KR20050057349A - Use of a quinazoline derivative for treating lower urinary tract symptoms - Google Patents

Abstract

The use of 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 treating LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis, is described.

Description

Use of a Quinazoline Derivative for Treating Lower Urinary Tract Symptoms}

The present invention relates to 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) Quinazolin (disclosed as Example 19 in International Patent Application Publication No. 98/30560) and its pharmaceutically acceptable derivatives. Mesylate salts are disclosed in International Patent Application Publication No. 01/64672 (such as Example 2). International Patent Application Publication Nos. 98/30560 and 01/64672 are incorporated herein by reference. It is specified to treat prostatic hyperplasia (BPH) and has the following structure.

Lower urinary tract symptoms (LUTS) include three symptoms: irritant, obstructive, and post-urination symptoms. Irritant symptoms include urgent bladder (OAB), pelvic floor dysfunction (PFD) or urgent urination, frequent urination and nocturia that may be associated with or without detrusor muscle hyperactivity.

Overactive bladder (OAB) is defined as urinary tract with or without urinary incontinence, usually with urinary and nocturia (Abrams et al., Neurourology and Urodynamics 21: 167-178 (2002)). OAB prevalence is similar in men and women, with approximately 16% of the US population suffering from this problem [Stewart et al, Prevalence of Overactive Bladder in the United States: Results from the NOBLE Program; Abstract Presented at the 2 ^nd International Consultation on Incontinence, July 2001, Paris, France].

Pelvic floor dysfunction (PFD) occurs when the pelvic floor muscles no longer adequately relax during urination as the bladder contracts. The muscles are stimulated and can often contract abnormally. PFD can result in irritating LUTS.

Chronic prostatitis is a prostate inflammatory disease, which may or may not be associated with urinary tract bacteria detected by standard microbial methodology. It is often characterized as having genitourinary pain or discomfort associated with irritating LUTS.

Pelvic floor dysfunction and prostatitis are generally diseases of middle-aged men, whereas overactive bladder can suffer at any age. Patients with any of these diseases may experience irritable lower urinary tract symptoms, and often the final diagnosis is empirical.

Surprisingly, 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quina Sleepiness has been shown to be useful for treating LUTS associated with OAB (with or without detrusor hyperactivity), pelvic floor dysfunction or chronic prostatitis.

Thus, according to the invention 4-amino-6,7-dimethoxy-2- (5) for the manufacture of a medicament for the treatment of LUTS associated with OAB (with or without detrusor hyperactivity), pelvic floor dysfunction or chronic prostatitis. Use of methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof is provided.

It is desirable that LUTS is associated with pelvic floor dysfunction. It is also desirable that LUTS is associated with chronic prostatitis.

Preferably 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) Quinazolin is a form of mesylate salt.

The compound or pharmaceutically acceptable derivative thereof may be administered alone or in combination with any convenient pharmaceutical formulation. Oral administration is preferred. In the present indication, a suitable dosage of the active site of the compound or a pharmaceutically acceptable derivative thereof is about 0.01 to 10.0 mg per kg of body weight, preferably about 0.05 to 1.0 mg. It may be administered in a single dose of 1 to 4 times daily, or preferably in a controlled release formulation as disclosed in WO 03/032956 (see especially Examples 1-5). When a patient may be restricted from access to the toilet, it may only be administered temporarily when needed, for example during a long trip.

The invention also provides 4-amino-6,7-dimethoxy-2- (5-methanesulfone for use in treating LUTS associated with OAB (with or without detrusor hyperactivity), pelvic floor dysfunction or chronic prostatitis. Amido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof.

The present invention also provides 4-amino-6,7-dimethoxy-2- (5- for patients requiring LUTS treatment associated with OAB (with or without detrusor hyperactivity), pelvic floor dysfunction or chronic prostatitis. Methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof Provide a method of treatment.

Example 1-5

4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -containing methocel ™ Methocel K4M Tablet formulation of 5- (2-pyridyl) quinazolin mesylate

The table below shows the components for preparing five tablet formulations each containing the active ingredients 1, 3, 6, 9 and 12 mg, expressed as free base according to International Patent Application Publication No. 03/032956.

