PYRIDAZINONE DERIVATIVES, THEIR PREPARATION AND USE

Abstract: Certain compounds of formula (I) are provided, and their salts, in which the compounds are selected from the following list: wherein, in this list, the following abbreviations are used: Bu butyl i Bu isobutyl s Bu sec-butyl Et ethyl Me methyl Pr propyl i Pr isopropyl.

Description: The present invention relates to specific novel 6-(4-substituted phenyl)-3(2 H )-pyridazinone derivatives and provides processes for their preparation, methods of using them and compositions containing them. The compounds of the invention are characterized by having a substituent on the 4-position of the phenyl group, which substituent is chosen from a limited class of substituted carbonylalkoxy groups. The compounds of the invention have exhibited a variety of valuable therapeutic activities, including myocardial contractivity (notably a stimulant activity arising from potentiation of the contractions of the heart), anti-hypertensive activity, the ability to inhibit gastric secretions and the ability to inhibit platelet aggregation; however, it is envisaged that the primary value of the compounds of the invention will arise as a result of their myocardial contractivity. A variety of 6-(substituted phenyl)-3(2 H )-pyridazinones is known, and some of these are known to have useful cardiac activities. For example, certain such compounds are said in Japanese Patent Applications Kokai (i.e. as laid open to public inspection) No. 18884/72 and No. 8015/83 to have cardiac and anti-hypertensive activities. Other, similar, compounds are disclosed in British Patent Specification No. 1,383,906 (equivalent to U.S. Patent Specifications No. 3,975,388 and No. 4,088,762) and these are said to have anti-hypertensive activity. British Patent Specification No. 1,488,330 discloses such compounds for use as β-adrenergic blocking agents. Certain other such compounds are disclosed in J. Het. Chem., 11 .755 (1974), but only in the context of the discussion of synthetic procedures and no utility is disclosed for such compounds. The prior art compounds referred to above differ from the compounds of the present invention in that the compounds of the invention all contain a substituted carbonylalkoxy or carbonylalkylthio substituent on the 4-position of the phenyl group and we have surprisingly found that certain compounds containing such a substituent possess significantly better myocardial contractivity than do the prior art compounds. The compounds of the invention may be represented by the formula (I): wherein: R¹ and R² are the same and each represents a hydrogen atom Q represents an oxygen atom; A represents a C₁-C₆ alkylene group; R³ represents a group of formula -(NH) n -NR⁶R⁷, wherein n is 0; and R⁶ represents a hydrogen atom, and R⁷ represents a substituted C₁-C₁₀ alkyl group having one C₁-C₆ alkoxy substituent: represents a hydrogen atom, and R⁴ represents a halogen atom or a C₁-C₆ alkyl group, the dotted line indicates a single carbon-carbon bond between the carbon atoms at the 4-and 5-positions of the pyridazinone system; and pharmaceutically acceptable acid addition salts thereof, which compounds are compounds 62a, 63a, 65a and 66a as illustrated in Table A hereinafter. The invention also provides methods of preparing the compounds of the invention, which are described in more detail hereafter. The invention still further provides the use of the specific compounds of formula (I) of the invention and pharmaceutically acceptable acid addition salts thereof for the manufacture of a medicament for the treatment of cardiac disorders and other prophylaxis and therapy. The compounds of the invention contain basic nitrogen atoms and hence can form acid addition salts. The nature of such salts is not critical to the present invention, except that, where the salts are to be used for therapeutic purposes, they must be pharmaceutically acceptable which, as is well known to those skilled in the art, means that the salts must not have an increased toxicity, or an unacceptably increased toxicity, or a reduced activity, or unacceptably reduced activity, as compared with the free bases. A wide variety of acids may be employed to form such salts and representative examples of such acids include: mineral acids, such a hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulphuric acid; and organic acids, such as acetic acid, oxalic acid, tartaric acid, citric acid, benzoic acid, glycolic acid, gluconic acid, glucuronic acid, succinic acid, maleic acid or fumaric acid. Such acid addition salts may be prepared by conventional methods. The compounds of the invention are selected