CARDIOTONIC HETEROCYCLOCARBONYL- AND ACETYL-THIAZOLONES

Abstract: Heterocyclocarbonyl- and acetyl-thiazolones enhance myocardial contractile force and are useful as cardiotonics in the treatment of heart failure.

Description: BACKGROUND OF THE INVENTION This invention relates to certain heterocyclo­ carbonyl- and acetyl-thiazolones, their use as cardiotonics in the treatment of heart failure, and their ability to enhance myocardial contractile force. Heart failure is that physiological condition re­ sulting from the inability of the ventricular myocardium to maintain adequate blood flow to the peripheral body tissues and includes congestive heart failure, backward and forward heart failure, right ventricular and left ventricular heart failure, and high-output and low-output heart failure. Heart failure can be caused by myocardial ischemia, myocardial infarction, excessive alcohol usage, pulmonary embolism, infection, anemia, arrhythmias, and systemic hypertension. Symptoms include tachycardia, fatigue with exertion, dyspnea, orthopnea and pulmonary edema. Treatment involves either removal or correction of the underlying cause or involves control of the heart failure state. Management or control can be accomplished by increasing cardiac output or by decreasing cardiac work load. While work load can be reduced by reduction of physical activities and physical and emotional rest, in­ creasing cardiac output has traditionally involved digitalis therapy. Digitalis stimulates contractile force of the heart which increases cardiac output and improves ventricular emptying. In this way, digitalis therapy normalizes venous pressure and reduces peripheral vaso­ constriction, circulatory congestion and organ hypoper­ fusion. Unfortunately, optimal doses of digitalis vary with the patient's age, size and condition and the therapeutic to toxic ratio is quite narrow. In most patients the lethal dose is only about five to ten times the minimal effective dose with toxic effects becoming apparent at only 1.5-2.0 times the effective dose. For these reasons, dose must be carefully tailored to suit the individual and frequent clinical examination and electrocardiogram is necessary to detect early signs of digitalis intoxication. Despite this care digitalis intoxication is reported in up to one-fifth of hospitalized patients undergoing therapy. The need for less toxic cardiotonic agents is readily apparent. Applicants have discovered certain thiazolones which possess potent cardiotonic activity and by comparison to digitalis have fewer toxic effects. Summary of the Invention The invention is directed to pharmaceutically active heterocyclocarbonyl- and acetyl-thiazolones of formula 1 wherein R₁ is a hydrogen or (C₁-C₄)alkyl group, and R₂ is a pyridyl or pyridylmethyl group optionally substituted with a member of the group con­ sisting of a (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)­ alkylsulfonyl, carboxy, carb(C₁-₄)alkoxy, halogen, trifluoromethyl and cyano, or R₂ is a furanyl, furanylmethyl, thienyl or thienylmethyl group. The formula 1 compounds enhance myocardial con­ tractile force and are useful as cardiotonics in the treatment of heart failure. Detailed Description of the Invention The formula 1 compounds exist in two tautomeric forms structurally depicted in formula 2 wherein R₁ and R₂ are as defined above. Throughout this disclosure, heterocyclocarbonyl- or acetyl-thiazolones of formula 1 are intended to include the tautomers of formula 2. The ring nitrogen of the formula 1 compounds can be substituted with a (C₁-C₄)alkyl group, an alkanoyl group such as an acetyl group, or a benzoyl group. These nitrogen substituted compounds are equivalent to the un­ substituted compounds primarily because the substituent is cleved upon administration to a patient but also because many of the nitrogen substituted compounds independently possess significant ability to enhance myocardial con­ tractile force and are useful cardiotonic agents. As used herein the term (C₁-C₄)alkyl and the alkyl portion of the alkoxy, alkylthio, alkylsulfinyl, alkyl­ sulfonyl, and carb alkoxy groups means a straight or branched alkyl group of from one to four carbon atoms. Illustrative examples of a (C₁-C₄)alkyl group are methyl, ethyl, isopropyl, butyl and sec -butyl. The term halogen means a fluoro, chloro, bromo or iodo group. Preferred compounds of this invention are those com­ pounds of formula 1 wherein R₁ is a hydrogen, methyl, or ethyl group. Also preferred are those formula 1 com­ pounds wherein R₂ is an optionally substituted pyridyl group. More preferred are those formula 1 compounds wherein R₂ is an unsubstituted pyridyl group. Most pre­ ferred are those formula 1 compounds wherein R₁ is a methyl group and wherein R₂ is a 4-pyridyl