U.S. patent application number 10/177989 was filed with the patent office on 2004-02-19 for testosterone derivative.
Invention is credited to Leysen, Dirk D., Van Der Voort H.A.A., Hendrikus Adrianus Antonius.
Application Number | 20040033999 10/177989 |
Document ID | / |
Family ID | 8233831 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040033999 |
Kind Code |
A1 |
Leysen, Dirk D. ; et
al. |
February 19, 2004 |
Testosterone derivative
Abstract
The invention is the novel androgen
(7.alpha.,17.beta.)-7-methyl-17-[(1-ox- oundecyl)oxy]estr-4en-3one
(MENT undecanoate). This compound distinguishes favourably from
other testosterone derivatives in that it has a good solubility in
oily media. It particularly exhibits a good dissolved potency
relative to testosterone. The compound is particularly suitable for
administration by means of injection.
Inventors: |
Leysen, Dirk D.; (Lommel,
BE) ; Van Der Voort H.A.A., Hendrikus Adrianus Antonius;
(Ch Veghel, NL) |
Correspondence
Address: |
INTERVET INC
405 STATE STREET
PO BOX 318
MILLSBORO
DE
19966
US
|
Family ID: |
8233831 |
Appl. No.: |
10/177989 |
Filed: |
June 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10177989 |
Jun 21, 2002 |
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09719927 |
Dec 18, 2000 |
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6437158 |
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Current U.S.
Class: |
514/170 |
Current CPC
Class: |
C07J 1/0074 20130101;
A61P 43/00 20180101; A61P 5/26 20180101; A61P 5/24 20180101; A61P
15/16 20180101 |
Class at
Publication: |
514/170 |
International
Class: |
A61K 031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 19, 1998 |
EP |
98202052.1 |
Claims
We claim:
1. A kit for male contraception, comprising: a means for the
administration of a progestagen and a means for the administration
of an androgen, wherein the latter means is a pharmaceutical
formulation, comprising:
(7.alpha.,17.beta.)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en--
3-one and a pharmaceutically acceptable carrier.
2. The kit for male contraception according to claim 1, wherein the
pharmaceutically acceptable carrier is a liquid in which
(7.alpha.,17.beta.)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one
is dissolved.
Description
[0001] The invention is in the field of androgenic hormones, more
specifically derivatives of testosterone.
[0002] Testosterone derivatives are known. Testosterone itself, the
natural male hormone, has many known drawbacks as far as methods of
administration are concerned. It has a short-lasting activity, is
insoluble in the usual pharmaceutically acceptable media, and is
not very potent. The more potent dihydrotestosterone
(5.alpha.-reduced form of testosterone) is considered a
health-risk, notably for the prostate. A somewhat better soluble
derivative is testosterone undecanoate, which is known as the
active substance in the product Andriol.RTM..
[0003] More potent androgens are 7.alpha.-methyl-19-nortestosterone
(MENT) and related compounds, such as disclosed in FR 4.521 M and
U.S. Pat. No. 5,342,834. However, MENT suffers from a bad
solubility and short duration of action.
[0004] New androgenic hormones are needed which inter alia satisfy
the demands connected with new areas of interest, such as male
contraception and male HRT (hormone replacement therapy). Thus,
e.g., male contraception may comprise a regimen of administration
of hormones in which a progestagen serves to achieve a
contraceptive effect and an androgen serves to supplement the
resulting decreased testosterone level. Another option is that male
contraception is performed with an androgenic hormone alone. The
regular androgen intake needed for this requires androgens which
are improved as to potency and duration of action, and for which a
practical way of administration is available. As low a frequency of
administration being desired, there is a demand for androgens which
have such physico-chemical properties as to be rendered into a
solution, particularly a solution by which the androgen can be
administered via injection, preferably once a week or less
frequent, or orally via a capsule to be taken, e.g., daily. This
means that a basic desired property for a novel androgen is that it
has an improved solubility in one or more pharmaceutically
acceptable liquids.
