Note: Descriptions are shown in the official language in which they were submitted.
93/1975Y. 21 3 3 4 ~ ~ PCT/US93J0314~i ~
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Composi~ons and Methods For Trea~ing Benign Prosta~ic Hypertrophy
This in~ention relates to a pharmaceutical composition containing N-
t-butyl-androst-3,5-diene-1713-carboxamide-3-carboxylic acid or a salt
thereofor 17~3-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic
acid or a salt thereof and an alpha-andrenergic receptor antagonist
compound and a pharmaceutically acceptable carrier or diluent. This
in~ention also relates to a method of treating benign prostatic hypertrophy
in a mammal, including a human, in need thereof which comprises
administering an ef~ective dose of N-t-butyl-androst-3,5-diene-1713-
carbo~amide-3-carboxylic acid or a salt thereof or 17J3-(N-t-
butylcarbo2amide-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof
and an alpha-andrenergic receptor antagonist compound to such mamrnal.
BACKGRQII~D QF '17~ E I~ TION
As one of the primary regulatoræ of peripheral vascular tone, oc
adrenoceptors long ha~e been the targets of ef~orts to develop agents
ef~ective in changing vascular tone for use in treating diseases, such as
hypertension, in which alterations in ~ascular resistance produce
r 30 therapeutic benefits.
Lafferty, et al. U.S. Patent No. 4,963,547 (hereinaflcer Laf~erty I)
- discloses that compounds which are alpha-andrenergic receptor
antagonists are usefill in treating cardiovascular.diseases in which
changes in vascular resistance are desirable, including hypertension,
p~monary hypertension, congestive heart failure, myocardial ischemia,
angina pectoris, and penpheral vascular disease.
wo 93tl975fs 2 1 3 3 4 ~ O ~Cr/l~S93/0~14' -
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Laf~erty I also discloses that said oompounds are useful in treating
vascular disorders such as diabetes, benign prostatic hypertrophy and
ocular hypertension.
Lafferty I does not disclose that compounds which are alpha-
andrenergic receptor antagonists as having utility in combination with
an inhibitor of steroid 5-cc-reductase.
N-t-butyl-androst-3,5-dienel713-carboxamide-3-carboxylic acid and
salts thereof (hereinafter (~ompound A) is disclosed and claimed in Holt,
et al. U.S. Patent No. 5,017,568 (Holt I).
Holt I discloses Compound A as a novel steroid s-a-reductase
inhibiting compound which exhibits the therapeutic e~ect of lowering
prostatic levels of dihydrotestosterone thereby reducing prostate size.
All of the compounds disclosed in Holt I as having 5-a-reductase
inhibiting acti~ity have utility in the invented compositions.
1~ Holt I does not disclose compound A in combination with an alpha-
andrenergic receptor antagonist compound.
1713-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic
acid and salts thereof (hereinafter Compound B) is disclosed and claimed
in Holt et al. U.S. Patent No. 4,954,446 (Holt II).
Holt II discloses compound B as a novel steroid 5-a-reductase
inhibiting compound which exhibits the therapeutic effect of lowenng
prostatic levels of dihydrotestosterone thereby reducing prostate size.
All of the compounds disclosed in Holt II as having ~-a-reductase
inhibiting activity have utility in the invented compositions.
Holt II does not disclose compound B as hanng utility in
combination with an alpha-andrener~ic receptor antagonist compound.
SUMMARY OF THE IN~ENTION
This invention relates to a pharmaceutical composition containing
N-t-butyl-androst-3,5-diene-17J3-carboxamide-3-carboxylic acid or a salt
thereof or 1713-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carbo~ylic
acid or a salt thereof and an alpha-andrenergic receptor antagonist
compound and a pharmaceutically acceptable carrier or diluent. This
invention also relates to a method of treating benign prostatic
hypertrophy in a mammal, including a human, in need thereof which
comprises administering an ef~ecti~e dose of N-t-butyl-androst-3,5-diene-
1713-carboxamide-3-carboxylic acid or a salt thereof or 1713-(N-t-
~ ~93J19758 2133~4Q j Pcr/US93~0314~
butylcarboxamide)-estra-1,3,5(1~)-triene-3-carboxylic acid or a salt
thereof and an alpha-andrenergic receptor antagonist compound to such
mammal.
