GB2195631A - Quinolone cardiac stimulants - Google Patents

Abstract

Quinolone cardiac stimulants have the formula:- <IMAGE> or a pharmaceutically acceptable salt thereof, wherein R is H or CH3; and "Het" is an imidazol-1-yl group substituted by a formyl group and, optionally, by one or two methyl groups. They selectively increase the force of myocardial contraction without producing significant increases in the heart rate, and thus are useful in the curative or prophylactic treatment of cardiac conditions, in particular in the treatment of congestive heart failure.

Description

SPECIFICATION Quinolones as cardiac stimulants and synthetic intermediates This invention relates to substituted quinolones which are cardiac stimulants and useful synthetic intermediates. In general the compounds selectively increase the force of myocardial contraction without producing significant increases in the heart rate, and thus are useful in the curative or prophylactic treatment of cardiac conditions, in particular in the treatment of congestive heart failure.

According to the invention there are provided substituted 2-(1H)-quinolones of the formula

and their pharmaceutically acceptable salts, where R is H or CH3, and "Het" is an imidazol- 1 -yl group substituted by a formyl group and optionally by one or two methyl groups.

Preferably R is CH3 and Het is a 4-formyl-2-methylimidazol-1-yl group.

The compounds of the formula (I) are also useful intermediates to the corresponding hydroxymethyl-imidazolyl quinolones which are disclosed in European patent application publication no.

0166533. Reduction of the formyl group to hydroxymethyl can be carried out conventionally, e.g. by the use of sodium borohydride. The reduction is typically carried out at room temperature in a suitable organic solvent, e.g. absolute ethanol.

Although the compounds of the formula (I) are written as 2-(1H)-quinolones, it should be realised that the following tautomerism can occur:

However, as the keto-form is considered the more stable tautomer, the end products herein will be named and illustrated as quinolones although those skilled in the art will realise that both tautomers may be present or that any particular compound so named may exist predominantly as the hydroxy tautometer and the following disclosure is to be interpreted to incorporate all tautomeric forms.

The pharmaceutically acceptable salts of the compounds of the formula (I) are either acid addition salts formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, methanesulphonate and ptoluenesulphonate salts, or are metal salts, particularly the alkalin earth or alkali metal salts. The preferred metal salts are the sodium and potassium salts.

All the salts are preparable by conventional techniques.

The cardiac stimulant activity of the compounds of the formula (I) is shown by their effectiveness in one or more of the following tests: (a) increasing the force of contraction in the "Starling" dog heart-long preparation measured via a left ventricular catheter; (b) increasing myocardial contractility (left ventricular dp/dt max.) in the anaesthetised dog measured via a left ventricular catheter; (c) increasing myocardial contractility in the conscious dog with an implanted left ventricular transducer (dp/dt max.) or an exteriorised carotid artery loop (systolic time intervals).

In test (a), the positive inotropic effect of the test compound following bolus administration is measured in the "Starling" dog heart-lung preparation.The selectivity for increase in force versus frequency of contraction of the test compound is obtained.

In test (b), the positive inotropic action of the test compound following intravenous administration is measured in the anaesthetised dog. The magnitude and duration of this action, and the selectivity for increase in force versus frequency of contraction of the test compound are obtained, as are the peripheral effects, e.g. the effect on blood pressure.

In test (c), the positive inotropic action of the test compound following intravenous or oral administration to a conscious dog with an implanted left ventricular transducer (dp/dt max.) or an exteriorised carotid artery loop (systolic time intervals) is measured. The magnitude of the inotropic action, the selectivity for increase in force versus frequency of contraction, and the duration of action of the inotropic effect of the test compound are all obtained.

The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

For administration to man in the curative or prophylatic treatment of cardiac conditions such as congestive heart failure, it is expected that oral dosages of the compounds of the invention will be in the range from 1 mg to 250 mg daily, taken in 1 to 3 divided doses per day, for an average adult patient (70 kg). Dosages for intravenous administration would be expected to be within the range 0.1 to 100mg per single dose as required, for example in the treatment of acute heart failure. Thus for a typical adult patient, individual tablets or capsules might contain 1.0 to 100mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.

Variations may occur depending on the weight and condition of the subject being treated as will be known to medical practitioners.