[0005] Even more desired is an androgen which has a favourable
relationship of potency and solubility, as a weak androgen will
require more of it to be dissolved in order to attain the same
activity as a more potent androgen. This means an androgen having
an improved relative "dissolved potency", hereinafter referred to
as RDP, wherein the RDP of a given androgen in a given medium is
the product of its androgenic potency relative to that of the
natural male hormone testosterone and its solubility in the medium
relative to that of testosterone.
[0006] It is an object of the invention to provide an androgenic
hormone which satisfies the above demand. To this end, the
invention is the compound
(7.alpha.,17.beta.)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-o-
ne, which has the following structural formula: 1
[0007] The compound of the invention is also to be referred to as
7.alpha.-methyl-19-nortestosterone undecanoate, in short MENT
undecanoate.
[0008] The compound of the invention has a significantly better
solubility than could be expected on the basis of the known
testosterone derivatives. Moreover, the compound of the invention
has a surprisingly higher RDP than the known compounds.
[0009] The compound of the invention can be prepared by
esterification of the 17-OH group of MENT with undecanoic acid or
derivatives thereof. This esterification may be carried out using
methods well known in the art or readily available from the
chemical literature, for example, using methods and catalysts
described in Advanced Organic Chemistry, J. March, 4th Ed, pages
1281-1282, 1992. MENT can be prepared as disclosed in FR 4.521 M
and U.S. Pat. No. 5,342,834.
[0010] The invention also pertains to the compound MENT undecanoate
as a medicine. The compound of the invention being a potent
androgen, it can be used in, inter alia, male contraception and
male or female hormone replacement therapy. Thus the invention also
pertains to a method of treatment of androgen insufficiency, by
administering to a human male or female an effective amount of MENT
undecanoate. The invention also is in the use of MENT undecanoate
for the preparation of a medicine for treating androgen
insufficiency. In the context of the invention, the term "androgen
insufficiency" is to be understood to pertain to all kinds of
diseases, disorders, and symptoms in which a male or a female
suffers from too low a testosterone level, such as in hypogonadal
men. In particular, the androgen insufficiency to be treated by the
compound of the invention is the reduction of the testosterone
level which a human male incurs as a result of age (the compound of
the invention is then used for male hormone replacement therapy),
or when he is subject to male contraception. In the context of male
contraception, the compound of the invention especially serves to
neutralise the effect of regimens of male hormone contraception in
which a sterilitant such as a progestagen or LHRH (luteinizing
hormone releasing hormone) is administered regularly, e.g. daily,
or it is used as the sole male contraceptive substance.
[0011] The invention also relates to pharmaceutical formulations
comprising MENT undecanoate and a pharmaceutically acceptable
carrier. Thus the carrier may be in a solid form or liquid form,
and the formulation may be an oral dosage unit such as a tablet or,
preferably, an oral solution, e.g. in a capsule. Methods and
compositions for making such dosage units are well-known to those
skilled in the art. For example, conventional techniques for making
tablets and pills, containing active ingredients, are described in
the standard reference, Gennaro et al, Remington's Pharmaceutical
Sciences, (18th ed., Mack Publishing Company, 1990, see especially
Part 8: Pharmaceutical Preparations and Their Manufacture). The
compound can also be administered via an implant, a patch, or any
other suitable device for the sustained release of an androgen
composition. The preferred oral dosage unit is that of a capsule
containing the compound of the invention taken up in a liquid
medium as described below.
[0012] In order to benefit most from the compound's androgenic
activity, administration of the compound dissolved in an oil is
preferred, i.e. either orally as above, and notably via
(intramuscular) injection. MENT undecanoate has a solubility in
oily media, which makes it particularly suitable for a liquid
pharmaceutical formulation comprising MENT undecanoate dissolved in
a pharmaceutically acceptable oil. Suitable oils are, e.g., arachis
oil, oleic acid, ricinus oil, sesam oil and the like. Arachis oil
is preferred.
[0013] For injection the preferred injection device is a needleless
injection system, e.g. as described in U.S. Pat. No. 5,599,302. To
this end the compound may also be suspended in an aqueous medium,
but the above solutions in oil are preferred. Methods and
compositions for making liquids suitable for parenteral
administration are known in the art, see e.g. Remington's, pages
1545 ff.
