CA1153763A - 1(2h)-isoquinolone compounds and acid addition salts thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel 1(2H)-isoquinolone compounds and the acid addition salts thereof are disclosed which exhibit excellent analgesic, anti-reserpine, anti-histaminic, anti-cholinergic, gastric secretion inhibiting and anti-ulcer activities in mammals and, therefore, are useful as pharmaceutical agents. The 1(2H)- iso-quinolone compounds according to the present invention are re-presented by the formula (I) (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, R1 rep-resents a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, an N-substituted carbamoyl group, a phenyl group or a sub-stituted 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 there-of.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to novel 1(2H)-isoquino-lone compounds and the acid addition salts thereof which exhibit useful analgesic, gastric secretion inhibitory, anti-depression, anti-histamine, anti-chlorinergic and anti-ulcer activities.

~.
X

- 2 -SU~ RY OF Tl-IE INVENTION
The present invention is thcrefore to provides novel 1(2H)-isoquinolone compounds having the formula (I) hereinafter described and the acid addition salts thereo~
which are useful as pharmaceutical agents.
BRIEF DESCRIPTION OF THE ~RAWINGS
Figures l(a) and l(b) are graphs showing effects of the known compounds and Compound C of ~l1is ~vention on the decrease in body temperature induced by administ-ration of reserpine.
Figures 2(a) and 2(b) are graphs showing the ! anti-histamine activity and the anti- chlorineryic activi-ty of Compound A of this invention.
Figures 3(a) and 3(b) are graphs showing the anti histamine activity and the anti-chlorinergic activity of Compound B of this invention.
Figures 4~a) and 4(b) are graphs showing the anti-histamine activity and the anti-chlorinergic activity of Gompound C of this invention.
DET~ILED DESCRIPTION OF TIIE INVENTION
- The 1(2~1)-isoquinolone compounds according to the present invention are represented by the formula (I) ~ ~3~;33 y ~ f N Z N -~R

wherein Y represents hydrogen, chlorine or a methoxy group, Z repres~nts a straight chain or branched chain divalent saturated aliphatic hydrocarbon group having 2 to 4 carbon atoms, Rl 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 tlle 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 alipha~ic 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, a methyltrimethylene group and the like.
The term "a lower alkoxycarbonyl group" as used herein means an alkoxycarbonyl group having 1 to 4 carbon 7~3 atoms in the alkoxy moiety such as a methoxycarbonyl group, an e-thoxycarbonyl group, propoxycarbon~l groups, butoxycarbonyl groups and the like.
The term "N-substituted carbamoyl group" as used herein means an N-alkylcarbamoyl group, an N,N-dialkyl-carbamoyl group wherein each alkyl group has 1 to 4 carbon atoms, a 4-methylpipera~inocarbonyl group, a morpholino-carbonyl 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 caTbon 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, sec-butyl and the like.
Examples of the heterocyclic group formed by R2 and R3 together with the nitrogen atom to which they are attached are a pyrrolidino group, a piperidino group, a 4-methylpiperazino group9 a 4-~ydroxyethylpiperazino group, a morpholino group, etc.
The term "acid 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~ hydrobrornide, methanesulfonate, maleate, tartarate, 7~

citrate, lactate and tl1e like.
fhe 1(2~ isoquinolone compounds of the formula (I) can be prepared by reacting a substituted-1~2~ isoquinolone having the formula ~II) Rl y )`\~ ,/~

wherein Y and ~l are as defined above, with a substituted-aminoalkyl halide of the formula ~III) ! .. X - Z N / (III) wherein X represents a halogen atom such as chlorine, bromine ancl the like and Z, R2 and R3 are as defined above~
in the presence o a basic catalyst.
More particularly, the above reaction between the compounds of the formulae (II) and (III) can be advantage-ously carried out by dissolving the substituted l~2~
iso~uinolone of the formula (II) in an organic solvent such as dimethylfoTmamide, dimethyl sulfoxi.de, toluene, ethanol, etc., adding thereto a basic catalyst, for example, alkali metal carbonates such as potassium carbonate, sodium carbonate and the like, sodium hydride, sodium amide, alkali metal alkoxides such as sodium methoxide, sodium 7~

ethoxide, potassiuln t-butoxide and the like, followed by, optionally, heating; then adding to tl1e resulting reaction mixture the substituted aminoalkyl halide of the -formula ~III) and heating thc mixture at a temperature of about 80 to about 140C for a period of about l to 5 hours.
In the above reaction~ the bas~c catalyst and the substituted aminoalkyl halide can be used in at least an equimolar amount to the substituted 1(21-1)-isoquinolone of the formula (II). Also, the substituted aminoalkyl halide ~III) can be used in the form of a salt with an inOTganiC acid such as hydrochloride and the like and, in such instance, the base is pre-Eera~ly used in an excess amount over the equimolar amount to the compound (II).
Most oE the substituted aminocllkyl halide of the formula (III) 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 l~2H)-isoquinolone of the formula ~II) via an a~lternative 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 hydroxy-alkyl halide of the formula (IV) X- Z- 0~1 ~IV) wherein X and Z are as clefined above, to produce the corres-~ ~5;~7~3 ponding 2-(hydroxyalkyl)-l(211)-isoquinolone compound of the formula (V) R
~h (v) y/~ ,N-- Z--011 O

l~herei.n Y, Z ancl Rl are as defined above, reacting the compound of the formula (V) with a halogenating agent ~o produce a 2-(haloalkyl)-1(211)-isoquinolone compound of B the formula (~I) , R

Y 1~N-- Z --X (VI) wherein Y, Z, Rl ahd X are as defined above, and reacting the compound of the formula (VI) with an amine of the formula (VII) ~IN ~ R2 ~ R3 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 abou~ l ~o about l.5 mol of the 7~3 hydroxyalkyl halide of the formùla (IV) per mol of the compound of the formula ~II) in an organic solvent such as dimethylformamide~ toluene and the like, in the presence o~ a base such as potassium charbonate, sodium carbonate, sodium hydride and the like in an amount of at least about Z mols per mol of the compound of the formula (II), at a temperature of about 80 to about 140C
for a period of about 1 to 5 hours.
The reaction of the thus obtained 2-(hydroxyalkyl)-- 10 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 examplcs of halogenating agents are thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus oxybromide ancl the like.
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~ carbon tetrachloride~ etc.
The subsequent reaction of the thus obtained 2-thaloalkyl)-1(2H)-isoquinolone oE the formula (VI) 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 exempli-fied before for the reaction of the compounds of the 7~

formulae (II) and ~III). T11e rcaction can be advantage-ously carried out using an organic solvent having a boiling point higher than that of the amine (VII) used? for example, xylene, tetralin~ ethylbenzene, etc. When the amine used has a relatively lo~ boiling point, the reaction is advanta-geously carried ou~ in a sealed reaction vessel.
The compounds of ~he formula (I) having a substituted carbamoyl group at the 4-position can also be prepared by heat-reacting thc ~-ester compound of the formula (I') Rl ~ / ~ N- Z- N
y / ~ R3 o wherein Rl is a lower alkoxycarbonyl group and Y, Z, R2 and R3 are as clcfined above, wi-th an aminc of the formula (VII) in an alcohol solvent.
I~lternatively, the 4-carbamoyl compounds of the lS formula (I') aboue can be obtained by hydrolyzing the 2-(hydroxyalkyl)-1(2~1)-isoquinolone compound of the formula (V) - R
q (V) Y b~

