WO2005089804A2

WO2005089804A2 - Combinations of hmg-coa reductase inhibitors and alpha1 adrenergic receptor antagonists

Info

Publication number: WO2005089804A2
Application number: PCT/IB2005/000574
Authority: WO
Inventors: Nicholas Pullen; Richard James Thurlow
Original assignee: Pfizer Limited; Pfizer Inc.
Priority date: 2004-03-16
Filing date: 2005-03-04
Publication date: 2005-09-29
Also published as: WO2005089804A3

Abstract

Combinations of an HMG-CoA reductase inhibitor, other than atorvastatin, and α1 adrenergic receptor antagonists, the use of such combinations in the treatment of benign prostatic hyperplasia (BPH), methods of treating BPH using such combinations and medicaments containing such combinations are described.

Description

Combinations of HMG-CoA reductase inhibitors and αi Adrenergic Receptor Antagonists

This invention relates to the combination of a HMG-CoA reductase inhibitor, other than atorvastatin, with an ctι adrenergic receptor antagonist. The use of such combinations in the treatment of benign prostatic hyperplasia (BPH) is also concerned, along with methods of treating BPH using the combinations. It also relates to medicaments containing the combinations.

BPH is a chronically progressive disease that can lead to complications such as acute urinary retention, recurrent urinary tract infections, bladder stones and renal dysfunction. The prevalence and average severity of lower urinary tract symptoms (LUTS) associated with BPH in men increases with age.

BPH leads to an increase in prostate volume, creating urethral and bladder outflow obstruction as well as secondary changes in bladder function. The effects of this are manifested by both storage (irritative) and voiding (obstructive) symptoms, giving rise to nocturia, urinary urgency and poor urinary flow.

In patients with BPH, blockade of sympathetic (adrenergic) nerve innervations of the prostate reduces intra-urethral pressure by about 50% (J. Urol., 1982, 128, 836), alleviating the symptoms of outflow obstruction. In particular, adrenergic receptors of the αi subtype predominate in the prostate and lower urinary tract and αi adrenoceptor-specific antagonists have been identified which preferentially relax prostatic smooth muscle compared with cardiovascular smooth muscle. Clinical trials have confirmed this hypothesis and several αi antagonists such as tamsulosin, terazosin, alfuzosin and doxazosin are now marketed for the treatment of BPH. Many reviews of α adrenoceptor antagonists are available, for example see Prostate Cancer Prostatic Dis. 2000, 3, 76-83; Annu. Rep. Med. Chem. 2000, 35, 221-230; Expert Opin. Invest. Drugs, 1999, 8, 2073-2094; Prostate Cancer Prostatic Dis., 1999, 2, 110-119; J. Med. Chem., 1997, 40, 1293; Pharm. Res., 1996, 33, 145.

While, the introduction of pharmacological therapies has heralded some improvement in the impact of the symptoms and the need for surgical intervention for BPH, the overall effects are moderate and the needs of patients and physicians are still largely unmet. Also there is no evidence that the currently available pharmacological therapies are effective at controlling either the bladder hypertrophy, detrusor instability, or prostate/bladder fibrosis associated with BPH.

Italian Patent Application No. 048658 describes the use of HMG-CoA reductase inhibitors for the treatment of BPH. JP56115717 discloses the use of two HMG-CoA reductase inhibitors (monacholin K and ML-236B) for treating prostatomegaly. US2002/0004521 describes the use of statins for the treatment of BPH. Combinations of 5α-reductase inhibitors with α-adrenergic receptor antagonists are described for use in the treatment of BPH in US Patent No. 5,753,641. WO 99/11260 concerns the combination of atorvastatin with an antihypertensive agent, which may comprise an α-adrenergic receptor antagonist. Such combinations are useful in the treatment of angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and for the treatment of subjects presenting with symptoms of cardiac risk.

This invention provides the use of a combination of (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the

HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) an α adrenergic receptor antagonist or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of BPH.

Further, it provides the use of a combination of (A) and (B) for the treatment of BPH in order to improve lower urinary tract symptoms and urinary flow rates, limit progression of the disease and reverse the pathological changes in the bladder and prostate associated with the disease, thus reducing the incidence of urinary retention and the requirement for surgery.

