GB2058783A - 1(2H)-Isoquinolone Compounds and Acid Addition Salts Thereof - Google Patents

Abstract

1(2H)-isoquinolone compounds of general formula <IMAGE> where Y is hydrogen, chlorine or methoxy, Z is a 2, 3 or 4 carbon atoms alkylene group optionally substituted with an alkyl* group, R1 is a cyano, alkoxy-carbonyl* carbamoyl (which may be N- substituted) or (substituted) phenyl group (e.g. halo- or alkoxyphenyl), R2 is hydrogen or alkyl*, R3 is alkyl, or R2 and R3 can together complete a heterocyclic group; *groups have 1 to 4 carbon atoms. 44 specific crystalline compounds are named, with their elementary analyses and melting points. Various syntheses are given, including from the starting materials <IMAGE> Acid addition compounds of compound (I) are prepared by reaction with an acid. Pharmaceutical compositions can be prepared, e.g. granules, tablets or capsules. Pharmaceutical and toxicity tests on animals are given for 4 compounds. The compounds and compositions have excellent analgesic, gastric secretion inhibitory, anti-depression, anti-histaminic, anticholinergic and anti-ulcer activities in mammals.

Description

SPECIFICATION 1 (2H)-lsoquinolone Compounds and Acid Addition Salts Thereof This invention relates to novel 1 (2H)-isoquinolone compounds and the acid addition salts thereof which exhibit useful analgesic, gastric secretion inhibitory, anti-depression, anti-histamine, anticholinergic and anti-ulcer activities.

The present invention provides novel 1 (2H)-isoquinolone compounds having the formula (I) hereinafter described and the acid addition salts thereof which are useful as pharmaceutical agents.

In the accompanying drawings: Figures 1 (a) and 1 (b) are graphs showing effects of the known compounds and Compound C of this invention on the decrease in body temperature induced by administration of reserpine.

Figures 2(a) and 2(b) are graphs showing the anti-histamine activity and the anticholinergic activity of Compound A of this invention.

Figures 3(a) and 3(b) are graphs showing the anti-histamine activity and the anticholinergic activity of Compound B of this invention.

Figures 4(a) and 4(b) are graphs showing the anti-histamine activity and the anticholinergic activity of Compound C of this invention.

The 1 (2H)-isoquinolone compounds according to the present invention are represented by the formula (I)

wherein Y represents hydrogen, chlorine or a methoxy group, Z represents a straight chain or branched chain divalent saturated aliphatic hydrocarbon group having 2 to 4 carbon atoms, R, represents a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, an N-substituted carbamoyl group, a phenyl group or a substituted phenyl group, R2 represents hydrogen or a lower alkyl group, R3 represents a lower alkyl group, or R2 and R3 can form, when taken together with the nitrogen atom to which they are attached, a heterocyclic group, and the acid addition salts thereof.

The term "a straight chain or branched chain divalent saturated aliphatic hydrocarbon group" as used herein means an alkylene group having 2 to 4 carbon atoms which can be substituted with an alkyl group having 1 to 4 carbon atoms, for example, an ethylene group, a trimethylene group, a methylethylene group or a methyltrimethylene group.

The term "a lower alkoxycarbonyl group" as used herein means an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety such as a methoxycarbonyl group, an ethoxycarbonyl group, propoxycarbonyl groups, butoxycarbonyl groups and the like.

The term "N-substituted carbamoyl group" as used herein means an N-alkylcarbamoyl group, an N,N-dialkylcarbamoyl group wherein each alkyl group has 1 to 4 carbon atoms, a 4methylpiperadinocarbonyl group, a morpholinocarbonyl group and the like.

The term "substituted phenyl group" as used herein means a halophenyl group such as a p chlorophenyl group or an alkoxyphenyl group having 1 to 4 carbon atoms in the alkoxy group, for example, a p-methoxyphenyl group.

The term "lower alkyl group" as used herein means a straight chain or branched chain alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or sec-butyl.

Examples of the heterocyclic group formed by R2 and R3 together with the nitrogen atom to which are attached are a pyrrolidino group, a piperidino group, a 4-methylpiperazino group, a 4hydroxyethylpiperazino group or a morpholino group.

The term 'iacid addition salts" as used herein for the compounds of the formula (I) means the salts with pharmaceutically acceptable inorganic or organic acids and preferred examples of the salts are hydrochloride, sulfate, hydrobromide, methanesulfonate, maleate, tartarate, citrate and lactate.

The 1 (2H)-isoquinolone compounds of the formula (I) can be prepared by reacting a substituted 1 (2H)-isoauinolone havina the formula (II)

wherein Y and R1 are as defined above, with a substituted-aminoalkyl halide of the formula (Ill)

wherein X represents a halogen atom such as chlorine or bromine and Z, R2and R3 are as defined above, in the presence of a basic catalyst.

More particularly, the above reaction between the compounds of the formulae (II) and (Ill) can be advantageously carried out by dissolving the substituted-l (2H)isoquinolone of the formula (II) in an organic solvent such as dimethylformamide, dimethyl sulfoxide, toluene or ethanol adding thereto a basic catalyst, for example an alkali metal carbonate such as potassium carbonate or sodium carbonate, sodium hydride, sodium amide, a alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium .t-butoxide, followed by, optionally heating; then adding to the resulting reaction mixture the substituted aminoalkyl halide of the formula (III) and heating the mixture at a temperature of 800 to 1 400C for a period of 1 to 5 hours.

In the above reaction, the basic catalyst and the substituted aminoalkyl halide can be used in at least an equimolar amount to the substituted 1 (2H)-isoquinolone of the formula (II). Also, the substituted aminoalkyl halide (Ill) can be used in the form of a salt with an inorganic acid such as the hydrochloride and, in such instance, the base is preferably used in an excess amount over the equimolar amount to the compound (II).

Most of the substituted aminoalkyl halides of the formula (Ill) are commercially available, but when the desired aminoalkyl halides are not available, the compounds of the formula (I) can also be prepared from the substituted 1 (2H)-isoquinolone of the formula (II) via an alternative route using an amine according to the following procedures.That is, the compounds of the formula (I) can be prepared by reacting the compound of the formula (II) with a hydroxyalkyl halide of the formula (IV) X--ZZ-OH (IV) wherein X and Z are as defined above, to produce the corresponding 2-(hydroxyalkyl)-1 (2H)isoquinolone compound of the formula (V)

wherein Y, Z and R, are as defined above, reacting the compound of the formula (V) with a halogenating agent to produce a 2-(haloalkyl)-1 (2H)-isoquinolone compound of the formula (Vl)

wherein Y, R, and X are as defined above, and reacting the compound of the formula (VI) with an amine of the formula (VII)

wherein R2 and R3 are as defined above.

In the above alternative procedure, the reaction between the compounds of the formulae (II) and (IV) can be carried out using about 1 to about 1.5 mol of the hydroxyalkyl halide of the formula (IV) per mol of the compound of the formula (Il) in an organic solvent such as dimethylformamide or toluene in the presence of a base such as potassium carbonate, sodium carbonate or sodium hydride in an amount of at least about 2 mols per mol of the compound of the formula (II), at a temperature of 800 to 1 400C for a period of 1 to 5 hours.

The reaction of the thus obtained 2-(hydroxyalkyl)-1 (2H)-isoquinolone compound of the formula (V) with a halogenating agent can be carried out by heating at reflux in the presence or absence of organic solvent for a period of about 30 minutes to about 2 hours. Suitable examples of halogenating agents are thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide. These halogenating agents may be used in a molar excess amount so as to serve as a solvent and in such case the organic solvent may not be used. Suitable examples of organic solvents are benzene and carbon tetrachloride.

The subsequent reaction of the thus obtained 2-(haloalkyl)-1 (2H)-isoquinolone of the formula (Vl) with an amine of the formula (VII) can be conducted while heating at reflux for a period of about 1 to 6 hours, optionally in the presence of an inorganic base as exemplified before for the reaction of the compounds of the formulae (II) and (III). The reaction can be advantageously carried out using an organic solvent having a boiling point higher than'that of the amine (VII) used, for example, xylene, tetralin, ethylbenzene. When the amine used has a relatively low boiling point, the reaction is advantageously carried out in a sealed reaction vessel.

The compounds of the formula (I) having a substituted carbamoyl group at the 4-position can also be prepared by heat-reacting the 4-ester compound of the formula (I')

wherein R, is a lower alkoxycarbonyl group and Y, Z, R2 and R3 are as defined above, with an amine of the formula (VII) in an alcohol solvent.

