EP1545541A1 - Use of a quinazoline derivative for treating lower urinary tract symptoms - Google Patents

Use of a quinazoline derivative for treating lower urinary tract symptoms

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Publication number
EP1545541A1
EP1545541A1 EP03797435A EP03797435A EP1545541A1 EP 1545541 A1 EP1545541 A1 EP 1545541A1 EP 03797435 A EP03797435 A EP 03797435A EP 03797435 A EP03797435 A EP 03797435A EP 1545541 A1 EP1545541 A1 EP 1545541A1
Authority
EP
European Patent Office
Prior art keywords
quinazoline
tetrahydroisoquinol
methanesulfonamido
dimethoxy
pyridyl
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.)
Withdrawn
Application number
EP03797435A
Other languages
German (de)
French (fr)
Inventor
Ian William Pfizer Global R & D MILLS
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.)
MILLS, IAN WILLIAM
Pfizer Ltd Great Britain
Original Assignee
Pfizer Ltd Great Britain
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 Pfizer Ltd Great Britain filed Critical Pfizer Ltd Great Britain
Publication of EP1545541A1 publication Critical patent/EP1545541A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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 new use of 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (disclosed as example 19 in International Patent Application Publication No. WO 98/30560), and its pharmaceutically acceptable derivatives.
  • the mesylate salt is disclosed in International Patent Application Publication No. WO 01/64672 (e.g. Example 2). Both WO 98/30560 and WO 01/64672 are incorporated herein by reference. It is indicated in the treatment of Benign Prostatic Hyperplasia (BPH) and has the following structure:
  • Lower urinary tract symptoms comprise three groups of symptoms, which are irritative, obstructive and post micturition symptoms. Irritative symptoms comprise urgency, frequency and nocturia, which can be associated with: overactive bladder (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
  • Over Active Bladder is defined as urgency, with or without urge incontinence, usually with frequency and nocturia [Abrams et al., Neurourology and Urodynamics 21 :167-178 (2002)].
  • Prevalence of OAB in men and women is similar, with approximately 16% of the population of the USA suffering from the condition [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 occurs when the muscles of the pelvic floor no longer relax properly during urination while the bladder contracts. The muscles may become irritated and often contract abnormally. PFD may result in irritative LUTS.
  • Chronic prostatitis is an inflammatory condition of the prostate, which may or may not be associated with uropathogenic bacteria detected by standard microbiological methodology. It is characterized by the presence of genitourinary pain or discomfort, often associated with irritative LUTS.
  • Overactive bladder may be suffered by individuals of any age, while pelvic floor dysfunction and prostatitis are conditions typically suffered by middle-aged men. Patients with any of these conditions are likely to experience irritative lower urinary tract symptoms, and often the eventual diagnosis is empirical.
  • LUTS 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 the manufacture of a medicament for the treatment of LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
  • OAB with or without concomitant detrusor over activity
  • pelvic floor dysfunction or chronic prostatitis.
  • the LUTS is associated with pelvic floor dysfunction.
  • the LUTS is preferably associated with chronic prostatitis.
  • the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is in the form of its mesylate salt.
  • the compound, or a pharmaceutically acceptable derivative thereof can be administered alone or in any convenient pharmaceutical presentation. Oral administration is preferred.
  • a suitable dosage of the compound, or of the active moiety in a pharmaceutically acceptable derivative thereof is from about 0.01 to 10.0 mg/kg of body weight, and preferably about 0.05 to 1.0 mg/kg is suitable.
  • Administration may be in single does of from 1 to 4 times daily or preferably it may be in a controlled release formulation such as is disclosed in International Application Publication No. WO 03/032956 (see in particular examples 1 to 5). Administration may be p.r.n. for occasions when the patient may have limited access to toilet facilities, e.g. during a long journey.
  • the invention further provides 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 use in the treatment of LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
  • the invention further provides a method of treating LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis, which comprises administering 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, to a patient in need of such treatment.
  • OAB with or without concomitant detrusor over activity
  • pelvic floor dysfunction or chronic prostatitis
  • the following table shows the ingredients for preparing five tablet formulations containing, respectively, 1 , 3, 6, 9 and 12 mg of active ingredient, expressed as free base, according to International Application Publication No. WO 03/032956.
  • the adipic acid was first screened through a suitable screen (e.g. 500 micron).
  • a suitable screen e.g. 500 micron.
  • the lactose monohydrate, hydroxypropylmethyl cellulose, 4-amino-6,7-dimethoxy- 2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, the screened adipic acid and calcium hydrogen phosphate, anhydrous were then added to a suitable blender (e.g. a tumble mixer) and blended.
  • the blend was screened through a suitable screen (e.g. 500 micron) and reblended. About 50% of the lubricant (magnesium stearate) was screened, added to the blend and blended briefly.
  • the blend was roller compacted through a suitable roller compactor.
  • the ribbon blend was then granulated, by screening through a suitable screen (e.g. 500 micron) and reblended. The remaining lubricant was screened, added to the blend and blended briefly.
  • the granules were then tabletted using appropriate 6 mm tooling to give 6 mm standard round convex white tablets with no engraving, which were then de- dusted.
  • IPSS International Prostate Symptom Score
  • the IPSS is composed of seven questions, each with potential responses of 0-5 on a Likert scale. These questions are grouped into two validated domains: the irritative domain (urgency, frequency and nocturia) and the obstructive domain (incomplete emptying, intermittency, weak stream and straining to begin).
  • a bladder diary was completed by each subject to provide baseline incidence of individual symptoms, and subsequently to demonstrate change in incidence of these symptoms following double blind treatment.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The use of 4-amino-ó,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