The combinations of the invention may have the advantage that, due to a synergistic interaction between the active ingredients, they are more potent, have a longer duration of action, more effectively reduce disease progression and, therefore, the requirement for surgical intervention, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in BPH without causing undesirable cardiovascular effects) or have other more useful properties than the prior art.

In one embodiment, there is provided the use of a combination of (A) an HMG- CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) an α adrenergic receptor antagonist or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of BPH.

The expression "pharmaceutically acceptable derivatives" includes pharmaceutically acceptable salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomeric forms, and isotopic variations of the compounds of the invention. Preferably, pharmaceutically acceptable derivatives of the compounds of the invention comprise pharmaceutically acceptable salts, solvates, esters and amides. More preferably, pharmaceutically acceptable derivatives of the compounds of the invention are pharmaceutically acceptable salts and solvates.

Any HMG-CoA reductase inhibitor, provided that it is not atorvastatin or a pharmaceutically acceptable derivative thereof, may be used in the combination of this invention. The term HMG-CoA reductase inhibitor refers to compounds, which inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Meth. Enzymol. 1981; 71 :455-509 and references cited therein).

A variety of these compounds are described and referenced below; however, other HMG-CoA reductase inhibitors will be known to those -skilled in the art. U.S. Patent No. 4,231 ,938 discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin (MEVACOR®). Also, U.S. Patent No. 4,444,784 discloses synthetic derivatives of the aforementioned compounds, such as simvastatin (ZOCOR®). U.S. Patent Nos. 4,739,073 and 5,354,772 also disclose certain substituted indoles, such as fluvastatin (LESCOL®). U.S. Patent No. 4,346,227 discloses ML-236B derivatives, such as pravastatin (PRAVACHOL®). Also U.S. Patent No. 5,260,440, International Published Patent Application WO 00/42024 and "M. Watanabe et al., Biorg. Med. Chem., 1997; 5:437-447" disclose certain pyrimidine derivatives, such as rosuvastatin (CRESTOR®). Additional HMG- CoA reductase inhibitors include pitavastatin, velostatin (US 4,448,784; US 4,450,171), dalvastatin (EP738510A2), fluindostatin (EP363934A1 ), dihydrocompactin (US 4,450,171), cerivastatin (US 5,502,199; EP617019), mevastatin (US 3,983,140) and compactin (US 4,804,770). Also included in this invention are the pharmaceutically acceptable salts, esters and lactones of the above HMG-CoA reductase inhibitor compounds, and mixtures thereof.

Particularly of interest are fluvastatin, lovastatin, simvastatin and pravastatin. HMG-CoA reductase inhibitors suitable for use as (A) in the invention may be identified using the following assays:

1.0 Rat Liver Microsomal Isolation Procedure: Male Charles River Sprague-Dawley rats were fed with 2.5% cholestyramine in rat chow diets for 5 days before sacrificing. Their livers were minced and homogenized in a sucrose homogenizing solution in an ice bath 10 times. The homogenates were diluted into a final volume of 200 mL, and centrifuged 15 min. with a Sorvall Centrifuge at 5°C, 10,000 rpm (12,000 x G). The upper fat layer was removed and the supernatant was decanted into fresh tubes. This step was repeated one more time before transferring the supernatant into ultracentrifuge tubes and centrifuging at 36,000 rpm (105,000 x G) for an hour at 5°C. The resulting supernatant was discarded and the pellet was added to a total of 15 mL 0.2 M KH₂PO₄. The pellets were homogenized gently by hand about 10 times. The samples were pooled and diluted into a total of 60 mL of buffer. The protein concentration of the homogenate was determined by the Lowry Method, using a BCA (Bicinchoninic acid) kit from Pierce Chemical Company. 1 mL aliquots of microsomes were kept frozen in liquid nitrogen.

