KR20050092519A - COMBINATIONS OF ATORVASTATIN AND α1 ADRENERGIC RECEPTOR ANTAGONISTS - Google Patents

Abstract

The present invention relates to combinations of atorvastatin and α ₁ -adrenergic receptor antagonists, use for the treatment of benign prostatic hyperplasia (BPH), methods of treating BPH using such combinations, and medicaments comprising such combinations.

Description

COMBINATIONS OF ATORVASTATIN AND α1 ADRENERGIC RECEPTOR ANTAGONISTS}

The present invention relates to a combination of atorvastatin and α ₁ -adrenergic receptor antagonists, the use of such a combination for the treatment of benign prostatic hyperplasia (BPH), a method of treating BPH using such a combination, and a medicament comprising the combination.

BPH is a chronically advanced disease that can cause complications such as acute urinary retention, recurrent urethral infections, bladder stones and kidney failure. The proportion and mean pain of lower urethral syndrome (LUTS) associated with BPH in men increases with age.

BPH increases prostate volume and causes urinary and bladder outflow obstruction as well as secondary changes in bladder function. This effect is amplified due to storage (sensitization) and emptying (obstructive) symptoms, causing nocturnal enuresis, frequent urination and poor urine flow.

In patients with BPH, obstruction of the sympathetic (adrenergic) nerve distribution of the prostate reduces the symptoms of outflow obstruction, reducing internal urethral pressure by about 50% (see J. Urol., 1982, 128, 836). . In particular, adrenergic receptors of type α ₁ are predominantly present in the prostate and lower urethra, and antagonists specific for α ₁ -adrenergic receptors have been found to relax prostate smooth muscle more as compared to cardiovascular smooth muscle. Clinical trials have confirmed this hypothesis and several α ₁ -antagonists such as tamsulosin, terazosin, alfuzosin, and doxazosin are commercially available for the treatment of BPH.

There are many reviews of α ₁ -adrenergic receptors, such as 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; And Pharm. Res., 1996, 33, 145.

Although the introduction of pharmacological treatments has made some improvements in terms of the effects of the symptoms of BPH and the need for surgical operations, the overall effect is mild and the needs of patients and physicians are still not quite met. In addition, there is no evidence that currently available pharmacological therapies are effective in inhibiting bladder hypertrophy, compression muscle instability, or prostate / bladder fibrosis associated with BPH.

The atorvastatin calcium salt disclosed in US Pat. No. 5,273,995 is currently sold as Lipitor (Lipitor®) and is represented by the following formula (R- (R ^* , R ^* )]-2- (4-fluorophenyl ) -α, α-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic hemicalcium salt:

It is known as a potent inhibitor of HMG-CoA reductase. The term statin as used herein is synonymous with "3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor" and "HMG-CoA reductase inhibitor". These terms may be used interchangeably.

Italian patent application 048658 describes the use of HMG-CoA reductase inhibitors for the treatment of BPH. Japanese Patent No. 56115717 discloses the use of two HMG-CoA reductase inhibitors (ie, monacoline K and ML-236B) for treating prostatic hyperplasia. US patent application 2002/0004521 describes the use of atorvastatin for the treatment of BPH. US Pat. No. 5,753,641 describes a combination of α-adrenergic receptor antagonists and 5α-reductase inhibitors for use in the treatment of BPH. WO 99/11260 refers to the combination of atorvastatin with antihypertensive agents, which may include α-adrenergic receptor antagonists. This combination is useful for the treatment of angina pectoris, atherosclerosis, hypertension and hyperlipidemia and for the treatment of problems with heart disease symptoms.

The present invention provides a use for the preparation of a medicament for treating BPH of a combination of (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) α ₁ -adrenergic receptor antagonist or a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable salts and pharmaceutically acceptable solvent compounds.

In addition, the present invention treats BPH to improve the flow rate of lower urethral syndrome and urine, to limit disease progression, to reverse pathological changes in the bladder and prostate associated with the disease, to reduce the incidence of urine retention and the need for surgical procedures. The use of the combination of (A) and (B) for providing is provided.

In one embodiment, the present invention provides a method of treating BPH in the treatment of BPH, comprising a combination of (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) α ₁ -adrenergic receptor antagonist or a pharmaceutically acceptable derivative thereof. ) And (B) for use in the manufacture of a medicament for a combination therapy wherein simultaneously, sequentially or separately.

