AU668157B2 - Compositions and methods for treating benign prostatic hypertrophy - Google Patents

Description

OPI DATE 08/11/93 AOJP DATE 13/01/94 APPLN. ID 39451/93 PCT NUMBER PCT/US93/03145 I AU9339451 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENI CUOPERA llN IKIAl Y (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/19758 A61K 31/56 Al (43) International Publication Date: 14 October 1993 (14.10.93) (21) International Application Number: PCT/US93/03145 (72) Inventors; and Inventors/Applicants (for US only) HIEBLE, Jacob, Paul (22) International Filing Date: 2 April 1993 (02.04.93) [US/US]; 685 Knox Road, Wayne, PA 19087 (US).

METCALF, Brian, Walter [AU/US]; 520 Woodland Drive, Radnor, PA 19087 (US).

Priority data: 07/862,117 2 April 1992 (02.04.92) US (74) Agents: DUSTMAN, Wayne, J. et al.; SmithKline Bee- 07/997,792 29 December 1992 (29,12.92) US cham Corporation, Corporate Patents UW2220, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406.0939 (US).

Parent Applications or Grants (63) Related by Continuation US 07/862,117 (CON) (81) Designated States: AU, CA, JP, KR, NZ, US, European Filed on 2 April 1992 (02.04.92) patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, US 07/997,792 (CON) LU, MC, NL, PT, SE).

Filed on 29 December 1992 (29,12.92) Published (71) Applicant (for all designated States except US): SMITH. With international search report.

KLINE BEECHAM CORPORATION [US/US]; Corporate Patents US., UW2220, 709 Swedeland Road, PO. Box 1539, King of Prussia, PA 19406.0939 (US).

668 5 7 (54) Title: COMPOSITIONS AND METHODS FOR TREATING BENIGN PROSTATIC HYPERTROPHY (57) Abstract Invented are pharmaceutical compositions containing N-t-butyl-androst-3,5-diene-17p-carboxamide)-3-carboxylic acid or a salt thereof or 170-(N-t-butylcarboxamide-estra-l,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.

WO 93/19758 PCT/US93/03145 -1- Compositions and Methods For Treating Benign Prostatic Hypertrophy This invention relates to a pharmaceutical composition containing Nt-butyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid or a salt thereof or or_ clt :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-17Bcarboxamide-3-carboxylic acid or a salt thereof orand an alpha-andrenergic receptor antagonist compound to such mammal.

BACKGROUND OF THE INVENTION As one of the primary regulators of peripheral vascular tone, a 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 (hereinafter Lafferty I) 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.

-2- 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 N-t-butyl-androst-3,5-diene- 17p-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-a-reductase inhibiting compound which exhibits the therapeutic effect of lowering prostatic levels of dihydrotestosterone thereby reducing prostate size.

All of the compounds disclosed in Holt I as having 5-a-reductase inhibiting activity have utility in the invented compositions.

Holt I does not disclose Compound A in combination with an alpha-adrenergic receptor antagonist compound.

S 15 SUMMARY OF THE INVENTION This invention relates to a pharmaceutical compositign containing N-t-butylandrost-3,5-diene-17p-carboxamide-3-carboxylic acid or a salt thereof and an alphaandrenergic receptor antagonist compound and a pharmaceutically acceptable carrier or diluent. This invention also relates to a method of treating benign prostatic hypertrophy 20 in a mammal, including a human, in need thereof which comprises administering an effective dose ofN-t-butyl-androst-3,5-diene-l 7p-carboxamide-3-carboxylic acid or a salt thereof 1130,p:opcrdab,394 Ilspc,2 WO 93/19758 WO 939758PUS93/0314A -3- .the~oiand an aipha-andrenergic receptor antagonist compound to such mammal.

D2ETAILED DESCRIPTON OF THE INYNTION Compounds which are aipha-andronergic receptor antagonists are disclosed in Lafferty I as representing a well known therapeutic class of compounds.

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.

By the term "ainsulosin" as used herein is meant a compound of the formula

CH

3 CH3 O

H-CNCHC

2

H

H

2 NO0 2 S

OCH

2

CH-

3 and salts, hydrates and solvates thereof.

Chemically, amsulosin is designated as ethoxyphenoxy)ethyllaminolpropyl)-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 "terazocjn" as used herein is meant a compound of the formula 0 11 N 0

CH

3 0 N

CH

3 0

N'

NH

2 ~anA ts, hydrates and solvates thereof.