Alternatively, the 4-carbamoyl compounds of the formula (I') above can be obtained by hydrolyzing the 2-(hydroxyalkyl)-1 (2H)-isoquinolone compound of the formula (V)

wherein R, represents a lower alkoxycarbonyl group, and Y and Z are as defined above, dissolved in an alkaline alcohol to obtain the corresponding 4-carboxy compound of the formula (VIII)

wherein Y and Z are as defined above, reacting the thus obtained 4-carboxy compound with a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus oxybromide in the presence of an organic solvent such as benzene or carbon tetrachloride, or in the absence of the organic solvent, for a period of about 1 to 3 hours to obtain the corresponding 4-acid halide compound of the formula (IX)

wherein X, Y and Z are as defined above, reacting the thus obtained 4-acid halide compound (IX) with an amine of the formula (VII) in an amount of at least about 2 mols per mol of the 4-acid halide compound (IX) in an organic solvent such as benzene, chloroform, diethyl ether at room temperature (about 15--300C) for a period of 1 to 5 hours to obtain the corresponding 4-carbamoyl compound of the formula (X)

wherein X, Y, Z, R2 and R3 are as defined above, and reacting the resulting 4-carbamoyl compound of the formula (X) with an amine of the formula (VII) in an organic solvent such as acetone, benzene, toluene at a temperature of 90 to 1 500C for a period of 1 to 6 hours to obtain the desired compound of the formula (I').

When the same amine is used in the amidation of the 4-acid halide compound (IX) and the amination of the 4-carbamoyl compound (X), these reactions are not necessarily conducted in two steps, and the desired compound of the formula (I') can be obtained in a single step by reacting the compound of the formula (IX) with an excess of the amine (VII) according to the procedure described above for the reaction between the compounds of the formula (VI) or (X) and the amine (VII).

The desired compounds of the formula (I) are generally obtained in the form of free base and, if desired, the free base can be easily converted into their acid addition salts by a conventional procedure well known in the art, for example, by reacting the free base with an inorganic or organic acid in a solvent such as ethanol, ethyl acetate or acetone or an aqueous acid solution at room temperature or elevated temperature.

The starting materials of the formula (II) wherein R, represents a cyano group or a lower alkoxycarbonyl group and Y represents chlorine or a methoxy group are novel compounds and can be obtained according to the following reaction scheme:

wherein Y is Cl or-OCH3, and R, is --CN, --COOR (R=CH3, C2Hs, C3H7 or C4Hg).

More specifically, 1 mol of a p-substituted phenylacetic acid lower alkyl ester of the formula (XI) (or an acetonitrile compound), about 1 to 1.5 mol of a sodium alkoxide and about 1.5 to 3 mols of ethyl formate are mixed in diethyl ether, and the mixture is allowed to react for about 10 to 24 hours at room temperature to obtain the formyl compound of the formula (XII). The resulting formyi compound and an equimolar amount of urethane are heat-refluxed in the presence of concentrated sulfuric acid in toluene to obtain the ethoxycarbonyl amino compound of the formula (Xlil) which is then heat under reflux in diphenyl ether to obtain the starting material of the formula (II).

The starting materials of the formula (II) having a lower alkoxycarbonyl group of 1 to 4 carbon atoms at the 4-position are novel compounds regardless of the type of substituent at the 7-position, and these compounds can be easily prepared by esterification of 4-carboxy compounds or transesterification of methoxy or ethoxycarbonyl compounds. These reactions can be achieved using a desired alcohol in the presence of concentrated sulfuric acid while heating at reflux for about 10 to 20 hours.

The object compounds of the formula (I) thus obtained exhibit excellent analgesic, anti-reserpine (anti-depressant), anti-histaminic, anticholinergic, gastric secretion inhibiting and anti-ulcer activities in mammals and, therefore, are useful as pharmaceutical agents.

The dose level of the compounds of the present invention as pharmaceutical agents varies depending upon the severity of conditions to be treated, the age of patients, the type of diseases or other factors, but generally ranges from 0.5 to 50 mg/kg of body weight per day in adult human administered as a single dose or multiple dose (divided into 2 to 3 doses).

The compounds of this invention can be administered orally, parenterally or intrarectally in various dosage forms such as tablets, capsules, granules, powders, injections, suppository, ointments and the like.

The above preparations are formulated as compositions comprising suitable carriers or excipients by the procedure generally used in preparing pharmaceutical compositions.

The tablets, capsules, granules powders, etc. for oral administration can be prepared from excipients generally used in the art, for example, calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, gelatin, polyvinylpyrrolidine, gum arabic, sorbitol, crystalline cellulose, polyethylene glycol, carboxymethylcellulose or silica. Also, tablets and granules can be coated according to the method well known in the art.

The injections can be aqueous or oily suspensions, solutions, or powder filled in ampoules or freeze-dried preparation which is instantly dissolved in a liquid medium just before the use, and these preparations can be be prepared according to the procedure well known in the art.

The suppositories can contain well-known carriers, for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides.

The ointments can be prepared from conventional base materials by the procedure well known in the art.

The present invention is further illustrated in greater detail by the following Examples and Reference Examples, but they are not to be construed as limiting the present invention. Unless other wise indicated, all parts, percents, ratios and the like are by weight.

Example 1 22 g of 4-phenyl-1 (2H)-isoquinolone and 30 g of anhydrous potassium carbonate were added to 100 ml of dimethylformamide and the mixture was stirred for 2 hours at 1200 C. 1 8 g of 3-N,Ndimethylaminopropyl chloride was added to the solution and the mixture was stirred for 3 hours at 100 C. After completion of the reaction, the solvent was distilled off and water and subsequently dichloromethane were added to the residue, followed by thoroughly shaking. The dichloromethane layer was separated, washed with water and dried over anhydrous sodium sulfate.The solvent was distilled off and the residue was recrystallized from ligroin to obtain 23 g of 2-(3-N,N dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone having a melting point of 95 OC as colorless prisms.

Elementary Analysis: Calcd for C2oH22N2O=306.411: C, 78.40; H, 7.24; N, 9.14(%) Found: C, 78.36; H, 7.32; N, 8.97 (%) 80 ml of a solution of 1 6 g of 2-(3-N,N-dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone in ethyl acetate and 100 ml of a solution of 8 g of tartaric acid in ethyl acetate were combined and the resulting mixture was warmed with stirring for a while. After allowing the mixture to cool, the precipitated crystals were filtered and recrystallized from a mixture of ethanol ether and petroleum ether to obtain 1 8 g of 2-(3-N,N-dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone tartrate having a melting point of 11 40C as colorless needles.

Elementary Analysis: Calcd for C20H22N20 . C4H606=456.500: C, 63.15; H, 6.18; N, 6.14(%) Found: C, 63.29; H, 6.23; N, 6.06 (%) Example 2 A mixture of 22.1 g of 4-phenyl-1 (2H)-isoquinolone, 20 g of anhydrous potassium carbonate and 100 ml of dimethyl-formamide was stirred for 2 hours at 100 C. Then, 11 g of 3-chloropropanol was added to the resulting solution and the mixture was stirred at 11 00C for 5 hours. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in dichloromethane. Water was added to the resulting solution and, after thoroughly stirring, the dichloromethane layer was separated and dried over anhydrous sodium sulfate.The solvent was distilled off, and the resulting residue was recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 23 g of 2-(3hydroxypropyl)-4-phenyl-1 (2H)-isoquinolone having a melting point of 840 C as colorless prisms.

Elementary Analysis: Calcd for C,8H,7NO2=279.342: C, 77.40; H, 6.13; N; N; 5.01 (%) Found: C, 77.47; H, 6.09; N,5.11 (%) Then, 23 g of 2-(3-hydroxypropyl)-4-phenyl-1 (2H)-isoquinolone was added to a mixture of 60 ml of benzene and 25 ml of thionyl chloride and the mixture was heated at reflux for 1 hour. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water and dried, and then the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 23.3 g of 2-(3-chloropropyl)-4-phenyl-1 (2 H)isoquinolone having a melting point of 1 380C as colorless prisms.

Elementary Analysis: Calcd for C,8H,6CINO=297.787: C, 72.60; H, 5.42; N, 4.70 (%) Found: C, 72.64; H, 5.40; N, 4.77 (%) Then, 14.9 g of 2-(3-chloropropyl)-4-phenyl-1 (2H)-isoquinolone, 7 g of anhydrous potassium carbonate and 40 ml of piperidine were mixed and heated at reflux for 5 hours. Thereafter, any excess of piperidine was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of diethyl ether and petroleum ether to obtain 1 5.6 g of 2-(3-piperidinopropyl)-4phenyl-1 (2H)-isoquinolone having a melting point of 11 7.50C as colorless prisms.

Elementary Analysis: Calcd for C23H26N20=346.476: C, 79.73; H, 7.56; N, 8.09 Found: C, 79.85; H, 7.55; N, 8.00 Then, 10.4 g of 2-(3-piperidinopropyl)-4-phenyl-1 (2H)-isoquinolone was dissolved in 80 ml of ethyl acetate and 4 g of maleic acid was added to the solution, followed by stirring while warming.