Α ₁ -adrenergic receptor antagonists useful as (B) include terrazosin (US Pat. No. 4,026,894), doxazosin (US Pat. No. 4,188,390), prazosin (US Pat. No. 3,511,836), bunazosin (US Pat. No. 3,920,636). ), Alfuzosin (US Pat. No. 4,315,007), naphthopidil (US Pat. No. 3,997,666), tamsulosin (US Pat. No. 4,703,063), silodosin (US Pat. No. 5,387,603); Compounds disclosed in WO 03/076427, in particular 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro [1,6] -naphti Lidin-6 (5H) -yl) -4 (3H) -quinazolinone (Example 11), and the compounds disclosed in WO 98/30560, in particular 4-amino-6,7-dimethoxy-2 -(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline (Example 19); And pharmaceutically acceptable salts thereof. Preferred α-adrenergic receptor antagonists doxazosin, 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-dihydro [1,6] -naphthyridine-6 ( 5H) -yl) -4 (4H) -quinazolinone and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2 -Yl) -5- (2-pyridyl) quinazolin and their pharmaceutically acceptable derivatives. 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin Mesylate salts are of particular interest (see WO01 / 64672).

Α ₁ -adrenergic receptor antagonists suitable for the present invention may also be identified using the following assays:

Contractile response of the human prostate

Prostate tissue is cut longitudinally (about 3 × 2 × 10 mm) and suspended in an organ bath under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl ( 119), KCl (4.7), CaCl ₂ (2.5), KH ₂ PO ₄ (1.2), MgSO ₄ (1.2), NaHCO ₃ (25), Glucose (11), and 95% O ₂ /5% CO ₂ Gas filling. The solution also contains 10 mM cocaine and 10 mM corticosterone. The tissue is exposed to a sensitization of (-)-noradrenaline (100 mM) and washed for at least 45 minutes. In response to the cumulative addition of (-)-noradrenaline, shrinkage of the same size occurs to obtain a control curve in all tissues. An additional curve is then obtained in the presence or absence of the antagonist incubated for 2 hours. Antagonist affinity (pA ₂ ) is quantified using a single concentration of competitive antagonist, with pA ₂ = -log [A] / (DR-1), where the dose ratio (DR) is the competitive antagonism and shield ( Schild) Given the regression approaching 1, for the corresponding control, it is calculated by the single concentration of antagonist [A].

Anesthesia model of prostate pressure and blood pressure

Mature male beagle (12-15 kg body weight) is anesthetized with pentobarbitone sodium salt (30-50 mg / kg intravenous injection) and tracheal cannula is inserted. Pentobarbitone injection maintains anesthesia. The animal is breathed using a Bird MK8 respirator (Bird Corp., Palm Springs, Calif.) And the blood gas is pO ₂ 90 to 110 mmHg, pCO ₂ 35 to 45 mmHg, pH 7.35 to 7.45 Adjust it to remain. The body temperature is maintained between 36 and 37.5 ° C. using a warmed working table. The catheter is placed in the left femoral artery to record blood pressure and in the left femoral vein for compound administration. Heart rate is recorded via Lead II ECG. Opening is performed to connect the two urethra with cannula to prevent changes in fluid volume in the bladder. A 7F cardiac catheter (with a 1.5 ml balloon tip) is inserted through the urethra into the bladder. Fill the balloon with air and pull the catheter until the balloon is in the prostate, which is confirmed by digital pressure. The balloon pressure is recorded via a Druck transducer. Prostate pressure and hemodynamic parameters were obtained on a Grass Polygraph (Grass Instruments, Quincy, Mass.) And obtained from a Motorola 68000-based microcomputer system (Temple, Arizona, USA). Data were obtained in a straight line using Motorola Inc. of Material. Compounds are prepared in PEG 300 and administered intravenously via a femoral intravenous catheter. A control dose-response curve (two control curves for each experiment) is obtained in response to phenylephrine (1-16 μg / kg intravenous injection in saline). The compound is administered at 10 to 300 μg / kg intravenously 5 minutes prior to preparation of the phenylephrine curve (to a maximum dose of 128 μg / kg in the presence of the test compound).

