EP0163683A1 - Chromone-2-carboxilic acid derivatives as cardiovascular agents - Google Patents

Chromone-2-carboxilic acid derivatives as cardiovascular agents

Info

Publication number
EP0163683A1
EP0163683A1 EP19840904149 EP84904149A EP0163683A1 EP 0163683 A1 EP0163683 A1 EP 0163683A1 EP 19840904149 EP19840904149 EP 19840904149 EP 84904149 A EP84904149 A EP 84904149A EP 0163683 A1 EP0163683 A1 EP 0163683A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
amide
alkyl
pulmonary
pharmaceutically acceptable
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Withdrawn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
EP19840904149
Other languages
German (de)
French (fr)
Inventor
Philip Sheard
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.)
Fisons Ltd
Original Assignee
Fisons Ltd
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 Fisons Ltd filed Critical Fisons Ltd
Publication of EP0163683A1 publication Critical patent/EP0163683A1/en
Withdrawn legal-status Critical Current

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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom

Definitions

  • This invention relates to a new therapeutic method.
  • US Patent No 3,686,412 there are described a large number of bis-chromonyl compounds and their use in the treatment of asthma. These compounds are described as being administered preferably by way of inhalation.
  • a number of compounds are also known as having anti SRS-A or anti-leukotriene activity, and these compounds have been described as being useful in the treatment of various allergic airways diseases notably asthma.
  • a method of treatment of a cardiovascular condition e.g. the cardiovascular sequelae of hypoxia, which method comprises administration of an effective amount of a compound of the formula I,
  • X is a polymethylene chain containing 3 to 7 carbon atoms inclusive, which chain may be substituted by an -OH group, or a pharmaceutically acceptable salt, alkyl C 1 to 10 ester, mono-alkyl C 1 to 10 amide, di-alkyl C 1 to 10 amide or unsubstituted amide thereof, or of an anti-leukotriene compound as hereinafter defined (as active ingredient), to a human patient suffering from the cardiovascular condition.
  • Suitable pharmaceutically acceptable salts of the compounds of formula I include, for example, ammonium salts, alkali metal salts (e.g. sodium, potassium and lithium), alkaline earth metal salts (e.g. magnesium and calcium), and salts with organic amines (e.g. mono di- or tri-alkyl C 1 to 6 amines, piperidine, and trialkanol C 1 to 6 amine salts).
  • alkali metal salts e.g. sodium, potassium and lithium
  • alkaline earth metal salts e.g. magnesium and calcium
  • organic amines e.g. mono di- or tri-alkyl C 1 to 6 amines, piperidine, and trialkanol C 1 to 6 amine salts.
  • Esters which may be mentioned include simple alkyl esters (e.g.
  • amides which may be mentioned include simple amides (for example amides with ammonia and lower alkylamines such as methylamine, ethylamine etc).
  • Specific examples of the group X are groups of the formula -(CH 2 ) 5 - and -CH 2 CHOHCH 2 -.
  • the chain -O-X-O- in formula I may link different or corresponding positions on the chromone nuclei.
  • a specific compound of formula I which may be used in this invention is 1,3-bis (2-carboxychromon-5-yloxy)-2- hydroxypropane. This compound may be used in the form of its pharmaceutically acceptable, e.g. its di-sodium, salt which is commonly known as sodium cromoglycate. It may also be used in the form of its di-ethyl ester, or of its simple amide derived from ammonia.
  • An anti SRS-A (anti-leukotriene) compound is able to antagonise the actions of SRS-A on an end-organ (e.g. bronchial or intestinal smooth muscle).
  • an end-organ e.g. bronchial or intestinal smooth muscle.
  • the anti-leukotriene compounds to be used in the present invention are those of British Patent Specifications Nos 1,384,530; 1,583,691 and European Patent Applications Nos 80300565.1; 81201386.0; 82200312.5 and 82201368.6.
  • the compound having anti-leukotriene activity may also have cyclo-oxygenase inhibitory activity, i.e. be able to block the production of prostaglandin E 2 from the microsomal fraction of bovine seminal vesicles (Mitchell et al, Biochem. Soc. Transactions 12, 839,1984).
  • Compounds which have anti SRS-A (anti-leukotriene) activity while they have been suggested for the same uses as sodium cromoglycate, e.g.
  • SRS-A slow-reacting substance of anaphylaxis
  • sodium cromoglycate and its biologues exert their activity by preventing the release of SRS-A and other mediators of anaphylaxis from mast cells.
  • the administration may be by any convenient route, for example oral inhalation; by infusion, e.g. for use in acute conditions; orally or rectally.
  • infusion e.g. for use in acute conditions
  • rectally e.g. for use in acute conditions
  • the infusion may be continuous over the period of treatment or may be intermittent, e.g. for periods of about two hours.
  • the drug may be worked up with inorganic or organic pharmaceutically acceptable adjuvants, carriers or excipients.
  • suitable adjuvants are, for inhalation compositions, dry powder diluents, e.g. lactose; water for nebuliser solutions, and aerosol propellents and surfactants for pressurised aerosol compositions.
  • Solutions e.g. sterile aqueous solutions, may be used for intravenous administration. The solutions preferably contain less than 10% w/w and more than 1% w/w of the active ingredient.
  • the drug may, if desired, be used in a specific form, e.g. having a mass median diameter of less than 10 microns.
  • the drug may also be used for inhalation in admixture with a bronchodilator, eg such as described in British Patent Specification Number 2,077,100A.
  • the dosage to be administered will of course vary with the compound used, the method of administration, the condition to be treated and with its severity. However, in general, a dosage of from about 1 to 50, and more preferably 5 to 40 mg of the drug administered 1 to 8, and preferably 1 to 4, times a day (i.e. a daily dosage of from 1 to 400, and preferably 5 to 160mg) is satisfactory.
  • the method of the invention is applicable to patients who have an allergic component to their condition, but more particularly to those who do not.
  • the primary cardiovascular complication in hypoxia is the development of pulmonary artery hypertension, which in turn is the principal cause of right ventricular enlargement and failure (cor pulmonale).
  • the pulmonary arterial hypertension may be severe and moreover the right ventricle is often faced with a pulmonary artery pressure which has risen rapidly in the course of an intercurrent acute illness.
  • the method of the invention may also be used to treat other cardiovascular conditions which are the sequelae of hypoxia, e.g. persistent neonatal pulmonary hypertension (or persistent foetal circulation), a condition in which the pulmonary arteries fail to dilate soon enough after birth; adult respiratory disease syndrome, a condition which manifests itself as pulmonary oedema with normal filling pressures in the left heart, greatly reduced pulmonary compliance, abnormal vasomotor activity and severe hypoxaemia (this syndrome may result from trauma, shock or endotoxaemia); or cyanotic congenital heart disease, a condition in which hypertension is a frequent complication.
  • the method of the invention may also be used in patients who have undergone cardio-pulmonary by-pass surgery in which in some patients (e.g.
  • the method of the invention may also be used to treat patients with myocardial infarcts due to hypoxia in which lipoxygenase products of arachidonic acid metabolism such as leukotrienes may be involved.
  • the method of the invention is also applicable to patients suffering from acute hypoxic pulmonary oedema (for example mountain sickness); destructive parenchymous lung disease such as tuberculosis, bronchiectasis or fibrosing alveolitis; chest wall deformities such as severe kyphoscolioses; primary alveolar hypoventilation; hypoxia induced cerebral vasoconstriction; and sleep apnoea syndrome.
  • acute hypoxic pulmonary oedema for example mountain sickness
  • destructive parenchymous lung disease such as tuberculosis, bronchiectasis or fibrosing alveolitis
  • chest wall deformities such as severe kyphoscolioses
  • primary alveolar hypoventilation a primary alveolar hypoventilation
  • hypoxia induced cerebral vasoconstriction and sleep apnoea syndrome.
  • the anti-SRS-A compounds are advantageous in that they exert their effect without affecting systemic blood pressure to a corresponding degree.