37~3 wherein Rl reprcsents a lo~er alkoxycarbonyl group, and Y and Z are as defined abovc, dissolved in an alkaline alcohol to obtaln the corresponding 4-carboxy compound of the formula (VIII) COO~I
,~\,q 1 11 (VIII) y / ~ ~ ~ N~ Z - 011 wherein Y and Z are as definecl above, reacting the thus obtained 4-carboxy compound wi-th a halogenating agent such as thionyl chloride, o~alyl chloride, phosphorus oxychloride, phosphorus oxybromide and the like in the presence.o:E an organic solvent such as benzene or carbon tetrachloride, or in the absence of tlle organic solvent, for a period of about 1 ~o 3 hours to obt~in the correspon-ding 4-acid halide compound of the formula ~IX) COX

y ~ N- Z - X ~IX) wherein X, Y and Z are as defined above, reacting the thus obtained 4-acicl halide compound ~IX) l~ith an amine of the formula (VII) in an amount of at least about 2 mols - lU -7~

per mol of the 4-acid halide compound ~IX) in an organic solvent such as benzene, chloroform, diethyl ether at room temperature ~about 15 - 30C) for à period of about 1 to 5 hours to obtain the corresponcling 4-carbamoyl compound of the formula ~X) CON \ 2 q~ ~ z - x (X) y O

. wherein X, Y, Z, R2 and R3 are as defined above, and reacti.ng 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 about 90 to about 150C for a period o:f about 1 to 6 hours to obtain the desired compound of the formula (I').
When the same amine is used in the ami(lation of the 4-acid halide compound (IX) and the amination of the 4-carbamoyl compound (X~, these reactions are not necessaryto conduct 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 as described above for the reaction between the compounds of the formula (VI) or (X) and the amine ~VII).

7~3 The object compounds of tlle 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 conventi.onal procedure ~ell known in the art, for example, by reacting the free base with an inorganic or organic acid in a solvent such as et1lanol, ethyl acetate, acetone and the like or an aqueous acid solution at room temperature or an elevated temperature.
The starting matcri.als of the :formula ~II) whercin Rl 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 ~ollowing reaction scheme:

1S ~ ~ 3 Y ~XI) Y ~XII) (XIII) ~II) where:i.n Y is Cl or -OC113, and Rl is -CN, -COOR ~R=C~-13, C2~15, C3117 or C4119).

7~3 ~ lore spcciEical~y, 1 mol of a p-substituted phenyl-acetic 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 diethy] ether, and the mixture is allowed to react for about 10 to 24 llours at room temperature to obtain the formyl compound of the formula (XII). Thc resulting formyl compound and an equimolar amount of urethane are hea~-refluxed in the presencc o:~ concentrated sulfuric acid in toluene to obtain the ethoxycarbonylamino compound of the formula ~XIII) which is then heated under reflux in diphenyl ether to obt~in the starting material of the fo~mula (II).
The starting materials of the ormula ~II) having a lower alkoxycarbonyl group of 1 to ~ 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 o-f 4-carboxy compounds or transesterification of methoxy- or cthoxycarbonyl compounds. rhese 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 b~6 3 useful as pharmaceutical ~gents.
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 ~ype of diseases or other factors, bu~ generally ranges from 0.5 to 50 mg/kg of body weight per day in adult human administcred as a single dose or multiple dose ~flivided into 2 to 3 doscs).
lhe compounds o-f this invcntion can be~ administered orally, parenterally or intrarectally in various dosnge 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.
Tllc tablets, ca~sulcs, granules, powdcrs, etc. -~or oral administration can be prepared from excipients generally used in the art, for example, calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc 3 magnesium stearate, geletin, polyvinylpyrrolidine, gum arabic, sorbitol, cystalline cellulose, polyethylene glycol, carboxymethyl-cellulose, silica and the like. Also, tablets and granules can be coated according -to the method well known in the art.
Tlle injections can be aqueous or oily suspensions, solutions, or powder filled in ampollles or rreeze-dried ~L5~763 1 preparation wh.ich is instantly dissolved in a liquid medium jus-t before the use~ and these preparations can 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, fatty acid triglycerides and the like.
The ointments can be prepared from conventional base materials by the procedure well known in the a.rt~

J~3 The present invention is further illustrated in greater detail by the -following Examples and Re~erence Examples, but they are not to be construed as limiting the present invention. Unless otherwise indicated, all parts, percents, rat;os ancl the like are by weight.
Example 22 g of 4-phenyl-1(21I)-isoquinolone and 30 g of anhydrous potassium carl)onate were added to 100 ml of dimethylformamide and the mixture was stirred for 2 hours at 120C. 18 g of 3-N,N-dimethylaminopropyl chloride was added to the solution and the mixturc was stirred for

3 hours at 100C. After completion of the reaction, the solvent was distilled oEf and water and subsequently dichloromethane were added to the residue, followed by lS thoroughly shaking. The dichlorollIethane layer was separated, washed ~/ith watcr and dricd ovcr anhydrous sodium sulfate.
The solvent was distilled off and the residue was recrystal-lized from ligroin to obtain 23 g oE 2-(3-N,N-dimethylamino-propyl)-4-phenyl-1(2II)-isoqunolone having a melting point of 95C as colorless prisms.
Elementary Analysis:
Calcd for C20~I22N2o 306.411 C, 78.40; }I, 7.24; N, 9.14 t~) Found: C, 78.36; II~ 7.32; N, 8.97 (%) 80 ml Or a solution of 16 g of 2-(3-N,N-climethylamino-propyl)-4-phenyl-1(2I-I)-isoquinolone in ethyl ace~ate and ~154371Eii3 1 100 ml of a solution of 8 g of tartaric acid in ethyl acetate were combined and the resulting mixture was warmed with stirr1ng for a while. After allowing the mixture to cool, the precipitated crystals were filtered and recrystal-lized from a mixture of ethanol and petroleum ether toobtain 18 g of 2-(3-N,N-dimethylaminopropyl)-4-phenyl-1(2H)-isoquinolone tartrate having a melting point of 114C
as colorless needles.
Elementary Analysis:
Calcd for C20EI22N2O C4H6 6 C, 63.15; H, 6.18; N, 6.14 (~) Found: C, 63.29; ~1, 6.23; N, 6.06 (%) Example 2 A mixture of 22.1 g of 4-phenyl-1(2H)-isoquino-lone, 20 g of anhydrous potassium carbonate and 100 ml of dimethylformamide was stirxed for 2 hours at 100C. Then, 11 g of 3-chloropropanol was added to the resulting solution and the mixture was stirred at 110C for 5 hour A~ter 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 dis-tilled off, and the resulting resi:due was recrystallized from a mixture of ethyl acetate and petroleum ether to ob-tain 23 g of 2-(3-hydroxypropyl)-4-phenyl-1(2H-isoquinolone having a melting point of 84C as colorless prisms~

~ ' .