from the following list, Table A. In this list, Table A, the following abbreviations are used: Et ethyl Me methyl Where a group identified by one of the above abbreviations can be attached to the remainder of the molecule through one of several of its atoms, the position of attachment is identified by the appropriate number preceding the abbreviation for that group; for example, in the case of the pyridyl group, this may be 3-Pyr, 2-Pyr etc. Also, where a group identified by one of the above abbreviations is substituted, the appropriate designation for its substituent or substituents precedes the abbreviation for the group so substituted and is itself (where appropriate) preceded by a number identifying the position of attachment of the substituent to the substituted group. For example, a 3-pyridyl group having an ethyl substituent at the 4-position would be identified as 4-Et-3-Pyr. Cpd No R¹ R² -Q-A-COR³ R⁴ R⁵ 62a H H OCH₂CONHCH₂CH₂OMe 3-Cl H 63a H H OCH₂CONHCH₂CH₂OEt 3-Cl H 65a H H OCH₂CONHCH₂CH₂OEt 3-Me H 66a H H OCH₂CONH(CH₂)₃OMe 3-Cl H The compounds of the invention may be prepared by a variety of methods, for example as illustrated below. Method A The compounds of the invention may be prepared from the corresponding 6-(4-hydroxy- phenyl) pyridazinone compounds as illustrated in the following reaction scheme: In the above formulae, R¹, R², R³, R⁴, R⁵, Q, A and the dotted line are as defined above. R¹⁰ represents a halogen atom or a C₁-C₆ alkoxy group, and R¹¹ represents a hydrogen atom. R¹² represents a hydroxy group, a C₁-C₆ alkoxy group, an aryloxy group, an aralkyloxy group, in which the alkyl part has from 1 to 6 carbon atoms or a group of formula -(NH) n -NR⁶R⁷, wherein R⁶, R⁷ and n are as defined above, but, in this case, any active groups or atoms therein may be protected. Also, in the case of certain groups which may be represented by R³, it may be convenient (albeit not essential) to prepare first a compound containing a different group and then convert it to another group by one of the optional reactions of step A2. Examples of the groups which may be represented by R¹⁰, R¹¹ and R¹² are given above. In step A1 of Method A, a compound of formula (II) is converted to an alkali metal salt thereof and then reacted with a halo compound of formula (V): XA-COR¹² (V) (in which R¹² and A are as defined above, and X represents a halogen atom, for example a chlorine, bromine or iodine atom). The reaction is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example: amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulphoxides, such as dimethyl sulphoxide; and nitriles, such as acetonitrile. The alkali metal salt to which the compound of formula (II) is converted is preferably a sodium, potassium or lithium salt. Conversion to this salt may be effected by treating the compound of formula (II) with an alkali metal compound, for example: an alkali metal hydride, such as sodium hydride or potassium hydride; or an organic lithium compound, such as lithium isobutyl cyclohexylamide or lithium dicyclohexylamide. This reaction may be effected over a wide range of temperatures, but suitably at a relatively low temperature, for example from -20°C to about ambient temperature. The reaction to produce the alkali metal salt will normally require a period of from 30 minutes to 2 hours. Reaction of the alkali metal salt of the compound of formula (II) with the compound of formula (V) is preferably effected in one of the above solvents at a temperature of from 0°C to 120°C. The time required for the reaction will vary widely, depending upon many factors, primarily the reaction temperature, but a period of from 30 minutes to 5 hours will normally suffice. The relative proportions of the alkali metal salt of the compound of formula (II) and the compound of formula (V) may vary widely, although approximately stoichiometric amounts are preferred. Although the reaction may be accelerated by employing an excess of the compound of formula (V), this can result in the introduction of a group of formula -A-COR¹² as a substituent on the nitrogen atom at the 2-position of the pyridazinone system, and although such compounds have some activity, they do not form part of the present invention. After completion of the reaction, the resulting compound of formula (Ia) may be recovered from the reaction mixture by conventional means. For example, one suitable recovery technique comprises: distilling the solvent from the reaction mixture; mixing the residue with ice-water; extracting the mixture with a water-immiscible organic solvent; washing with water and then drying the extract; and finally distilling the solvent from the extract to give the desired product. If desired, this may be further purified by conventional techniques, for example recrystallization or the various chromatography techniques, particularly column chromatography. The compounds of formula (II) employed as starting materials in this process are either already known or may be prepared by known methods, for example as described in the Journal of Medicinal Chemistry. 