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WO1993019758A1 - Compositions et procedes permettant de traiter l'hypertrophie prostatique benigne - Google Patents

Compositions et procedes permettant de traiter l'hypertrophie prostatique benigne Download PDF

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Publication number
WO1993019758A1
WO1993019758A1 PCT/US1993/003145 US9303145W WO9319758A1 WO 1993019758 A1 WO1993019758 A1 WO 1993019758A1 US 9303145 W US9303145 W US 9303145W WO 9319758 A1 WO9319758 A1 WO 9319758A1
Authority
WO
WIPO (PCT)
Prior art keywords
alpha
compound
receptor antagonist
steroid
carboxylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1993/003145
Other languages
English (en)
Inventor
Jacob Paul Hieble
Brian Walter Metcalf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to AU39451/93A priority Critical patent/AU668157B2/en
Priority to EP93908738A priority patent/EP0633781A4/fr
Priority to JP5517741A priority patent/JPH07505398A/ja
Publication of WO1993019758A1 publication Critical patent/WO1993019758A1/fr
Anticipated expiration legal-status Critical
Priority to KR1019940703522A priority patent/KR950700746A/ko
Ceased legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • This invention relates to a pharmaceutical composition containing N- t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid or a salt thereof or 17 ⁇ -(N-t-butylcarboxamide)-estra-l,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 invention also relates to a method of treating benign prostatic hypertrophy in a mammal, including a human, in need thereof which comprises administering an effective dose of N-t-butyl-androst-3,5-diene-17 ⁇ - carboxamide-3-carboxylic acid or a salt thereof or 17 ⁇ -(N-t- butylcarboxamide-estra-l,3,5(10)-triene-3-carboxylic acid or a salt thereof and an alpha-andrenergic receptor antagonist compound to such mammal.
  • ⁇ adrenoceptors long have been the targets of efforts to develop agents effective in changing vascular tone for use in treating diseases, such as hypertension, in which alterations in vascular resistance produce therapeutic benefits.
  • Lafferty, et al. U.S. Patent No. 4,963,547 discloses that compounds which are alpha-andrenergic receptor antagonists are useful in treating cardiovascular diseases in which changes in vascular resistance are desirable, including hypertension, pulmonary hypertension, congestive heart failure, myocardial ischemia, angina pectoris, and peripheral vascular disease.
  • Lafferty I also discloses that said compounds 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- ⁇ -reductase.
  • Compound A N-t-butyl-androst-3,5-dienel7 ⁇ -carboxamide-3-carboxylic acid and salts thereof (hereinafter Compound 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 5- ⁇ -reductase inhibiting compound which exhibits the therapeutic effect of lowering prostatic levels of dihydrotestosterone thereby reducing prostate size.
  • Holt I All of the compounds disclosed in Holt I as having 5- ⁇ -reductase inhibiting activity have utility in the invented compositions.
  • Holt I does not disclose compound A in combination with an alpha- andrenergic receptor antagonist compound.
  • Compound B 17B-(N-t-butylcarboxamide)-estra-l,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- ⁇ -reductase inhibiting compound which exhibits the therapeutic effect of lowering prostatic levels of dihydrotestosterone thereby reducing prostate size.
  • Holt II All of the compounds disclosed in Holt II as having 5- ⁇ -reductase inhibiting activity have utility in the invented compositions.
  • Holt II does not disclose compound B as having utility in combination with an alpha-andrenergic receptor antagonist compound.
  • This invention relates to a pharmaceutical composition containing N-t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid or a salt thereof or 17 ⁇ -(N-t-butylcarboxamide)-estra-l,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 invention also relates to a method of treating benign prostatic hypertrophy in a mammal, including a human, in need thereof which comprises administering an effective dose of N-t-butyl-androst-3,5-diene- 17 ⁇ -carboxamide-3-carboxylic acid or a salt thereof or 17 ⁇ -(N-t- butylcarboxamide)-estra-l,3,5(10)-triene-3-carboxylic acid or a salt thereof and an alpha-andrenergic receptor antagonist compound to such mammal.
  • Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention include amsulosin, terazocin, doxazosin, alfuzosin, indoramin and prazosin and 7-chloro-2-ethyl- 3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef]-[3]benzazepine.
  • amsulosin as used herein is meant a compound of the formula
  • amsulosin is designated as (-)-(R)-5-[2-[[2-(0- ethoxyphenoxy)ethyl]amino]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.
  • terazocin as used herein is meant a compound of the formula
  • terazocin is designated as l-(4-amino-6,7-dimethoxy-2 quinazolinyl)-4-[(tetrahydro-2-f royl)carbonyl]piperazine.
  • Terazocin is disclosed in U.S. Patent Number 4,251,532.
  • doxazosin as used herein is meant a compound of the formula
  • doxazosin is designated as l-(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-l,4-benzodioxin-2- yl)carbonyl]-piperazine.
  • alfiizosin as used herein is meant a compound of the formula
  • Chemically alfiizosin is designated as N-[3-[(4-amino-6,7- di ⁇ ethoxy-2-q ⁇ inazolinyl)methylamino]propyl3tetrahydro-2- furancarboxamide.
  • Alfiizosin is disclosed in U.S. Patent Number 4,315,007.
  • indoramin as used herein is meant a compound fo the formula
  • prazosin as used herein is meant a compound of the formula
  • Chemically prazosin is designated as l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4-(2-furanylcarbonyl)piperazine.