1.1 HMGCoA (3-Hvdroxy-3-methylαlutaryl CoA) Reductase Assay:

Materials and Methods:

[3-¹⁴C]-HMGCoA (57.0 mCi/mmol) was purchased from Amersham Biosciences, UK. HMGCoA, mevalonolactone, β-NADPH (β-Nicotinamide Adenine Dinucleotide Phosphate, Reduced form) were purchased from Sigma Chemical Co. AG 1-8X resin was purchased from Bio-Rad Laboratory.

One μL of dimethyl sulfoxide (DMSO) or 1 μL of DMSO containing a test compound at a concentration sufficient to give a final assay concentration of between 0.1 nM to 1 mM was placed into each well of a Corning 96 well plate. A Volume of 34 μL of buffer (100 mM NaH₂PO₄, 10 mM Imidazole and 10 mM EDTA [Ethylenediaminetetra acetic acid]) along with 50 μg/mL rat liver microsomes was added into each well. After incubation for 30 min. on ice, 5 μL of ¹⁴C-HMGCoA (0.024 μCi) with 15 mM NADPH, 25 mM DTT, (Dithiothreitol) was added and incubation continued at 37°C for an additional 45 min. The reaction was terminated by the addition of 10 μL of HCI followed by 5 μL of mevalonolactone. The plates were incubated at room temperature overnight to allow lactonization of mevalonate to mevalonolactone. The incubated samples were applied to columns containing 300 μL of AG1-X8 anion exchange resin in a Corning filter plate. The eluates were collected into Corning 96 well capture plates. Scintillation cocktail (Ultima-Flo-M) was added into each well and the plates were counted on a Trilux Microbeta Counter. The IC₅₀ values were calculated with GraphPad software (Prism).

Procedure: 1. Add 1 μL DMSO or compounds into the wells according to the protocol. 2. Add 35 μL incubation buffer with the rat microsomes into each well. Incubate for 30 min. at 4°C. 3. Add 15 μL ¹⁴C-HMGCoA. Incubate for 45 min. at 37°C. 4. Add 10 μL HCI stop reagent. 5. Add 5 μL mevelonolactone. Incubate overnight at room temperature. 6. Apply the containing into the AG 1-X8 anion exchange resin in Corning filter plate. 7. Collect the eluate into Corning capture plate. 8. Add scintillation cocktail Ultima-Flo-M. 9. Count on a Trilux Microbeta Counter. 10. Calculate IC₅₀ values.

2.0 Protocol for Sterol Biosynthesis in Rat Hepatocytes:

Cell culture, compounds treatment and cell labeling: Frozen rat hepatocytes purchased from XenoTech(cat# N400572) were seeded on 6-well collagen I coated plates at a density of 10⁵ cells/per well. The cells were grown in DMEM, (Dulbecco's Modified Eagle Medium) (Gibco, #11054- 020) containing 10% FBS (Fetal Bovine Serum) and 10 mM HEPES, (N-2- hydroxyethyl-piperazine-N¹-2-ethane sulfonic acid) (Gibco # 15630-080) for 24 hours. The cells were pre-incubated with compounds for 4 hours and then labeled by incubating in medium containing 1 uCi/per mL of ¹⁴C acetic acid for an additional 4 hours. After labeling, the cells were washed twice with 5 mM MOPS (3-[N-morpholino]propane sulfonic acid) solution containing 150 mM NaCI and 1 mM EDTA and collected in the lysis buffer containing 10% KOH an 80%(vol.) ethanol.

Cholesterol extraction and data analysis:

In order to separate labeled cholesterol from labeled non-cholesterol lipids, the cells lysates were subjected -to saponification at 60°C for 2 hours. The lysates were then combined with 0.5 volume of H₂O and 2 volumes of hexane, followed by 30 minutes of vigorous shaking. After the separation of the two phases, the upper-phase solution was collected and combined with 5 volumes of scintillation cocktail. The amount of ¹ C cholesterol was quantified by liquid scintillation counting. The IC₅o values were calculated with GraphPad software (Prism 3.03).

Compounds suitable for use as (A) in the invention exhibit a range of IC₅o values of less than about 1000 nM, preferably less than about 500 nM, even more preferably less than about 100 nM. Even still more preferably less than about 20 nM.