17 , 273 (1974) or by a method similar to that described in steps B1 and B2 of Method B. The reactions represented by step A2 in the above reaction scheme are optional and include the following series of reactions, which, where two or more are to be employed, may be selected and combined in any appropriate order: hydrolysis of any ester group (e.g. an aliphatic acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group); conversion of a carboxy group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group to a substituted carbamoyl group; conversion of a carboxy group to an alkoxycarbonyl group; salification. Hydrolysis of an ester may be carried out by conventional means. For example, a suitable reaction comprises treating the compound of formula (Ia) with an alkali metal hydroxide (such as sodium hydroxide or potassium hydroxide) in an inert solvent (such as aqueous ethanol) at a suitable temperature, e.g. from 0°C to 100°C, for a period of from 10 minutes to 2 hours. Conversion of an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group or a carboxy group to a substituted carbamoyl group may be carried out by reacting the compound of formula (Ia) (before or after one or more other optional reactions of step A2) with an amine derivative of formula (VI): H-(NH) n -NR⁶R⁷ (VI) (in which n , R⁶ and R⁷ are as defined above) in an inert solvent. The nature of the solvent employed is not critical to the reaction, provided that it has no adverse effect on the reaction. Suitable solvents include those exemplified in relation to step A1 above, as well as alcohols, such as methanol or ethanol. The reaction will take place over a wide temperature range, but we normally prefer to carry it out at a temperature within the range from 0 to 150°C. The time required for the reaction will vary depending upon many factors, particularly the reaction temperature and the nature of the reagents, but a period of from 30 minutes to 24 hours will normally suffice. Conversion of a carboxylic acid into an amide may be carried out by reacting the corresponding compound of formula (Ia) (before or after one or more of the other optional reactions of step A2) with a compound of formula (VI), defined above, in the presence of a dehydrating agent and of an inert solvent. Suitable dehydrating agents include, for example: carbodiimides, such as dicyclohexylcarbodiimide; and cyanophosphoric acid esters, such as diethyl cyanophosphonate or dimethyl cyanophosphonate; of these, the cyanophosphoric acid esters are preferred. Suitable solvents include those illustrated in relation to step A1. This reaction is preferably effected in the presence of a base, more preferably an organic amine, such as triethylamine, pyridine or 4-dimethylaminopyridine. The reaction will take place over a wide temperature range, but we generally prefer a temperature within the range from 0 to 50°C. The time required for the reaction will vary, depending upon many factors, notably the reaction temperature and the nature of the reagents, but a period of from 2 to 24 hours will normally suffice. Alternatively, the same reaction may be effected by first converting the carboxylic acid into a reactive derivative thereof and then reacting this reactive derivative with the amine compound of formula (VI). Suitable reactive derivatives of the carboxylic acid include: acid halides, such as the acid chloride; mixed acid anhydrides of the carboxylic acid with another organic carboxylic acid, such as acetic acid, propionic acid or pivalic acid; and active esters of the carboxylic acid, such as the isobutoxycarbonyl ester. These reactive derivatives can be prepared by treating the corresponding carboxylic acid with a suitable halogen compound, such as thionyl chloride, acetyl chloride, pivaloyl chloride or isobutoxycarbonyl chloride. Where a reactive derivative of the carboxylic acid is employed, the reaction between the reactive derivative and the amine of formula (VI) is preferably effected in the presence of an inert solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents for this reaction include: hydrocarbons, which may be aliphatic, cycloaliphatic or aromatic, particularly benzene or hexane; and ethers, such as