DETAILED DE$CRIPTION OF THE INVE~TIQN
5 Compounds which are alpha-andrenergic receptor antagonists aredisclosed in Lafferty I as representing a well known therapeutic class of
compounds.
Preferred alpha-andrenergic receptor antagonists for use in the
compo~tions and methods of the invention include amsulosin, terazocin,
doxazosin, alfuzosin, indoramin and prazosin and 7-chloro-2-ethyl-
3,4,6,6-tetrahydro-4-methylthieno[4,3,2-ef~-[3]benzazepine.
By the term "amsulosin" as used herein is meant a compound of
the fo~nula
CH,~CH2'(~NHCH2CH20~3
H2NO2S H OCH2C~3
and salts, hydrates and solvates thereof.
(~hemically, amsulosin is designated as (-)-(R)-5-[2-[[2-(O-
ethoxyphenoxy)ethyl3amino]propyl]-2-methoxybenzenesulfonamide .
Amsulosin is disclosed in U.S. Patent Number 4,703,063 and
claimed in U.S. Patent Number 4,987,125 as being useful in treating
lower urinary tract dysfunction.
By the term "terazocin" as used herein is meant a compound of the
formula
R
~`N'
CH,O~N ~,~N~J
CH~OJ~ ~N
NH2
and salts, hydrates and solvates thereof.
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Chemically, tera~ocin is designated as 1-(4-amino-6,7-dimetho~y-2
quinazolinyl)-4-~(tetrahydro-2-furoyl)carbonyl]piperazine. Terazocin is
disclosed in U.S. Patent Number 4,251,532. -
~
By the term doxazosin as used herein is meant a compound of the
5 formula
~N~O~O~
H3CO ~N ~N~J ~ ~J
H3CO~: N
NH2
and salts, hydrates and solvates thereof.
Chemically "doxazosin" is designated as 1-(4-amino-6,7-
dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro- 1 ,4-benzodioxin-2-
yl)carbonyl]-piperazine .
Doxazosin is discolsed in U.S. Patent Number 4,1~8,390.
By the term "alfuzosin" as used herein is meant a compound of the
15 formula
CH3
~N N~
NH2
and salts, hydrates and solvates thereof.
Chemically alfuzosin is designated as N-[3-[(4-amino-6,7-
dimethoxy-2-quinazolinyl3methylamino]propyl]tetrahydro-2-
20 furancarbo~amide.
Alfuzosin is disclosed in U.S. Patent Number 4,315,007.
By the term "indoramin" as used herein is meant a compound fo
the formula
CH2CH2 N3NHC~
~ 1 33 4~ ~
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and salts, hydrate~ and solvates thereof.
Chemically indoramin as designated N-[[1-[2-(lH-indol-3-
yl)ethyl]-4-pipendinyl]benzamine.
Indoramin i8 disclosed in U.S. Patent Nurnber 3,~27,761.
By the term "prazosin" as used herein is meant a compound of the
formula
~N C;O~
CHlO~N ~N~J
CH30~
NH2
and salts, hydrates and solvates thereof.
Chemically prazosin is designated as 1-(4-amino-6,7-dimethoxy-2-
quinazolinyl)-4-(2-furanylcarbonyl)piperazine.
Prazosin is disclosed in U.S. Patent Number 3,511,836.
The term "7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-
methylthieno[4,3,2-ef~-~3]benzazepine" as used herein includes salts,
hydra~es and soluates thereof. 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-
methylthieno[4,3,2-ef~-[3]benzazepine is disclosed in U.S. patent number
~,006,521. Additionally, all compounds disclosed in U.S. patent number
5,006,521 as alpha-andrenergic receptor antagonist are preferred alpha- -
20 andrenergic receptor antagonist as used herein.