After cooling, the precipitated crystals were filtered and recrystallized from a mixture of diethyl ether and petroleum ether to obtain 12.2 g of 2-(3-piperidinopropyl)-4-phenyl-1 (2H)-isoquinolone maleate having a melting point of 1 60.50C as colorless prisms.

Elementary Analysis: Calcd for C23H26N20 . C4H404=462.551: C, 70.11; H, 6.54; N, 6.06 (%) Found: C, 70.05; H, 6.58; N, 6.02 (%) The corresponding hydrobromic acid salt was obtained by the following procedure: 10.4 g of 2-(3-piperidinopropyl)-4-phenyl-1 (2H)-isoquinolone was dissolved in 50 ml of acetone and 10 ml of a 47% aqueous solution of hydrobromic acid was added thereto and the mixture was warmed. After cooling, the precipitated crystals were filtered and recrystallized from a mixture of methanol and petroleum ether to obtain 11.6 g of 2-(3-piperidinopropyl)-4-phenyl-f (2H)-isoquinolone hydrobromide having a melting point of 3000C as colorless needles.

Elementary Analysis: Calcd for C23H26N20 . HBr=427.393: C, 64.64; H, 6.37; N, 6.55 (%) Found: C, 64.75; H, 6.37; N, 6.46 (%) Example 3 22 g of 7-chloroXethoxywarbonyl-1 (2H)-isoquinolone and 0.5 g of sodium hydride were added to 100 ml of toluene, and the mixture was heated at reflux. Thereafter, 20 g of N,N-dimethylaminopropyl chloride was added to the reaction mixture, followed by stirring for 2 hours at 100 C. The reaction mixture was then worked up in the same manner as described in Example 1 and the resulting crystals were recrystallized from petroleum ether to obtain 22.3 g of 7-chloro-2-(3-N,N-dimethylaminopropyl) 4-ethoxywarbonyl-1 (2H)-isoquinolone having a melting point of 600C as colorless needles.

Elementary Analysis: Calcd for Cl7H21CIN203=336.822: C, 60.62; H, 6.28; N, 8.32 (%) Found: C, 60.55; H, 6.32; N, 8.21 (%) Then, 7-chloro-2-(3-N,N-dimethylaminopropyl)-4-ethoxycarbonyl- 1 (2H)-isoquinolone was reacted with maleic acid in the same manner as described in Example 2 and the resulting crystals were recrystallized from a mixture of ethanol and petroleum ether to obtain 7-chloro-2-(3-N,Ndimethylaminopropyl)-4-ethoxycarbonyl-1 (2H)-isoquinolone maleate. 1/2 hydrate having a melting point of 146.50C as colorless needles.

Elementary Analysis: Calcd for C17H21ClN203 . C4H404. 1/2H20=461 .904: C, 54.61; H, 5.67; N, 6.06 (%) Found: C, 54.78; H, 5.53; N, 5.95 (%) Example 4 25 g of 7-chloro-4-ethoxywarbonyl-1 (2H)-isoquinolone was dissolved in 100 ml of dimethylformamide while warming, and 27 g of anhydrous potassium carbonate was added to the solution, followed by stirring for 2 hours at 11 00C. Then, 14 g of 3-chloropropanol was added thereto and the stirring was continued for 5 hours at 1 1 OOC. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethanol and petroleum ether to obtain 20.1 g of 7-chloro-4-ethoxycarbonyl-2-(3-hydroxypropyl)-1 -(2H)-isoquinolone having a melting point of 1 930C as colorless prisms.

Elementary Analysis: Calcd for C1sH1E;CINO4=309.752: C, 58.16; H, 5.21; N, 4.52 (%) Found: C, 58.29; H, 5.26; N, 4.53 Then, 20.1 g of 7-chloro-4-ethoxycarbonyl-2-(3-hydroxypropyl)-1 (2H)-isoquinolone was dissolved in 50 ml of ethanol, and 100 ml of an ethanolic solution of 5.5 g of potassium hydroxide was added to the resulting solution, followed by thoroughly stirring. The resulting solution was then poured into ice-water and the mixture was filtered. The filtrate was rendered neutral with dilute acetic acid and the precipitated crystals were filtered and washed with water.Recrystallization from a mixture of ethanol and petroleum ether gave 16.4 g of 4-carboxy-7-chloro-2-(3-hydroxypropyl)-1 (2H)isoquinolone having a melting point of 1 930C as colorless prisms.

Elementary Analysis: Calcd for C13H,2CINO4=281.698: C, 55.43; H, 4.29; N, 4.97 (%) Found: C, 55.40; H, 4.38; N, 4.86 (%) Then, 16.4 g of 4-carboxy-7-chloro-2-(3-hydroxypropyl)-1 (2H)-isoquinolone was suspended in 100 ml of benzene, and 25 g of thionyl chloride was added to the suspension. The resulting mixture was heated at reflux for 3 hours and the solvent was distilled off. The residue was dissolved in dichloromethane and the solution was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 15.6 g of 7-chloro-4-chlorocarbonyl-2-(3-chloropropyl)-1 (2H)-isoquinolone having a melting point of 1250C as colorless prisms.

Elementary Analysis: Calcd for C13H1oCI3NO2=318.589: C, 49.01; H, 3.16; N, 4.40 (%) Found: C, 49.20; H, 3.10; N, 4.26 (%) Then, a mixture of 3.2 g of 7-chloro4-chlorocarbonyl-2-(3-ch loropropyl)-l (2H)-isoquinolone, 100 ml of a 20% solution of dimethylamine in acetone and 2.5 g of anhydrous potassium carbonate was heated at 900C in an autoclave for 6 hours. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off.The resulting crystals were recrystallized from a mixture of ethanol and petroleum ether to obtain 2.5 g of 7-chloro-2-(3-N,N-dimethylaminopropyl)-4-N,N-dimethylcarbamoyl-1 (2H)-isoquinolone having a melting point of 1 450C as colorless prisms.

Elementary Analysis: Calcd for C,2H22CIN302=335.837 C, 60.80; H, 6.60; N, 12.51 (%) Found: C, 60.92; H, 6.63; N,12.41 (%) Example 5 A mixture of 21.6 g of 4-ethoxywarbonyl-1 (2H)-isoquinolone, 25 g of anhydrous potassium carbonate and 100 ml of dimethylformamide was heated at 1 000C for 2 hours. Then, 14 ml of 3chloropropanol was added thereto and the mixture was heated at 11 00C for 4 hours. The solvent was distilled off and the residue was extracted with dichloromethane. The extract was washed with water, dried and the solvent was distilled off. 120 ml of an ethanolic solution of 5.5 g of potassium hydroxide was added to the residue, and the mixture was warmed.After cooling, the reaction mixture was poured into ice-water and then filtered. The filtrate was rendered neutral with dilute acetic acid, and the precipitated crystals were filtered and recrystallized from a mixture of ethanol and petroleum ether to obtain 12.5 g of 4-carboxy-2-(3-hydroxypropyl)-1(2H)-isoquinolone having a melting point of 2050C as colorless prisms.

Elementary Analysis: Calcd for C13H13NO4=247.253: C, 63.15; H, 530; N, 5.66 (%) Found: C, 63.23; H, 5.36; N, 5.54 (%) Then, 12.5 g of 4-carboxy-2-(3-hydroxypropyl)-1 (2H)-isoquinolone was added to a mixture of 50 ml of carbon tetrachloride and 25 ml of thionyl chloride, and the resulting mixture was heated at reflux for 2 hours. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 12.8 g of 4-chiorocarbonyl- 2-(3-chloropropyl)-1 (2H)-isoquinolone having a melting point of 101 OC as colorless prisms.

Elementary Analysis: Calcd for C13H11Cl2N02=284.1 44: C, 54.95; H, 3.90; N, 4.93 (%) Found: C, 54.83; H, 3.92; N, 4.86 (%) Then, 12.8 g of 4-chlorocarbonyl-2-(3-chloropropyl)-1-(2H)-isoquinolone was dissolved in 1 50 ml of chloroform, and a mixture of 6.6 g of n-butylamine and 20 ml of triethylamine was added thereto while stirring. After 5 hours, the reaction mixture was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 10 g of 4-N-n-butylcarbamoyl-2-(3-chloropropyl)-1 (2H)-isoquinolone having a melting point of 1 490C as colorless prisms.