7~i3 Elementary Analysis:
for Cl8 l7N2 279.342.
C, 77.40; ~I, 6.13; N, 5.01 (%) Found: C, 77.47; ~1, 6.09; N, 5.11 (%) Then,23;g of 2-(3-hydroxypropyl)-4-phenyl-1~2H)-isoquil1olone was added to a mixture of 60 ml of benzene and 25 ml of thionyl chloride and the mixture was heated at reflux for l hour. The solvent was distilled off and the residue was dissolved in dichloromethane. The soltuion 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-l(21l)-isoqllinolone having a melting point of 138C as colorless prisms.
Elementary Analysls:
Calcd for Cl811l6ClN0 297.787:
C, 72.60; ~1, 5.42; N, 4.70 (%) Iound: C, 72.64; H, 5.40; N, 4.77 (%) Then, ]4.9 g of 2-~3-chloropropyl)-4-phenyl-1(211)-isoquinolone, 7 g oE anhydrous potassium carbonate and 40 ml o-f piperidine were mixed an;l 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. 'lhe resulting crystals were recrystallized ~S,~7~

1 from a mixture oE die-thyl ether and p~troleum ether to obtain 15.6 g of 2-(3 piperidinopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 117.5C as color less prisms.
S Elementary Analysis:
Calcd for C23H26N2 = 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 160.5C as colorless prisms.
Elementary Analysis:
calcd for C23H26N2 C4H404 C, 70.11; H, 6.54; N, 6.~6 ~) 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 ~,~L5~P763 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-1(2~ isoqu;inolone hydrobro~;de having a melting point of 300C as colorless needles.
Elementary ~nalysis:
Calcd for C23ll26N2 ~lBr = 427.393 C9 64.64; }I, 6.37; N, 6.55 (%) Found: C, 64.75; 1-1, 6.37; N, 6.46 (%) Example 3 22 g of 7-chloro-4-ethoxycarbonyl-1(2H)-isoquinolone and 0.5 g of sodium hydr;de were added to 100 ml of toluene 7 and the mixture was heatcd at reflux. I`hereafter, 20 g of N,N-dimethylamillopropyl chloride was added to the reaction mix~ure, fvllo~cd by stirring Eor 2 hours ~It loaoc. l'he reaction mixture was then worked up in ~he 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-ethoxycarbonyl-1(2~1)-isoquinolone having a melting point of 60C as color-less needles.
Elementary ~nalysis:
17 21 lN2O3 336.~22:
C, 60.62; ~1, 6.28; N, 8.32 (~) Found: C, 60.55; Il, 6.32; N, 8.21 (~) 7~

Then, 7-chloro-2-(3-N,N-dimethylaminopropyl)-4-e~hoxycarbonyl-1(2~l)-isoquinolone was reactccl 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,N-dimethylaminopropyl)-4-ethoxycarbonyl-l(~H)-isoquinolone maleate-l/2 hydra-tc hav:ing a melting point of 146.5C as colorlcss needles.
Elementary ~nalysis:
Ci7~121ClN23 c4~ 04-1/2~l2o = 461.904 C, 54.61; H, 5.67; N, 6.06 ~) Found: C, 54.78; ~-1, 5.53; N, 5.95 ~%) Example 4 Z5 g of 7-chIoro-4-ethoxycarbonyl-1(2}l)-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 110C. Then, 14 g of 3-chloropropanol was added thereto and~the stirring was continued for 5 hours at 110C. The solvent was distilled off and the residue was dissolved in dichloro-methane. 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-(21-l~-isoquinolone having a melting ~3763 point of 193C as colorless prisms.
Elementary Analysis:
Calcd for C15l16ClN4 309.752:
C, 58.16; H~ 5.21; N, 4.52 (%) Founcl: C, 58.29; }I, 5.26; N, 4.53 Then, 20.1 g of 7~chloro-4 ~ ethoxycarbonyl-2-(3-hydroxy~ropyl)-1(2ll)-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 thorvughly stirring. The resultin~ 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 etller gave 16.4 g o~ 4-carboxy-7-chloro-2-~3-hydroxypropyl)-lt2~l)-isoquinolone having a melting point of 193C as colorless prisms.
Elementary ~nalysis:
Calcd for C13lll2ClNO4 = 281.69~: -20C, 55.43, Il, 4.29; N, 4.97 ~) Found: C, 55.40; ~I, 4.38; N, 4.86 ~%) Then, 16.4 g of 4-carboxy-7-chloro-2-(3-hydroxy-propyl)-1(21~)-isoquinolone was suspended in 100 ml of benzene, and 25 g of thionyl chloride was added to the 25 - suspension. The resul~ing mixture was heated at reflux for 3 hours and the solvent was distillcd off. The residue was dissolved in dichloromethane and the solution was washed with water and dried. The solvent was distilled off and the rcsulting crystals were recrystallized from a mixturc of ethyl acetatc and petroleum ether to obtain 15.6 g of 7-chloro-4-clllorocarbollyl-2-(3-cllloropropyl)-1(2ll)-iso(luinolollc h.l.Villg a mclting point of 125C as color]ess prisms.
Elemcntary ~nalysis:
Calcd for C13ll10(13No2 3 C, 49.01; ~1, 3.16; N, 4.40 (~) Found: C, 49.20; Il, 3.10; N, 4.26 ~%) Tllcn, a mixturc of 3.2 g of 7^chloro-4-chlorocarbonyl-2-(3-chloropropyl)-1(2ll)-isoquillolonc, 100 ml of a 20~
solution of dimcthylaminc in acctollc and 2.5 g of anhydrous t.lSSiUI1l carl~ollate was he.ltc~d at ~0C in an autoclave for 6 hours. 'I'hc solvcnt was clistillccl off and the residue was dissolvc(l in dichloroll)ctll.lnc. Ihc solution was washed Witll w.ltel, dricd arld thc solvcnt was distilled off. The resultillg crystals were recrystallized from a mixture of ethanol and pctrolcum ether to obtain 2.5 g of 7-chloro-2-(3-N,N-dimetllylaminopropyl)-4-N,N-dimct}lylcarbamoyl-1(2H)-isoquinolone having a melting point of 145C as colorless prisms.