diethyl ether or tetrahydrofuran. Although the reaction can be carried out over a wide range of temperatures, we generally find it most convenient to effect the reaction at about ambient temperature. At such a temperature, the time required for the reaction will normally be within the range from 30 minutes to 3 hours. Conversion of a carboxy group to an alkoxycarbonyl group is a conventional esterification reaction. It may, for example, be carried out by reacting the corresponding carboxy compound with a diazoalkane corresponding to the alkoxy group of the alkoxycarbonyl group which it is desired to prepare, for example diazomethane, diazoethane or diazopropane. The reaction is preferably effected in the presence of an inert solvent, the nature of which is not critical, provided that it has no adverse effect on the reaction; suitable solvents include ethers, such as diethyl ether. The reaction temperature is likewise not critical, and we generally find it convenient to carry out the reaction at about ambient temperature. Alternatively, this esterification may be carried out by reacting the corresponding carboxy compound with an alkanol, such as methanol, ethanol or butanol, in the presence of a dehydrating agent. Reagents and reaction conditions to be employed in this reaction are similar to those discussed above in relation to the reaction of a carboxylic acid with an amine. At the end of any of these reactions, the desired compound may be recovered from the reaction mixture by conventional means. For example, one suitable recovery procedure comprises: pouring the reaction mixture either directly or after distilling off the solvent into ice-water; if necessary, neutralising the resulting mixture; extracting the mixture with a water-immiscible organic solvent; washing with water and then drying the extract; and finally distilling the solvent from the extract to give the desired product. If necessary, this may be further purified by conventional means, for example recrystallization or the various chromatography techniques, particularly column chromatography. Method B In this Method, the compounds of the invention are prepared by reacting a phenyl derivative with succinic or maleic anhydride, or a derivative thereof, and then reacting the product with hydrazine, as illustrated in the following reaction scheme:- In the above formulae, R¹, R², R³, R⁴, R⁵, R¹², Q, A and the dotted line are as defined above. Step B1 of this Method comprises reacting the phenyl derivative of formula (III) with the succinic or maleic anhydride or derivative thereof of formula (VII). The reaction is preferably effected in the presence of an acid catalyst and in an inert solvent. The nature of the acid catalyst employed is not critical and any acid catalyst commonly used in Friedel-Crafts reactions may be employed. Examples of such acid catalysts include: Lewis acids, such as aluminium chloride, zinc chloride, ferric chloride, titanium tetrachloride or boron trifluoride; and protonic acids, such as hydrofluoric acid or sulphuric acid. Of these, aluminium chloride is preferred. There is no particular limitation on the nature of the inert solvent to be employed in this reaction, provided that it does not interfere with the reaction. Examples of suitable solvents include: halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride; and amides, such as dimethylformamide and dimethylacetamide. Of these, methylene chloride is preferred. The reaction will take place over a wide range of temperatures, but we normally find it convenient to carry out the reaction at a temperature of from 0 to 50°C. The time required for the reaction will vary, depending upon many factors, notably the reaction temperature and the nature of the reagents, but a period of from 1 hour to 5 hours will normally suffice. After completion of this reaction, the resulting compound of formula (IV) may be recovered from the reaction mixture by conventional means. For example, one suitable recovery technique comprises: pouring the reaction mixture into ice-water; extracting the mixture with a water-immiscible organic solvent; washing the extract with water and then drying it; and finally distilling the solvent from the extract to give the required compound. If desired, this compound may be further purified by conventional methods, for example recrystallization or the various chromatography techniques, particularly column chromatography. In step B2 of this method, the compound of formula (IV), obtained in step B1, is reacted with hydrazine in an inert solvent, to give the compound of formula (Ib). The nature of the solvent employed in this process is not