Persons skilled in the art can readily determine if a compound
other than one specifically referred to herein is a alpha-andrenergic
receptor antagonist by utilizing the assay described in Lafferty I. Thus,
all such compounds are included within the scope of the term "alpha-
2~ andrenergic receptor antagonist" as used herein.
By the term "administering" as used herein is meant either
simultaneous administration or any manner of consecutive
administration of compound A or compound B and an alpha-andrenergic
receptor antagonist compound. Preferably, if the administration is not
simultaneous, the two compounds are admirlistered in a close time
prwQmity to each other. Furthermore, it does not matter if the
compounds are both administered in the same dosage form, e.g. one
WO93/197~8 2l~33~l4b'` P~/US93/0314
compound may be administered by injection and the other compound
may be administered orally.
The compo6itions of this invention alleviate the symptoms
associated with the disease state of benign prostatic hypertrophy to a
greater extent than can be achieved by either component alone.
The claimed pharmaceutical compositions are incorporated into
convenient dosage forms such as capsules, tablets, or injectable
preparations. Solid or liquid pharmaceutical carriers are employed. Solid
carriers include starch, lactose, calcium sulfate dihydrate, terra alba,
10 sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearicacid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
Similarly, the carrier or diluent may include any prolonged release
material, such as glyceryl monostearate or glyceryl distearate, alone or
with a wax. The amount of solid carrier varies widely but, preferably, will
15 be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is
used, the~preparation will be in the form of a sy~rup, elixir, emulsion, soflc
gélatin capsule,~ sterile injectable liquid such as an ampoule, or an aqueous
or nonaqueous liquid suspension. ~ ~
The~pharmaceutical preparations are made following conventional
20 ~ t echniques of a ~pharmaceutical chemist involving mixing, granulating, andcompressing,~when~necessa~ for tablet forms, or mixing, filling and
dissohring~the~ingredients, as appropriate, to give the desired oral or
parenteral products. ~ ~
The~ pharmaceutical properties of each active component of the
pharmaceutical composition of the invention must be contemplated when
form~ating~conventiona~l dosage regimens. Both components can be
incorpora~ed into a timed~ release dosage unit form in which several doses
are treated for delayed or sustained release of the medicament. Such
dosage units may compnse sustained release granules, sugar centered
spheres~ or multilayered tablets in each of which the availability of the
acti~e ingredientis controlled by coating with a lupid or polymeric
material.
This invention also relates to a method of treating bemgn prostatic
~ hypertraphy in a mammal, including a human, in need thereof which
; ~ 35 comprises admiI~iste~ing N-t-butyl-androst-3,5-diene-17~-carboxamide-3-
~ carbaxylic acid or a salt thereof or 17~-(N-t-butylcarboxamide)-estra-
~ 1 3 3 ~ L¦ ~J ~ '
'- ~ 93/197~;8 ` `: PCI`/US93/0314
1,3,5(10)-triene-3-carboxylic acid or a salt thereof and an alpha-
andrenergic receptor antagonist compound to such mammal.
Both prophylactic and therapeutic induction are contemplated. One
of skill in the art will recognize that the exact dosage and treatment
regimen to be utilized in any particular situation vrill necessarily depend
on the exact disease state to be treated, the age, weight, sex and health of
the particular animal being treated and that such optimums can be
determinèd by conventional techniques.
To maximize its therapeutic effect, the individual compounds of the
10 claimed combinations~ can be administered ~as a 6ingle pharmaceutical
composition or consecutively in separate pharmaceutical compositions,
whichever administration scheme may be appropriate. One of s~ill in the
art using conventional techniques can determine the most appropriate way
to administer the two compounds tconsecutively versus simultaneously~
15 ~ ~ depending on such factors as the age, sex weight and health of the patient
and~the-disease~stàte to~betreated. ~
~ Doseg of the present combination in a pharmaceutical dosage unit
as descFibed ~above~will ~be an efficacious, non toxic quantity preferably
selected from the range of 0~.01-100 mgll~g of each active compound,
20 ~ 50 mg/~ The selècted dose is adrninistered to a patient
in ~neéd of treatment for b~enign prostatic hypertrophy preferably from 1-
6times daily,;orally, or~parenterally. ~Prefèrred~forms of parenteral .
ad~inistr~on inc~ude topically, rectally, transdermally, by injection
d co tin~owlyb~rinfusion. ~Oraldosage~units~forhuman ~
25~ ~ ad~inistration preferably~contain from l~ 500~mg of active compound.