- 2~ -Elementary Analysis:
Calcd for C17~l22ClN32 C, 60.80; ~I, 6.60; N, 12.51 (%) Found: C, 60;92; I-l, 6.63; N, 12.41 (%) Example 5 A mixturc of 21.6 g of 4-ethoxycarbonyl-1~2~l)-isoquinolone, 25 g of anhydrous potassium carbonate and 100 ml of dimethyl~orlllalnide ~as heated at lOODC for 2 llours.
Then, 14 ml of 3-chloropropallol was adcled thereto and the mixture was heated at 110C for 4 hours. The solvent was distilled o-f-f and the residue was extracted with dichloromethane. The extract was washed with water, dried and thc solvent was distilled off. 120 ml oE an ethanolic solution of 5.5 g of ~otassium hydroxide was added to the residue, and the mixture was warmed. AEter 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 recrystal-lized from a mixturc of ethanol and petroleum ether to obtain 12.5 g of 4-carboxy-2-(3-hydroxypropyl)-1(2~
isoquinolone having a melting point of 205C as coloTless prisms.
Elementary Analysis:
Calcd for C13~l13N4 = 247-253 C, 63.15; ~19 5.30; N, 5.66 (%) Found: C, 63.23; ~-I, 5.3G; N, 5.54 (%) ,'P~l7~3 Thcn, 12.5 g of 4-carboxy-2-t3-hydroxypropyl)-1~2H)-isoquinolone was added to a mixture of 50 ml of carbon tetrachlor;de and 25 ml of thionyl chloride, and the Tesulting mixture was heated at reflux for 2 hours.
'I'he solvcnt was distilled oEf and the residue was dissolved in dichloromethanc. The solution was washecl witll water, dried and tlle solvent was distilled off. The resulting crystals were recrystalliæed -from a mixture of ethyl acetate and petroleum ether to obtain 12.8 g of 4-chlorocarbonyl-102-~3-chloropropyl)-1~2~-1)-isoquinolone having a melting point of 101C as colorless prisms.
Elementary Analysis:
Calcd for Cl~HllC12N2 C, 5~.95; Il, 3.~0; N, 4.93 (~) 15Found: C, 5~.83; Il, 3.92; N, 4.86 (%) Then, 12.8 g of ~-chlorocarbonyl-2-(3-chloropropyl)-1-(21-l)-isoquinolone was dissolved in 150 ml of chloroform, and a mixture of 6.6 g of n-butylamine and 20 n~l of triethyl-amine was added thereto while stirring. ~fter 5 hours, the reaction mixture was washed with water and dried.
The solvent was distilled off and the resulting crystals were recrystalli~ed from a mixture of ethyl acetate and petroleum ether to obtain 10 g of 4-N-n-butylcarbamoyl-2 (3-chloropropyl)-1(2~1)-isoquinolone having a melting point of 1~9C as colorless prisms.

7ç~3 Elementary Analysis:
Calcd for C17~121ClN22 C, 63.65; 1-1, 6.60; N, 8.73 (%) Found: C, 63.79; ~-1, 6.53; N, 8.70 (%) Then, 10 g of 4-N-n-butylcarbamoyl-2-(3-chloroprGpyl)-1(2l-1)-iso~luinolonc, 9.5 g of anhydro-ls potassiwn carbonate and 200 ml of a 20% solution of dimcthylamine in acetaone were placed in an autoclave, and the mi.xture was heated a-t 90C for 5 hours. Therea-fte~, -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 recrystallizcd from a mixtur~ of methanol and diethyl ether to obtain 7.5 g of 4-1~-n-butylcarbamoyl-2-(3-N,N-dimethylaminopropyl)-1(21-1)-iso~uinolone oxalate ha~ing a melting point of 211C (with dccomposition) as colorless prisms.
Elementary Analysis:
Calcd for C19~127N302 C2~124 C, 60.13; 1-1, 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 desribed in the foregoing Examples 1 to 5.

37~3 Examr)le 6 2-(2-N,N-Dimethylaminoet]lyl3-4-phenyl-lt2H)-isocuinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 89C.
Elcmcntary Analysis:
lc ror C191120N2 292.384:
C, 78.05; 1-1, 6.89; N, 9.58 ~) Found: C, 78.09; ~1, 6.79; N, 9.63 (%) 2-(2-N,N-Dimethylaminoe~hyl)-4-phenyl-1~21-1)-isoquinolone hydrochloride. Recrystallized from a mixt~re .
of ethanol and petroleum ether. Colorless needles having a melting point of 258.5C.
Elementary Analysis:
Calcd for C19}12oN2~ -lCl = 328.845:
C, 69.40; 1-1, 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(21-1~-isoquinolone. Recrystallized from petroleum ether.
Colorless leaflets having a melting point of 41C.
Elementary Analysis:
Calcd for C221126N2 334-465 C, 79.01; 1-1, 7.84; N, 8.38 ~%) Found: C, 78.95; H, 7.91; N, 8.25 ~%) i .?, j~716; 3 2-(3-N,N-Diethylaminopropyl)-4-phenyl-1(2~
isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl etller. Colorl~ss prisms having melting point of 140C.
Elementary Analysis:
Calcd for C221l26N20 C4l-l~0~ 150.539:
(:, 69.31; ~I, 6.71; N, 6.22 ~%) Found: C, 69.42; ~I, 6.73; N, 6.09 ~%) 2-~3-N,N-Diethylaminopropyl)-4-phenyl-1(2}l)-isoquinolone hydrobromicle. Recrystallized from a mixture oE mcthanol and petroleum ethcr. Colorlcss prisms havin~
a melting point of 1'16.5C.
Elementary Analysis:
Calcd for C22ll26N20 I r 15.
15C, 63.62; ~I, 6.55; N, 6.74 ~%) Found: C, 63.75; I-l, 6.46; N, 6.69 (%) Example 8