Abstract

Procédé de traitement de troubles cardio-vasculaires, par exemple des séquelles cardio-vasculaires de l'hypoxie, consistant à administrer à un patient humain souffrant de troubles cardio-vasculaires une quantité efficace d'un composé de formule (I), où X est une chaîne de polyméthylène contenant de 3 à 7 atomes de carbone, cette chaîne pouvant être substituée par un groupe -OH, ou alors X est un sel pharmaceutiquement acceptable, un ester d'alkyle comportant de 1 à 10 C, un amide de monoalkyle comportant de 1 à 10 C, un amide de di-alkyle comportant de 1 à 10 C ou son amide non substitué, ou d'un composé anti-leucotrine ainsi qu'il est défini ici (comme ingrédient actif).A method of treating cardiovascular disorders, for example cardiovascular sequelae of hypoxia, comprising administering to a human patient suffering from cardiovascular disorders an effective amount of a compound of formula (I), where X is a polymethylene chain containing from 3 to 7 carbon atoms, this chain possibly being substituted by an -OH group, or else X is a pharmaceutically acceptable salt, an alkyl ester comprising from 1 to 10 C, a monoalkyl amide comprising from 1 to 10 C, a di-alkyl amide comprising from 1 to 10 C or its unsubstituted amide, or from an anti-leucotrin compound as defined here (as active ingredient).

