WO1994002144A1 - Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine - Google Patents

Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine Download PDF

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Publication number
WO1994002144A1
WO1994002144A1 PCT/EP1992/001640 EP9201640W WO9402144A1 WO 1994002144 A1 WO1994002144 A1 WO 1994002144A1 EP 9201640 W EP9201640 W EP 9201640W WO 9402144 A1 WO9402144 A1 WO 9402144A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinolone
methyl
treatment
fluoro
administered
Prior art date
Application number
PCT/EP1992/001640
Other languages
English (en)
Inventor
Mervyn Busson
John Andrew Rees
Original Assignee
The Boots Company Plc
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 The Boots Company Plc filed Critical The Boots Company Plc
Priority to EP92916001A priority Critical patent/EP0651640A1/fr
Priority to AU23451/92A priority patent/AU2345192A/en
Priority to PCT/EP1992/001640 priority patent/WO1994002144A1/fr
Publication of WO1994002144A1 publication Critical patent/WO1994002144A1/fr

Links

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the present invention relates to a method for the treatment of angina pectoris in humans .
  • Angina pectoris arises from an imbalance between myocardial oxygen supply and demand. Typically the condition results -from narrowing of the coronary arteries through atherosclerosis. This reduces blood flow, and thus oxygen supply, to the heart muscles, resulting in a severe cardiac oxygen deficiency which can cause severe pain to the sufferer. The condition can, in extreme form, be life-threatening. Attacks of angina pectoris are commonly brought on by exercise or by stress which increase oxygen demand in the cardiac muscles to a point where it cannot be met by the reduced supply of blood thereto.
  • European Patent Publication No. 0149519A discloses the use, in the treatment of heart failure, of quinolones of the following general formula (I) :
  • R- j _ is lower alkyl optionally substituted by hydroxy, - j __ alkoxycarbonyl or - ] __ ⁇ alkoxy; allyl; propynyl or phenyl-lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 C- j __4 alkoxy groups or 1 or 2 C ⁇ __4 alkyl groups;
  • R 2 is C ⁇ __4 alkyl, ⁇ 2 - * i alkenyl or ⁇ ⁇ ⁇ alkynyl with the proviso that, when n is 0, R 2 is methyl; and
  • R3, R4 and R5, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoro ethyl or lower alkylthio.
  • ischaemic heart disease includes angina and myocardial infarction.
  • British Patent Application No. 8400905 makes no specific reference to use of the particular quinolone 7-fluoro-l-methyl-3-methyl sulphinylmethyl-4-quinolone in treatment of ischaemic heart disease in any form, still less in the particular . form known as angina pectoris.
  • this particular compound is a positive inotrope teaches the skilled worker away from use in treatment of angina pectoris.
  • angina pectoris results inter alia from cardiac oxygen deficiency caused by inadequate blood supply to the heart muscles. Accordingly, by causing the heart to work harder, the administration of a positive inotrope to a patient suffering from angina pectoris would be expected to exacerbate the existing oxygen deficiency by increasing oxygen demand in the very muscles where oxygen supply is scarce, thus causing a deterioration rather than an improvement, in the patient's condition.
  • the known vasodilatory action of the present quinolone might cause preferential vasodilation of non-ischaemic coronary vessels, thus diverting blood from diseased ischaemic coronary vessels and further reducing oxygen supply to the affected muscles of the heart.
  • This effect known as "coronary steal” might cause further deterioration in the condition of angina.
  • a method for the treatment of angina pectoris in a human in need of such treatment which comprises the administration to said human of a therapeutically effective amount of 7-fluoro-l-methyl-3-methylsulphinyl- 4-quinolone.
  • treatment includes the therapeutic treatment of a human suffering from angina pectoris and the prophylactic treatment of a human at risk from angina pectoris. Therefore, the invention includes a method of preventing angina pectoris attack in a human susceptible to such attack, by administering to said human an effective amount of 7-fluoro-l-methyl-3- methylsulphinyl-4-quinolone.
  • the method of the invention is used in the long term prophylactic management of angina attacks.
  • the method of the invention may be used in humans who do or do not suffer from heart failure.
  • the active compound denotes 7-fluoro-1-methyl-3-methylsulphiny1-4-quinolone
  • flosequinan is naturally converted into the corresponding sulphone compound 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone by metabolism following administration.