A variety of αi-adrenergic receptor antagonists may be used in the combination of the invention. Such antagonists may be readily determined by those skilled in the art according to standard assays. ch-Adrenergic receptor antagonists useful for (B) are referenced below, however other a adrenergic receptor antagonists will be known to those skilled in the art: terazosin (US Patent No. 4,026,894), doxazosin (US Patent No. 4,188,390), prazosin (US Patent No. 3,511 ,836), bunazosin (US Patent No. 3,920,636), alfuzosin (US Patent No. 4,315,007), naftopidil (US Patent No. 3,997,666), tamsulosin (US Patent No. 4,703,063), silodosin (US Patent No. 5,387,603); the compounds disclosed in International Application Publication No. WO 03/076427 in particular 5-cyclopropyl-7-methoxy-2-(2-morpholin-4-yImethyl-7,8- dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone (example 11), and the compounds disclosed in International Application Publication No. WO 98/30560 in particular 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoiine (example 19); and pharmaceutically acceptable derivatives thereof. Preferred α-adrenergic receptor antagonists are doxazosin, 5-cyclopropyl-7-methoxy-2-(2-morpholin-4- ylmethyl-7,8-dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone and 4- Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2- yl)-5-(2-pyridyl)quinazoline and pharmaceutically acceptable derivatives thereof. The mesylate salt of 4-Amino-6,7-dimethoxy-2-(5- methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is of particular interest (see WO 01/64672).

α Adrenergic receptor antagonists suitable for the present invention may be identified using the following assays:

3.0 Contractile responses of human prostate

Prostatic tissue was cut into longitudinal strips (approximately 3x2x10 mm) and suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCI (119), KCI (4.7), CaCI₂ (2.5), KH₂PO₄ (1.2), MgSO₄ (1.2), NaHCO₃ (25), glucose (11 ), and gassed with 95% O₂/5% CO₂. The solution also contains 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to a sensitising dose of (-)- noradrenaline (100 mM) and washed over a period of 45 minutes. Isometric contractions were obtained in response to cumulative additions of (-)- noradrenaline to obtain control curves in all tissues. A further curve was then generated in the presence or absence of antagonist (incubated for 2 hours). Antagonist affinity estimates (pA₂) were determined using a single concentration of competing antagonist, pA₂ = -log jA]/(DR-1) where the dose ratio (DR), relative to corresponding controls, was produced by a single concentration of antagonist [A], assuming competitive antagonism and Schild regression close to unity.

4.0 Anaesthetised dog model of prostatic pressure and blood pressure Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg/kg i.v.) and a tracheal cannula was inserted. Subsequent anaesthesia was maintained using pentobarbitone infusion. The animals were respirated with air using a Bird Mk8 respirator(Bird Corp., Palm Springs, CA, USA) adjusted to maintain blood gasses in the range pO₂ 90-110 mm Hg, pCO 35-45 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5°C using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration. Heart rate was recorded via the lead II E.C.G. A laparotomy was performed to cannulate both ureters to prevent change of fluid volume within the bladder. A 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon was filled with air and the catheter was withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments, Quincy, Mass, U.S.A.) and the data was measured on line using a Motorola 68000- based microcomputer system (Motorola Inc., Temple, AZ, U.S.A.). Compounds were made up in PEG 300 and were administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 μg/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds were administered (in terms of compound base) at 10-300 μg/kg i.v. 5 min., before phenylephrine curves were constructed (constructed up to a maximum dose of 128 μg/kg in the presence of test compound).

Due to i-related dysrhythymic properties of phenylephrine, absolute maximal responses were not obtained but were taken as 10 % greater than the control response obtained with 16 μg/kg phenylephrine. Drug concentrations were calculated on the basis of molar weight of compound/kg body weight thus allowing a "pseudo pA2" calculation by Schild analysis using dose ratios derived from shifts in the phenylephrine dose-response curves.

One embodiment of the invention comprises a pharmaceutical composition comprising (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) doxazosin or a pharmaceutically acceptable derivative thereof.

An alternative embodiment comprises a pharmaceutical composition comprising (A) as hereinbefore described, and (B) 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)- quinazolinone or a pharmaceutically acceptable salt thereof.