Due to the α ₁ -associated rhythm of phenylephrine, no absolute maximum response is obtained but is thought to be 10% greater than the control response obtained with 16 μg / kg phenylephrine. The drug concentration is calculated based on the molar weight of the compound per kg of body weight, so the "pseudo pA ₂ " calculation by the shield assay is used using the dose ratio inferred from the change in the phenylephrine dose-response curve.

The expression “pharmaceutically acceptable derivatives” includes pharmaceutically acceptable salts, solvent compounds, complexes, isotopes, drug precursors, stereoisomers, geometric isomers, tautomers, and isotopic variants of the compounds of the invention. do. Preferably, pharmaceutically acceptable derivatives of the compounds of the present invention include pharmaceutically acceptable salts, solvent compounds, esters and amides. More preferably, pharmaceutically acceptable derivatives of the compounds of the present invention are pharmaceutically acceptable salts and solvent compounds.

One aspect of the invention includes a pharmaceutical composition comprising (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) doxazosin or a pharmaceutically acceptable derivative thereof.

Optional embodiments include (A) atorvastatin or a pharmaceutically acceptable salt 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 salt thereof.

Further embodiments include (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydro Pharmaceutical compositions comprising isoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof.

Further embodiments include pharmaceutical compositions comprising (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) doxazosin or a pharmaceutically acceptable derivative thereof.

Further embodiments include (A) 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) quinazolin or pharmaceutically acceptable derivatives thereof individually or together, and administered simultaneously, sequentially or separately in the treatment of BPH Provide medication.

Also in an optional embodiment, (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) 5-cyclopropyl-7-methoxy-2- (2-morpholin-4-ylmethyl-7,8-di Hydro [1,6] -naphthyridin-6 (5H) -yl) -4 (3H) -quinazolinone or a pharmaceutically acceptable salt thereof, individually or together, simultaneously, sequentially in the treatment of BPH Provided are medications that are administered as or separately.

Further embodiments further comprise (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) doxazosin or a pharmaceutically acceptable salt thereof separately or together and simultaneously, sequentially or separately in the treatment of BPH. It includes a drug to be administered.

Further embodiments provide pharmaceutical compositions comprising an effective amount of a mixture of (A) and (B) as defined above, optionally together with a pharmaceutically acceptable carrier.

In the pharmaceutical composition of the present invention, (A) is present in an amount in the range of 10 mg to 80 mg per dose, and (B) is present in an amount in the range of 0.1 mg to 20 mg per dose. In either case, the physician will determine the actual dosage that is most appropriate for the individual patient, depending on the age, weight and responsiveness of the particular patient. The dosage is representative of the average case. Of course, there may be occasions where more or less dosage ranges are suitable, and such cases are within the scope of the present invention.

The pharmaceutical compositions of the present invention may be administered alone but are generally administered in admixture with appropriate pharmaceutical excipients, diluents or carriers selected with respect to the intended route of administration and standard pharmaceutical practice. For example, pharmaceutical compositions are immediate release, delayed release, modified release, sustained release, pulsed release or controlled release formulations, and may include tablets, capsules, multiparticulates, gels, films, which may include flavoring or coloring agents. In the form of a suppository, elixir, solution or suspension, it may be administered orally, orally or sublingually. The pharmaceutical compositions may also be administered in quick-dispersion or quick-dissolve formulations and in the form of high energy dispersions or in the form of coated particles. Suitable formulations of the pharmaceutical composition may be in coated or uncoated form.

Solid pharmaceutical compositions such as 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 glycolate, croscarmellose sodium and certain complex silicates; And granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

The pharmaceutical compositions may also be administered in the form of suppositories for rectal administration. Such compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt and release the drug in the rectum. Such excipients include cocoa butter and polyethylene glycols.

Combinations of the invention may also be administered in the form of controlled release formulations, such as sustained or immediate release formulations. Controlled release formulations of this combination of the invention can be prepared according to methods well known to those skilled in the art.

The pharmaceutical composition according to the present invention may contain 0.1% to 95%, preferably 1% to 70% of the compound of the present invention.

Furthermore, the present invention provides a method of treating BPH comprising administering to a subject a therapeutically effective amount of (A) and (B) as described above when used together.

Furthermore, the present invention provides a pharmaceutical composition comprising (A) and (B) as described above as a combined formulation for simultaneous, separate or sequential use in the treatment of BPH.