group. As examples of compounds of formula 1 there can be mentioned the following: 4-methyl-5-(4-pyridylcarbonyl)-2(3 H )-thiazolone; 4-ethyl-5-(3-pyridylcarbonyl)-2(3 H )-thiazolone; 5-[4-(2-methylpyridyl)carbonyl]-2(3 H )-thiazolone; 4-isopropyl-5-(2-furanylacetyl)-2(3 H )-thiazolone; 4-ethyl-5-(2-pyridinylacetyl)-2(3 H )-thiazolone; and 4-propyl-(5-thienylcarbonyl-2(3 H )-thiazolone. The formula 1 compounds can be prepared in any manner by standard techniques analogously known by those skilled in the art. For example the formula 1 compounds can be prepared by a Friedel-Crafts acylation of a thiazolone of formula 3 wherein R₁ is as defined above.The acylating reagent can be an acid halide of formula 4 X--R₂ wherein R₂ is as defined above and X is a bromo group or preferably 7 chloro group. In addition the acylating reagent of the Friedel-Crafts reaction can be the free acid or acid anhydride corresponding to the formula 4 acid halide. Mixed acid anhydrides may also be utilized. The Friedel-Crafts reaction is well known to those skilled in the art and has been reviewed by P.H. Gore in "Friedel-­ Crafts and Related Reactions", G.A. Olah, editor, Vol. III, Part 1, Interscience Publications, New York, 1964. The Friedel-Crafts reaction is performed by premixing about 1 molar equivalent of the appropriate thiazolone of formula 3 with about 1 molar equivalent to about 10 molar equivalents, preferably about 2 to 3 molar equivalents, of a Lewis acid catalyst in a suitable solvent, for example, petroleum ethers; a chlorinated aromatic, such as 1,2,4-­ trichlorobenzene or o-dichlorobenzene; carbon disulfide; nitrobenzene; or a chlorinated hydrocarbon such as carbon tetrachloride, ethylene chloride, methylene chloride, chloroform or preferably tetrachloroethane. About 1 molar equivalent to about 10 molar equivalents, preferably about 1.1 molar equivalents of the appropriate acid halide of formula 4 is added, preferably dropwise, to the mixture of thiazolone, Lewis acid, and solvent and the reaction is allowed to proceed for about 1/2 hour to about 100 hours, preferably from about 1 hour to about 10 hours depending on the reactants, the solvent, and the temperature which can be from about -78° to about 150°C, preferably about 60° to about 150°C, most preferably about 100-120°C. Preferably the solvent is removed by distillation. The resulting heterocyclo- or acetyl- thiazolone may be isolated from the reaction mixture by any suitable art-­ known procedure, preferably by quenching the reaction mixture with ice water and subsequently removing the product by filtration or extraction and solvent removal or by quenching the cooled reaction mixture with hydrochloric acid and subsequently collecting the solid product by filtration. Purification can be accomplished by, for example, recrystallization, preferably from ethanol. Lewis acid catalysts suitable for use in the Friedel-­ Crafts reactions described herein are, for example, a metal, such as aluminum, cerium, copper, iron, molybenum, tungsten or zinc; a Bronstead acid, such as a phosphoric acid, sulfuric acid, sulfonic acid, or a hydrohalic acid, such as hydrochloric or hydrobromic acid; halogen sub­ stituted acetic acids, such as chloroacetic or tri­ fluoroacetic acids; or a metallic halide, such as a boron halide, zinc chloride, zinc bromide, berryl chloride, copper chloride, iron(III) bromide, iron(III) chloride, mercury(II) chloride, mercury(I) chloride, antimony bro­ mide, antimony chloride, titanium(IV) bromide, titanium(IV) chloride, titanium(III) chloride, aluminum bromide or preferably aluminum chloride. The thiazolones of formula 3 are generally available or can be readily prepared by standard laboratory pro­ cedures. For example 4-methyl-2(3 H )-thiazolone is pre­ pared by reaction of chloroacetone and potassium thio­ cyanate in the presence of aqueous sodium bicarbonate by the procedure of Tcherniac, J. Chem. Soc., 115 , 1071 (1919). The compounds of formula 1 are cardiotonic agents useful in the treatment of heart failure. These compounds can also be used in the treatment of any other condition requiring enhanced myocardial contractile force. The utility of formula 1 compounds as cardiotonics may be determined by administering the test compound (0.1-­ 100 mg/kg) intravenously, intraperitoneally, intra­ duodenally or intragastrically in a suitable vehicle to a mongrel dog (either sex). The test dogs are anesthetized and prepared by isolating a suitable artery (e.g., femoral or common carotid) and vein (e.g., femoral or external jugular) introducing polyethylene catheters filled with 0.1% Heparin-Na to record arterial blood pressure and administer compounds, respectively. The chest is opened by splitting the sternum at the midline or by an incision at the