanol/sesame oil or ethyl oleate was used
as a vehicle. Five rats from each group were sacrificed at weekly
or biweekly intervals and seminal vesicle and ventral prostate
glands were excised, cleaned of adherent fat and connective tissue
and weighed to the nearest 0.1 mg. Ventral prostate weight was used
as the endpoint because it is the more sensitive organ to
androgenic stimulation. Area under the curve (AUC) was calculated
by the trapezoidal rule.
Serum levels of testosterone and CDB-1321 were determined as
follows. Rats from a duration of androgenic activity study were
exsanguinated at autopsy, serum prepared by allowing blood to clot
at room temperature and the sample frozen for subsequent
radioimmunoassay. A radioimmunoassay for the free alcohol, 7a,
11.beta.-dimethyl-19-nortestosterone, was developed using antisera
generated in rabbits against the 3-carboxymethyloxime-BSA conjugate
and employing the corresponding histamine conjugate for iodination
as tracer. The assay was validated for rat serum and exhibited high
specificity for the free alcohol, CDB-1321.
Results of the androgenic assays of CDB-4718 (2a), 4719 (2c), 4730
(2d), and 4731 (2b) are shown in FIGS. 5 and 6. Each data point
represents the mean (n=10) and standard error of the mean (SEM)
prostate weight for each dose level. The potency ratio and 95%
confidence index are set forth below.
TABLE-US-00001 ANDROGENIC ACTIVITY CDB No. Potency Ratio 95% C.I.
4718 2.609.sup.1 1.554-4.381 4719 5.486-8.992.sup.1,2 -- 4730
0.97-3.82.sup.1,2 -- 4731 1.18-3.27.sup.1,2 -- 4718 vs. 4719 3.016
1.824-4.988 .sup.1CDB 110 (Methyl testosterone) = 1.000 assigned.
.sup.2Did not pass all significance test.
Fitted Lines:
TABLE-US-00002 O CDB-4718: Y = 31.31 log (x) + 41.95 .DELTA.
CBD-4719: Y = 44.41 log (x) + 53.7 .quadrature. CBD-110B: Y = 27.45
log (x) + 31.77
TABLE-US-00003 ANDROGENIC ACTIVITY CDB No. Potency Ratio 95% C.I.
4718 10.4-47.5.sup.1,2 -- 4719 0.64 0.42-0.98 4730 0.05.sup.1,2
0.03-0.11 4731 32.0.sup.1,2 4.2-241.2 .sup.1CBD-111 (Testosterone)
= 1.000 assigned .sup.2Did not pass all significance tests.
CDB-4718, 7.alpha.,11.beta.-Dimethyl-19-nortestosterone
17-methylcarbonate (2a), exhibited about two and one-half times the
oral activity of the standard, methyltestosterone, but 10.4-47.5
times testosterone following subcutaneous injection in sesame oil
vehicle. These findings were completely unexpected since
testosterone and its esters are poorly active on oral
administration. The potent activity following subcutaneous
injection was also surprising given the short duration of action
following a single subcutaneous injection in aqueous vehicle. The
subcutaneous standard, testosterone, exhibited the expected
activity. Similar findings were observed following both routes of
administration using seminal vesicle weight as an endpoint.
CDB-4719, 7.alpha.,11.beta.-dimethyl-19-nortestosterone
17-decylcarbonate (2c), exhibited five to nine times the oral
activity of methyltestosterone but was no more potent than
testosterone standard upon subcutaneous injection. On the other
hand, it was far more potent than testosterone in the duration of
activity test.
CDB-4730, 7.alpha.,11.beta.-dimethyl-19-nortestosterone
17-dodecylcarbonate (2d), exhibited 0.97-3.82 times the oral
activity of methyltestosterone standard but only 5% of the potency
of the subcutaneous standard, testosterone. However, it was far
more potent in the duration of androgenic activity test.