  • Prazosin is disclosed in U.S. Patent Number 3,511,836.
  • -[3]benzazepine" as used herein includes salts, hydrates 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 5,006,521. Additionally, all compounds disclosed in U.S. patent number 5,006,521 as alpha-andrenergic receptor antagonist are preferred alpha- andrenergic receptor antagonist as used herein.
  • alpha-andrenergic receptor antagonist 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- andrenergic receptor antagonist" as used herein.
  • administering is meant either simultaneous administration or any manner of consecutive administration of compound A or compound B and an alpha-andrenergic receptor antagonist compound.
  • the two compounds are administered in a close time proximity to each other.
  • the compounds are both administered in the same dosage form, e.g. one compound may be administered by injection and the other compound maybe administered orally.
  • compositions of this invention alleviate the symptoms associated wit the disease state of benign prostatic hypertrophy to a greater extent than can be achieved by either component alone.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • 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 be firom about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • each active component of the pharmaceutical composition of the invention must be contemplated when formulating conventional dosage regimens. Both components can be incorporated into a timed release dosage unit form in which several doses are treated for delayed or sustained release of the medicament.
  • dosage units may comprise sustained release granules, sugar centered spheres or multilayered tablets in each of which the availability of the active ingredient is controlled by coating with a lupid or polymeric material.
  • This invention also relates to a method of treating benign prostatic hypertrophy in a mammal, including a human, in need thereof which comprises administering N-t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3- carboxylic acid or a salt thereof or 17 ⁇ -(N-t-butylcarboxamide)-estra- l,3,5(10)-triene-3-carboxylic acid or a salt thereof and an alpha- andrenergic receptor antagonist compound to such mammal.
  • the individual compounds of the claimed combinations can be administered as a single pharmaceutical composition or consecutively in separate pharmaceutical compositions, whichever administration scheme may be appropriate.
  • One of skill in the art using conventional techniques can determine the most appropriate way to administer the two compounds (consecutively versus simultaneously) depending on such factors as the age, sex weight and health of the patient and the disease state to be treated.
  • Doses of the present combination in a pharmaceutical dosage unit as described above will be an efficacious, non toxic quantity preferably selected from the range of 0.01-100 mg/kg of each active compound, preferably 0.1-50 mg kg.
  • The. selected dose is administered to a patient in need of treatment for benign prostatic hypertrophy preferably from 1- 6 times daily, orally, or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • a 5 ⁇ -reductase inhibiting compound, other than compound A and compound B, in a pharmaceutical composition with an alpha-andrenergic receptor antagonist is contemplated.
  • Persons skilled in the art can readily determine if a compound, other than compound A and compound B, is a 5 ⁇ -reductase inhibiting compound by methods well known in the art, such as those described in Levy et al: J. Steroid Biochem 34: 571-575, (1989). Thus, all such compounds-are included within the scope of the term "5 ⁇ -reductase inhibitor" as used herein.
  • the following examples illustrate preparation of the claimed pharmaceutical compositions. The examples are not intended to limit the scope of the invention as defined hereinabove and as claimed below.
  • EXAMPLE 1 Gelatin Capsule An oral dosage form for administering the claimed compounds and compositions is produced by screening, mixing and filling into hard gelatin capsules the ingredients in the proportions shown in Table I below.
  • lactose, microcrystalline cellulose and claimed compounds and compositions shown in Table II below are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • N-t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid 50 mg
  • amsulosin 50 mg
  • EXAMPLE 4 The following compounds (expressed as base weight) are mixed 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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques contenant de l'acide N-t-butyl-androst-3,5-diène-17β-carboxamide)-3-carboxylique ou son sel, ou bien de l'acide 17β-(N-t-butylcarboxamide-estra-1,3,5 (10)-triène-3-carboxylique ou son sel, ainsi qu'un antagoniste des récepteurs α-adrénergiques. L'invention se rapporte également à des procédés utilisant ces compositions en vue de traiter l'hypertrophie prostatique bénigne.
PCT/US1993/003145 1992-04-02 1993-04-02 Compositions et procedes permettant de traiter l'hypertrophie prostatique benigne Ceased WO1993019758A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU39451/93A AU668157B2 (en) 1992-04-02 1993-04-02 Compositions and methods for treating benign prostatic hypertrophy
EP93908738A EP0633781A4 (fr) 1992-04-02 1993-04-02 Compositions et procedes permettant de traiter l'hypertrophie prostatique benigne.
JP5517741A JPH07505398A (ja) 1992-04-02 1993-04-02 良性前立腺肥大症の治療用組成物および方法
KR1019940703522A KR950700746A (ko) 1992-04-02 1994-10-04 양성 전립선 비대를 치료하는 조성물 및 방법(Compositions and Methods For Treating Benign Prostatic Hypertrophy)

