Androgenic steroid compounds and a method of making and...

Details Androgenic steroid compounds and a method of making and... Androgenic steroid compounds and a method of making and...

2002-01-22

2003-12-30

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S647000

Reexamination Certificate

active

06670352

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to androgenic steroid compounds and a method of making and using the same.
2. Discussion of the Background
Testosterone is the principal male hormone and is required for the development and maintenance of secondary sexual characteristics, libido and spermatogenesis. Testosterone also has anabolic properties, in promoting in muscle growth and maintenance. Lower than normal testosterone levels in men have been associated with low energy, frailty, depression, decreased libido, weakness, lethargy, loss of lean body and bone mass and impotence. A second androgen, dihydrotestosterone (DHT), is produced from testosterone. DHT is a potent androgen. It is believed to be responsible for prostate growth and inhibitors of the enzyme that forms it have been used to treat prostatic hypertrophy and benign prostate hyperplasia.
Testosterone is rapidly metabolized in the body. Since the liver metabolizes most orally administered testosterone before it reaches the systemic blood circulation, large oral doses are necessary in order to have the desired effect. To some extent, this difficulty may be overcome by using the drug in the form of a fatty acid ester and administering the same by intramuscular injection, nevertheless, doses of 200 mg must still be given at weekly or bi-weekly intervals. Although testosterone can be administered by skin patch, large patches must be used due to low activity and rapid metabolism. Recently, a permeation-enhanced back patch was reported, however, this still requires the use of two large, i.e. 37 cm
2
patches for a total area of 11.5 in
2
or about 30% more area than an ordinary playing card.
Hence, a need exists for an androgenic compound that has enhanced potency relative to testosterone, which would permit more facile procedures for administration, such as the use of smaller skin patches, implantable devices or even oral or buccal administration.
SUMMARY OF THE INVENTION
In accordance with the present invention, androgenic steroid compounds are provided which exhibit enhanced activity relative to testosterone.
The present invention also provides a method of making the androgenic steroid compounds.
The present invention also provides a therapeutic method for the administration of the present androgenic steroid compounds and compositions containing the same.
Accordingly, the above objectives and others are provided by an androgenic steroid compound having the ring numbering system and the formula (I):
wherein R
1
is H or lower alkyl;
Y—Z is CH═C or CH
2
—CH, wherein H is &agr; to the rings, or Y—CH wherein H is &agr; to the rings and Y is S, O, or NR
10
, wherein R
10
is H or lower alkyl;
R
2
is an &agr;-substituent which is unsubstituted lower alkyl or fluoro-substituted lower alkyl;
R
3
is C
1
-C
8
alkyl, or C
2
-C
8
alkenyl or alkynyl, which are optionally substituted; or R
3
is C
4
-C
8
cycloalkyl which is unsubstituted or substituted; or R
3
is C
6
-C
18
aryl which is unsubstituted or substituted; or R
3
is a 5- to 15-membered heterocycle which is unsubstituted or substituted, and further wherein any of the above may be substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or
R
3
is H or an acyl group (CO)—R
4
, wherein R
4
is C
1
-C
18
alkyl, or C
2
-C
18
alkenyl or alkynyl which are optionally substituted; or R
4
is C
4
-C
18
cycloalkyl or substituted cycloalkyl; or R
4
is C
6
-C
18
aryl or substituted aryl; or R
4
is a 5- to 15-membered heterocycle or substituted heterocycle, and wherein R
4
may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both;
R
5
is &agr;-H, and R
6
is &bgr;-lower alkyl, alkenyl or alkynyl which are optionally substituted; or R
5
R
6
is ═CH
2
; and
X is O, H
2
, (H, OH) or (H
1
, OCOR
4
), wherein R
4