7*r WO 93/19758 WO 9319758PCT/US93/03145 -4- Chemically, terazocin is designated as 1-(4-amino-6,7-dimethoxy-2 quinazolinyl)-4-[(tetrahydro-2-fiiroyl)carbonyllpiperazine. Terazocin is disclosed in U.S. Patent Number 4,251,532.

By the term doxazosin as used herein is meant a compound of the formula r N-CO 0

H

3 C0 \1J~ NJ

H

3 00

N

NH

2 and salts, hydrates and solvates thereof.

Chemically "doxazosin" is designated as 1-(4-amino-6,7dimethoxy-2-quinazolinyl)-4-[(2 ,3-dihydro- 1,4-benzodioxin-2yl )carbonylj-piperazine.

Doxazosin is discolsed in U.S. Pat~nt Number 4,188,390.

By the term "alfuzosin" as used herein is meant a compound of the formula

OH

3 I H

H

3 CO N

H

3 00

NH

2 and salts, hydrates and solvates thereof.

Chemically alfuzosin is designated as N4[3-[(4-amino-6,7dimethoxy-2-quinazolinyl)methylaminolpropylltetrahydro-2furancarboxainide.

Alfuzosin is disclosed in U.S. Patent Number 4,315,007.

By the term "indorarmin" as used herein is meant~ a compound fo the formula

H

CH

2 CH41 -NHC WO 93/19758 PCT/US93/03145 and salts, hydrates and solvates thereof.

Chemically indoramin as designated N-[[1-[2-(1H-indol-3yl)ethyl]-4-piperidinyl]benzamine.

Indoramin is disclosed in U.S. Patent Number 3,527,761.

By the term "prazosin" as used herein is meant a compound of the formula SN-CO0- I

CH

3 0 N

CHO

N

NH

2 and salts, hydrates and solvates thereof.

Chemically prazosin is designated as 1-(4-amino-6,7-dimethoxy-2quinazolinyl)-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-4methylthieno[4,3,2-ef]-[3]benzazepine" as used herein includes salts, hydrates and soluates thereof. 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4methylthieno[4,3,2-efJ-[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 alphaandrenergic 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 "alphaandrenergic 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 T mp pn-d and an alpha-andrenergic receptor antagonist compound. Preferably, if the administration is not simultaneous, the two compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are both administered in the same dosage form, e.g. one WO 93/19758 PCT/US93/03145 -6compound may be administered by injection and the other compound may be administered orally.

The compositions 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, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. 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 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 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.

The pharmaceutical properties of 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. Such 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-17B-carboxamide-3carboxylic acid or a salt thereof r- "tyflabf -q r.- WO 93/19758 PCT/US93/03145 -7t. ,'and an alphaandrenergic 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 will necessarily depend on the exact disease st% a to be treated, the age, weight, sex and health of the particular animal 4i o treated and that such optimums can be determined by conventional techniques.

To maximize its therapeutic effect, 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.

No unacceptable toxicological effects are expected when compositions of the invention are adminiered in accordance with the present invention.

The use of a 5a-reductase inhibiting compound, other than compound A,an4dcompound-. 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 5a-reductase inhibiting compound by methods well j"EfT~l J~i 7"c~" WO 93/19758 PCT/US93/03145 -8known 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 "5ac-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.

TableI Ingredientj Amounts N-t-butyl-androst-3,5-diene,7J3- 50 mg carboxamide-3-carboxylic acid Terazocin 50 mg Magnesium stearate 10 mg Lactose 150 mg EXAMPLE 2- Tablet The lactose, microcrystalline cellulose and claimed compounds and compositions shown in Table II below, are mixed ant graiulated 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.

WO 93/19758 PCf/US9/031 -9- Tale IE Inaeredieniz Amr~ouna N-t-butyl-androst-3 ,5-diene- 17f3-carboxaide-3- 50 mg carboxylic acid Doxazosin 50 mg Calcium sulfate dihydrate 715 mg Sucrose 20 mg Starch 10 ng Talc 5 mg Stearic acid 5 mg EXAMPLE 3 Tniectabl erPeppration N-t-butyl-androst-3,5-diene-173-carboxamide-3-carboxylic acid mg) and amsulosin (50 mg), are dispersed in 25 ml of normal saline to prepare an injectable preparation

EXAMPLEJEE:

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 capt, les are administered from 1-6 times daily to a patient in need of treatment of bt *gn prostatic hypertrophy, A. N-t-butyl-androst-3,5-diene-1?7--carboxamide-3-carboxylic acid mg; prazosin 50 mg.