critical, provided that it has no adverse effect upon the reaction. Examples of suitable solvents include: alcohols, such as methanol, ethanol and propanol; ethers, such as diethyl ether or tetrahydrofuran; water; and mixtures of one or more of the above organic solvents with water. Of these, we prefer the alcohols. The reaction will take place over a wide range of temperatures, but we generally find it convenient to carry out the reaction at a temperature of from 0 to 100°C. The time required for the reaction will vary, depending upon many factors, notably the reaction temperature and the nature of the reagents, but a period of from 2 to 10 hours will normally suffice. After completion of the reaction, the desired compound of formula (Ib) may be recovered from the reaction mixture by conventional means. For example, one suitable recovery procedure comprises: pouring the reaction mixture into ice-water, optionally after distilling off the solvent; extracting the mixture with a water-immiscible organic solvent; washing the extract with water and drying it; and finally distilling the solvent from the extract. If necessary, this product may be further purified by such conventional techniques as recrystallization or the various chromatography techniques, particular column chromatography. If the carbonyl group (>C=0) attached to the group represented by R³ is converted by this reaction into a hydrazone group (>C=N-NH₂), the carbonyl group may be regenerated by treating the resulting compound with an acid in an inert solvent. Suitable acids include: organic carboxylic acids, such as acetic acid or propionic acid; and dilute mineral acids, such as dilute hydrochloric acid or dilute sulphuric acid. The nature of the solvent employed is not critical, provided that it does not interfere with the reaction. Suitable solvents include, for example: water; alcohols, such as methanol or ethanol; ethers, such as diethyl ether or dioxane; and mixtures of one or more of the above organic solvents with water. The reaction will take place over a wide range of temperatures, but we generally find it convenient to employ a temperature within the range from 20 to 100°C. The time required for the reaction will vary, depending upon many factors, notably the reaction temperature and the nature of the reagents, but a period of from 10 minutes to 3 hours will normally suffice. Step B3 includes the same optional reactions as described in relation to step A2 and may be carried out in the same way. Biological Activity The compounds of the present invention have been found to possess excellent myocardial contractivity, anti-hypertensive activity and other similar activities, which appear to be better than those of the known pyridazinone compounds. Accordingly, it is anticipated that the compounds of the invention will be of considerable therapeutic use as cardiac stimulants, anti-hypertensive drugs and anti-thrombotic agents. The cardiac activity of the compounds of the invention is illustrated by the following tests. Cardiac Activity in the Dog Heart Following the method reported by Alousi et al [Circulation Research 45 , 666 (1979)], a fine catheter, having a pressure sensor built in at the top was inserted into the carotid artery of an anaesthetised dog in the direction of the heart. The top part of the catheter was placed in the left ventricle and the pressure waveform obtained was recorded by its linear differential value. The value for the contraction of the left ventricle was taken as the maximum value of this pressure wave. Each test compound was dissolved either in 0.1 N hydrochloric acid or in dimethylformamide and administered intravenously (Table 1) or intraduodenally (Table 2) and the percentage increase in contractive power from its level immediately prior to administration, as well as the recovery time (in minutes) are shown in the following Tables. The recovery time measured was the time taken, after administration of the test compound, for the heart contractive power to return to its level immediately prior to administration. For purposes of comparison, two prior art compounds were similarly tested. Compound A is 4,5-dihydro-6-( p -methoxyphenyl)-3(2 H )-pyridazinone, one of the compounds disclosed in Japanese Patent Application Kokai No. 8015/83; Compound B is amrinone, whose systematic name is 5-amino-(3,4'-bipyridin)-6(1 H )-one, which is currently used as a cardiotonic. Cpd No. Dosage (mg/kg) Contractive power (% increase) Recovery time (minutes) 63a 0.010 54 31 Cpd. A 0.010 18 15 Cpd. B 0.300 21 27 As can be seen from the above results, particularly those in Table 1, the compounds of the invention