left fifth intercostal space, and a pericardial cradle is formed to support the heart. A Walton-Brodie strain gage is sutured to the right or left ventricle to monitor myocardial contractile force. An electromagnetic flow probe may be placed around the root of the ascending aorta for measuring cardiac output less coronary blood flow. Heart failure is induced by administering sodium pentobarbital (20 to 40 mg/kg) followed by a continuous infusion of 0.25-2 mg/kg/min. or propranalol hydrochloride (4 mg/kg) followed by a continuous infusion of 0.18 mg/kg/min. to the blood perfusing the heart. Following administration of either of these cardiac depressants, the right atrial pressure dramatically increases and cardiac output is severly depressed. Reversal of these effects by the test compound indicates cardiotonic activity. The compounds may be administered in various manners to achieve the desired effect.The compounds may be administered alone or in the form of pharmaceutical pre­ parations to the patient being treated either topically, orally or parenterally, that is, intravenously or intra­ muscularly. The amount of compound administered will vary with the patient, the severity of the cardiac failure and the mode of administration. For topical, oral, or parenteral administration the cardiotonically effective amount of compound and the amount required to enhance myocardial contractile force is from about 0.1 mg/kg of patients body weight per day up to about 400 mg/kg of patient body weight per day and pre­ ferably from about 0.3 mg/kg of patient body weight per day up to about 120 mg/kg of patient body weight per day. For oral administration a unit dosage may contain, for example, from 5 to 700 mg of the active ingredient, preferably about 15 to 235 mg of the active ingredient. For parenteral administration a unit dosage may contain, for example, from 5 to 700 mg of the active ingredient, preferably about 15 to 210mg. Repetitive daily administration of the compounds may be desired and will vary with the condition of the patient and the mode of administration. As used herein, the term "patient" is taken to mean warm blooded animals, for example, birds, such as chickens and turkeys, and mammals, such as sheep, horses, bovine cows and bulls, pigs, dogs, cats, rats, mice and primates, including humans. For oral administration the compounds can be form­ ulated into solid or liquid preparations such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions.The solid unit dosage forms can be a capsule which can be of the ordinary gelatin type containing, for example, lubricants and inert filler, such as lactose, sucrose or cornstarch. In another embodiment the compounds of general formula 1 can be tableted with conventional tablet bases such as lactose, sucrose or cornstarch in combination with binders, such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. For parenteral administration the compound may be administered as injectable dosages of a solution or sus­ pension of the compounds in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water, alcohols, oils and other acceptable organic solvents with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol or 2-pyrrolidone are preferred liquid carriers, particularly for injectable solutions. The compounds can be administered in the form of a depot injection or implant preparation which may be form­ ulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic®, a silicone rubber manufactured by the Dow-Corning Corporation. The following specific examples further illustrate the preparation and use of the compounds of formula 1 but are not intended to limit the scope of the invention. EXAMPLE 4-Methyl-5-(4-Pyridinylcarbonyl)-­ 2(3H)-Thiazolone A mixture of methylene chloride (100 ml), 4-methyl-­ 2(3 H )-thiazolone (11.5 g, 0.1 mol), and aluminum chloride (39.9 g, 0.3 mol) was stirred at room temperature for 20 minutes. Isonicotinoyl chloride (12.5 g, 0.1 mol) in methylene chloride (50 ml) was then added dropwise over 10 minutes and, subsequently, the solvent was removed by dis­ tillation. The reaction mixture was heated to 115°C for 3 hours, then cooled and quenched with water. Aqueous sodium bicarbonate was added to adjust the acidity of the mixture to pH=6. After filtering to remove the solid aluminum salts the solvent was evaporated. The residue was chromatographed on silica gel and then recrystallized from methanol to give purified title compound, m.p. 255-­ 257°C. In a like manner but substituting nicotinoyl chloride, furoyl chloride or 2-thienylacetyl chloride for isonicotinoyl chloride in the example above results in 4-methyl-5-(3-pyridinylcarbonyl)-2(3 H )-thiazolone 4-methyl-5-(2-furoyl)-2(3 H )-thiazolone or 4-methyl-5-(2-thienylacetyl)-2(3 H )-thiazolone.