Elementary Analysis: Calcd for C17H21CtN202=320.822: C, 63.65; H, 6.60; N, 8.73 (%) Found: C, 63.79; H, 6.53; N, 8.70 (%) Then, 10 g of 4-N-n-butylcarbamoyl-2-(3-chloropropyl)-1 (2H)-isoquinolone, 9.5 g of anhydrous potassium carbonate and 200 ml of a 20% solution of dimethylamine in acetone were placed in an autoclave, and the mixture was heated at 900C for 5 hours. Thereafter, the reaction mixture was filtered and the solvent was distilled off from the filtrate. The resulting oily substance was reacted with oxalic acid in the same manner as described in Example 1 for the preparation of tartaric acid salt.The resulting crystals were recrystallized from a mixture of methanol and diethyl ether to obtain 7.5 g of 4 N-n-butylcarbamoyl-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone oxalate having a melting point of 211 OC (with decomposition) as colorless prisms.

Elementary Analysis: Calcd for C1gH27N3 02. C2H204=419.482 C, 60.13; H, 6.97; N, 10.02 (%) Found: C, 60.29; H, 6.90; N, 10.08 (%) The following compounds were prepared in the same manner as described in the foregoing Examples 1 to 5.

Example 6 2-(2-N,N-Dimethylaminoethyl)-4-phenyl-1 (2H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 890C.

Elementary Analysis: Calcd for C19H2oN20=292.384: C, 78.05; H, 6.89; N, 9.58 (%) Found: C, 78.09; H, 6.79; N, 9.63 (%) 2-(2-N,N-Dimethylaminoethyl)-4-phenyl-1 (2H)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and petroleum ether. Colorless needles having a melting point of 258.50C.

Elementary Analysis: Calcd for C19H20N20 . HCl=328.845: C, 69.40; H, 6.44; N, 8.52 (%) Found; C, 69.49; H, 6.46; N, 8.53 (%) Example 7 2-(3-N,N-Diethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone. Recrystallized from petroleum ether.

Colorless leaflets having a melting point of 41 OC.

Elementary Analysis: Calcd for C22H26N20=334.465: C, 79.01; H, 7.84; N, 8.38 (%) Found: C, 78.95; H, 7.91; N, 8.25 (%) 2-(3-N,N-Diethylaminopropyl)-4-phenyl- 1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 1400 C.

Elementary Analysis: Calcd for C22H26N20 . C4H404=450.539: C, 69.31; H, 6.71; N, 6.22 (%) Found: C, 69.42; H, 6.73; N, 6.09 (%) 2-(3-N,N-Diethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone hydrobromide. Recrystallized from a mixture of methanol and petroleum ether. Colorless prisms having a melting point of 1 46.50C.

Elementary Analysis: Calcd for C22H26N20. HBr=41 5.382: C, 63.62; H, 6.55; N, 6.74 (%) Found: C, 63.75; H, 6.46; N, 6.69 (%) Example 8 4-Phenyl-2-(3-pyrrolidinopropyl)-1 (2H)-isoquinolone. Recrystallized from diethyl ether and petroleum ether. Colorless prisms having a melting point of 11 50C.

Elementary Analysis: Calcd for C22H24N20=332.449: C, 79.48; H, 7.28; N, 8.43 (%) Found: C, 79.59; H, 7.33; N, 8.40 (%) 4-Phenyl-2-(3-pyrrolidinopropyl)-1 (2H)-isoquinolone hydrobromide. Recrystallized from a mixture of methanol and petroleum ether. Colorless needles having a melting point of 2770C.

Elementary Analysis: Calcd for C22H24N20 . HBr=413.366: C, 63.93; H, 6.10; N, 6.78 (%) Found: C, 63.85; H, 6.16; N, 6.70 (%) Example 9 2-(3-Morpholinopropyl)-4-phenyl-1 (2H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 101 OC.

Elementary Analysis: Calcd for C22H24N202=348.449: C, 75.83; H, 6.94; N, 8.04 (%) Found: C, 75.95; H, 6.99; N, 7.95 (%) 2-(3-Morpholinopropyl)-4-phenyl-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless leaflets having a melting point of 1 920C.

Elementary Analysis: Calcd for C22H24N202. C4H404=464.523: C, 67.23; H, 6.08; N, 6.03 (%) Found: C, 67.41; H, 6.15; N, 5.90 (%) 2-(3-Morpholinopropyl)-4-phenyl-1 (2H)-isoquinolone hydrobromide. Recrystallized from a mixture of methanol and petroleum ether. Colorless needles having a melting point higher than 2900C.

Elementary Analysis: Calcd for C22H24N202. HBr=429.366: C, 61.54; H, 5.87; N, 6.52 (%) Found: C, 61.63; H, 5.89; N, 6.44 (%) Example 10 2-f 3-(4-Methylpiperazin-1 -yl)propyl )-4-phenyl- (2 H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 11 60C.

Elementary Analysis: Calcd for C23H27N30=361.491 .491: C, 76.42; H, 7.53; N, 11.62(%) Found: C, 76.49; H, 7.50; N, 11.63 (%) Example 11 2-[3-14-(2-Hydroxyethyl)piperazin-1 -yl lpropyl]-4-phenyl-1 (2H)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having a melting point of 1 31 OC.

Elementary Analysis: Calcd for C24H29N302=391 .518: C, 73.63; H, 7.47; N, 10.73 (%) Found: C, 73.56; H, 7.49; N, 10.72 (%) 2-[3-(4-(2-Hydroxyethyl)piperazin-1 -yljpropyl]-4-phenyl-1 (2H)-isoquinolone dimaleate.

Recrystallized from ethanol. Colorless prisms having a melting point of 1 920C.

Elementary Analysis: Calcd for C24H29N302. (C4H404)2=623.666: C, 61.63; H, 5.98; N, 6.74 (%) Found: C, 61.83; H, 6.02; N, 6.63 (%) Example 12 2-(3-N-lsopropylaminopropyi)-4-phenyl-1 (2H)-isoquinolone hydrobromide. Recrystallized from a mixture of ethanol and petroleum ether. Colorless needles having a melting point of 1 390C.

Elementary Analysis: Calcd for C2,H24N20 . HBr=401.355: C, 62.85; H, 6.28; N, 6.98 (%) Found: C, 62.89; H, 6.35; N, 6.96 (%) Example 13 2-(2-N,N-Dimethylaminopropyl)-4-phenyl-7 (2H)-isoquinolone. Recrystallized from a mixture of ethanol and n-hexane. Colorless flakes having a melting point of 1 070C.

Elementary Analysis: Calcd for C2oH22N20=306.411 1 : C, 78.40; H, 7.24; N, 9.14 (%) Found: C, 78.51; H, 7.30; N, 9.00 (%) 2-{2-N,N-Dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 1 390C.

Elementary Analysis: Calcd for C20H22N20 . C4H404=422.485: C, 68.23; H, 6.20; N, 6.63 (%) Found: C, 68.35: H, 6.26; N, 6.69 (%) Example 14 2-(3-N,N-Dimethylamino-2-methylprnpyl)-4-phenyt-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of methanol and diethyl ether. Colorless prisms having a melting point of 1 740 C.

Elementary Analysis: Calcd for C2,H24N20 . C4H404=436.5 12 C, 68.79; H, 6.47; N, 6.42 (%) Found: C, 68.74; H, 6.56; N, 6.29 (%) Example 15 2-(3-N,N-Dimethylaminopropyl)-7-methoxy-4-(p-methoxyphenyl)- 1(2 H)-isoquinolone.

Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless needles having a melting point of 740C.

Elementary Analysis: Calcd for C22H26N2O3=366.464: C, 72.11; H, 7.15; N, 7.64 (%) Found: C, 72.25; H, 7.15; N, 7.54 (%) 2-(3-N,N-Dimethylaminopropyl)-7-methoxy-4-(p-methoxyphenyl)- 1 (2H)-isoquinolone maleate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 1460C.

Elementary Analysis: Calcd for C22H26N203. C4H404=482.538: C, 64.72; H, 6.27; N, 5.81 (%) Found: C, 64.86; H, 6.15; N, 5.90 (%) Example 16 4-Cyano-2-(2-N,N-diethylaminoethyl)-1 (2H)-isoquinolone. Recrystallized from ligroin. Colorless prisms having a melting point of 900 C.

Elementary Analysis: Calcd for C16H,9N30=269.349: C,71.35;H,7.11;N, 15.60(%) Found: C, 71.29; H, 7.16; N, 15.52 (%) 4-Cyano-2-(2-N,N-diethylaminoethyl)-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 1 450C.

Elementary Analysis: Calcd for C16H1gN30 . C4H404=385.423: C, 62.33; H, 6.02; N, 10.90 (%) Found: C, 62.20; H, 5.89; N, 10.85 (%) Example 17 4-Cyano-2-(3-N,N-dimethyla minopropyl- 1 (2H)-isoquinolone monohydrate. Recrystallized from petroleum ether. Colorless needles having a melting point of 600C.