4-Phenyl-2-(3-pyrrolidinopropyl)-1(21-1)-isoquinolone.
Recrystallized from diethyl ether and petroleum ether.
Colorless prisms having a melting point oE 115C.
Elementary Analysis:
Calcd for C22ll24N20 = 332-449:
C, 79.48; ~1, 7.28; N, 8.43 (%) Found: C, 79.59; ~I, 7.33; N, 8.40 (%) 4-Phenyl-2-(3-pyrrolidinopropyl)-1(211~-isoquinolone hydrobromide. Recrystallized ~rom a mixture o-f methanol and pctroleum ether. Colorless needles having a melting point of 277C.
Elementary /~nalysis:
Calcd for C221124N2O
C, 63.93; Il, 6.10; N, 6.78 ~%) Found: C, 63.85; Il, 6.:1G; N, 6.70 (~) Exalllple 9 2-(3-~lorpholinopropyl)-4-phenyl-1(21i)-isoquinolone.
Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melt;ng point of 101C.
Elementary Analysis:
Calcd for C22ll24N22 C, 75.83; H, 6.94; N, 8.04 (%) Found: C, 75.95; H, 6.99; N, 7.95 (%) 2- (3-~orpholinopropyl)-4-p}lenyl-1(21-l)-isoquinolone maleate. Recrystallized from a m;xture of et~anol and diethyl ether. Colorlcss leclflets haVill~ a melting point of 192C.
Elementary Analysis:
Calcd for C22H24N22 C41144 C, 67.23; H, 6.08; N, 6.03 (%) Found: C, 67.41; Il, 6.15; N, 5.90 (%) 2-(3-Morpholinopropyl)-4-phenyl-1(21l)-isoquinolonc hydrobromide. Recrystallized Erom a mixture of methanol and petroleum cther. Colorless n~cdles having a melting point higher than 290C.
Elementary Analysis:
Calcd for CZ2ll24N22 IIB
C, 61.54; ~I, 5.87; N, 6.52 ~%) Found: C, 61.63; Il, 5.89; N, 6.44 (%) x~ le 10 2-~3-~4-Methylpiperclzin-l-yl)yropyl~-4-pllenyl-1(2 isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 116C.
Elementary Analys;s:
lS Calcd for C23ll27N3O
C, 76.42; ~I, 7.53; N, 11.62 ~) Found: C, 76.49; fl, 7.50; N, 11.63 (%) Example 1l 2-~3-{4-(2-llydroxyethyl)piperazin-1-yl~propyl]-4-phenyl-1~2l-l)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having a melting point of 131C.
Elementary Analysis:
CalCd for C24fl29N32 C, 73.63; }1, 7.47; N, 10.73 ~%) r:ound: C, 73.56; ~I, 7.49; N, 10.72 ~%) ~3~ 3 2-[3-~4-~Z-I-Iydroxyethyl)piperazin-l-yl}propyl]-4-phenyl-1~21l)-isoquinolone dimalcate. Rccrystallized from ethanol. Colorless prisms having a melting point of 192C.
Elementary Analysis:
Calcd for C24ll29N3o2 (C4ll44)2 C, 61.63; ~l, 5.98; N, 6.74 (%) Found: C, 61.83; l-l, 6.02; N, 6.63 (%) Example 12 2-t3-N-Iso~ropylaminopropy])-4-phenyl-1(2~
iso~uinolone hydrobromide. Rccrystallized from a mixture of ethanol and petroleum ethcr. Colorless necdles having a melting ~oint of 139C.
~lementary ~nalysis:
lS Calcd for C211l24N2 ~IBr C, 62.85; i-l, 6.28; N, 6.98 (~) Found: C, 62.89; H, 6.35; N, 6.96 (%) Example 13 2-(2-N,N-Dimethylaminopropyl)-4-phenyl-l(211)-isoquinolone. Recrystallized from a mixture of ethanol and n-hexane. Colorl~ss flakes having a melting point of 107C.
Elementary Analysis:
Calcd for C20~122N2O
C, 78.40; H, 7.24; N, 9.14 (%) Found: C, 78.51; ~1, 7.30; N, 9.00 (%) 2-(2-N,N-Dimethylaminopropyl)-4-phellyl-1(2~
isoquinolone maleate. Recrystallized ~rom a mixture of ethanol and diethyl ether. Colorless needles having a mclting point of 139C.
Elementary ~nalysis:
C~lcd for C2oll22N20 C411404 =422-485 C, 68.23; Il, 6.20; N, 6.63 (%~
Found: C, 68.35; Il, 6.26;;N, 6.69 ~) Exam le 14 2-(3-N,N-I)imethylamillo-2-mct}~ylpropyl)-4-phenyl-1~2}-l)-isoquinolone malcate. Recrystallized from a mixture of methanol and cliethyl ether. Colorless prisms having a melting point of 174C.
Elementary Analysis:
Calcd for c21~l24N20 C4~l44 C, 68.79; I-l, 6.47; N, 6.42 (%) Found: C, 68.74; ~1, 6.56; N, 6.29 ~) Example 15 2-~3-N,N-Dimethylaminopropyl)-7-methoxy-4-~p-methoxyphenyl)-1~21-1)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ethcr. Colorless needles having a melting pOillt oE 74C.
Elementary l~nalysis:
or C221126N23 366.464:
C, 72.11; Il, 7.15; N, 7.64 (%) Fountl: C, 72.25; Il, 7.15; N, 7.54 ~%) 37~`~