As used herein, an "effective amount" is an amount of (A) and (B) that represents a biological or medical reaction to be obtained. The daily dosages of (A) and (B) used in the method of treatment are similar to those described for use in the pharmaceutical compositions described above. In the treatment method according to the invention (A) and (B) may be administered in combination in a single dosage form, or separately, essentially simultaneously, in each dosage form but as part of the same treatment program, and (A ) And (B) may be administered separately at different times and at different routes.

The utility of the combination of the invention as a medicament in the treatment of BPH is evidenced by the activity of the combination in the protocol described below:

Atorvastatin and α for Benign Prostatic Hyperplasia (BPH) in Spontaneously Hypertensive Rats (SHR) _One Efficacy of Adrenergic Receptor Antagonists

This study was conducted to investigate the characteristics of bladder function (analysis of urine flow through bladder pressure measurement, ie, measurement of urine flow through bladder / urethra) and overall prostate morphology (prostate weight, substrate / epithelial volume) in spontaneously hypertensive rats (SHR). , Designed to investigate the effect of co-treatment with atorvastatin and 0.1 mg / kg of doxazosin at 10 and 30 mg / kg.

SHR has increased prostate size (increased stroma and epithelial growth) and bladder hyperactivity as compared to the Wistar-Kyoto (WKY) control of normal blood pressure. These changes in bladder function and prostate morphology reflect the symptoms observed in men with BPH. All tissue samples collected (prostate) were examined for size and total cell morphology (substrate content and epithelial thickness) as signs of BPH.

Animal groups raised under a 12:12 hour light: dark cycle were used. They followed the standard rat diet and water was provided randomly.

100 naturally occurring hypertensive rats (SHR; Harlan UK) of 12 week old males were randomly divided into 5 treatment groups; (i) a placebo-administered group, (ii) a group orally administering a combination at a rate of 1 mg / kg / day, (iii) a group orally administering a combination at a rate of 10 mg / kg / day, (iv) a combination of 30 mg / kg Orally administered at the rate of / day and (v) doxazosin at the rate of 0.1 mg / kg / day. A control group consisting of 20 rats of normal blood pressure, Wister-Kyoto (WKY), is included in the study, and these animals receive placebo.

SHR and WKY animals were each administered orally for a period of 60 days. Urination parameters (frequency for 2 hours, void volume and total volume) were analyzed for subgroups of animals on days 0, 25 and 50 of this study.

At 30 and 60 days of the present experiment, 10 animals were randomly selected from each treatment group and a peripheral anesthesia study was performed to determine bladder / urethral function (by bladder pressure measurement, ie, urine flow through the bladder / urethra). Analysis) and the effect of treatment on prostate size.

Animals were anesthetized using urethane (1.2 g / kg, intraperitoneal). Depth of anesthesia was measured by the stability of blood pressure and heart rate and the absence of a shrunk leg in response to pinching the foot. Urethane (0.1 g / kg, intravenous injection) was supplemented if necessary. A tube was inserted into the trachea to maintain the airway. A cannula was inserted into the left cervical vein for drug administration, and heparinized cannula (20 units / ml heparin, 0.9% w / v saline) in the left common carotid artery for arterial blood pressure measurement and arterial blood sampling for blood gas analysis. Cannula was inserted.

Blood pressure was measured using a blood pressure transducer (Gould Statham P23Db) and electrically online derived heart rate (HR) from blood pressure using PoneMah (Linton Pty Ltd, UK). ) Was measured. Body temperature was monitored using a rectal temperature probe and maintained at 36-38 ° C. using a constant temperature blanket system (Harvard, UK).

Animals were spontaneously breathed or artificially breathed and blood gases were maintained at 90-130 mmHg Po2, 40-50 mmHg PCo2 and pH 7.3-7.4. If necessary, the supplemental oxygen amount (voluntarily breathing animal) and the respiratory pump rate and volume (artificial breathing animal) were adjusted to maintain blood gas and pH balance.

The bladder was exposed with a midline abdominal incision. An incision was made in the bladder dome and a double lumen cannula (0.52 mm inner diameter and 1.2 mm outer diameter) was inserted into the bladder, one of which was connected to a pressure transducer (Gould Statham P23Db) to record bladder internal pressure, and the other Is connected to a syringe pump for the injection of saline (0.9% w / v) to cause urination reflexes. The saline infusion rate (0.046 ml / min) into the bladder was chosen to stimulate the maximum hourly diuretic rate (Klevmark, 1974).

