CA2133440A1 - Compositions and methods for treating benign prostatic hypertrophy - Google Patents
Compositions and methods for treating benign prostatic hypertrophyInfo
- Publication number
- CA2133440A1 CA2133440A1 CA002133440A CA2133440A CA2133440A1 CA 2133440 A1 CA2133440 A1 CA 2133440A1 CA 002133440 A CA002133440 A CA 002133440A CA 2133440 A CA2133440 A CA 2133440A CA 2133440 A1 CA2133440 A1 CA 2133440A1
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- Prior art keywords
- alpha
- compound
- receptor antagonist
- steroid
- reductase
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Steroid Compounds (AREA)
Abstract
Invented are pharmaceutical compositions containing N-t-butyl-androst-3,5-diene-17.beta.-carboxamide)-3-carboxylic acid or a salt thereof or 17.beta.-(N-t-butylcarboxamide-estra-1,3,5(10)-triene-3-carboxylic acid or a salt thereof and an alpha-adrenergic receptor antagonist compound, and methods of using these compositions to treat benign prostatic hypertrophy.
Description
93/1975Y. 21 3 3 4 ~ ~ PCT/US93J0314~i ~
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' -. . .
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' -. . .
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
and salts, hydrates and solvates thereof.
WO 93/197~8 2 1 3 3 4 4 Q PCr/US93/0314~
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
and salts, hydrates and solvates thereof.
WO 93/197~8 2 1 3 3 4 4 Q PCr/US93/0314~
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
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 ~N N~
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~ ~
`'-') 93/19758 . ` PC~/US93/0314 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~
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 ~ , .
wo 93/19758 ~ 1 3 3 ~ ~ O PCl /US93/0314 t ;:
. . .
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.
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.
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
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 ~N N~
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~ ~
`'-') 93/19758 . ` PC~/US93/0314 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~
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 ~ , .
wo 93/19758 ~ 1 3 3 ~ ~ O PCl /US93/0314 t ;:
. . .
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.
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.
Claims (10)
1. A pharmaceutical composition comprising a steroid 5-.alpha.-reductase inhibiting compound and an alpha-andrenergic receptor antagonist compound and a pharmaceutically acceptable carrier or diluent.
2. A pharmaceutical composition comprising N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid or a salt thereof and an alpha-andrenergic receptor antagonist compound and a pharmaceutically acceptable carrier or diluent.
3. A composition of claim 2 in which the alpha-andrenergic receptor antagonist is terazocin.
4. A composition of claim 2 in which the alpha-andrenergic receptor antagonist is selected from alfuzosin, indoramin, doxazosin, prazosin, amsulosin and 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef]-[3]benzazepine.
5. A composition according to anyone of claims 1 to 4 for use in therapy.
6. A composition according to anyone of claims 1 to 4 in the manufacture of a medicament for use as a steroid 5-.alpha.-reductase inhibitor.
7. A composition according to anyone of claims 1 to 4 in the manufacture of a medicament for use in treatment to reduce prostate size.
8. Use of a composition according to anyone of claims 1 to 4 in the manufacture of a medicament for use as a 5-.alpha.-reductase inhibitor.
9. The use of a steroid 5-a-reductase inhibiting compound and an alpha-receptor antagonist compound as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a steroid 5-.alpha.-reductase inhibiting compound and an alpha-receptor antagonistcompound.
?? 93/19758 PCT/US93/03145
?? 93/19758 PCT/US93/03145
10. The use of a steroid 5-.alpha.-reductase inhibiting compound and an alpha-receptor antagonist compound in the manufacture of a medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a 5-.alpha.-reductase inhibiting compound and an alpha receptor antagonist compound.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86211792A | 1992-04-02 | 1992-04-02 | |
| US07/862,117 | 1992-04-02 | ||
| US99779292A | 1992-12-29 | 1992-12-29 | |
| US07/997,792 | 1992-12-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2133440A1 true CA2133440A1 (en) | 1993-10-14 |
Family
ID=27127672
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002133440A Abandoned CA2133440A1 (en) | 1992-04-02 | 1993-04-02 | Compositions and methods for treating benign prostatic hypertrophy |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0633781A4 (en) |
| JP (1) | JPH07505398A (en) |
| KR (1) | KR950700746A (en) |
| AU (1) | AU668157B2 (en) |
| CA (1) | CA2133440A1 (en) |
| MX (1) | MX9301939A (en) |
| NZ (1) | NZ251658A (en) |
| WO (1) | WO1993019758A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ241979A (en) * | 1991-03-20 | 1996-01-26 | Merck & Co Inc | Treatment of benign prostatic hyperplasia using 5alpha-reductase inhibitor and an alpha1-adrenergic recepter blocker |
| DE69431662T2 (en) * | 1993-09-03 | 2003-09-18 | Smithkline Beecham Corp | STABILIZED TABLET FORMULATION |
| EP0755392A4 (en) * | 1994-04-14 | 1997-05-02 | Merck & Co Inc | Alpha1c adrenergic receptor antagonists |
| US5543417A (en) * | 1994-10-21 | 1996-08-06 | Merck & Co., Inc. | Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents |
| US5595996A (en) * | 1994-10-25 | 1997-01-21 | Merck & Co., Inc. | 7-substituted 4-aza cholanic acid derivatives and their use |
| US5952003A (en) * | 1996-08-01 | 1999-09-14 | Novartis Corporation | Terazosin capsules |
| ES2486791T3 (en) | 2010-09-02 | 2014-08-19 | Grünenthal GmbH | Tamper resistant dosage form comprising an inorganic salt |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA883034B (en) * | 1987-04-29 | 1989-03-29 | Smithkline Beckman Corp | Steroid 5-alpha-reductase inhibitors |
| US4963547A (en) * | 1988-06-01 | 1990-10-16 | Smithkline Beecham Corporation | Alpha-andrenergic receptor antagonists and use thereas |
| NZ241979A (en) * | 1991-03-20 | 1996-01-26 | Merck & Co Inc | Treatment of benign prostatic hyperplasia using 5alpha-reductase inhibitor and an alpha1-adrenergic recepter blocker |
| US5308832A (en) * | 1992-07-27 | 1994-05-03 | Abbott Laboratories | Nutritional product for persons having a neurological injury |
-
1993
- 1993-04-02 CA CA002133440A patent/CA2133440A1/en not_active Abandoned
- 1993-04-02 JP JP5517741A patent/JPH07505398A/en active Pending
- 1993-04-02 NZ NZ251658A patent/NZ251658A/en unknown
- 1993-04-02 AU AU39451/93A patent/AU668157B2/en not_active Ceased
- 1993-04-02 WO PCT/US1993/003145 patent/WO1993019758A1/en not_active Application Discontinuation
- 1993-04-02 MX MX9301939A patent/MX9301939A/en unknown
- 1993-04-02 EP EP93908738A patent/EP0633781A4/en not_active Withdrawn
-
1994
- 1994-10-04 KR KR1019940703522A patent/KR950700746A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0633781A4 (en) | 1995-04-19 |
| MX9301939A (en) | 1994-08-31 |
| WO1993019758A1 (en) | 1993-10-14 |
| AU668157B2 (en) | 1996-04-26 |
| EP0633781A1 (en) | 1995-01-18 |
| NZ251658A (en) | 1996-08-27 |
| AU3945193A (en) | 1993-11-08 |
| KR950700746A (en) | 1995-02-20 |
| JPH07505398A (en) | 1995-06-15 |
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