Description

CHROMONE-2-CARBOXILIC ACID DERIVATES AS CARDIOVASCULAR AGENTS
This invention relates to a new therapeutic method. In US Patent No 3,686,412 there are described a large number of bis-chromonyl compounds and their use in the treatment of asthma. These compounds are described as being administered preferably by way of inhalation.
A number of compounds are also known as having anti SRS-A or anti-leukotriene activity, and these compounds have been described as being useful in the treatment of various allergic airways diseases notably asthma.
Surprisingly we have now found that a selected group of the compounds of US Patent 3,686,412 and some anti-leukotriene compounds are useful in the treatment of a variety of cardiovascular conditions, e.g. the cardiovascular sequelae of hypoxia.
At present the main effective treatment for the cardiovascular sequelae of hypoxia is to administer oxygen for 15 or more hours per day. However, the administration of oxygen for such protracted periods is very inconvenient for the patient, and is expensive.
According to the invention there is provided a method of treatment of a cardiovascular condition, e.g. the cardiovascular sequelae of hypoxia, which method comprises administration of an effective amount of a compound of the formula I,
wherein X is a polymethylene chain containing 3 to 7 carbon atoms inclusive, which chain may be substituted by an -OH group, or a pharmaceutically acceptable salt, alkyl C 1 to 10 ester, mono-alkyl C 1 to 10 amide, di-alkyl C 1 to 10 amide or unsubstituted amide thereof, or of an anti-leukotriene compound as hereinafter defined (as active ingredient), to a human patient suffering from the cardiovascular condition.
Suitable pharmaceutically acceptable salts of the compounds of formula I include, for example, ammonium salts, alkali metal salts (e.g. sodium, potassium and lithium), alkaline earth metal salts (e.g. magnesium and calcium), and salts with organic amines (e.g. mono di- or tri-alkyl C 1 to 6 amines, piperidine, and trialkanol C 1 to 6 amine salts). Esters which may be mentioned include simple alkyl esters (e.g. methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl esters) and amides which may be mentioned include simple amides (for example amides with ammonia and lower alkylamines such as methylamine, ethylamine etc). Specific examples of the group X are groups of the formula -(CH2)5- and -CH2CHOHCH2-.
The chain -O-X-O- in formula I may link different or corresponding positions on the chromone nuclei. A specific compound of formula I which may be used in this invention is 1,3-bis (2-carboxychromon-5-yloxy)-2- hydroxypropane. This compound may be used in the form of its pharmaceutically acceptable, e.g. its di-sodium, salt which is commonly known as sodium cromoglycate. It may also be used in the form of its di-ethyl ester, or of its simple amide derived from ammonia.
An anti SRS-A (anti-leukotriene) compound is able to antagonise the actions of SRS-A on an end-organ (e.g. bronchial or intestinal smooth muscle). This can be established by use of the isolated guinea-pig ileum preparation (Augstein et al. Nature, New Biology, 1973, 245, 215) in which contractions induced by SRS-A (i.e. leukotrienes C4, D4 and E4) will be expected to be antagonised by the compound at concentrations of less than 1 μg/ml.
The anti-leukotriene compounds to be used in the present invention are those of British Patent Specifications Nos 1,384,530; 1,583,691 and European Patent Applications Nos 80300565.1; 81201386.0; 82200312.5 and 82201368.6. We prefer the compounds of British Patent Specifications Nos 1,384,530; 1,583,691 and especially those of European Patent Applications Nos 80300565.1 and 82.201368.6. Specifically we prefer 7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, and 7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-propanoic acid, and the pharmaceutically acceptable salts, e.g. the sodium or lysine salts, of either thereof. The compound having anti-leukotriene activity may also have lipoxygenase inhibitory activity, i.e. be able to block the production of lipoxygenase products from rat basophilic leukaemia cells (Casey et al, Prostaglandins 25,1,1983). The compound having anti-leukotriene activity may also have cyclo-oxygenase inhibitory activity, i.e. be able to block the production of prostaglandin E2 from the microsomal fraction of bovine seminal vesicles (Mitchell et al, Biochem. Soc. Transactions 12, 839,1984). Compounds which have anti SRS-A (anti-leukotriene) activity, while they have been suggested for the same uses as sodium cromoglycate, e.g. the treatment of asthma, exert their activity in an entirely different manner to sodium cromoglycate. Thus anti SRS-A compounds antagonise the effects of slow-reacting substance of anaphylaxis (SRS-A) (leukotrienes) once it has been released from whatever source, whereas sodium cromoglycate and its biologues exert their activity by preventing the release of SRS-A and other mediators of anaphylaxis from mast cells.