B. N-t-butyl-androst3,5-diene-17-carb-,amide-3-carboxylic acid mg; alfuzosin 50 mg.

C. N-t-butyl-androst-3,5-diene-17B.carboxamide-3-carboxylic acid mg indoraznif 50 mg.

While the preferred embodiments of the invention aejJlustratC by the above, it is to be understood that thainvYenttoi'fs- riot limited to t~iL-t precise irstructon her-euciaii ed and that the right to all ,%oatioi coming within the scope of the following clams is riserved.

tl 9a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers, While the preferred embodiments of the invention are illustrated 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 claims is reserved,

I

giecho i 4

I

0 4*0*

I

i o

I

7~ L 051 130pape abb 45 hpe.4

Claims (6)

1. A pharmaceutical composition comprising N-t-butyl-androst-3,5-diene-17p- carboxamide-3-carboxylic acid or a salt thereof and an alpha-andrenergic receptor antagonist compound and a pharmaceutically acceptable carrier or diluent.

2. A composition of claim 1 in which the alpha-andrenergic receptor antagonist is terazocin.

3. A compositon of claim 1 in which the alpha-adrenergic receptor antagonist is selected from alfuzosin, indoramrn, doxazosin, prazosin, amsulosin and 7-chloro-2-ethyl- 3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef]-[3]benzazepine,

4. A method of treatment to reduce prostate size which comprises administering the 15 composition according to any one of claims 1 to 3 to a subject in need thereof.

S A method for the treatment of benign prostatic hypertrophy which comprises separate, sequential or simultaneous administration o N-t-butyl-androst-3,5-diene-17p- carboxamide-3-carboxylic acid or a salt thereof and an alpha receptor antagonist 20 compound to a subject in need thereof.

6. Pharmaceutical compositions or uses or methods involving them, substantially as hereinbefore described with reference to the Examples. DATED this 16th day of February, 1996 SmithKline Beecham Corporation By Its Patent Attorneys DAVIES COLLISON CAVE 9~Q~,cpcrab.145l spcIO I I I INTERNATIONAL SM ARCH REPORT PCT/US93/03 145 A. CLASSIFICATION OF SUBJECT MATTER [PC(S) :A6lK 31156 US CL :514/171 According to Internaional Patent Classification or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classiicatiow, symbols) U.S. 514/171 514/254,258,323.651 Documeno'ton searched other than minimum documentation to the extent thAt such documents arm included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C, DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of documient, with indication, where appropriate. of the relevant passages Relevant to claim No Y USA, 4,963,547 (Lafferty et al.) 16 October 1990 See the entire 1-10 document. Y USA 5,017,568 (Holt et al.) 21 May 1991 See the entire 1-10 document. LIFurther documents are listed Wn the continuation of Box C. 11 See patent family annex, SPecW "aks of aie dcmea: Ltt docwawa peiht~M iftr the uonuctaid filng date at pnonty A do~d.h~ the Kate ~dae and ex0in coajlk with the 6"40~cu" b-aw ie to raaand the doumdh *ae jeto atatie, raw~e a i nw isot-vdr prvacipk at theory undoriyhta the inveanto 0E. awfer CVAM 4 C ttt W WfftQ~lM10 d& cneadervid sovl of coan bo consdered to Ivlve an Inventive mep, W doctm"A Wh"~ My Whow 4oubt ais peky Claws) oW Whi What the domunw" W tiae 610o0 Ckadtoeh~ the 60W bA maIN- dat 0( ahef dt" of othe 'Y doue Ofpwk oom. wcdwNsu can"o be .0 oua fretng to an oald dmclcew. ue. oxhibitionato otce combined with ane ore otltedt c CUmena, su~h coenbuwta mewn bein obviotouos perow akilled in the arl .r dowsoft lhe prior to dee kisterdoWe Aling damehe bo cr the &M docwdat washe, hei t"M potnt femiiy Date of the actual completion of the international se "oh Data of mailing of the international search report 243JUNE 1993 Nam and malling address of the ISAIUS Authorized officer 4 Cotnnieeioagr of Pateau and Tradermarks OiSHNKAma.'t i. Box PCT .EK t15 -4 Wabaltoo. D.C. 20231 ~i~ERNATio1MAL DrVZCZ Facsimile No, NOT APPLICASLE I~ Telephom No. (703) 309S.123? Form Pcr/ISA/210 (second shect)(iuly 1992)*