Thus the present invention provides a pharmaceutical composition comprising a compound of the formula (I) as defined above or pharmaceutically acceptable diluent or carrier.

The invention also provides a method of stimulating the heart of a human being, which comprises administering to said human a compound of formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above, in an amount sufficient to stimulate the heart of said human.

The invention yet further provides a compound of the formula (I) or pharmaceutically acceptable salt thereof, for use as a medicament, in particular for use in stimulating the heart of a human being suffering from congestive heart failure.

The invention yet further provides the use of a compound of the formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a cardiac stimulant.

The compounds of formula (I) can be prepared by the formulation of the corresponding iodosubstituted imidazolyl-quinolones. The conversion of iodo to formyl is preferably carried out by reaction of the iodo-substituted imidazolyl-quinolone with carbon monoxide in the presence of tetrakis (triphenylphosphine) palladiium (0) and tri-n-butyl tin hydride in a suitable organic solvent at, say, 400-90C. Tetrahydrofuran is a preferred solvent.

The iodo-substituted imidazolyl-quinolones can be prepared as described in European patent application publication no. 0166533, and in the additional material placed in the file of that application in November 1985.

The following Examples illustrate the invention: Example 6-(4-Formyl-2-methylimidazol- 1 -yl)-8-methyl-2-( 1H)-quinolone, 0.67 H20.

A solution of tri-n-butyl tin hydride (0.96g) in tetrahydrofuran (THF) (100cm3) was added dropwise over 4 hours to a stirred solution of 6-(4-iodo-2-methylimidazol- 1 -yl)-8-methyl-2-( 1 H)- quinolone (1.1g) and tetrakis (triphenylphosphine) palladium (0) (0.39) in THF (100 cm3) heated to 50"C under an atmosphere of carbon monoxide. After a further 15 minutes the mixture was evaporated in vacuo and a saturated aqueous solution of potassium flouride (50cm3) was added with stirring. This mixture was extracted with chloroform (3x 100cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on solica (Merck "MK 60.9385" [Trademark]). Elution with methanol: chloroform, 1:20 by volume, followed by combination and evaporation of appropriate fractions gave the crude aldehyde (0.61g), a sample of which was recrystallised from dichloromethane/methanol/ethyl acetate to afford an analytical sample of the title compound, m.p. > 325 C.

Analysis %: Found: C,64.8; H,5.1; N,14.4; Calculated for: C15H13N302, 0.67H2O C,64.5; H,5.1; N,15.0.

6-(4-lodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone was prepared similarly to Example 12 of European patent application publication no. 0166533 by the reaction of trans-1-[4-(N-(3 ethoxypropenamido))-3-methylphenyl]-4-iodo-2-methylimidazole with 98% w/w sulphuric acid.

Example 2 6-(4-Hydroxymethyl-2-methylimidazol- 1 -yi)-8-meThyl-2-( 1H)-quinolone, 0.25H20.

Sodium borohydride (0.04g) was added to a stirred suspension of 6-(4-formyl-2-methylimida zol-1-yl)-8-methyl-2-(1 H)-quinolone (0.279) from part (A) in absolute ethanol (10 cm3). After 15 minutes a saturated aqueous solution of ammonium chloride (5 cm3) was added followed by basification of the mixture to pH 9 by the addition of a 1% aqueous solution of sodium carbonate. This mixture was extracted with dichloromethane (3 x 50 cm3) and the combined and dried (MgS04) organic extracts were evaporated in vacuo to give a solid which was recrystallised from ethyl acetate to afford the title compound, m.p. 268-71", (0.49).

Analysis 96 Found: C,64.7; H,5.5; N,14.8; Calculated for C,5H,5N302, 0.5H20: C,64.8; H,5.8; N,15.1.

Claims (5)

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R is H or CH3; and "Het" is an imidazol-1-yl group substituted by a formyl group and, optionally, by one or two methyl groups.

2. A compound as claimed in claim 1 wherein R is CH3 and , 'Het" is 4-formyl-2-methylimidazol-1-yl.

3. A pharmaceutical composition comprising a compound of the formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

4. A compound of the formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a medicament.

5. The use of a compound of the formula (I) as claimed in claim 1 or 2, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as an antiarrhythmic agent.