The administration may be by any convenient route, for example oral inhalation; by infusion, e.g. for use in acute conditions; orally or rectally. When the drug is given by infusion the infusion may be continuous over the period of treatment or may be intermittent, e.g. for periods of about two hours.
In order to produce suitable compositions the drug may be worked up with inorganic or organic pharmaceutically acceptable adjuvants, carriers or excipients. The type of formulation will vary with the mode of administration to be used. Examples of suitable adjuvants are, for inhalation compositions, dry powder diluents, e.g. lactose; water for nebuliser solutions, and aerosol propellents and surfactants for pressurised aerosol compositions. Solutions, e.g. sterile aqueous solutions, may be used for intravenous administration. The solutions preferably contain less than 10% w/w and more than 1% w/w of the active ingredient.
The drug may, if desired, be used in a specific form, e.g. having a mass median diameter of less than 10 microns. The drug may also be used for inhalation in admixture with a bronchodilator, eg such as described in British Patent Specification Number 2,077,100A.
The dosage to be administered will of course vary with the compound used, the method of administration, the condition to be treated and with its severity. However, in general, a dosage of from about 1 to 50, and more preferably 5 to 40 mg of the drug administered 1 to 8, and preferably 1 to 4, times a day (i.e. a daily dosage of from 1 to 400, and preferably 5 to 160mg) is satisfactory.
The method of the invention is applicable to patients who have an allergic component to their condition, but more particularly to those who do not.
The primary cardiovascular complication in hypoxia is the development of pulmonary artery hypertension, which in turn is the principal cause of right ventricular enlargement and failure (cor pulmonale). The pulmonary arterial hypertension may be severe and moreover the right ventricle is often faced with a pulmonary artery pressure which has risen rapidly in the course of an intercurrent acute illness.
The method of the invention may also be used to treat other cardiovascular conditions which are the sequelae of hypoxia, e.g. persistent neonatal pulmonary hypertension (or persistent foetal circulation), a condition in which the pulmonary arteries fail to dilate soon enough after birth; adult respiratory disease syndrome, a condition which manifests itself as pulmonary oedema with normal filling pressures in the left heart, greatly reduced pulmonary compliance, abnormal vasomotor activity and severe hypoxaemia (this syndrome may result from trauma, shock or endotoxaemia); or cyanotic congenital heart disease, a condition in which hypertension is a frequent complication. The method of the invention may also be used in patients who have undergone cardio-pulmonary by-pass surgery in which in some patients (e.g. those who had raised pulmonary artery pressures before the operation, particularly in mitral valve replacement subjects) there is a reduced cardiac performance with high pulmonary vascular resistance for some hours after the operation. During the operation the lungs are not normally ventilated or perfused and may have become hypoxic.
The method of the invention may also be used to treat patients with myocardial infarcts due to hypoxia in which lipoxygenase products of arachidonic acid metabolism such as leukotrienes may be involved.
The method of the invention is also applicable to patients suffering from acute hypoxic pulmonary oedema (for example mountain sickness); destructive parenchymous lung disease such as tuberculosis, bronchiectasis or fibrosing alveolitis; chest wall deformities such as severe kyphoscolioses; primary alveolar hypoventilation; hypoxia induced cerebral vasoconstriction; and sleep apnoea syndrome.
We believe that the drugs are effective in that they have a direct action on the pulmonary arterial response to hypoxia.
The anti-SRS-A compounds, and particularly the preferred compounds, are advantageous in that they exert their effect without affecting systemic blood pressure to a corresponding degree.