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
WO1993019758A1 true WO1993019758A1 (fr) 1993-10-14

Family

ID=27127672

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/003145 Ceased WO1993019758A1 (fr) 1992-04-02 1993-04-02 Compositions et procedes permettant de traiter l'hypertrophie prostatique benigne

Country Status (8)

Country Link
EP (1) EP0633781A4 (fr)
JP (1) JPH07505398A (fr)
KR (1) KR950700746A (fr)
AU (1) AU668157B2 (fr)
CA (1) CA2133440A1 (fr)
MX (1) MX9301939A (fr)
NZ (1) NZ251658A (fr)
WO (1) WO1993019758A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006461A1 (fr) * 1993-09-03 1995-03-09 Smithkline Beecham Corporation Formulation stabilisee pour comprimes
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
WO1998005308A3 (fr) * 1996-08-01 1998-04-23 Ciba Geigy Ag Gelules de terazosine
US5753641A (en) * 1991-03-20 1998-05-19 Merck & Co., Inc. Method of treatment for benign prostatic hyperplasia
US5760054A (en) * 1994-04-14 1998-06-02 Merck & Co., Inc. Alpha IC adrenergic receptor antagonists
US5843953A (en) * 1994-10-25 1998-12-01 Merck & Co., Inc. 7-substituted 4-aza cholanic acid derivatives and their use
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963547A (en) * 1988-06-01 1990-10-16 Smithkline Beecham Corporation Alpha-andrenergic receptor antagonists and use thereas
US5017568A (en) * 1987-04-29 1991-05-21 Smithkline Beecham Corporation Steriod 5-alpha-reductase inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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
US5308832A (en) * 1992-07-27 1994-05-03 Abbott Laboratories Nutritional product for persons having a neurological injury

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017568A (en) * 1987-04-29 1991-05-21 Smithkline Beecham Corporation Steriod 5-alpha-reductase inhibitors
US4963547A (en) * 1988-06-01 1990-10-16 Smithkline Beecham Corporation Alpha-andrenergic receptor antagonists and use thereas

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0633781A4 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5753641A (en) * 1991-03-20 1998-05-19 Merck & Co., Inc. Method of treatment for benign prostatic hyperplasia
US6046183A (en) * 1991-03-20 2000-04-04 Merck & Co., Inc. Method of synergistic treatment for benign prostatic hyperplasia
WO1995006461A1 (fr) * 1993-09-03 1995-03-09 Smithkline Beecham Corporation Formulation stabilisee pour comprimes
US5665390A (en) * 1993-09-03 1997-09-09 Smithkline Beecham Corporation Stabilized tablet formulation
US5882681A (en) * 1993-09-03 1999-03-16 Smithkline Beecham Corporation Stabilized tablet formulation
US5760054A (en) * 1994-04-14 1998-06-02 Merck & Co., Inc. Alpha IC 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
US5843953A (en) * 1994-10-25 1998-12-01 Merck & Co., Inc. 7-substituted 4-aza cholanic acid derivatives and their use
WO1998005308A3 (fr) * 1996-08-01 1998-04-23 Ciba Geigy Ag Gelules de terazosine
US5952003A (en) * 1996-08-01 1999-09-14 Novartis Corporation Terazosin capsules
US6110493A (en) * 1996-08-01 2000-08-29 Novartis Corporation Terazosin capsules
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt

Also Published As

Publication number Publication date
EP0633781A1 (fr) 1995-01-18
MX9301939A (es) 1994-08-31
EP0633781A4 (fr) 1995-04-19
KR950700746A (ko) 1995-02-20
AU3945193A (en) 1993-11-08
CA2133440A1 (fr) 1993-10-14
NZ251658A (en) 1996-08-27
JPH07505398A (ja) 1995-06-15
AU668157B2 (en) 1996-04-26

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