  • the active compound may be administered enterally or parenterally.
  • Enteral administration may be oral or rectal.
  • Parenteral administration may be intravenous, intramuscular, or topical.
  • Oral administration is preferred for the treatment of chronic angina, but intravenous administration may be preferred in treating the acute stage of the disease.
  • the active compound is generally administered in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising the active compound together with a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions may take the form of any of the known pharmaceutical compositions for enteral or parenteral administration.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
  • the compositions of the invention suitably contain 0.1-90% by weight of active compound.
  • the compositions of the invention are often prepared in unit dosage form.
  • the active compound is administered in a dose of at least about 50 mg per day since it has been found that doses below about 50 mg do not always provide the benefit of the invention.
  • the dose is at least about 75 mg per day, suitably between 75 mg and 150 mg per day, preferably between 75 mg and 125 mg per day, for example about 100 mg per day.
  • the active compound is administered as a single dose, once a day.
  • This procedure has the advantage of being convenient to the patient and medical personnel alike, and minimises the risk that the administration of medication will be overlooked.
  • smaller doses could be provided several times a day to provide a total dose of the size described.
  • compositions for oral administration are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions.
  • the excipients used in the preparation of these compounds are the excipients known in the pharmacist's art.
  • Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner.
  • Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • compositions for use in the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
  • Compositions for use in the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example, sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent. Typically such forms might be solutions of glucose or sodium chloride.
  • compositions for topical administration may comprise a matrix in which the active compound is dispersed so that the compound can be held in contact with the skin in order to administer the active compound transdermally.
  • the active compound may be dispersed in a cream or ointment base.
  • the compounds of the present invention in the form of particles of very small size, for example, as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients, for example, nitrates (such as glyceryl trinitrate, pentaerythritol tetranitrate, isosorbide dinitrate and isosorbide mononitrate) , ⁇ -blockers (such as acebutolol, atenolol, bisoprolol, metaprolol, carteolol, nadolol, oxprenolol, pinodol, propanolol, sotalol and timolol) , calcium antagonists (such as veraprimil, amlodipine, nicardipine, nifedipine and diltiazem) and Angiotensin Converting Enzyme (ACE) inhibitors (such as enalapril, lisinopril and captopril) .
  • nitrates such as
  • the invention provides a method as defined above, wherein the quinolone is administered simultaneously, sequentially or separately with a therapeutically effective amount of a calcium antagonist, a nitrate compound, or an ACE inhibitor.
  • a product comprising 7- fluoro-l-methyl-3-methylsulphinyl-4-quinolone and a calcium antagonist or a nitrate compound, as a combined preparation for simultaneous, sequential or separate administration in the treatment of angina pectoris in humans.
  • a therapeutic composition for the treatment of angina pectoris which comprises a therapeutically effective amount of 7-fluoro-l-methyl-3- methylsulphinyl-4-quinolone and a therapeutically effective amount of a calcium antagonist or a nitrate compound.
  • the present invention also provides the use of 7- fluoro-1-methyl-3-methylsulphinyl-4-quinolone in the treatment of angina pectoris in humans.
  • the invention also provides the use of 7-fluoro-l- methyl-3-methylsulphinyl-4-quinolone in the manufacture of a medicament for the treatment of angina pectoris in humans.
  • the dosage and manner of administration of the active compound are as described above.
  • the active compound may be present in the form of a therapeutically acceptable acid addition salt thereof.
  • composition 1 The following are examples of compositions which may be used in accordance with the method of the present invention.
  • Composition 1 The following are examples of compositions which may be used in accordance with the method of the present invention.