[0014] For oral administration, any capsule made from a
pharmaceutically acceptable wall material can be employed. Methods
and compositions for making capsules suitable for oral
administration are known in the art, see e.g. Remington's, pages
1658 ff. A preferred material is a softgel such as used for
Andriol.RTM. capsules.
[0015] The invention also pertains to a method of treatment of
androgen insufficiency, by administering to a human male, by
injection or by means of an oral dosage unit, an effective amount
of MENT undecanoate dissolved in a pharmaceutically acceptable oil.
The invention also is in the use of MENT undecanoate for the
preparation of a medicine for treating androgen insufficiency by
injecting into a human male an effective amount of MENT undecanoate
dissolved in a pharmaceutically acceptable oil, or by orally
administering such an oily solution.
[0016] The dose of and regimen of administration MENT undecanoate,
or a pharmaceutical composition thereof, to be administered will
obviously depend on the therapeutic effect to be achieved and will
vary with the route of administration, and the age and condition of
the individual subject to whom the medicament is to be
administered, and/or or the particular contraceptive or HRT regimen
in which it is used. Typical doses are 100 mg or more per three
months upon intramuscular administration and 50-250 mg, more
preferably 80 mg per day upon oral administration.
[0017] The invention will be further explained hereinafter with
reference to the following Examples.
EXAMPLE 1
[0018]
(7.alpha.,17.beta.)-7-Methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one.
[0019] A total of 2.23 grams of commercially available undecanoyl
chloride were added to a stirred solution of 1.58 grams of
(7.alpha.,17.beta.)-17-- hydroxy-7-methylestr-4-en-3-one at
0-5.degree. C. The reaction mixture was allowed to reach room
temperature and stirred overnight. Thereafter, ice was added and
after stirring for another 2 hours the reaction mixture was poured
into ice-water, containing 4 ml of conc. H.sub.2SO.sub.4, followed
by ethyl acetate extraction. The organic layers were washed with
water, cold 1 N NaOH solution and brine, dried on sodium sulfate,
filtered and evaporated in vacuo. The residue was chromatographed
over silica. Elution with heptane-ethylacetate (4:1) and
evaporation gave a greasy solid that was collected. Yield 1.42 g,
[.alpha.].sub.D.sup.20=+36.degree. (c=1; dioxane), MS (ESI):
456.
[0020] (17.beta.)-17-[(1-Oxoundecyl)oxy]androst-4-en-3-one
[0021] "Testosterone undecanoate" is commercially available.
EXAMPLE 2
[0022] About 20-30 mgs of compound were powdered and then dissolved
in as little solvent as necessary to dissolve all the visible
particles. Dissolution was accomplished by heating in a waterbath
of 50.degree. C. and shaking on a Vortex.TM. shaker for 15 minutes.
The solubility was calculated by determining the amount of compound
(in mg) dissolved per ml of solvent.
COMPARATIVE EXAMPLE
[0023] The solubility and the androgenic potency of the compound of
the invention and three reference compounds was used to determine
RDP. The results are given in the tables below. With regard to
clinically desirable anabolic and antigonadotropic effects
(androgenic effects), MENT is ten times more potent than
testosterone in rats (Kumar N et al, Endocrinology 130: 3677-3683
(1992) and J Steroid Biochem Molec Biol 52: 105-112 (1995)) and
monkeys (Cummings D et al, J Clin Endocrinol Metab 83, 4212-4219
(1998)). The RDP is determined as follows: 1 Solubility of compound
Solubility of testosterone .times. potency of compound relative to
that of testosterone
1TABLE 1 solubility solubility compound arachis oil oleic acid
testosterone <<0.1 mg/ml .about.25 mg/ml MENT .ltoreq.0.1
mg/ml .about.15 mg/ml testosterone undecanoate .about.45 mg/ml
200-250 mg/ml MENT undecanoate >200 mg/ml .gtoreq.500 mg/ml
[0024] From the table it can be learned that the solubility of MENT
undecanoate in arachis oil is much better than that of any of the
other androgens. The solubility of MENT undecanoate in oleic acid
is also better than expected in view of that of the known
androgens.
* * * * *