CDB-4731, 7.alpha.,11.beta.-dimethyl-19-nortestosterone
17-hexylcarbonate (2b), exhibited 1.18-3.27 times the oral activity
of methyltestosterone but 32 times the potency of the subcutaneous
standard, testosterone.
The potent oral activity may be explained, in part, by the fact
that the ester may be protected from degradation in the
gastrointestinal tract and/or rapid metabolism by the liver. It is
also possible that the lipophilic nature of some esters
(particularly the decylcarbonate) permits absorption through the
thoracic lymph thus avoiding direct entrance into the portal system
and "first-pass" metabolism in the liver. The oral activity of
these esters cannot be predicted but must be determined by direct
in vivo bioassay. Within a certain range of carbon chain length,
there is probably some correlation with lipophilicity.
The lack of potent subcutaneous activity of the decylcarbonate and
dodecylcarbonate in the standard Hershberger test probably reflects
the slow release (and possibly metabolism) of the drug from the
injection site over the 7-day administration period. This is the
very property that conveys long-acting activity upon parenteral
administration in an aqueous vehicle.
Results of the duration of androgenic activity test are shown in
FIG. 7-8. Each data point represents the mean (n=5) and standard
error of the mean (SEM) prostate weight for each time period. FIG.
7 shows ventral prostate weights at weekly intervals over a 14-week
period following a single subcutaneous injection of 0.6 and 1.2 mg
of the dimethandrolone 17-methylcarbonate (CDB-4718) and the
dimethandrolone 17-decylcarbonate (CDB-4719) as aqueous
microcrystalline suspensions. In FIG. 8, the data for 1.2 mg dose
groups are shown together with historical data for testosterone
undecanoate in aqueous suspension and testosterone enanthate in
sesame oil as standards. Both testosterone undecanoate and
testosterone enanthate are commercially available. CDB-4719 (2c) in
aqueous suspending vehicle exhibited the most dramatic increase and
maintenance of ventral prostate weight with the area under the
curve (AUC) for the 14-week observation period calculated as 2764
mgweeks. This was more than three times greater than that for the
commercial preparation of testosterone enanthate in sesame oil
(AUC=760) and more than five times greater than that for
testosterone undecanoate (AUC=494).
CDB-4730 (2d), the dodecylcarbonate, but not CDB-4731 (2b), the
hexylcarbonate, exhibited similar long-acting activity. CDB-4719
(2c) and 4730 (2d) remain at the injection site following
administration as a microcrystalline aqueous suspension forming a
depot from which the drug is slowly leached. Hydrolysis to the
corresponding free alcohol probably occurs prior to binding to
tissue specific androgen receptors and the initiation of
transcription and pharmacological activity.
FIG. 9 depicts the serum concentration of dimethandrolone and
immunoreactive metabolites following a single subcutaneous
injection to castrate Sprague-Dawley rats of 1.2 mg of CDB-4718
(2a, open circles, 0.6 mg; filled circles, 1.2 mg), CDB-4719 (2c,
open squares, 0.6 mg; filled squares, 1.2 mg) in an aqueous
suspending vehicle (n=5). The AUC's (area under the curves, mgweek)
were as follows: open circles, 2848; filled circles, 3336; open
squares, 4151; and filled squares, 6010. `F` is aqueous control
vehicle, with an AUC of 1590 mgweek.
Serum samples from rats taken at autopsy showed the presence of the
free alcohol as measured by a highly specific radioimmunoassay,
which decreased with time over the 14-week observation period (FIG.
10A-B). The free alcohol itself produced serum levels barely above
the limit of detection of 63 pg/ml during the first 3 weeks.
FIG. 11 shows the androgenic activity (ventral prostate weight) as
a function of dose of CDB-4757, 11.beta.-methyl-19-nortestosterone
17.beta.-decylcarbonate. The androgenic activities of CDB-4756
(dimethandrolone decanoate) and CDB-110B (methyltestosterone
standard) are also shown. The potency ratio and 95% confidence
index are set forth below.
TABLE-US-00004 BIOLOGICAL ACTIVITY DRUG Potency Ratio 95% C.I.