potentiated the contractions of the heart significantly better than the two known compounds, including amrinone, which is sold commercially for this specific purpose; moreover, the effect of the compounds of the invention was more durable. The compounds of the invention can be administered as conventional pharmaceutical formulations, depending upon the intended route of administration. For example, for oral administration, they may be formulated as powders, granules, tablets, capsules or similar orally administerable formulations, which can be produced by mixing the active compound with carriers, excipients or diluting agents, such as glucose, sucrose, lactose, sorbitol, starch, polyvinylpyrrolidone, mannitol, calcium carbonate, calcium phosphate, sodium chloride or boric acid. For parenteral administration, they may be formulated as conventional injections suitable for, for example, intravenous injection. The dose will vary, depending upon the nature of the disorder, the route of administration, and the symptoms, age and body weight of the patient; however, for an adult human patient, a suitable dose would be from 0.001 mg to 50 mg per day, which could be given in a single dose or in divided doses. The invention is further illustrated by the following Examples, which illustrate the preparation of various of the compounds of the invention. The preparation of certain of the starting materials employed in these Examples is illustrated in the subsequent Preparations. EXAMPLE 1 1.79 g of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2 H )-pyridazinone (prepared as in Preparation 1) was dissolved in 15 ml of anhydrous dimethylformamide. 0.35 g of a 55% w/w suspension of sodium hydride in mineral oil was added, and the solution was stirred for 1 hour. To this solution, was added, whilst ice-cooling, 1 ml of a dimethylformamide solution containing 1.34 g of ethyl bromoacetate, and the mixture was stirred for 1 hour at room temperature and then for 3 hours at 80°C. At the end of this time, the dimethylformamide was distilled off under reduced pressure and the mixture was diluted with water and then extracted with ethyl acetate. The extract was washed with water, dried and then evaporated to dryness. The addition of hexane precipitated 1.85 g of 6-[3-Chloro-4-(ethoxycarbonylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as white needles melting at 134-136°C. Elemental Analysis: Calculated for C₁₄H₁₅N₂O₄Cl: C, 54.11%; H, 4.87%; N, 9.01%; Cl, 11.41%. Found: C, 54.16%; H, 4.87%; N, 8.63%; Cl, 11.23%. EXAMPLE 2 6 ml of a dimethylformamide solution containing 0.8 g of 6-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl]-4,5-dihydro-3(2 H )-pyridazinone prepared as described in Example 1) and 4 ml of butylamine was stirred for 7 hours at 120°C. This solution was then poured into ice-water and the crystals which precipitated were collected by filtration. Recrystallization of these from dimethylformamide gave 0.6 g (yield 62.8%) of 6-[3-Chloro-4-(N-butylcarbamoylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as white crystals melting at 140-141°C. Compound 63a was prepared by the procedure described in Example 2, as indicated in the following table. Cpd No melting at (°C) prepared as in Example No 63a 164-166 2 ) PREPARATION 6-(3-Methyl-4-hydroxyphenyl)-4,5-dihydroxy-3(2H)-pyridazinone (a) 4-(3-Methyl-4-hydroxyphenyl)-4-oxobutyric acid 24.5 g of O -methylanisole and 20.0 g of succinic anhydride were dissolved in 230 ml of methylene chloride. Holding the temperature of the reaction solution below 5°C, 84 g of aluminium chloride were slowly added. After the addition was complete, the reaction mixture was stirred for 1 hour at a temperature below 5°C and for an additional 5 hours at room temperature. It was then allowed to stand for one day and overnight at room temperature, after which the reaction mixture was poured into ice-cooled dilute hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed and then dissolved in ethanol. This solution was dried by azeotropic distillation and then evaporated to dryness. 4.16g of the title compound were obtained as an oil. Infrared Absorption Spectrum (liquid film) ν max cm⁻¹ : 1715, 1690. (b) 6-(3-Methyl-4-hydroxyphenyl)-4,5-dihydroxy-3(2H)-pyridazinone 41.6 g of the compound prepared as described in step (a) were dissolved in 400 ml of ethanol. To this solution were slowly added, with ice-cooling, 8.2 g of 80% v/v aqueous hydrazine hydrate. After the addition was complete, the reaction mixture was stirred for 20 minutes and then heated under reflux, with stirring, for 3 hours. This reaction mixture was then allowed to stand for one day and overnight, after which it was cooled in ice-water. The resulting precipitate was collected by filtration and recrystallized from a mixture of ethanol and ethyl acetate, to give 22.7 g of the title compound melting at 265-267°C. Following the same procedure as described above, the pyridazinone derivative of formula (IIa) shown below was also obtained:

Claims: Compounds of formula (I): wherein: R¹ is a hydrogen atom; R² is a hydrogen atom; Q is an oxygen atom; A represents a C₁-C₆ alkylene group; R³ represents a group of formula -(NH) n -NR⁶R⁷, wherein n is O, R⁶ is a hydrogen atom, and R⁷ is a C₁-C₁₀ alkyl group substituted with one C₁-C₆ alkoxy group; R⁴ is a halogen atom or a C₁-C₆ alkyl group; R⁵ is a hydrogen atom; and the dotted line indicates a single bond; and pharmaceutically acceptable acid addition salts thereof; wherein the compound is selected from the following list: R¹ R² -Q-A-COR³ R⁴ R⁵ 62a H H OCH₂CONHCH₂CH₂OMe 3-Cl H 63a H H OCH₂CONHCH₂CH₂OEt 3-Cl H 65a H H OCH₂CONHCH₂CH₂OEt 3-Me H 66a H H OCH₂CONH(CH₂)₃OMe 3-Cl H wherein, in this list, the following abbreviations are used: Et ethyl Me methyl. A pharmaceutical composition comprising a compound as claimed in claim 1 in admixture with a pharmaceutically acceptable carrier or diluent. The use of a compound as claimed in claim 1 in the manufacture of a medicament for the treatment of cardiac disorders and other prophylaxis and therapy. A process for the preparation of a compound as claimed in claim 1, which process comprises the steps: (A) reacting a compound of formula (IIIa) [wherein: Q, R⁴ and R⁵ are as defined in claim 1; and Z represents either (i) a hydrogen atom or (ii) a group of formula -A-COR¹² in which A is as defined in claim 1 and R¹² represents a hydroxy group, a C₁-C₆ alkoxy group, an aryloxy group, an aralkyloxy group in which the alkyl part has from 1 to 6 carbon atoms or a group of formula -(NH) n -NR⁶R⁷, wherein R⁶, R⁷ and n are as defined in claim 1] under Friedel-Crafts reaction conditions with a compound of formula (VIIa): (wherein R¹, R² and the dotted line are as defined in claim 1), to give a compond of formula (IVa): (wherein R¹, R², R⁴, R⁵, Q, Z and the dotted line are as defined above); (B) reacting said compound of formula (IVa) with hydrazine, to give a compound of formula (Ic): (wherein R¹, R², R⁴, R⁵, Q, Z and the dotted line are as defined above); (C) where Z represents (i) a hydrogen atom, at any appropriate time before, during or after either of steps (A) or (B), reacting the compound containing the hydrogen atom represented by Z in the form of its alkali metal salt with a compound of formula (V): X-A-COR¹² (V) (wherein R¹² and A are as defined above and X represents a halogen atom); and (D) optionally, any one or more of the following reactions in any appropriate order: hydrolysis of any ester group; conversion of a carboxy group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group to a substituted carbamoyl group; conversion of a carboxy group to an alkoxycarbonyl group; salification. A process as claimed in claim 4 which comprises the steps: (C') reacting an alkali metal salt of a compound of formula (II): (wherein R¹, R², Q and the dotted line are as defined in claim 1, R¹⁰ and R¹¹ represent the groups and atoms represented by R⁴ and R⁵) with said compound of formula (V), to give a compound of formula (Ia): (wherein R¹, R², Q and A and the dotted line are as defined in claim 1 and R¹² is as defined in claim 4); and (D) if necessary any one or more of the reactions defined in step (D) of claim 4. A process as claimed in claim 4 which comprises the steps: (A'') reacting a compound of formula (III) (wherein R⁴, R⁵, Q, A and R¹² are as defined in claim 5) under Friedel-Crafts reaction conditions with a compound of formula (VII): (wherein R¹, R² and the dotted line are as defined in claim 1) to give a compound of formula (IV): (wherein R¹, R², R⁴, R⁵, Q, A, R¹² and the dotted line are as defined in claim 5); (B'') reacting said compound of formula (IV) with hydrazine, to give a compound of formula (Ib): (wherein R¹, R², R⁴, R⁵, Q, A, R¹² and the dotted line are as defined in claim 5); and (D) optionally any one or more of the reactions defined in step (D) of claim 4.

Inventors: KATAOKA, MITSURU SANKYO CHEMICAL RESEARCH LAB., KOBAYASHI, SHINSAKU SANKYO BIOLOGICAL RESEARCH LAB, KOIKE, HIROYUKI SANKYO BIOLOGICAL RESEARCH LAB., KUMAKURA, SEIJI SANKYO BIOLOGICAL RESEARCH LAB., MORISAWA, YASUHIRO SANKYO CHEMICAL RESEARCH LAB.
Applicants: SANKYO COMPANY LIMITED
Application year: 1985
Main classification: C07D237
IPC codes: C07D237, A61P7, A61P1, A61P9, A61K31, C07D521, C07D401, C07D403