Elementary Analysis: Calcd for C,5H,7N30 . H20=273.338: C, 65.91; H, 7.01; N, 15.37 (%) Found: C, 65.84; H, 6.85; N, 15.35 (%) 4-Cyano-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone tartrate hemihydrate.

Recrystallized from a mixture of methanol and petroleum ether. Colorless prisms having a melting point of 1780C.

Elementary Analysis: Calcd for C,5H"N30 . C4H606. 1/2 H2O=41 4.416: C, 55.07; H, 5.83; N, 10.14 (%) Found: C, 55.16; H, 5.66; N, 9.97 (%) Example 18 4-Cyano-2-(3-N,N-dimethylaminopropyl)-7-methoxy- 1(2 H)-isoqu inolone. Recrystallized from ligroin. Colorless prisms having a melting point of 11 60C.

Elementary Analysis: Calcd for C16H,9N302=285.349: C, 67.35; H, 6.71; N, 14.73 (%) Found: C, 67.43; H, 6.75; N, 14.60 (%) 4-Cyano-2-(3-N,N-dimethylaminopropyl)-7-methoxy-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 1 740 C.

Elementary Analysis: Calcd for C16H19N302. C4H404=401.423: C, 59.84; H, 5.78; N, 10.47 (%) Found: C, 59.73; H, 5.76; N, 10.55 (%) Example 19 2-(3-N,N-dimethylaminopropyl)-4-ethoxycarbonyl- 1 t2H)-isoquinolone tartrate hemihydrate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 1 840C (with decomposition).

Elementary Analysis: Calcd for C17H22N2O3. C4He06. 1/2 H20: C, 54.42; H, 6.31; N, 6.04 (%) Found: C, 54.60; H, 6.25; N, 6.23 (%) Example 20 2-(3-N,N-Dimethylaminopropyl)-4-ethoxycarbonyl-7-methoxy-1 (2H)-isoquinolone. Recrystallized from petroleum ether. Colorless needles having a melting point of 500 C.

Elementary Analysis: Calcd for C,8H24N204=332.403: C, 65.04; H, 7.28; N, 8.43 (%) Found: C, 65.10; H, 7.22; N, 8.43 (%) 2-(3-N,N-dimethylaminopropyl)-4-ethoxycarbonyl-7-methoxy- 1(2 H)-isoquinolone maleate hemihydrate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless leaflets having a melting point of 121 C.

Elementary Analysis: Calcd for C,8H24N204 . C4H404. 1/2 H20: C, 57.76; H, 6.39; N, 6.12 (%) Found: C, 57.73; H, 6.21; N, 6.19 (%) Example 21 7-Chloro4-(p-chlorophenyl)-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone. Recrystallized from ligroin. Colorless prisms having a melting point of 1 000C.

Elementary Analysis: Calcd for C2oH2ocl2N2o=37 5.3 1: C, 64.01; H, 5.37; N, 7.46 (%) Found: C, 64.20; H, 5.31; N, 7.47 (%) 7-Chloro-4-(p-chlorophenyl)-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone tartrate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless crystalline powder having a melting point of 1 920C.

Elementary Analysis: Calcd for C20H20CI2N20 . C4H6O6=525.390: C, 54.87; H, 4.99; N, 5.33 (%) Found: C, 54.97; H, 4.96; N, 5.46 (%) Example 22 7-Chloro-2-(3-N,N-dimethylaminopropyl)-4-N,N-dimethylcarbamoyl-1 (2H)-isoquinolone oxalate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 2230C.

Elementary Analysis: Calcd for C,7H22ClN302 . C2H204=425.873: C, 53.59; H, 5.68; N, 9.87 (%) Found: C, 53.46; H, 5.62; N, 9.88 (%) Example 23 7-Chloro-4-(4-methylpiperazin-1 -yl-carbonyl)-2-{3-(4-methylpiperazin-1 -yl)-propylJ-1(2H)- isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 1 280C.

Elementary Analysis: Calcd for C23H32ClN502=445.997: C, 61.94; H, 7.23; N, 15.70 (%) Found: C, 62.06; H, 7.36; N, 15.61 (%) 7-Chloro-4-(4-methylpiperazin- 1 -yl-carbonyl)-2-{3-(4-methylpiperazin- 1 -yl)propyl 1-1 (2 H)- isoquinolone tri-maleate. Recrystallized from a mixture of methanol and diethyl ether. Colorless crystalline powder having a melting point of 1 460C.

Elementary Analysis: Calcd for C23H32CINs02 . 3C4H404=794.219: C, 52.93; H, 5.58; N, 8.82 (%) Found: C, 52.86; H, 5.66; N, 8.70 (%) Example 24 7-Chloro-4-morpholinocarbonyl-2-(3-morpholinopropyl)-1 (2H)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having a melting point of 1 780C.

Elementary Analysis: Calcd for C2,H26CIN304=419.912: C, 60.07; H, 6.24; N, 10.01 (%) Found: C, 60.16; H, 6.22; N, 9.83 (%) 7-Chloro-4-morpholinocarbonyl-2-(3-morpholinopropyl)-1 (2H)-isoquinolone maleate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 1780C.

Elementary Analysis: Calcd for C21H26ClN304. C4H404=535.986: C, 56.02; H, 5.64; N, 7.84 (%) Found: C, 56.16; H, 5.70; N, 7.88 (%) Example 25 4-Carbamoyl-2-(3-N,N-dimethylaminopropyl (2H)-isoquinoline monohydrate. Recrystallized from a mixture of ethanol and petroleum ether. Colorless crystalline powder having a melting point of 1 590C (with decomposition).

Elementary Analysis: Calcd for C,5H19N302 . H20=291 .353: C, 61.84; H, 7.27; N, 14.42 (%) Found: C, 61.79; H, 7.30; N, 14.55 (%) 4-Carbamoyl-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone oxalate. Recrystallized from a mixture of ethanol and petroleum ether. Colorless crystalline powder having a melting point of 1 560C.

Elementary Analysis: Calcd for C, > H19N302 . C2H204=363.373: C,56.19;H,5.83;N, 11.56(%) Found: C, 56.32; H, 5.72; N, 11.46 (%) Example 26 2-(3-N,N-Diethyla minopropyl)-4-N,N-diethylcarbamoyl- 1 (2H)-isoquinolone oxalate.

Recrystallized from a mixture of methanol and diethyl ether. Colorless prisms having a melting point of 1680C.

Elementary Analysis: Calcd for C2,H31N302 C2H2(54=447.536: C, 61.73; H, 7.43; N, 9.39 (%) Found: C, 61.65; H, 7.49; N, 9.30 (%) Example 27 4-n-Butoxycarbonyl-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 1 420C.

Elementary Analysis: Calcd for C1gH28N203. C4H404=446.505: C, 61.87; H, 6.77; N, 6.27 (%) Found: C, 61.99; H, 6.76; N, 6.24 (%) Example 28 2-(2-N,N-Diethylaminoethyl)-4-phenyl-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 1 97.50C.

Elementary Analysis: Calcd for C21H24N20 . C4H404=436.512: C, 68.79; H, 6.47; N, 6.42 (%) Found: C, 68.93; H, 6.55; N, 6.39 (%) Example 29 4-P henyl-2-(2-pyrrolidinoethyl)-1 (2H)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having melting point of 131 .50C.

Elementary Analysis: Calcd for C21K22N20=31 8.422: C, 79.21; H, 6.96; N, 8.80 (%) Found: C, 79.16: H, 7.04; N, 8.69 (%) 4-Phenyl-2-(2-pyrrolidinoethyl)-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 1 76.50C.

Elementary Analysis: Calcd for C2tH22N20 . C4H4O4=434.496: C, 69.11; H, 6.03; N, 6.45 (%) Found: C, 69.29; H, 5.91; N, 6.55 (%) Example 30 2-(2-N,N-Diethylaminopropyl)-4-phenyl- 1 (2H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 920C.

Elementary Analysis: Calcd for C22H26N20=334.465: C, 79.01; H, 7.84; N, 8.38 (96) Found: C, 79.00; H, 7.69; N, 8.45 (%) 2-(2-N,N-Diethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone hydrochloride. Recrystallized from a mixture of methanol and diethyl ether. Colorless needles having a melting point of 203 C.

Elementary Analysis: Calcd for C22H25N20 . HCl=370.926: C, 71.24; H, 7.34; N, 7.55 (96) Found: C, 71.32; H, 7.31; N, 7.38 (%) 2-(2-N,N-Diethylaminopropyl)-4-phenyl- 1 (2H)-isoquinolone maleate. Recrystallized from a mixture of methanol and diethyl ether. Colorless prisms having a melting point of 1420C.