A further embodiment comprises a pharmaceutical composition comprising (A) as hereinbefore described, and (B) 4-amino~6,7-dimethoxy-2-(5- methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline or a pharmaceutically acceptable derivative thereof.

In a further embodiment there is provided a medicament containing, separately or together, (A) as hereinbefore described, and (B) 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl)quinazoline or a pharmaceutically acceptable derivative thereof, for simultaneous, sequential or separate administration in the treatment of BPH.

In an alternative embodiment there is provided a medicament containing, separately or together, (A) as hereinbefore described, and (B) 5-cyclopropyl-7- methoxy-2-(2-morpholin-4-ylmethyl-7,8-dihydro[1,6]-naphthyridin-6(5H)-yl)- 4(3H)-quinazolinone or a pharmaceutically acceptable salt thereof, for simultaneous, sequential or separate administration in the treatment of BPH.

A further embodiment comprises a medicament containing separately or together, (A) as hereinbefore described, and (B) doxazosin or a pharmaceutically acceptable salt thereof, for simultaneous, sequential or separate administration in the treatment of BPH.

In a further embodiment there is provided a pharmaceutical composition comprising a mixture of effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined, optionally together with a pharmaceutically acceptable carrier.

In the pharmaceutical compositions of the present invention, (A) is present in an amount ranging from 10 mg to 80 mg per dose, and (B) is present in an amount ranging from 0.1 mg to 20 mg per dose. The physician in any event will determine the actual dosage that will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.

The pharmaceutical compositions of the present invention can be administered alone but will generally be administered in a mixture with a suitable pharmaceutical excipient, diluent or carried selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the pharmaceutical compositions can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The pharmaceutical compositions may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of the pharmaceutical compositions may be in coated or uncoated form.

Solid pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

The pharmaceutical compositions may also be administered in the form of a suppository for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipients which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The combination of this invention may also be administered in a controlled- release dosage formulation such as a slow release or a fast release formulation. Such controlled release formulations of the combination of this invention may be prepared according to methods well known to those skilled in the art.

Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compounds of this invention, preferably 1 %-70%.

Still further provided by the present invention is a method of treating BPH comprising administering to a subject in need of such treatment amounts of (A) as hereinbefore described and (B) as hereinbefore described which are together effective.

Yet further, there is provided by the present invention a pharmaceutical product containing (A) and (B) as hereinbefore defined, as a combined preparation for simultaneous, separate or sequential use in treating BPH.

"Effective amounts" as used herein is an amount of (A) and (B) that will elicit the biological or medical response being sought. The daily dose of (A) and (B) employed in the method of treatment is similar to the doses described for use in the pharmaceutical compositions hereinbefore described. In the method of treatment according to the present invention (A) and (B) can be administered together combined in a single dosage form, or they can be administered separately, essentially concurrently, each in its own dosage form but as part of the same therapeutic treatment program, and it is envisaged that (A) and (B) may be separately administered, at different times and by different routes.

The utility of the combination of the present invention as medical agents in the treatment of BPH is demonstrated by the activity of the combination in the protocol described below: 5.0 Clinical Studies of the Efficacy of the combination of an HMG-CoA reductase inhibitor and an ch-Adrenergic Receptor Antagonist.

In a 12-Week Study in men with symptomatic BPH, the IPSS (International Prostate Symptom Score) was recorded at baseline, during and at the end of double-blind treatment. The IPSS is composed of seven questions, each with potential responses of 0 to 5 on a Likert scale. Higher scores indicate more severe lower urinary tract symptoms. The primary endpoint in this study was mean change in IPSS from baseline to end of study in the intent-to-treat population. In this study, the αi-adrenergic receptor antagonist used was 4- amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2- yl)-5(2-pyridyl)quinazoline (described in WO 98/30560 and WO 01/64672) and there were four treatment groups: 1mg a adrenergic receptor antagonist, 3mg αi-adrenergic receptor antagonist, 6mg αi-adrenergic receptor antagonist and placebo. Concomitant medication was recorded at the Screening visit. Efficacy in subjects receiving an HMG-CoA reductase inhibitor has been compared with efficacy in subjects who were not receiving statin therapy. HMG-CoA reductase inhibitors used in the study were fluvastatin, lovastatin, pravastatin and simvastatin. This comparison has demonstrated that, for each dose group of αi-adrenergic receptor antagonist, greater efficacy was seen in the an HMGCoA reductase inhibitor treated group than in the an HMG-CoA reductase inhibitor untreated group, when compared with the placebo response in each group:

Table 1. Placebo-adjusted mean change in IPSS from Baseline to Week 12 in subjects who were not receiving HMG-CoA reductase inhibitor therapy (No HMG-CoA reductase inhibitor) vs. subjects who were receiving an HMG-CoA reductase inhibitor.

Claims

CLAIMS:

1. The use of a combination of (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) an αi-adrenergic receptor antagonist or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of BPH.

2. The use of a combination as defined in claim 1 for the treatment of BPH.

3. The use of a combination of (A) as defined in claim 1 and (B) as defined in claim 1 for the manufacture of a medicament for combination therapy by simultaneous, sequential or^" separate administration of (A) and (B) in the treatment of BPH.

4. The use according to any of claims 1 to 3, wherein (A) is selected from fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, pitavastatin, velostatin, dalvastatin, fluindostatin, dihydrocompactin, cerivastatin, mevastatin, compactin or a pharmaceutically acceptable derivative thereof.

5. The use according to claim 4, wherein (A) is selected from fluvastatin, lovastatin, pravastatin and simvastatin, or a pharmaceutically acceptable derivative thereof.

6. The use according to any of claims 1 to 5, wherein (B) is selected from terazosin, doxazosin, prazosin, bunazosin, alfuzosin, naftopidil, tamsulosin, silodosin, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 , 2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)- quinazolinone, or a pharmaceutically acceptable derivative thereof.

7. The use according to claim 6, wherein (B) is doxazosin or a pharmaceutically acceptable derivative thereof.

8. The use according to claim 6, wherein (B) is 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline or a pharmaceutically acceptable derivative thereof.

9. The use according to claim 6, wherein (B) is 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro[1 ,6]-naphthyridin-6(5H)-yl)-4(3H)- quinazolinone, or a pharmaceutically acceptable derivative thereof.

10. A method of treating BPH comprising administering to a subject in need of such treatment amounts of (A) and (B) as defined in claims 1 to 9 which are together effective.

11. A pharmaceutical product containing (A) and (B) as defined in claims 1 to 9, as a combined preparation for simultaneous, separate or sequential use in treating BPH.

12. A pharmaceutical composition comprising (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) doxazosin or a pharmaceutically acceptable derivative thereof.

13. A pharmaceutical composition comprising (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline or a pharmaceutically acceptable derivative thereof.

14. A pharmaceutical composition comprising (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) 5-cyclopropyl-7-methoxy-2-(2-morpholin- 4-ylmethyl-7,8-dihydro[1,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone or a pharmaceutically acceptable derivative thereof.

15. A medicament containing, separately or together, (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative .thereof, and (B) doxazosin or a pharmaceutically acceptable derivative thereof, for simultaneous, sequential or separate administration in the treatment of BPH.

16. A medicament containing, separately or together, (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl)quinazoline or a pharmaceutically acceptable derivative thereof, for simultaneous, sequential or separate administration in the treatment of BPH.

17. A medicament containing, separately or together, (A) an HMG-CoA reductase inhibitor or a pharmaceutically acceptable derivative thereof, provided that the HMG-CoA reductase inhibitor is not atorvastatin or a pharmaceutically acceptable derivative thereof, and (B) 5-cyclopropyl-7- methoxy-2-(2-morpholin-4-ylmethyl-7,8-dihydro[1,6]-naphthyridin-6(5H)-yl)- 4(3H)-quinazolinone or a pharmaceutically acceptable derivative thereof, for simultaneous, sequential or separate administration in the treatment of BPH.

18. A medicament according to any of claims 15 to 17' which is a pharmaceutical composition comprising an effective amount of a combination of (A) and (B) as defined in any of claims 15 to 17, optionally together with a pharmaceutically acceptable carrier.