Claims

What we cla im is : -
1. A method for the treatment of a cardiovascular condition which method comprises administration of an effective amount of a compound of the formula I,
wherein X is a polymethylene chain containing 3 to 7 carbon atoms inclusive, which chain may be substituted by an -OH group, or a pharmaceutically acceptable salt, alkyl C 1 to
10 ester, mono-alkyl C 1 to 10 amide, di-alkyl C 1 to 10 amide or unsubstituted amide thereof, or of an anti-leukotriene compound as hereinbefore defined (as active ingredient), to a human patient suffering from the cardiovascular condition.
2. A method according to Claim 1, wherein the active ingredient also has lipoxygenase inhibitory activity.
3. A method according to Claim 1 or 2, wherein the active ingredient also has cyclo-oxygenase inhibitory activity.
4. A method according to Claim 1, wherein the active ingredient is sodium cromoglycate.
5. A method according to Claim 1, wherein the active ingredient is 7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
6. A method according to Claim 1, wherein the active ingredient is 7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-propanoic acid or a pharmaceutically acceptable salt thereof.
7. A method according to any one of the preceding claims, wherein a daily dosage of from 1 to 400mg of active ingredient is administered.
8. A method according to any one of the preceding claims, wherein the active ingredient is administered by infusion, by inhalation or orally.
9. A method according to any one of the preceding claims, wherein the cardiovascular condition involves pulmonary artery hypertension.
10. A method according to any one of the preceding claims, wherein the cardiovascular condition is cor pulmonale, persistent neonatal pulmonary hypertension, adult respiratory disease syndrome, cyanotic congentinal heart disease, myocardial infarct, hypoxic pulmonary oedema, destructive parenchymous lung disease, primary alveolar hypoventilation, hypoxia induced cerebral vasoconstriction, sleep apnoea syndrome or is in a patient suffering from chest wall deformity or who has undergone cardio-pulmonary by-pass surgery.
EP19840904149 1983-12-06 1984-11-19 Chromone-2-carboxilic acid derivatives as cardiovascular agents Withdrawn EP0163683A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8332450 1983-12-06
GB838332450A GB8332450D0 (en) 1983-12-06 1983-12-06 Method of treatment

Publications (1)

Publication Number Publication Date
EP0163683A1 true EP0163683A1 (en) 1985-12-11

Family

ID=10552857

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840904149 Withdrawn EP0163683A1 (en) 1983-12-06 1984-11-19 Chromone-2-carboxilic acid derivatives as cardiovascular agents

Country Status (4)

Country Link
EP (1) EP0163683A1 (en)
AU (1) AU3611784A (en)
GB (1) GB8332450D0 (en)
WO (1) WO1985002541A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265749B2 (en) 2014-02-10 2016-02-23 Patara Pharma, LLC Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
WO2017027402A1 (en) 2015-08-07 2017-02-16 Patara Pharma, LLC Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
US10583113B2 (en) 2016-10-07 2020-03-10 Respivant Sciences Gmbh Cromolyn compositions for treatment of pulmonary fibrosis
EP3725311A1 (en) 2014-02-10 2020-10-21 Respivant Sciences GmbH Methods for the treatment of lung diseases with mast cell stabilizers
WO2021094296A1 (en) 2019-11-12 2021-05-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of mast cell stabilizer for the treatment of heart failure with preserved ejection fraction