Elementary Analysis: Calcd for C22H28N20 . C4H404=450.539: C, 69.31; H, 6.71; N, 6.22 (96) Found: C, 69.51; H, 6.78; N, 6.25 (56) Example 31 2-{2-(4-methylpiperazin-1-yl)-ethyl}4-phenyl-1 (ZH)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having a melting point of 1 03.50C.

Elementary Analysis: Calcd for C22H25N30=347.464: C, 76.05; H, 7.25; N, 12.09 (%) Found: C, 75.92; H, 7.31; N, 11.95 (%) 2-{2-(4-methylpiperazin-1-yl)ethyl}-4-phenyl-1 (2H)-isoquinolone dimaleate. Recrystallized from a mixture of dimethylformamide and methanol. White crystalline powder having a melting point of 2070C (with decomposition).

Elementary Analysis: Calcd for C22H2sN3O . 2C4H404=579.61 2: C, 62.17; H, 5.74; N, 7.25 (%) Found: C, 62.30; H, 5.65; N, 7.10 (%) Example 32 4-Phenyl-2-(2-pyrrolidinopropyl)- 1 (2H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 840 C.

Elementary Analysis: Calcd for C22H24N20=332.449: C, 79.48; H, 7.28; N, 8.43 (%) Found: C, 79.44; H, 7.25; N, 8.41 (%) 4-Phenyl-2-(2-pyrrolidinopropyl)-l (2H)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 2370C (with decomposition).

Elementary Analysis: Calcd for C22H24N20. HCI=368.9 10: C, 71.63; H, 6.83; N, 7.59 (%) Found: C, 71.56; H, 6.90; N, 7.66 (%) Example 33 4-Phenyl-2-(2-piperizinopropyl)-1 (2H)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and diethyl ether. White crystalline powder having a melting point of 2500C (with decomposition).

Elementary Analysis: Calcd for C23H26N20 . HCl=382.937: C, 72.14; H, 7.11; N, 7.32 (O/o) Found: C, 72.26; H, 7.13; N, 7.20 (%) Example 34 2-{2-(4-Methylpiperazin-1 -yl)propyl}-4-phenyl-1 (2H)-isoquinolone dimaleate. Recrystallized from a mixture of dimethylformamide and ethanol. White crystalline powder having a melting point of 1 89.50C.

Elementary Analysis: Calcd for C23H27N30 . 2C4H404=593.639: C, 62.72; H, 5.94; N, 7.08 (%) Found: C, 62.93; H, 5.81, 7.15 (%) Example 35 7-Chloro-4-(p-chlorophenyl)-2-(2-N,N-diethylaminoethyl)-1 (2H)-isoquinolone. Recrystallized from petroleum ether. Colorless prisms having a melting point of 900 C.

Elementary Analysis: Calcd for C21H22Cl2N20=389.328: C, 64.79; H, 5.70; N, 7.20 (%) Found: C, 64.71; H, 5.73; N, 7.14 (%) 7-Chloro-4-(p-chlorophenyl)-2-(2-N,N-diethylaminoethyl)-1 (2H)-isoquinolone maleate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 1340C.

Elementary Analysis: Calcd for C2,H22CI2N2CI . C4H404=505.402: C, 59.41; H, 5.19; N, 5.54 (%) Found: C, 59.27; H, 5.25; N, 5.63 (%) Example 36 7-Chloro-4-(p-chlorophenyl)-2(2-N,N-diethylaminopropyl)-1 (2H)-isoquinolone. Recrystallized from petroleum ether. Colorless prisms having a melting point of 1070C.

Elementary Analysis: Calcd for C22H24CI2N20=403.355: C, 65.51; H, 6.00; N, 6.95 (%) Found: C, 65.68; H, 6.11; N, 6.87 (%) 7-Chloro-4-lp-chlorophenyl)-2-(2-N,N-diethylaminopropyl)-1 (2H)-isoquinolone hydrochloride.

Recrystallized from aqueous ethanol. Colorless prisms having a melting point of 1 950C.

Elementary Analysis: Calcd for C22H24Cl2N20. HCI=439.816: C, 60.08; H, 5.73; N, 6.37 (%) Found: C, 60.18; H, 5.62; N, 6.49 (%) 7-Choro-4-(p-chlorophenyl)-2-(2-N,N-diethylaminopropyl)- 1 (2H)-isoquinolone maleate.

Recrystallized from a mixture of ethanol and diethyl ether. White crystalline powder having a melting point of 1 120C.

Elementary Analysis: Calcd for C22H24CI2N20 . C4H404= 51 9.429: C, 60.12; H, 5.43; N, 5.39 (%) Found: C, 60.06; H, 5.55; N, 5.26 (%) Example 37 2-(2-N,N-Diethylaminoethyl)-7-methoxy-4-(p-methoxyphenyl)-1 (2H)-isoquinolone ma leate.

Recrystallized from a mixture of methanol and diethyl ether. Colorless prisms having a melting point of 161 C.

Elementary Analysis: Calcd for C23H28N203 . C4H404=496.565: C, 65.31; H, 6.50; N, 5.64 (%) Found: C, 65.48; H, 6.48; N, 5.53 (%) Example 38 2-(2-N,N-Diethylaminoethyl)-4-ethoxycarbonyl-7-methoxy-1 (2 H)-isoquinolone. Recrystallized from petroleum ether. Colorless prisms having a melting point of 470C.

Elementary Analysis: Calcd for C1gH26N204=346.430: C, 65.88; H, 7.56; N, 8.09 (%) Found: C, 65.81; H, 7.62; N, 8.06 (%) 2-(2-N,N-Diethylaminoethyl)-4-ethoxycarbonyl-7-methoxy-1 (2 H)-isoquinolone maleate.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of.

1350C.

Elementary Analysis: Calcd for C19H26N204. C4H404=462.504: C, 59.73; H, 6.54; N, 6.06 (%) Found: C, 59.90; H, 6.50; N, 6.14 (%) Example 39 2-(2-N,N-Diethylaminopropyl)-7-methoxy-4-(p-methoxyphenyl)- 1 (2H)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 2440C.

Elementary Analysis: Calcd for C24H30N203. HCI=430.979: C, 66.89; H, 7.25; N, 6.50 (%) Found: C, 66.76; H, 7.28; N, 6.48 (%) Example 40 2-(2-N,N-Diethylaminopropyl)-4-ethoxycarbonyl-7-methoxy-1 (2 H)-isoquinolone. Recrystallized from petroleum ether. Colorless prisms having a melting point of 100 C.

Elementary Analysis: Calcd for C2oH26N204=360.457: C, 66.64; H, 7.83; N, 7.77 (%) Found: C, 66.78; H, 7.70: N, 7.65 (%) Example 41 2-(2-N,N-Diethylamino-1 -methylethyl)-4-phenyl-1 (2H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 950C.

Elementary Analysis: Calcd for C22H26N20=334.465: C, 79.01; H, 7.84; N, 8.38 (%) Found: C, 79.10; H, 7.90; N, 8.25 (%) 2-(2-N,N-Diethylamino-1 -methylethyl)-4-phenyl-1 (2H)-isoquinolone hydrochloride.

Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 1 980C (with decomposition).

Elementary Analysis: Calcd for C22H26N20. HCI=370.926: C, 71.24; H, 7.34; N, 7.55 (%) Found: C, 71.16; H, 7.45; N, 7.60 (%) Example 42 4-Cyano-2-(2-N,N-diethylaminopropyl)-1 (2H)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 930C.

Elementary Analysis: Calcd for C,7H2,N30=283.376: C, 72.06; H, 7.47; N, 14.83 (%) Found: C, 71.91; H, 7.55; N, 14.79 (%) 4-Cyano-2-(2-N,N-diethylaminopropyl)-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of methanol and diethyl ether. Colorless prisms having a melting point of 1480C.

Elementary Analysis: Calcd for C,7H2,N30 . C4H404=399.451: C, 63.15; H, 6.31; N, 10.52 (%) Found: C, 63.31; H, 6.22; N, 10.44 (%) Example 43 4-Cyano-2-(2-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having a melting point of 141 OC.

Elementary Analysis: Calcd for C,5H,7N30=255.322: C, 70.56; H, 6.71; N, 16.46 (%) Found: C, 70.44; H, 6.71; N, 16.59 (%) 4-Cyano-2-(2-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone maleate. Recrystallized from a mixture of methanol and diethyl ether. White crystalline powder having a melting point of 1 770C.

Elementary Analysis: Calcd for C,5H,7N30 . C4H404=371.396: C, 61.45; H, 5.70; N, 11.31 (%) Found: C, 61.61; H, 5.78; N, 11.33 (%) Example 44 2-(2-N,N-Diethylaminopropyl)-4-phenyl-7-methoxy-1 i2H)-isoquinolone maleate. Recrystallized from a mixture of ethyl acetate and diethyl ether. Colorless needles having a melting point of 980C.