2-~3-N,N-~imethylaminopropyl)-7-mcthoxy-4-(p-methoxyphenyl)-1(211)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 146C.
Elementary Analysis:
Calc~l for C221126N23 C~ 4 C, 64.72; Il, 6.27; N, 5.81 (%) Found: C, 64.86; ~1, 6.15; N, 5.90 (%) Examr~le 16 4-Cyano-2-(2-N,N-diethylaminoethylj-1~2H)-isoquino-lone. Recrystallized from ligroin. Colorless prisms having a melting point of 90C.
Elementary Analysis:
Calc(l for C16~119~l3 = 269.349:
C, 71.35; Il, 7.11; N, 15.60 (%) Found: C, 71.29; Il, 7.16; N, 15.52 (%) 4-Cyano-2-(2-N,N-diethylaminoethyl~-1(2~1)-iso-quinololle maleate. Rec~ystallized from a mixture of ethanol and diethyl ether. Colorless needles having a meltin~ point of 145C
Elcmentary Analysis:
Calcd for C16~119N30 C4114~)4 C, 62.33; ~-1, 6.02; N~ 10.90 (%) Found: C, 62.20; ~1, 5.89; N, 10.85 (%) r.~ 7~3 Exam~le 17 4-Cy~no-2-~3-N,N-dime-thylaminopropyl-1(21~
isoquinolone monohydrate. Recrys~allized from pctroleum ethcr. Colorless needlcs having a melting point o-E 60C.
Elementary Analysis:
Calcd Eor C1SII17N30-~l2O 7 C, 65.91; }1, 7.01; N, 15.37 (%) Found: C, 65.84; H, 6.85; N, 15.35 (%) 4-Cyano-2-~3-N,N-dime-thylaminopropyl)-1(2}1)-iso~uinolone tartrate hemihydrate. Recrystallized froma mixture of methanol and petroleum ether. Colorless prisms having a melting point of 178C.
Elementary Analysis:
Calcd or Clsl-ll7N30-C4ll66 1/ 2 C, 55.07; I-l, 5.83; N, 10.14 (%) POUJId: C, 55.16; ~I, 5.66; N, 9.~7 (%) EXamP1e 18 4-Cyano-2-(3-N,N-dimethylaminopropyl)-7-methoxy-1(2ll)-isoquinolone. Recrystallized from ligroin.
Colorless ~risms having a melting point of 116C.
Elementary Analysis:
Calcd for C16H19N32 C, 67.35; ~I, 6.71; N, 14.73 (%) Found: C, 67.43; ~1, 6.75; N, 14.60 (%) 4-Cyano-2-(3-N,N-dimetllylaminopropyl)-7-methoxy-lt2~l)-isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 174~C.
Elementary Analysis:
Calcd for Cl6}llgN32 C4H404 C, 59.84; 1-l, 5.78; N, 10.47 ~%) Found: C, 59.73; Il, 5.76; N, 10.55 ~%) Example l9 2-~3-N,N-dimethylaminopropyl)-4-ethoxycarbonyl-1(2H)-isoquinolone tartrate hemihydrate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 184C ~ith decomposi-tion).
Elementary Analysis:
Calcd for Cl7ll22N23 C4ll66 / 2 C; 54.42; Il, 6.31; N, 6.04 ~%) Found: C, 54.60; ~I, 6.25; N, 6.23 ~%) Example 20 2-~3-N,N-Dimethylaminopropyl)-4-ethoxycarbonyl-7-mcthoxy-1(21-l)-isoquinolone. Recrystallized frcm petroleum ether. Colorless needles having a melting point of 50C.
Elementary Analysis:
Calcd for Clg~l24N24 332.403:
C, 65.04; Il, 7.28; N, 8.43 ~%) Found: C, 65.10; ~I, 7.22; N, 8.43 (%) - ~5 -.37~i3 2-~3-N,N-dimethylaminopropyl~-4-ethoxycarbonyl-7-methoxy-1(2~1)-isoquinolone maleate hemihydrate.
Recrystallizcd from a mi~ture of ethanol and diethyl ether.
Colorless leaflets having a melting point of 121C.
Elementary Analysis:
Calccl for cl8~-l24N2O~ c4ll4O4 1/ 2 C, 57.76; I-l, 6.39; N, 6.12 (%) Found: C, 57.73; Il, 6.21; N, 6.19 ~%) Example 21 7-Chloro-4-(p-chlorop}lenyl)-2-(3-N,N-dimethylamino-propyl)-1(2H~-iso~uillolone. Recrystallized from ligroin.
Colorless prisms having a melting point of 100C
Elcmentary Analysis:
Calcd -for C20}l20C12N2 = 375-301 t', 64.01; ~I, 5.37; N, 7.46 (%) Found: C, 64.20; I-l, 5.31; N, 7.47 (%) 7-Chloro-4-(p-chlorophenyl)-2-~3-N,N-dimethylamino-propyl)-1~2}1)-isoquinolone tartrate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless crystalline powder having a melting point of 192C.
Elementary Analysis:
Calcd for C20~-l20C12N2 C4~166 C, 54.87; }-I, 4.99; N, 5.33 (%) Found: C, 54.97; }I, 4.96; N, 5.46 (%) 7 ~ 3 Example 22 7-Chloro-2-(3-N,N-dimethylaminopropyl) 4-N,N-dimethylcarbamoyl-1~21l)-isoquinolone oxalate. Recrystal-lized from a mixture of ethanol and diethyl ether.
Colorless needlcs having a melting pOillt of 223C.
Elementary ~nalysis:
Calcd for C17ll22ClN32 C21124 C, 53.59; Il, 5.68; N, 9.87 ~%) Found: C, 53.46; ~1, 5.62; N, 9.88 (%) Example 23 7-Chloro-4-(4-methylpiperazin-1-yl-carbonyl)-2-t 3-(4-methylpiperazin-1-yl~propyl}-1(21-1)-isoquinolone.
Recrystallized from a mixture of diethyl ether and petro-leum ether. Colorless prisms ha~ing a melting point o~
128C.
Elcmentary Analysls:
Calcd or C23~132ClN5O2 = 445.997:
C, 61.94; }1, 7.23; N, 15.70 (%~
Found: C, 62.06; Il, 7.36; N~ 15.61 ~0) 7-Chloro-4-(4-methylpiperazin-1-yl-carbonyl)-2-~3-(4-methylpiperazin-1-yl)propyl}-1(2~1)-isoquinolone tri-maleate. Recrystallized from a mixture of methanol and diethyl ether. Colorless crystalline powder having a melting point of 146C.

i43~i3 Elementary Analysis:
Calcd for C23~l32ClN52 3C4~l4O4 C, 52.93; Il, 5.58; N, 8.82 ~%) Found: C, 52.86; H, 5.66; N, 8.70 ~%) Example 24 7-Chloro-4-morpholinocarbonyl-2-~3-morpholino-propyl)-1(2l-1)-isoquinolone. Recrystallized -from a mixture of ethyl acetate and petroleum ether~ Colorless prisms having a melting point o-f 178C.
Elementary Analysis:
Calcd for C21l-126ClN3O4 = 419.912:
C, 60.07; 1-1, 6.24; N, lû.01 (%) Found: C, 60.16; }I, 6.22; N, 9.83 (%) 7-Chloro-4-morpholinocarbonyl-2-(3-morpllolino-propyl)-1(21-l)-isotluinolone malea-te. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needlcs having a melting pOillt of 178C.
Elementary Analysis:
Calcd for C21ll26ClN34 C4~144 20C, 56.02; Il, 5.64; N, 7.84 (%) Found: C, 56.16; ~I, 5.70; N, 7.88 ~%) Example 25 4-Carbamoyl-2- ~3-N,N-dimethylaminopropyl)-1(2l-l)-isoquinolone monohydrate. Recrystallized from a mixture of ethanol and petroleum ether. Colorless crystalline powder having a meltin~ point o-f 159C (Wit]l decomposition).

7~3 Elementary Analysis:
Calcd for C15~ 9N32 ~l2 C, 61.84; ~I, 7.27; N, 14.42 (%) Found: C, 61.79; ~I, 7,30; N, 14.55 (%) 4-Carbamoyl-2-~3-N,N-dime-thylaminopropyl)-1~2ll~-isoquinolone oxalatc. Recrystallized from a mixturc of ethanol and pctrolcum cthcr. Colorlcss crystalline powder having a melting point of 156C.
Elementary Analysis:
; 10 calcd for C15lll9N302 C2}l24 C, 56.19; H, 5.83; N, 11.56 ~%) Found: C, 56.32; }I, 5.72; N, 11.46 (%) Example 26 2-~3-N,N-Diethylaminopropyl)-4-N,N-diethylcarbamoyl-1(2~1)-isoquinolone oxalate. Recrystallized from a mixture of metllanol and diethyl ether. Colorless prisms haYing a melting point of 168C.
Elementary Analysis:
Calcd for C21~l31N3~2 C2~l24 C, 61.73; ~-I, 7.43; N, 9.39 (%) Found: C, 61.65; 1-1, 7.49; N, 9.30 (%) Example 27 4-n-Butoxycalbonyl-2-(3-N,N-dimethylaminopropyl)-1(211)-isoquinolone maleate. Recrystallized from a mix-ture of ethanol and diethyl ether. Colorless prisms having a - 3'~ --- ~o -melting point of 142~C.
Elementary Analysis:
calcd for clgll26N2O3 C4~1404 C~ 61.87; Il, 6.77; N, 6.27 t~) 5Found: C, 61.99; }1, 6.76; N, 6.24 ~%) Exa~ le 28 2-(2-N,N-Diethylaminoethyl)-4-phenyl-1(211)-iso-quinolone maleate. RecIystallized from a mixture oF
ethanol and dietllyl ether. Colorless needles having 10a melting point of 197.5C.
Elementary Analysis:
Calcd for C21~124N2'C411404 C, 68.79; ~I, 6.47; N, 6.42 ~%) Found: C, 68.93; Il, 6.55; N, 6.39 ~%) 15~,xample 29 4-Phenyl-2-(2-pyrrolidinoethyl)-1~2f-1)-isoquinolone.
Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms having a melting point of 131.5C.
Elementary Analysis:
Calcd for C211122N2O 318.422:
` C, 79.21; Il, 6.96; N, 8.80 (%) Found: C, 79.16; ~I, 7.04; N, 8.69 ~) 4-Phenyl-2- (2-pyrroliclinoethyl)-1(2ll)-iso~uinolone maleate. Recrystallized from a mixture of ethanol and dietilyl ether. (,olorless nc,~edles having a melting point - ~0 --.q~7~