is as defined above; or X is (H, OR
3
), wherein R
3
is as defined above; or X is NOR
7
, wherein R
7
is H or C
1
-C
8
alkyl, or C
2
-C
8
alkenyl or alkynyl which are optionally substituted; or R
7
is C
4
-C
8
cycloalkyl or substituted cycloalkyl; or R
7
is C
6
-C
18
aryl or substituted aryl; or R
7
is a 5- to 15-membered heterocycle or substituted heterocycle, and R
7
may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or X is (OR
8
, OR
9
), where R
8
and R
9
are lower alkyl or (OR
8
, OR
9
) is a cyclic structure containing 2 to 3 carbon atoms, optionally substituted with lower alkyl, or 1 or 2 heteroatoms or halogens.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, certain androgenic steroid compounds are provided which exhibit surprisingly enhanced activity relative to testosterone. Due to the enhanced potency of the present compounds, their administration is quite facile. For example, by virtue of the present invention, it is now possible to significantly reduce the size of skin patches required for skin administration. This also provides greater flexibility in the design of the patches. Moreover, the compounds of the present invention exhibit long-lasting effects after injection.
Generally, the present invention provides androgenic steroid compounds of the formula (I):
wherein:
R
1
is H or lower alkyl;
Y—Z is CH═C or CH
2
—CH, wherein H is &agr; to the rings; or Y—CH wherein H is &agr; to the rings and Y is S, O, or NR
10
, wherein R
10
is H or lower alkyl;
R
2
is an &agr;-substituent which is unsubstituted lower alkyl or fluoro-substituted lower alkyl;
R
3
is C
1
-C
8
alkyl, or C
2
-C
8
alkenyl or alkynyl which are optionally substituted; or R
3
is C
4
-C
8
cycloalkyl which is unsubstituted or substituted; or R
3
is C
6
-C
18
aryl which is unsubstituted or substituted; or R
3
is a 5- to 15-membered heterocycle which is unsubstituted or substituted, and further wherein any of the above may be further substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or
R
3
is H or an acyl group (CO)—R
4
, wherein R
4
is C
1
-C
18
alkyl, or C
2
-C
18
alkenyl or alkynyl which are optionally substituted; or R
4
is C
4
-C
18
cycloalkyl or substituted cycloalkyl; or R
4
is C
6
-C
18
aryl or substituted aryl; or R
4
is a 5- to 15-membered heterocycle or substituted heterocycle, and wherein R
4
may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both;
R
5
is &agr;-H, and R
6
is &bgr;-lower alkyl, alkenyl or alkynyl which are optionally substituted; or R
5
R
6
is ═CH
2
; and
X is O, H
2
, (H, OH) or (H, OCOR
4
), wherein R
4
is as defined above, or X is (H, OR
3
), wherein R
3
is as defined above; or X is NOR
7
, wherein R
7
is H or C
1
-C
8
alkyl or C
2
-C
8
alkenyl or alkynyl, optionally substituted; or R
7
is C
4
-C
8
cycloalkyl which is unsubstituted or which is unsubstituted or substituted, and R
7
may be optionally substituted with 1 to 3 heteroatoms or 1 to 5 halogen atoms or both; or X is (OR
8
, OR9), where R
8
and R
9
are lower alkyl, or (OR
8
, OR
9
) is a cyclic structure containing 2 to 3 carbon atoms, optionally substituted with lower alkyl, or 1 to 2 heteroatoms or halogen atoms or both.
In the above formula, it is preferred that R
1
is H, R
2
is CH
3
, R
3
is H, or is an acyl group of the formula R
4
(CO), wherein R
4
is CH
3
, C
2
H
5
, n-C
6
H
13
, (CH
3
)
2
CH, cyclopentyl-CH
2
—CH
2
, trans-(4-n-butyl)cyclohexyl, n-C
9
H
19
, (CH
2
)
2
(CO)(CH
2
)
5
CH
3
, phenyl-CH
2
or 3-pyridyl, or R
3
is CH
3
, C
2
H
5
, CH
2
OCH
3
, Si(CH
3
)
3
, CCl
3
—CH(OH), or 2-tetrahydropyranyl; R
5
is &agr;-H and R
6
is &bgr;-CH
3
or R
5
R
6
is ═CH
2
; and X is O, NOH or NOCH
3
.
More preferably, compounds, such as 7&agr;,11&bgr;-dimethyl-17&bgr;-hydroxyestr-4-en-3-one, 17&bgr;-hydroxy-7&agr;-methyl-11-methyleneestr-4-en-3-one, 7&agr;,11&bgr;-dimethyl-17&bgr;-heptanoyl-oxyestr-4-en-3-one, 7&agr;,11&bgr;-dimethyl-17&bgr;-[[(2-cyclopentylethyl)carbonyl]oxy]estr-4-en-3-one, 7&agr;,11&bgr;-dimethyl-17&bgr;-(phenacetyloxy)estr-4-en-3-one, 7&agr;,11&bgr;-dimethyl-17&bgr;-[&lsq

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