CHROMONE-2-CARBOXILIC ACID DERIVATIVES AS CARDIOVASCULAR AGENTS

Abstract: 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 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 unsubsituted amide hereof, or of an anti-leukotrine compound as herein defined (as active ingredient), to a human patient suffering from the cardiovascular condition.

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-iA 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, _ OMPI 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 alkyla ines such as methylamine, ethyla ine etc) . OMPI Specific examples of 'the group X are groups of the formula -(CH-,) 5 - and -CH 2 CHOHCH 2 -. The chain -0-X-O- in formula I may link different or corresponding positions on the chromone nuclei, c 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 * Q 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). j _5 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 C-, D. and E.) will be expected to be antagonised by the compound at concentrations of 20 less than 1 ug/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; 25 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-l-benzopyran-2-σarboxylic acid, and 7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2- hydroxypropoxy]-4-oxo-8-propyl-4H-l-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 25rl,1983) . The compound having anti-leukotriene activity may also have cyclo-oxygenase inhibitory activity, i.e. be able to block the production of prostaglandin E- 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 _OMPI_ 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,Q77,100A. 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 parenσhymous lung disease such as tuberculosis, bronchiectasis or fibrosing alveolitis; chest wall deformities such as severe kyphosσolioses; 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. Q u OaMiPnI "

Claims: What we cla im is ; - 1. A method for the treatment of a cardiovascular condition. hich 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 • σondition. 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- l-benzopyran-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 5 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-l-benzopyran-2-propanoic acid or a pharmaceutically acceptable salt thereof. 7. A method according to any one of the preceding 0 claims, wherein a daily dosage of from 1 to 400rag 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. 5 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 20. pulmonale, persistent neonatal pulmonary hypertension, adult respiratory disease syndrome, cyanotic σongentinal " heart disease, myocardial infarct, hypoxic pulmonary oedema, destructive parenchymous lung disease, primary alveolar hypoventilation, hypoxia induced cerebral 25 vasoconstriction, sleep apnoea syndrome or is in a patient suffering from chest wall deformity or who has undergone cardio-pulmonary by-pass surgery. "g R£-T ( O PI {-fa WIPO ^^NATlQ!

Inventors: SHEARD PHILIP, SHEARD, PHILIP
Applicants: FISONS PLC
Application year: 1984
Main classification: A61K31
IPC codes: A61K31