OF A QUINAZOLINE DERIVATIVE FOR TREATING LOWER URINARY TRACT SYMPTOMS
This invention relates to a new use of 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (disclosed as example 19 in International Patent Application Publication No. WO 98/30560), and its pharmaceutically acceptable derivatives. The mesylate salt is disclosed in International Patent Application Publication No. WO 01/64672 (e.g. Example 2). Both WO 98/30560 and WO 01/64672 are incorporated herein by reference. It is indicated in the treatment of Benign Prostatic Hyperplasia (BPH) and has the following structure:
Lower urinary tract symptoms (LUTS) comprise three groups of symptoms, which are irritative, obstructive and post micturition symptoms. Irritative symptoms comprise urgency, frequency and nocturia, which can be associated with: overactive bladder (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
Over Active Bladder (OAB) is defined as urgency, with or without urge incontinence, usually with frequency and nocturia [Abrams et al., Neurourology and Urodynamics 21 :167-178 (2002)]. Prevalence of OAB in men and women is similar, with approximately 16% of the population of the USA suffering from the condition [Stewart et al, Prevalence of Overactive Bladder in the United States: Results from the NOBLE Program; Abstract Presented at the 2nd International Consultation on Incontinence, July 2001 , Paris, France].
Pelvic floor dysfunction (PFD) occurs when the muscles of the pelvic floor no longer relax properly during urination while the bladder contracts. The muscles may become irritated and often contract abnormally. PFD may result in irritative LUTS.
Chronic prostatitis is an inflammatory condition of the prostate, which may or may not be associated with uropathogenic bacteria detected by standard microbiological methodology. It is characterized by the presence of genitourinary pain or discomfort, often associated with irritative LUTS.
Overactive bladder may be suffered by individuals of any age, while pelvic floor dysfunction and prostatitis are conditions typically suffered by middle-aged men. Patients with any of these conditions are likely to experience irritative lower urinary tract symptoms, and often the eventual diagnosis is empirical.
Surprisingly it has been found that 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is useful in the treatment of LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
Thus, in accordance with the present invention, there is provided 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 the manufacture of a medicament for the treatment of LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis. Preferably the LUTS is associated with pelvic floor dysfunction. Alternatively, the LUTS is preferably associated with chronic prostatitis.
Preferably the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is in the form of its mesylate salt.
The compound, or a pharmaceutically acceptable derivative thereof, can be administered alone or in any convenient pharmaceutical presentation. Oral administration is preferred. In the present indication, a suitable dosage of the compound, or of the active moiety in a pharmaceutically acceptable derivative thereof, is from about 0.01 to 10.0 mg/kg of body weight, and preferably about 0.05 to 1.0 mg/kg is suitable. Administration may be in single does of from 1 to 4 times daily or preferably it may be in a controlled release formulation such as is disclosed in International Application Publication No. WO 03/032956 (see in particular examples 1 to 5). Administration may be p.r.n. for occasions when the patient may have limited access to toilet facilities, e.g. during a long journey.
The invention further provides 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 use in the treatment of LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
The invention further provides a method of treating LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis, which comprises administering 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, to a patient in need of such treatment. Examples 1-5
Tablet formulations of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate containing Methocel™ K4M
The following table shows the ingredients for preparing five tablet formulations containing, respectively, 1 , 3, 6, 9 and 12 mg of active ingredient, expressed as free base, according to International Application Publication No. WO 03/032956.
(1) Equivalent to 1.0 mg 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, in the form of its free base (2) DAB is the Deutsches Arzneibuch (German Pharmacopoeia) Method
The adipic acid was first screened through a suitable screen (e.g. 500 micron). The lactose monohydrate, hydroxypropylmethyl cellulose, 4-amino-6,7-dimethoxy- 2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, the screened adipic acid and calcium hydrogen phosphate, anhydrous were then added to a suitable blender (e.g. a tumble mixer) and blended. The blend was screened through a suitable screen (e.g. 500 micron) and reblended. About 50% of the lubricant (magnesium stearate) was screened, added to the blend and blended briefly.
The blend was roller compacted through a suitable roller compactor. The ribbon blend was then granulated, by screening through a suitable screen (e.g. 500 micron) and reblended. The remaining lubricant was screened, added to the blend and blended briefly.
The granules were then tabletted using appropriate 6 mm tooling to give 6 mm standard round convex white tablets with no engraving, which were then de- dusted.
Example 6: In vivo study
A 12-Week Study in men with lower urinary tract symptoms was undertaken in which 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 0-5 on a Likert scale. These questions are grouped into two validated domains: the irritative domain (urgency, frequency and nocturia) and the obstructive domain (incomplete emptying, intermittency, weak stream and straining to begin). In addition, a bladder diary was completed by each subject to provide baseline incidence of individual symptoms, and subsequently to demonstrate change in incidence of these symptoms following double blind treatment. The average daily incidence of urgency, daytime micturition frequency and nocturia (the irritative symptoms) for each subject were derived from this diary. In this study, there were five treatment groups: 6mg fixed dose of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, 6mg escalated to 12mg at Week 4 of the compound, and placebo. Controlled release formulations according to International Application Publication No. WO 03/032956 were used in each case.
For those subjects with irritative LUTS at baseline, improvement in these symptoms was confirmed in the compound 6mg fixed dose group and the 12mg dose escalation group, compared with the placebo treated group. In subjects with baseline IPSS irritative domain score ≥8 at baseline, improvement in this domain of the IPSS was similarly confirmed in both the compound 6mg fixed dose group and the 12mg dose escalation group.
The results of the study are illustrated in figures 1 to 4 which show 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl)quinazoline produced a clinically significant attenuation of irritative LUTS.