CDB-119B 1.00 (assigned) CDB-4756 2.13-7.56 -- CDB-4757 1.96
1.04-367
FIG. 12 shows the duration of androgenic activity of CDB-4719 (2c)
and 4730 (2d) over a period of 8 weeks following a single dose
administered by subcutaneous injection in an aqueous suspending
vehicle on week 0.
FIG. 13 shows the duration of androgenic activity of CDB-4754 (8b)
and 4750A (4c) over a period of 14 weeks following a single dose
administered by subcutaneous injection on week 0. The AUC (mgweek)
were as follows: CDB-4754, 0.6 mg, 564; CDB-4754, 1.2 mg, 974;
CDB-4750A, 0.6 mg, 326; and CDB-4750A, 1.2 mg, 759.
Carbonates of the invention, in embodiments, can be used to
suppress luteinizing hormone in a mammal for extended periods of
time. This is illustrated in FIG. 14, which shows that serum levels
of the hormone remains suppressed for several weeks even after the
administration of a carbonate of the invention was stopped.
CDB-4719A (dimethandrolone 17.beta.-decylcarbonate) was
administered to castrate male rats, daily at 12 mg/kg oral doses,
and CDB-4521C (dimethandrolone 17.beta.-undecanoate) was
administered in 10% ethanol/sesame oil, on days 0-13. The serum
level of the hormone remained suppressed for both groups of animals
during the administration of the drug. When the administration of
the drug was discontinued, the hormone level, as expected, bounced
back and increased beyond the pretreatment level (at week -1 or 0)
for the ester drug. However, with the carbonate, unexpectedly and
surprisingly, the hormone level remained suppressed for several
weeks. This observation could have advantageous clinical
implications, for example, in obtaining sustained suppression of
the luteinizing hormone or hormone replacement therapy. In
addition, this could have an advantage by providing a facile
treatment using oral compositions such as tablets or capsules of
the carbonates of the invention in suppressing hormone levels. Such
treatment can be advantageous relative to a treatment involving
parenteral (e.g., subcutaneous) administration of a drug such as
the ester drug. Patient compliance is better with oral formulations
than injections.
FIG. 15 provides a comparison between CDB-4719A (dimethandrolone
17.beta.-decylcarbonate) and CDB-4521C (dimethandrolone
17.beta.-undecanoate). A single dose (12 mg/kg) of the compound was
administered to castrate male rats by subcutaneous injection in an
aqueous suspending vehicle on day 0. The serum rLH concentration
was monitored over a 22-week period and beyond. Up to 16 weeks post
administration, the serum level remains suppressed. The serum
hormone level rose after 16 weeks for the undecanoate but the serum
hormone level remained past the 16-week period for the carbonate.
The serum level remained suppressed even at week 22.
In another experiment, the serum levels of CDB-1321
(dimethandrolone) and immunoreactive metabolites were monitored
after the administration of a single subcutaneous dose of CDB-4730
(dimethandrolone 17.beta.-dodecylcarbonate) in an aqueous
suspending vehicle. FIG. 16 shows that the serum levels of
dimethandrolone and immunoreactive metabolites decreased with time
as expected.
All references, including publications, patent applications, and
patents, cited herein are hereby incorporated by reference to the
same extent as if each reference were individually and specifically
indicated to be incorporated by reference and were set forth in its
entirety herein.
The use of the terms "a" and "an" and "the" and similar referents
in the context of describing the invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. The terms "comprising," "having,"
"including," and "containing" are to be construed as open-ended
terms (i.e., meaning "including, but not limited to,") unless
otherwise noted. Recitation of ranges of values herein are merely
intended to serve as a shorthand method of referring individually
to each separate value falling within the range, unless otherwise
indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein. All
methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as") provided herein, is intended merely to better
illuminate the invention and does not pose a limitation on the
scope of the invention unless otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
Preferred embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Variations of those preferred embodiments may become
apparent to those of ordinary skill in the art upon reading the
foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
* * * * *