of 176.5C.
~lementary Analysis:
Calcd for C2~ 22N2 C4ll~4 43 -C, 69.11; ~I, 6.03; N, 6.45 (%) ~ound: C, 69.29; H, 5.91; N, 6.55 (%) Ex.lm~le 30 2-(2-l~,N-Llicthylaminol)ropyl)-4-~henyl-1(21l)-isoquinolone. Recryst~llized from a mixture o-f diethyl ethel and petroleum ether. Colorless prisms having a melting point of 92C.
Elementary Analysis:
Calcd -for C 1I N 0 = 334.465:
C, 79.01; }I, 7.84; N, 8.38 (%) Found: C, 79.00; Il, 7.69; N, 8.45 (~) lS 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 203C.
Elementary ~nalysis:
Calcd for C221l26N2 IICl C, 71.24; Il, 7.34; N, 7.55 (%) Found: C, 71.32t ~I, 7.31; N, 7.38 ~%) 2-(2-N,N-Diethylaminopropyl)-4-phenyl-1(2~
isoquinolone maleate. Recrystallized from a mixture of methanol and diethyl ether. Colorless prigms having a - ~1 -7Ç;3 melting point oE 142C.
Elementary Analysis:
Calcd for C22ll26N2 C411404 C, 69.31; ~1, 6.71; N, 6.22 (%) 5Found: C, 69.51; 11, 6.78; N, 6.25 (%) Example 31 2-[2-~4-metllylpiperazin-1-yl)ethyl]-4-phenyl-1~2~1)-isoquinolone. Recrystallized from a mixture of ethyl acetate and petroleum ether. Colorless prisms 10having a melting point of 103.5C.
Elementary l~\nalysis:
Calcd for C22~125N3 = 347-464 C, 76.05; ~1, 7.25; N, 12.09 (%) Found: C, 75.92; 11, 7.31; N, 11.95 ~) 2-[2-~4-methylpiperazin-1-yl)ethyl] -4-phenyl-1(2}1)-isoquinolonc dimaleate. Recrystalli~ed from a mixture of dimethylfoImamide and methanol. ~hite crystalline powder having a melting point of 207C
(with decomposition).
Elemelltary Analysis:
Calcd for C22}125N3 2C411404 C, 62.17; }19 5.74; N, 7.25 ~%) Found C, 62.30; H, 5.65; N, 7.10 (%) Example 32 4-Phenyl-2- ~2-pyrrolidinopropyl)-1(2~1)-isoquinolone.

7~3 - ~3 -Recrystallized -from a mixture of di~thyl ether and petro-leum etllcr. Colorless prisms having a melting point of 84C.
Elementary Analysis:
Calcd for C22ll24N2 3 C, 79.48; Il, 7.28; N, 8.43 (%~
Found: C, 79.44; H, 7.25; N, 8.41 (%) 4-Phenyl-2-(2-pyrrolidinopropyl)-1(2~l)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles having a melting point of 237C (-~ith decomposition).
Elementary Analysis:
Calcd for C22H24N2 IICl C, 71.63; ~I, 6.83; N, 7.59 (%) Found: C, 71.56; H, 6.90; N, 7.66 (%) Bxample 33 4-Phenyl-2-~2-pipcrizinopropyl)-1~2EI)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and diethyl ether. l~hite crystalline powder having a melting point of 250C ~with decomposition).
Elementary Analysis:
Calcd for C23ll26N2 ~lCl = 382-937 C, 72.14, ~I, 7.11; N, 7.32 (%) Found: C, 72.26; H, 7.13; N, 7.20 (%) Example 34 2-~2-(4-Me~hylpiperazin-l-yl)propyl}-4-phenyl-1~2H)-isoquinolone dimaleate. Recr-ystallized from a i376~

mixture of dimethylormamide and ethallol. White crystal-linc powder having a melting point of 189.5C.
; Elementary Analysis:
Calcd for C231127N3 2C411404 C, 62.72; Il, 5.94; N, 7.08 ~%) Found: C, 62.93; ~1, 5.81; N, 7~15 (~) Example 35 7-Cllloro-4-(p-chlorophenyl)-2-~2-N,N-diethylamino-ethyl)-1(2~1)-isoquinolone. Recrystallized from petroleum ether. Colorless prisms ha~ring a melting point of 90C.
Elementary Analysis:
Calcd Eor C21~122C12N2 C, 64.79; Il, 5.70; N, 7~20 (%) E:oun~: C, 64.71; 1-!, 5.73; N, 7.1~ (%) 7-Chloro-4-(p-chlorophenyl)-2-~2-N,N-diethylamino-ethyl)-1(2H)-iso~llinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms having a melting point of 134C.
Elementary Analysis:
Calcd for C21~122C12N2-C4~144 C, 59.41; Il, S.l9; N, 5.54 (%) Found: C, 59.27; ~1, 5.25; N, 5.63 ~%) Examplc 36 7-Chloro-4-~p-chlorophenyl)-2-(2-N,N-diethylamino-propyl)-l~l)-isoquinolone. Recrystallized from petroleum - ~5 -ether. Colorless pr;sms having a melting point o~` 107C.
Elementary Analysis:
Calcd for C22~-l2~C12N2 = 403-355 C, 65.51; Il, 6.00; N, 6.95 ~%) Found: C, 65.68; H, 6.11; N, 6.87 (%) 7-Chloro-4-(p-chlorophenyl)-2- (2-N,N-diethylamino-propyl)-1(211)-isoquinolone hydrochloride. Recrystallized from aqueous ethanol. Colorless prisms having a meltin~
point of 195C.
Elementary Analysis:
Calcd for C22~124C12N2 HCl = 439-~16 C, 60.08; ~1, 5.73; Nt 6.37 (%) Found: C, 60.18; }1, 5.62; N, 6.49 (%) 7-Chloro-4-(p-chlorophenyl)-2-(2-N,N-diet:hylamino-propyl)-1(2~l~-isoquinolonc maleate. Recrystallized from a mixture of ethanol and diethyl ether. I\~hite crystalline powder having a melting point of 112C.
Elementary Analysis:
Calcd for C22~124C12N2 C4~144 20C, 60.12; H, 5.43; N, 5.39 (~) Found: C, 60.06; }19 5.55; N, 5.26 (~) Example 37 2-~2-N,N-Diethylaminoethyl)-7-methoxy-4-~p-methoxy-phenyl)-1(211)-isoquinolone malea~e. Recrystallized from a mixture of methanol and diethyl ether. Colorless prisms having a melting point of 161C.