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3331522A1 (en) 2015-08-07 2018-06-13 Patara Pharma LLC Methods for the treatment of mast cell related disorders with mast cell stabilizers
EP3506893A4 (en) 2016-08-31 2020-01-22 Respivant Sciences GmbH Cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8502541A1 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265749B2 (en) 2014-02-10 2016-02-23 Patara Pharma, LLC Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
US9707206B2 (en) 2014-02-10 2017-07-18 Patara Pharma, LLC Mast cell stabilizers treatment for systemic disorders
US9962363B2 (en) 2014-02-10 2018-05-08 Patara Pharma, LLC Mast cell stabilizers treatment for systemic disorders
US9968586B2 (en) 2014-02-10 2018-05-15 Patara Pharma, LLC Mast cell stabilizers treatment for systemic disorders
EP3653207A1 (en) 2014-02-10 2020-05-20 Respivant Sciences GmbH Mast cell stabilizers treatment for systemic disorders
EP3725311A1 (en) 2014-02-10 2020-10-21 Respivant Sciences GmbH Methods for the treatment of lung diseases with mast cell stabilizers
US10835512B2 (en) 2014-02-10 2020-11-17 Respivant Sciences Gmbh Methods of treating respiratory syncytial virus infections
WO2017027402A1 (en) 2015-08-07 2017-02-16 Patara Pharma, LLC Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
US10583113B2 (en) 2016-10-07 2020-03-10 Respivant Sciences Gmbh Cromolyn compositions for treatment of pulmonary fibrosis
WO2021094296A1 (en) 2019-11-12 2021-05-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of mast cell stabilizer for the treatment of heart failure with preserved ejection fraction

Also Published As

Publication number Publication date
AU3611784A (en) 1985-06-26
GB8332450D0 (en) 1984-01-11
WO1985002541A1 (en) 1985-06-20

Similar Documents

Publication Publication Date Title
US6054486A (en) Use of 9-Deoxy-2',9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylen e)-13,14-dihydro-prostaglandin f1 to treat peripheral vascular disease
US5153222A (en) Method of treating pulmonary hypertension with benzidine prostaglandins
CA2191129C (en) Drugs containing metronidazole or a synergistic mixture of metronidazole and clindamycin
EP0109561B1 (en) Celiprolol for the treatment of glaucoma
EP0469075B1 (en) Use of lipoxin a 4? and its derivatives as antagonists for slow-reacting substances of anaphylaxis
US4302471A (en) Method of treating cardiac and renal failures
PT97905B (en) METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING CISTINE DERIVATIVES
JPS62501364A (en) Anti-asthmatic compositions and methods of using 8,11,14,17↓-eicosatetraenoic acid
EP0163683A1 (en) Chromone-2-carboxilic acid derivatives as cardiovascular agents
US5028628A (en) Methods of treating pulmonary hypertension
DE69812028T2 (en) Creatine derivatives for asthma
EP0543855A1 (en) Use of aryl hydroxyurea compounds for the treatment of atherosclerosis
EP0149519B1 (en) Use of quinolones for the manufacture of a composition for the treatment of heart failure.
Perlstein et al. Fatal effects of prolonged complete curarization
KR900701278A (en) Bile acids for the treatment of viral infections
US4271191A (en) Method of treating hyperuricemia and gout
JPH01503780A (en) Topically applied agents containing prostacyclin derivatives
Jones et al. Volume expansion and vasodilators in the treatment of idiopathic postural hypotension
JP3057226B2 (en) A therapeutic agent for leishmaniasis containing a glucopyranose derivative as an active ingredient
EP0519925A1 (en) Use of optically pure s(-) atenolol for the treatment of cardiovascular disorders
US4105794A (en) Process of mitigating cholelithiasis
EP0075029B1 (en) Agent for treating chronic obliterative lung disease
US5472947A (en) Application of 4-carbamoyl-1-β-D-ribofuranosyl imidazolium-5-olate to the treatment of multiple sclerosis
JPH0445494B2 (en)
WO1991006298A1 (en) New use of condensed quinoline compound

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19851107

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SHEARD, PHILIP