Claims

CLAIMS:
1. 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 the manufacture of a medicament for the treatment of LUTS associated with: OAB (with or without concomitant detrusor overactivity); pelvic floor dysfunction; or chronic prostatitis.
2. 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 use in the treatment of LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis.
3. A method of treating LUTS associated with: OAB (with or without concomitant detrusor over activity); pelvic floor dysfunction; or chronic prostatitis, comprising administering 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, to a patient in need of such treatment.
4. A use or method as claimed in any of claims 1 to 3, wherein the 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl)quinazoline is in the form of its mesylate salt.
5. A use or method as claimed in any of claims 1 to 4, wherein the LUTS is associated with pelvic floor dysfunction.
6. A use or method as claimed in any of claims 1 to 4, wherein the LUTS is associated with chronic prostatitis.
EP03797435A 2002-09-17 2003-09-04 Use of a quinazoline derivative for treating lower urinary tract symptoms Withdrawn EP1545541A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0221582 2002-09-17
GBGB0221582.0A GB0221582D0 (en) 2002-09-17 2002-09-17 Method of treatment
PCT/IB2003/003905 WO2004026312A1 (en) 2002-09-17 2003-09-04 Use of a quinazoline derivative for treating lower urinary tract symptoms

Publications (1)

Publication Number Publication Date
EP1545541A1 true EP1545541A1 (en) 2005-06-29

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ID=9944253

Family Applications (1)

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EP03797435A Withdrawn EP1545541A1 (en) 2002-09-17 2003-09-04 Use of a quinazoline derivative for treating lower urinary tract symptoms

Country Status (12)

Country Link
EP (1) EP1545541A1 (en)
JP (1) JP2006501276A (en)
KR (1) KR20050057349A (en)
CN (1) CN1681506A (en)
AU (1) AU2003259464A1 (en)
BR (1) BR0314381A (en)
CA (1) CA2495311A1 (en)
GB (1) GB0221582D0 (en)
MX (1) MXPA05002912A (en)
PL (1) PL374730A1 (en)
TW (1) TW200409770A (en)
WO (1) WO2004026312A1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9700504D0 (en) * 1997-01-11 1997-02-26 Pfizer Ltd Pharmaceutical compounds
IL141235A (en) * 2000-02-09 2012-04-30 Novartis Int Pharm Ltd Combined use of an alpha-adrenoceptor antagonist and a muscarinic antagonist in the manufacture of a medicament for the treatment of benign prostatic hyperplasia
IL150634A0 (en) * 2000-03-03 2003-02-12 Pfizer 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate and polymorphs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004026312A1 *

Also Published As

Publication number Publication date
KR20050057349A (en) 2005-06-16
WO2004026312A1 (en) 2004-04-01
AU2003259464A1 (en) 2004-04-08
BR0314381A (en) 2005-07-19
JP2006501276A (en) 2006-01-12
CN1681506A (en) 2005-10-12
PL374730A1 (en) 2005-10-31
GB0221582D0 (en) 2002-10-23
TW200409770A (en) 2004-06-16
MXPA05002912A (en) 2005-09-30
CA2495311A1 (en) 2004-04-01

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