Ingredient (mg) (see standard) Example 1 Example 2 Example 3 Example 4 Example 5 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin mesyl Rate (Pfizer) 1.189 ⁽¹⁾ 3.567 7.134 10.701 14.268 HPMC (Methocell K4M, European Pharmacopoeia) 30.000 30.000 30.000 22.500 22.500 Lactose Monohydrate (European Pharmacopoeia) 13.203 10.108 9.216 10.200 9.308 Anhydrous calcium hydrogen phosphate (European Pharmacopoeia) 39.608 30.325 27.650 30.599 27.924 Adipic acid [DAB ⁽²⁾ ] 15.000 25.000 25.000 25.000 25.000 Magnesium Stearate (European Pharmacopoeia) 1.000 1.000 1.000 1.000 1.000 Tablet weight (mg) 100.000 100.000 100.000 100.000 100.000 ⁽¹⁾ 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2 in free base form 1.0 mg equivalent to pyridyl) quinazolin ⁽²⁾ DAB is a German medicinal book (German Pharmacopoeia).

Way

Adipic acid was first screened through a suitable screen (such as 500 microns). Then lactose monohydrate, hydroxypropylmethyl cellulose, 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin mesylate, screened adipic acid and anhydrous calcium hydrogen phosphate were added to a suitable blender (such as a tumble mixer) and combined. The blend was screened through a suitable screen (such as 500 microns) and recombined. About 50% of the lubricant (magnesium stearate) was screened, added to the formulation and blended briefly.

The blend was roller compacted through a suitable roller compactor. The ribbon formulation was then granulated, screened through a suitable screen (such as 500 microns) and recombined. Residual lubricant was screened, added to the formulation and blended briefly.

The granules were then tableted with a suitable 6 mm indenter to obtain 6 mm standard round convex white tablets without engraving and then the flour was removed.

Example 6 In Vivo Studies

Men with lower urinary tract symptoms were subjected to double blind treatment to conduct a 12 week study, recording IPSS (International Prostate Symptom Score) at baseline, during treatment and at the end of treatment. The IPSS consists of seven items, each with a possible response of 0 to 5 on the Likert scale. These items fall into two proven areas: irritant areas (urgent urine, frequent urination and nocturnal urination) and obstructive areas (residual feeling, lack of yoga, difficulty in starting urination and urination). In addition, each patient completed a bladder diary to obtain a baseline incidence of individual symptoms, and then measured the change in incidence of these symptoms after double blind treatment. The daily average incidence of urgent emergency, daytime urinary and nocturia (irritant symptoms) of each patient was determined from this diary. This study included 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) There were three treatment groups: quinazoline 6 mg fixed administration, 4 weeks later, 6 mg of the compound increased to 12 mg, and placebo administration. In each case a controlled release type according to International Patent Application Publication No. 03/032956 was used.

For patients with irritant LUTS at baseline, improvement of these symptoms was identified in the compound 6 mg fixed dose and 12 mg incremental dose groups compared to the placebo treated group. In patients with a baseline IPSS irritant area score of 8 or higher at baseline, improvements in this area of IPSS were similarly identified in both the compound 6 mg fixed dose group and the 12 mg incremental dose group.

The results of this study were described as 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl Illustrated with FIGS. 1-4 showing that quinazoline significantly clinically reduces irritant LUTS.

Claims (6)

4-amino-6,7-dimethoxy- for the manufacture of a medicament for the treatment of lower urinary tract symptoms (LUTS) associated with overactive bladder (OAB), pelvic floor dysfunction or chronic prostatitis (with or without detrusor hyperactivity) Use of 2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof. 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido- for use in the treatment of LUTS associated with OAB, pelvic floor dysfunction or chronic prostatitis (with or without detrusor muscle hyperactivity) 1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof. 4-amino-6,7-dimethoxy-2- (5-methanesulfonami) in patients in need of treatment of LUTS associated with or without OAB, pelvic floor dysfunction or chronic prostatitis 1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazolin or a pharmaceutically acceptable derivative thereof. 4. Amino acid according to any one of claims 1 to 3, wherein 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2- (I) -5- (2-pyridyl) quinazolin is in the form of its mesylate salt. The use or method of any one of claims 1-4, wherein the LUTS is associated with pelvic floor dysfunction. Use or method according to any one of claims 1 to 4, wherein LUTS is associated with chronic prostatitis.