  • capsules 100 parts by weight of 7-fluoro-l-methyl-3-methylsulphinyl-4-quinolone and 290 parts by weight of lactose are deaggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 100 mg of active compound.
  • Tablets are prepared from the following ingredients:
  • the active compound, lactose, microcrystalline cellulose and maize starch are deaggregated and blended.
  • the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in denatured ethanol.
  • the dry, sized granulate is blended with the magnesium stearate.
  • the mixture is then " compressed in a tabletting machine to give tablets containing 100 mg of flosequinan.
  • the tablets are coated with a mixture of the methylhydroxypropyl cellulose, propylene glycol and titanium dioxide with water and denatured ethanol. All of the titanium dioxide and part of the methylhydroxy propyl cellulose are added as a suspension in denatured ethanol available under the trade name 'Opaspray White' .
  • Tablets are prepared from ingredients:
  • the active compound, lactose, microcrystalline cellulose and croscarmellose sodium are deaggregated and blended.
  • the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in denatured ethanol.
  • the dry, sized granulate is blended with the magnesium stearate.
  • the mixture is then compressed in a tabletting machine to give tablets containing 100 mg of flosequinan.
  • the tablets are coated with a mixture of the methylhydroxypropyl cellulose, propylene glycol and titanium dioxide with water and denatured ethanol. All of the titanium dioxide and part of the methylhydroxy propyl cellulose are added as a suspension in denatured ethanol available under the trade name Opaspray White' .
  • Tablets are prepared from the following ingredients:
  • the active compound, lactose, microcrystalline cellulose and croscarmellose sodium are deaggregated and blended.
  • the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in denatured ethanol.
  • the dry, sized granulate is blended with the magnesium stearate.
  • the mixture is then compressed in a tabletting machine to give tablets containing 100 mg of flosequinan.
  • the tablets are coated with a mixture of the methylhydroxypropyl cellulose, propylene glycol and titanium dioxide with water and denatured ethanol. All of the titanium dioxide and part of the methylhydroxy propyl cellulose are added as a suspension in denatured ethanol available under the trade name Opaspray White' .
  • a formulation for intravenous injection is prepared to the following composition:
  • the formulation is sterilised in the course of manufacture.
  • a formulation for intravenous injection is prepared to the following composition:
  • the formulation is sterilised in the course of manufacture.
  • a clinical study was carried out in the form of a double-blind placebo controlled crossover trial conducted in two centres in the U.K. Patients fulfilling the entry criteria requiring a diagnosis of chronic, stable angina pectoris of at least three months duration, without evidence of heart failure, myocardial infarction or stroke in the previous six months were eligible for the study. During a short run in period patients were weaned off any anti-anginal therapy, ⁇ except emergency nitro-glycerine. They were then randomised to receive 100 mg of flosequinan daily, by oral administration, for seven days followed by a seven day wash out period and then seven days of placebo, or the treatments in the reverse order.
  • a Bruce Protocol Treadmill Test was used to elicit anginal symptoms and electrocardiographic changes and the times to these end points used as indicators of treatment efficacy.
  • Adverse events and nitro-glycerine consumption were recorded throughout the trial.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un procédé et à son utilisation dans le traitement de l'angine de poitrine chez l'être humain. Ce procédé consiste à administrer une quantité efficace de 7-fluoro-1-méthyl-3-méthylsulphinyl-4-quinolone à un être humain nécessitant ce traitement. De préférence, le composé actif est administré en une dose d'au moins environ 50 mg par jour.
PCT/EP1992/001640 1992-07-21 1992-07-21 Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine WO1994002144A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP92916001A EP0651640A1 (fr) 1992-07-21 1992-07-21 Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine
AU23451/92A AU2345192A (en) 1992-07-21 1992-07-21 Use of 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone in the treatment of angina pectoris
PCT/EP1992/001640 WO1994002144A1 (fr) 1992-07-21 1992-07-21 Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1992/001640 WO1994002144A1 (fr) 1992-07-21 1992-07-21 Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine

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WO1994002144A1 true WO1994002144A1 (fr) 1994-02-03

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PCT/EP1992/001640 WO1994002144A1 (fr) 1992-07-21 1992-07-21 Utilisation de 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone dans le traitement de l'angine de poitrine

Country Status (3)

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EP (1) EP0651640A1 (fr)
AU (1) AU2345192A (fr)
WO (1) WO1994002144A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000007595A1 (fr) * 1998-08-03 2000-02-17 Basf Corporation Utilisation de pyridinones pour traiter les dysfonctionnements sexuels
EP1079764A1 (fr) * 1998-05-01 2001-03-07 RT Alamo Ventures Inc. Traitement des troubles de la sexualite chez certains groupes de patients
US6426084B1 (en) 2000-06-19 2002-07-30 Neal R. Cutler Treatment of sexual dysfunction in certain patient groups
US6458804B1 (en) 2001-01-26 2002-10-01 R.T. Alamo Venturesi, Llc Methods for the treatment of central nervous system disorders in certain patient groups
US6562838B2 (en) 2001-01-26 2003-05-13 R. T. Alamo Ventures I, L.L.C. Treatment of cardiovascular disease with quinolinone enantiomers
KR20040035302A (ko) * 2002-10-21 2004-04-29 송영채 내부순환을 가진 고온-중온 공상 혐기성소화방법
WO2005000275A1 (fr) * 2003-06-26 2005-01-06 Bayer Healthcare Ag Comprimes contenant de l'enrofloxacine et des agents aromatisants et/ou des aromes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0149519A2 (fr) * 1984-01-13 1985-07-24 The Boots Company PLC Utilisation de quinolones pour la fabrication d'une composition pour le traitement de maladies cardiaques.
WO1990010445A1 (fr) * 1989-03-15 1990-09-20 The Boots Company Plc Agents therapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0149519A2 (fr) * 1984-01-13 1985-07-24 The Boots Company PLC Utilisation de quinolones pour la fabrication d'une composition pour le traitement de maladies cardiaques.
WO1990010445A1 (fr) * 1989-03-15 1990-09-20 The Boots Company Plc Agents therapeutiques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AMERICAN HEART JOURNAL vol. 121, no. 3, 1991, pages 974 - 983 D.B. YATES ET AL. 'PHARMACOLOGY OF FLOSEQUINAN' *
CHEMICAL ABSTRACTS, vol. 103, no. 22, 1985, Columbus, Ohio, US; abstract no. 183569e, 'USE OF QUINOLONES FOR TREATING CORONARY INSUFFICIENCY' *
DRUGS OF THE FUTURE vol. 11, no. 3, 1986, pages 177 - 178 R. MANNHOLD 'BTS-49465' *
INTERNATIONAL JOURNAL OF CARDIOLOGY vol. 24, 1989, pages 73 - 76 A. SCHNEEWEISS ET AL. 'THE EFFECT OF FLOSEQUINAN IN PATIENTS WITH HEART FAILURE OF ACUTE ONSET COMPLICATING ACUTE MYOCARDIAL INFARCTION' *
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY vol. 15, no. 6, 1990, pages 900 - 910 S. GREENBERG ET AL. 'POSITIVE INOTROPY CONTRIBUTES TO THE HEMODYNAMIC MECHANISM OF ACTION OF FLOSEQUINAN IN THE INTACT DOG' *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1079764A1 (fr) * 1998-05-01 2001-03-07 RT Alamo Ventures Inc. Traitement des troubles de la sexualite chez certains groupes de patients
EP1079764A4 (fr) * 1998-05-01 2001-09-12 Rt Alamo Ventures Inc Traitement des troubles de la sexualite chez certains groupes de patients
WO2000007595A1 (fr) * 1998-08-03 2000-02-17 Basf Corporation Utilisation de pyridinones pour traiter les dysfonctionnements sexuels
US6426084B1 (en) 2000-06-19 2002-07-30 Neal R. Cutler Treatment of sexual dysfunction in certain patient groups
US6458804B1 (en) 2001-01-26 2002-10-01 R.T. Alamo Venturesi, Llc Methods for the treatment of central nervous system disorders in certain patient groups
US6562838B2 (en) 2001-01-26 2003-05-13 R. T. Alamo Ventures I, L.L.C. Treatment of cardiovascular disease with quinolinone enantiomers
US6995173B2 (en) 2001-01-26 2006-02-07 R.T. Alamo Ventures I, Llc Methods for the treatment of central nervous system disorders in certain patient groups
KR20040035302A (ko) * 2002-10-21 2004-04-29 송영채 내부순환을 가진 고온-중온 공상 혐기성소화방법
WO2005000275A1 (fr) * 2003-06-26 2005-01-06 Bayer Healthcare Ag Comprimes contenant de l'enrofloxacine et des agents aromatisants et/ou des aromes
AU2004251003B2 (en) * 2003-06-26 2010-09-16 Bayer Intellectual Property Gmbh Tablets containing enrofloxacin and flavouring agents and/or flavours

Also Published As

Publication number Publication date
EP0651640A1 (fr) 1995-05-10
AU2345192A (en) 1994-02-14

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