;~ 0~1 ~dministration,~which~uses lower~dosages is preferred. Parenteraladministration, at high dosages, however, also can be used when safe
and convenient for the patient.
- ~ No unaccep:table to~cological effects are expected when
-compositions of the invention are administered in accordance with the
present in~ention.
The use of a 5a-reductase inhibiting compound, other than
compound A and compound B, in~ a pha~aceutical composition with an
alpha-andrenergic receptor antagonist is contemplated. Persons skilled
in the art can readily determiné if a compound, other than compound A
and compound B, is a 5a-reductase inhibiting compound by methods well
~ ,
.
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known in the art, such as those described in Levy et al: ~, Steroid
Biochem 34: 571-575, (1989). Thus, all such compounds are included
within the scope of the tenn "5a-reductase inhibitor" as used herein.
The following e~camples illustrate preparation of the claimed
5 pharmaceutical compositions. The examples are not intended to limit
the scope of the invention as defined hereinabove and as claimed below.
EXAMPLE 1- Gelatin Ga~sule
~An oral dQssge form for administering the claimed compounds and
10 compositions is produced by screening, mixing and filling into hard
gelatin caps~es the ingredients in the proportions shown in Table I
below.
Table I
~redients ~ Amounts
N-t-butyl-androst-3,5-dlene-1713- 50 mg
carboxamide-3-carbo~ylic acid
Terazocin ~ ; 50 mg
Magnesium stearate 10 mg
Lactose 150 mg
Ea~PLE 2-Tablet
The lactose, microcrystalline cellulose and claimed compounds and
compositions shown in Table II below, are mixed and ~ranulated in the
- - proportions ~sho:wn ~with a lO~o gelatin solution. The wet granules are
20 ~ screened, dned, ~mixed with the starch, talc and stea~c acid, screened
~; and-compressed into a tablet. ~ ~
`~93/197,~ ~133~
PCI ~US93/0314~
g
T~ble II
In~redients ~mounts
N-t-butyl-androst-3,5-diene-17J3-carboxamide-3- 50 mg
carbo~ylic acid
Do~azosin 50 mg
Calcium sulfate dihydrate 75 mg
Sucrose 20 mg
Starch 10 mg
Talc 5 mg
Stearic acid 5 mg
EXAMPLE 3 - Inieçtable Preparati~n
N-t-butyl-androst-3,5-diene-1713-carboxamide-3-carboxylic acid (50
5 mg) and amsulosin (50 mg), are dispersed in 25 ml of no~mal saline to
prepare an injectable preparation.
EXAMPLE 4
The following compounds (e~pressed as base weight) are mixed
10 together with 250 mg of lactose and 10 mg of magnesium stearate then
filled into a hard gelatin capsule. These capsules are administered from
1-6 times daily to a patient in need of treatment of benign prostatic
hypertrophy.
A. N-t-butyl-androst-3,~-diene-17J3-carboxamide-3-carboxylic acid
50 mg; prazosin 50 mg.
B. N-t-butyl-androst-3,5-diene-1713-carboxamide-3-carboxylic acid
50 mg; alfuzosin 50 mg.
C. N-t-butyl-androst-3,6-diene-1713-carbo~amide-3-carboxylic acid
50 mg indoramin ~0 mg.
While the preferred embodiments of the invention are illustrated
Z~ by the above, it is to be understood that the invention is not limited to
the precise instructions herein disclosed and that the right to all
modifications coming within the scope of the following cla~ms is reserved.