Elementary Analysis: Calcd for C23H28N202. C4H404=480.560 C, 67.48; H, 6.71; N, 5.83 (%) Found: C, 67.31; H, 6.66; N, 5.88 (%) Example 45 4-(p-Methoxyphenyl)-2-(2-N,N-diethylaminoethyl)- 1(2 H)-isoquinolone hydrochloride hemihydrate. Recrystallized from a mixture of ethanol and diethyl ether. White needles having a melting point of 1 930C.

Elementary Analysis: Calcd for C22H26N202. HCI . 1/2 H20=395.933: C, 66.74; H, 7.13; N, 7.07 (%) Found: C, 66.74; H, 6.91; N, 7.18 (%) Example 46 4-(p-Chlorophenyl)-2-(2-N,N-diethylaminoethyl)-1 (2H)-isoquinolone hydrochloride hemihydrate.

Recrystallized from a mixture of methanol and diethyl ether. White crystalline powder having a melting point of 1 940C.

Elementary Analysis: Calcd for C2,H23CIN20 . HCl. 1/2 H2=400.343: C, 63.00; H, 6.29; N, 7.00 (%) Found: C, 62.97; H, 6.17; N, 7.30 (%) The pharmacological activities, acute toxicity and pharmaceutical preparations of typical examples of the compounds of this invention having the formula (I) are illustrated below, in comparison with typical known compounds.

Test Compounds Compound A: 2-(3-N,N-dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone tartrate (prepared in Example 1) Compound B: 2-(2-N,N-dimethylaminoethyl)-4-phenyl-1 (2H)-isoquinolone hydrochloride (prepared in Example 6) Compound C: 4-cyano-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone tartrate 1/2 hydrate (prepared in Example 17) Compound D: 2-(2-N,N-dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone maleate (prepared in Example 13) Analgesic Activity According to the acetic acid stretching method described by Koster et al [Fed. Pro., 18, 412 (1959)], Compound A was administered orally to ddy male mice (body weight 20 to 25 g) fasted overnight before test.One hour after administration of Compound A, a 0.6% aqueous acetic acid solution was administered intraperitoneally at a dose of 0.35 ml per mouse and the stretching of the mice was observed 10 minutes after the administration of the acetic acid solution for a period of 10 minutes, and the percent inhibition was calculated.

The results obtained are shown in Table 1 below. These results clearly indicate that Compound A inhibited the pain reaction induced by acetic acid injection, at the dose of 50 and 100 mg/kg of Compound A depending on the dose level.

Table 1 Analgesic Activity Dose Number of Number of Percent Compound (mg/kg) Animals Stretchings Inhibition ( /0) Control 8 36.5+6.5 Compound A 25 8 33.8+8.2 Compound A 50 8 16.9+4.8* 53.7 Compound A 100 8 1 0.0+2.8** 72.6 *p < 0.05 **P < O.O 1 Anti-Reserpine Activity (Anti-Depression Activity) Reserpine was administered subcutaneously to ddy male mice (body weight, 25 to 30 g) at a dose of 2 mg/kg and, after fasting for 18 hours, reserpine was again administered subcutaneously at a dose of 2 mg/kg.Five hours after the second administration of reserpine, the mice which indicated a constant decrease in body temperature were selected and administered orally with the test compound (Compound e), followed by measuring the rectal temperature of the mice at one hour intervals.

The results obtained are shown in Figure 1 (a) and Figure 1(b). These results indicate that Compound C increases at a dose of 50 and 100 mglkg significantly the rectal temperature which has been decreased by the pretreatment with reserpine. Results are also shown in Figure 1 (a), for Imipramine (10, 11 dihydro-N,N-dimethyl-5H4ibenz[b,f]azepine-5-propanamine) and Amitriptyline (3 (10,11 -dihydrn-5H-dibenzo[a,dj-cyclohepten-.5-ylidene)-N,N-dimethyl-1 -propanamine) which were used as typical examples of known compounds, for comparison.

Anti-histamine and Anticholinergic Activities The ileum of guinea pig (body weight, 300 to 400 g) was extracted and suspended in a Magnus tube containing Tyrode's solution (saturated with oxygen) at 31 OC and the inhibitory activity of the test compounds on the contraction indued by administration of histamine or acetylcholine was determined.

The treatment with the test compounds was conducted 30 seconds before inducing the contraction.

The results obtained are shown in Figure 2(a) and Figure 2(b) for Compound A, Figure 3(a) and Figure 3(b) for Compound B and Figure 4(a) and Figure 4(b) for Compound C. As is apparent from these figures, Compounds A, B and C shift the histarnine-induced contraction curve determined in guinea pig ileum to the right direction on the figures in parallel. This indicates that Compounds A, B and C possess a specific anti-histamine activity. Also, Compounds A and B were found to have a non-specific anticholinergic activity.

Gastric Secretion Inhibitory Activity The pylorus of Wister male rats (body weight, 180 to 200 g) fasted for 24 hours was ligated under ether anesthesia and, immediately thereafter, the test compound was administered into the duodenum. Four hours after the administration, the stomach was extracted and gastric juice was collected and centrifuged at 3,000 r.p.m. for 1 5 minutes. The volume of gastric juice, the pH value and the degree of acid secretion were then determined with respect to the supernatant.

The results obtained are shown in Table 2 below. As is apparent from the results, Compounds A and C reduce the volume of gastric juice and the acid secretion and increase the pH value.

Table 2 Gastric Secretion Inhibitory Activity Dose Number of Amount of Gastric Amount of Output Compound (mg/kg) Rats Juice (mll pH Value Secretion ( Eq.) Control 9 2.51+0.32 1.71+0.11 184+27.2 Compound A 100 10 0.53+0.12** 3.06+0.44* 22+ 5.9** Compound C 100 10 1.85+0.35 1.88+0.10 72+ 5.3** Atropine 5 10 0.90+0.09** 2.22+0.25 57+ 6.0** *p < O.05 **P < O.O 1 Anti-ulcer Activity i) Stress Ulcer The test compound was administered orally to Wister male rats (body weight, 200 to 230 g) and then the rates were tied up with a steel wire and dipped in water at 230C in a tank to the level of the xiphisternum of rats. After allowing the rats to stand for 7 hours in water, the rats were sacrificed and the stomach was extracted. 10 ml of a 1% formalin solution was injected into the stomach cavity and the stomach was dipped in a 1% formalin solution for 1 5 minutes to semiharden the stomach. The stomach was excised along the greater curvature thereof and the ulcer generated in the portion of corpus ventriculi was observed. The results obtained are shown in Table 3 below. As is apparent from the results, Compound A inhibits the ulcer generation caused by water-dipping restriction stress at the dose of 25, 50 and 100 mg, with dependency upon the dose.

Table3 Anti-ulcer Activity (Stress) Dose Number Ulcerous Percent Compound (mg/kg) ofRats Index (mum) Inhibition { /OJ Control 6 75.8 Compound A 25 6 58.0 23.5 Compound A 50 6 48.2 36.4 Compound A 100 6 25.3 66.0 Sulpiride* 100 6 71.0 Atropine 5 6 5.3 93.0 *Sulpiride=5-(a minosulfonyl)-N-I( (1 -ethyl-2-pyrrolidinyl)methyl)-2-methoxybenzamide ii) Indomethacin Ulcer A suspension of indomethacin in 0.25% CMC was administered subcutaneously at a dose of 20 mg/kg to Wister male rats (body weight, 125-150 g) fasted for 24 hours. The test Compound was administered orally 30 minutes before the administration of indomethacin. Seven hours after the administration of indomethacin, the rates were sacrificed by dislocation of neck and the stomach was extracted. 7.5 ml of 1% formalin solution was injected into the stomach cavity, and the stomach was hardened. The linear-type ulcer generated in the mucous membrane of the stomach was then observed.

The results obtained are shown in Table 4. As is apparent from the results, Compounds B and D inhibit the indomethacin-induced ulcer at a dose of 50 mg/kg.

Table 4 Anti-ulcer Activity (Indomethacin) Dose Number Ulcerous Percent Compound (mg/kg) ofRats Index (mum) Inhibition {%J Control 8 15.4 Compound B 50 8 6.0 61.0 Compound D 50 8 4.1 73.0 Sucralphate* 300 8 2.9 81.1 *Sucralphate=basic aluminum sucrose sulphate Acute Toxicity The test compound was administered to ddy male mice (body weight, 20 to 25 g) fasted overnight before administration. After administration, general conditions of mice were observed for 7 days and 50% lethal dose LD50 (mg/kg) was determined. The results obtained are shown in Table 5 below.