Claims: 1. A thiazolone of the formula wherein R₁ is a hydrogen or (C₁-C₄)alkyl group and R₂ is a pyridyl or pyridylmethyl group optionally substituted with a member of the group consisting of a (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)alkylsulfonyl, carboxy, carb-(C₁-C₄)alkoxy, halogen, trifluoromethyl and cyano, or R₂ is a furanyl, furanylmethyl, thienyl or thienylmethyl group. 2. A thiazolone of claim 1 wherein R₁ is a hydrogen, methyl, or ethyl group. 3. A thiazolone of claim 1 wherein R₂ is a pyridyl or substituted pyridyl group. 4. A thiazolone of claim 2 wherein R₂ is a pyridyl or substituted pyridyl group. 5. A thiazolone of claim 1 wherein R₂ is a 4-pyridyl group. 6. A thiazolone of claim 2 wherein R₂ is a 4-pyridyl group. 7. A thiazolone of claim 1 wherein R₁ is a methyl group and R₂ is a 4-pyridyl group. 8. A process for preparing a compound of claims 1, 2, 3, 4, 5, 6, or 7 which comprises adding from about 1 to 10 molar equivalents of an acid halide of the formula X--R₂ wherein R₂ is as defined above and X is a bromo or chloro group to a mixture consisting essentially of a compound of the formula wherein R₁ is as defined above, from about 1 to 10 molar equivalents of a Lewis acid catalyst and a suitable solvent, allowing the reaction to proceed for about 1 to 10 hours at from about 60 to 150°C and isolating the product. 9. A compound of claims 1, 2, 3, 4, 5, 6 or 7 for use as a medicine. 10. Use of a compound of claims 1, 2, 3, 4, 5, 6 or 7 for the preparation of a medicament for treating heart failure and enhancing myocardial contractile force. 11. A pharmaceutical composition which comprises a compound of claims 1, 2, 3, 4, 5, 6 or 7 in admixture with a pharmaceutically acceptable carrier. Claims for the following Contracting State : AT 1. A process for preparing thiazolones of the formula wherein R₁ is a hydrogen or (C₁-C₄)alkyl group and R₂ is a pyridyl or pyridylmethyl group optionally substituted with a member of the group consisting of a (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, carboxy, carb-(C₁-C₄)alkoxy, halogen, trifluoromethyl and cyano, or R₂ is a furanyl, furanylmethyl, thienyl or thienylmethyl group which comprises adding from about 1 to 10 molar equivalents of an acid halide of the formula X--R₂ wherein R₂ is as defined above and X is a bromo or chloro group to a mixture consisting essentially of a compound of the formula wherein R₁ is as defined above, from about 1 to 10 molar equivalents of a Lewis acid catalyst and a suitable solvent, allowing the reaction to proceed for about 1 to hours at from about 60 to 150°C and isolating the product. 2. A process according to claim 1 for preparing a compound wherein R₁ is a hydrogen, methyl or ethyl group. 3. A process according to claim 1 for preparing a compound wherein R₂ is a pyridyl or substituted pyridyl group. 4. A process according to claim 1 for preparing a compound wherein R₁ is a hydrogen, methyl or ethyl group and R₂ is a pyridyl or substituted pyridyl group. 5. A process according to claim 1 for preparing a compound wherein R₂ is a 4-pyridyl group. 6. A process according to claim 1 for preparing a compound wherein R₁ is a hydrogen,methyl or ethyl group and R₂ is a 4-pyridyl group. 7. A process according to claim 1 for preparing a compound wherein R₁ is a methyl group and R₂ is a 4-pyridyl group.

Inventors: DAGE, RICHARD C., GRISAR, J. MARTIN, SCHNETTLER, RICHARD A.
Applicants: MERRELL DOW PHARMACEUTICALS INC.
Application year: 1986
Main classification: C07D417
IPC codes: A61K31, C07D333, A61P9, C07D417