The animals were allowed to stabilize for 30 minutes after the surgical stage. After the stabilization period, bladder internal pressure measurement was performed. Bladder / urethral function and total void volume were measured for 60 minutes.

Microsphere technology was applied to measure the effect of treatment on prostate and bladder blood flow (see, eg, Das et al., 2002). In brief, 2 million Nuflow fluorescent red microspheres (IMT; 15 μm diameter suspended in 0.4 ml of 0.9% saline and 0.01% Tween-80) were injected via a carotid catheter. Blood samples were collected before, during, and after injection of the microspheres. Five minutes after injection, rats were euthanized, bladder, urethra and prostate were collected and blood flow was measured. Changes in prostate size change bladder blood flow and improve bladder function.

After bladder pressure measurement, 2 ml of blood samples were collected in heparinized tubes and plasma prepared as soon as possible and stored at −20 ° C. until the combination was analyzed.

Prostate rats were collected immediately after the end of the experiment, weighed, and stored in 10% formalin until a full morphological examination of the thickness of the substrate and epithelium was performed.

Differences between treatment groups were investigated using ANOVA.

Atorvastatin and α _One- Clinical study on the efficacy of the combination of adrenergic receptor antagonists

In a 12-week study of men with signs of BPH, the International Prostate Symptom Score (IPSS) was recorded at the beginning, in the process, and at the end of the double blind treatment. The IPSS consists of seven questions, each with a potential answer of 0 to 5 on the Likert rating. The higher the score, the more severe the lower urethra syndrome. The first endpoint in this study was the mean change in IPSS from the beginning to the end of the study in the treatment group. In this study, the α _1- adrenergic receptor antagonist used was 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl ) -5- (2-pyridyl) quinazolin (as described in WO98 / 30560 and WO01 / 64672), and was treated in four treatment groups: 1 mg α _1- adrenergic receptor antagonist, 3 mg α _1- adrenergic receptor antagonist A treatment group of 6 mg α ₁ -adrenergic receptor antagonist and placebo was used.

Concurrent dosing treatments were recorded in a screening visit. Efficacy in animals receiving atorvastatin was compared to efficacy in animals not receiving statin treatment. This comparison showed that the group treated with atorvastatin showed greater efficacy in the group treated with the α _1- adrenergic receptor antagonist compared to the placebo response in each group. .

The combination of the present invention, due to the synergy between the active ingredients, is more powerful, more durable than the prior art, more effectively reduces the progression of the disease, reducing the need for surgical treatment, and a wider range of It is applicable, has fewer side effects, is more selective (especially has a beneficial effect on BPH without causing undesirable cardiovascular effects) and has other more useful properties.

Claims (10)

A pharmaceutical composition for treating benign prostatic hyperplasia (BPH) comprising a combination of (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) α ₁ -adrenergic receptor antagonist or a pharmaceutically acceptable derivative thereof . The method of claim 1, Pharmaceutical compositions administered simultaneously, sequentially or separately. The method of claim 1, (B) is terrazosin, doxazosin, prazosin, bunazosin, alfuzosin, naphthopidyl, tamsulosin, silodosin, 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido -1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin, 5-cyclopropyl-7-methoxy-2- (2-morpholine-4- Monomethyl-7,8-dihydro [1,6] -naphthyridin-6 (5H) -yl) -4 (3H) -quinazolinone, and pharmaceutically acceptable derivatives thereof, Pharmaceutical compositions. The method of claim 3, wherein A pharmaceutical composition, wherein (B) is doxazosin or a pharmaceutically acceptable derivative thereof. The method of claim 3, 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. The method of claim 3, 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. A pharmaceutical agent comprising (A) atorvastatin or a pharmaceutically acceptable salt thereof and (B) doxazosin or a pharmaceutically acceptable derivative thereof, individually or together, administered simultaneously, sequentially or separately in the treatment of BPH. (A) atorvastatin or a pharmaceutically acceptable derivative thereof and (B) 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol- A medicament comprising 2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof individually or together and administered simultaneously, sequentially or separately in the treatment of BPH. (A) 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, individually or together and administered simultaneously, sequentially or separately in the treatment of BPH drugs. The method according to any one of claims 7 to 9, A pharmaceutical agent comprising a pharmaceutical composition comprising an effective amount of a combination of (A) and (B), optionally together with a pharmaceutically acceptable carrier.