Table 5 Acute Toxicity Compound LD50(mg/kg) Compound A 662 Compound B 195 Compound C 699 Compound D 505 Preparation Examples 1. Granules Compound A 200 mg Lactose 500 mg Corn Starch 280 mg Hydroxypropylcellulose 20 mg 1,000 mg per pack The granule preparation was prepared in a conventional manner using the above formulation.

2. Tablets Compound B 100 mg Lactose 85 mg Crystalline Cellulose 50 mg Hydroxypropylcellulose 30 mg Talc 4 mg Magnesium Stearate 1 mg 270 mg per tablet The tablet preparation was prepared in a conventional manner using the above formulation.

3. Capsules Compound C 200 mg Lactose 100 mg Crystalline Cellulose 1 8 mg Magnesium Stearate 2 mg 400 mg per capsule The tablet preparation was prepared in a conventional manner using the above formulation.

As described before, some of the starting materials having the formula (II) are novel compounds.

The preparations of typical examples of the novel starting materials are described in the following Reference Examples.

Reference Example 1 20 g of ethyl p-chlorophenyl acetate, 10 g of sodium ethoxide and 15 g of ethyl formate were added in that order to 200 ml of diethyl ether and the mixture was stirred for 1 6 hours at room temperature. Thereafter, water in an equal amount to the reaction mixture was added to the reaction mixture and, after thoroughly shaking, the aqueous layer was separated. The aqueous layer was rendered neutral with 2N hydrochloric acid and the liberated oily substance was extracted with dichloromethane. The extract was washed with water and the solvent was distilled off to obtain 14.2 g of ethyl p-chlorophenyl-(a:-formyl)-acetate having a melting point of 500 C.

Then, 14.2 g of ethyl p-chlorophenyl-(a-formyl)-acetate and 6.5 g of urethane were added to 50 ml of toluene containing 0.3 ml of concentrated sulfuric acid, and the mixture was heated at reflux while distilling out water which was formed during the reaction until no further water was distilled out.

Thereafter, the solvent was distilled off, and the residue was extracted with diethyl ether while hot. The solvent was distilled off from the extract to obtain 13.7 g of ethyl p-chlorophenyl-( a- ethoxycarbonylaminomethylene)acetate having a melting point of 720C.

Then, 13.7 g of ethyl p-chlorophenyl-(cg-ethoxycarbonylaminomethylene)acetate was added to 50 ml of diphenyl ether and the mixture was heated at reflux for 3 hours. After cooling, benzene and petroleum ether were added to the reaction mixture, and the precipitated crystals were filtered and recrystallized from a mixture of dimethylformamide and ethanol to obtain 7 g of 7-chloro-4ethoxycarbonyl-1 (2H)-isoquinolone having a melting point of 2430C as colorless prisms.

Elementary Analysis: Calcd for C12H1QClN03=251 .671: C, 57.27; H, 4.01; N, 5.57 (%) Found: C, 57.36; H, 4.05; N, 5.53 (%) Reference Example 2 The procedure described in Reference Example 1 was repeated but using ethyl pmethoxyphenylacetate as a starting material instead of the ethylp-methoxyphenylacetate, and the resulting crystals were recrystallized from a mixture of dimethylformamide and ethanol to obtain 4 ethoxycarbonyl-7-methoxy-1 (2H)-isoquinolone having a melting point of 1 91 0C as colorless prisms.

Yield, 64%.

Elementary Analysis: Calcd for C,3H,3NO4=247.253: C, 63.15; H, 5.30; N, 5.66 (%) Found: C, 63.27; H, 5.28; N, 5.72 (%) Reference Example 3 The procedure described in Reference Example 1 was repeated but using p-methoxyacetonitrile as a starting material instead of the ethyl p-methoxyphenylacetate, and the resulting crystals were recrystallized from a mixture of dimethylformamide and ethanol to obtain 4-cyano-7-methoxy-1 (2H)isoquinolone having a melting point of 2640C. Yield, 58%.

Elementary Analysis: Calcd for C1,H8N202=200.199: C, 66.00; H, 4.03; N, 13.99 (%) Found: C, 66.16; H, 4.20; N, 13.88 (%) Reference Example 4 A mixture of 1 9 g of 4-carboxy-1 (2H)-isoquinolone, 10 ml of concentrated sulfuric acid and 1 liter of n-butanol was heated at reflux for 20 hours. The solvent was distilled off and petroleum ether was added to the residue, followed by allowing the mixture to stand. The solidified substance was separated by filtration and recrystallized from a mixture of n-butanol and petroleum ether to obtain 1 7 g of 4-n-butoxyearbonyl-1 (2H)-isoquinolone as colorless needles having a melting point of 1 700C.

Elementary Analysis: Calcd for C,4H,5NO3=245.281: C, 68.56; H, 6.16; N, 5.71 (%) Found: C, 68.62; H, 6.11; N, 5.58 (%)

Claims (19)

1. Claims 1. 1 (2H)-lsoquinolone compounds represented by the general formula (I)

   wherein Y represents hydrogen, chlorine or a methoxy group, Z represents a divalent saturated alkylene group having 2 to 4 carbon atoms optionally substituted with an alkyl group having 1 to 4 carbon atoms, R, represents a cyano group, an alkoxycarbonyl group having 1 to 4 carbon atoms, a carbamoyl group, an N-substituted carbamoyl group, a phenyl group or a substituted phenyl group, R2 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, R3 represents an alkyl group having 1 to 4 carbon atoms or R2 and R3 can form, when taken together with a nitrogen atom to which they are attached, a heterocyclic group.
2. 2. A compound as claimed in Claim 1, wherein R2 and R3 complete a pyrrolidono, piperidino, 4- methylpiperazino, 4-hydroxyethylpiperazino or morpholino group.
3. 3. A compound as claimed in Claim 1 or 2, wherein R, represents a halophenyl group or an alkoxyphenyi group having 1 to 4 carbon atoms in the alkoxy group.
4. 4. An acid addition salt of a compound as claimed in Claim 1,2 or 3.
5. 5. Any of the compounds according to Claim 1 or 4, named in Examples 1 to 44 hereinbefore.
6. 6.2-(3-N,N-Dimethylaminopropyl)-4-phenyl-1 (2H)-isoquinolone or an acid addition salt thereof.
7. 7. 2-(2-N,N-Dimethylaminoethyl)-4-phenyl-1 (2H)-isoquinolone or an acid addition salt thereof.
8. 8. 4-Cyano-2-(3-N,N-dimethylaminopropyl)-1 (2H)-isoquinolone or an acid addition salt thereof.
9. 9. 2-(2-N,N-Dimethylaminoethyl)-4-phenyl-1 (2H)-isoquinolone or an acid addition salt thereof.
10. 10. A method of preparing a compound as claimed in any preceding claim, which comprises reacting a substituted-l (2H)-isoquinolone compound of the general formula (II) shown and defined hereinbefore with a substituted aminoalkyl halide of the general formula (III) shown and defined hereinbefore.
11. 11. A method as claimed in Claim 10, wherein the reaction is carried out in an organic solvent with a basic catalyst with heating to 800 to 1400C for a period of 1 to 5 hours.
12. 12. A method of preparing a compound as claimed in any of Claims 1 to 9, which comprises reacting a hydroxyalkyl halide of the general formula (IV), X--ZZ-OH, with a compound of the general formula (it), both as shown and defined hereinbefore, reacting the product with a halogenating agent and reacting the halogenated product with an amine of the formula (VII), R2-HN-R3, wherein R2 and R3 are as defined in Claim 1 or 2.
13. 13. A method as claimed in Claim 12, wherein the first step is carried out in an organic solvent with a basic catalyst in an amount of at least 2 mols per mol of the compound of formula (II), at a temperature of 800 to 1 400C for a period of 1 to 5 hours.
14. 14. A method as claimed in Claim 12 or 13, wherein the halogenation step is carried out by heating for a period of 30 minutes to 2 hours.
15. 1 5. A method as claimed in Claim 1 2, 1 3 or 14, wherein the halogenating agent is thionylchloride, oxalyl chloride, phosphorus oxychloride or phosphorus oxybromide.
16. 1 6. A method of preparing a compound as claimed in any of Claims 1 to 9, substantially as hereinbefore described with reference to any of Examples 1 to 5.
17. 17. A pharmaceutical composition which comprises a pharmaceutically active amount of a compound as claimed in any of Claims 1 to 9 or made by a method as claimed in any of Claims 10 to 16.
18. 1 8. A composition as claimed in Claim 17, substantially as hereinbefore described in any of the Preparation Examples.
19. 19. A compound as claimed in any of Claims 1 to 9 or prepared by a method as claimed in any of Claims 10 to 16, or a composition as claimed in Claim 16, when used for analgesic, gastric secretion inhibition, anti-depressive, anti-histaminic, anti-chli.inergic or anti-ulcer therapy in man or other mammals.