- ~6 -E~lementary Analysis:
Calcd for C23~128N23 C41~404 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-e~hoxycarbonyl-7-methoxy-1~2~1)-isoquinolone. Recrystallized from petro-leum ether. Colorless prisms having a melting point of Elementary Analysis:
Calcd Eor C191126N24 = 346 43Q
C, 65.88; Il, 7.56; N, 8.09 (%) Found: C, 65.81; ~I, 7.62; N, 8.06 ~%) 2-(2-N,N-Diethylaminoethyl)-4-ethoxycarbonyl-7-methoxy-1~2}1)-isoquinolone maleate. Recrystallized from a mixture of eth~nol and diethyl ether. Colorless needles having a melting point o~ 135C.
Elementary Analysis:
Calcd for cl9~l26N2o4 C4~1404 20C, 59.73; ~1, 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-(I)-methoxy-phenyl)-1(2H)-isoquinolone hydrocllloridc. Recrystallized from a mixture of ethanol and diethyl ether. Colorless - l~6 -7~3 prisms having a melting point of 244C.
Elementary Analysis:
Calcd for C24~l30N23 C, 66.89; ~I, 7.25; N, 6.50 ~%) Found: C, 66.76; Il, 7.28; N, 6.48 ~%) Example 40 2-(2-N,N-Diethylaminopropyl)-4-etlloxycarbonyl-7-methoxy-1~2H)-isoquinolone. Recrystallized from petroleum ether. Colorless prisms having a melting point of 100C.
Elementary Analysis:
Calcd for C20H28N20~ 360.457 C, 66.64; H, 7.83; N, 7.77 ~%) Found: C, 66.78; 1-l, 7.70; N, 7.65 (~) Example 41 2-(2-N,N-Diethylamino-l-methylethyl)-4-phenyl-1(2~l)-isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point o-f 95C.
Elementary ~nalysis:
Calcd for C22~l26N20 334.4 C, 79.01; H, 7.84; N, 8.38 (%) Found: C, 79.10; H, 7.90; N, 8.25 ~%) 2-~2-N,N-Diethylamino-l-methylethyl)-4-phenyl-1(2H)-isoquinolone hydrochloride. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prism~

- ~7 -7~'3 having a melting point of 198C (~ith decomposition).
Elementary Analysis:
Calccl for C22I-I26N20 I-ICl = 370.926:
C, 71.24; ~I, 7.34; N> 7.55 ~%) Found: C, 71.16; II~ 7.45; N9 7.60 (%) Example 42 4-Cyano-2-(2-N,N-diethylaminopropyl)-1(21-I)-iso-quinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms having a melting point of 93C.
Elementary Analysis:
Calcd for C17II21N30 283.376:
C, 72.06; II, 7.47; N, 14.83 (%~
Found: C, 71.91; Il, 7.55; N, 14.79 (%) 4-Cyano-2-~2-N,N-dietllylaminopropyl)-1(2~I)-iso-quinolone maleate. Recrystallized from a mixture o~
methanol and diethyl ether. Colorless prisms havillg a melting point of 148C.
Elementary Analysis:
Calcd for cl7I-I21N30 C4~1404 C, 63.15; H, 6.31; N, 10.52 1%~
Found: C, 63.31; I-I, 6.22; N, 10.4 Example 43 4-Cyano-2-~2-N~N-dimethylaminopropyl)-1(2H)-iso quinolone. Recrystallized from a mixtuTe oE e~hyl acetate - ~8 -i3~3 ~9 and ~etroleum etller. Col.orless prisms having a melting point of 141C.
Elementary Analysis:
Calcd ~or ~15H17N30 255.322:
C, 70.56; Il, 6.71; N, 16.46 {%) Found: C, 70.44; Il, 6.71; N, 16.59 (%) 4-Cyano-2-(2-N,N-dimethylaminopropyl~-1(2l-l)-isoquinolone maleate. Recrystallizecl fro~n a mixture of methanol and diethyl ether. White crystalline powder having a melting point of 177C.
Elementary Analysis:
Calcd for C15lll7N30 C4~l40~ = 371.396:
C, 61.~5; Il, 5.70; ~, 11.31 ~%) ~ound: C, 61.61; Il, 5.78; N, 11.33 ~%) The pharmacological activities, acu~e toxicity and pharmaceutical ~reparations o typical ~xamples of the comyounds of this invention having the formula tI~ are illustrated below, in comparison with the typical known compounds.

2-(2-N,N-Diethylaminopropyl)-4-phenyl-7-methoxy 1(2H)-isoquinolone malea-te. Recrystallized from a mixture of ethyl acetate and diethyl ether. Colorless needles having a melting poin-t of 9BC.
Elementary Analysis:
Calcd for c23H2gN22 C4H4 4 ~9 7~3 1 C, 67.48; H, 6.71; N, 5.83 (%) Found: C, 67~31; H, 6.66; N, 5.88 (%) 4-(p-Methoxyphenyl)-2-(2-N,N-diethylaminoethyl)-1(2H)~isoquinolone hydrochloride hemihydrate. Recrys-tall-ized from a mixture of ethanol and diethyl ether. White needles having a melting point of 193 C.
Elementary Analysis:
Calc~ for C22H26N22 HCl 1/2 H2O
C, 66.74; H, 7.13; N, 7.07 (~) Found: C, 66.74; H, 6.91; N, 7.18 ~%) 4-(p-Chlorophenyl)-2-(2-N,N-diethylaminoethyl)-1(2H)-isoquinolone hydrochloride hemihydrate. Recrystall-ized from a mixture of methanol and diethyl ether. White crystalline powder having a melting point of 194 C.
Elementary Analysis:
C21H23ClN2O HCl^l/2 H2O = 400 3~3:
C, 63.00; H, 6.29i N, 7.00 (%) Found: C, 62.97; H, 6.17; N, 7.30 (%) Test Compounds Compound A: 2-(3-N,N-dimethylaminopropyl)-4-phenyl-1(2H)-isoquinolone tartarate (prepared in Example 1) Compound B: 2-(2-N,N-dimethylaminoethyl)-4-phenyl 1(2II)-isoquinolone hydrochloride (prepared in Example 6) -49a-- so -Compound C: 4-cyano-2-(3-N,N-dim~thylaminopropyl)-1(2H)- isoquinololle tartra-te l/2 hydrate (prepared in Example 17) Com~oun~ D: 2-(2-N,N-dimetllyl~minol)ropyl)-4-phenyl-l(211)-isoquinolone malea~e (prepared in Example l3) Anal~esic ~ctivity ~ccording to the acetic acid stretching méthod describe~ by Koster et al [Fed. Pro., l~, 412 ~l959~], Compoun~ A was administered orally to ddy male mice (body weight, 20 to 25 g) fasted overnight before test.
One hour aftcr administration of Compound A, a 0.6% aqueous acetic acid solution was a~ministered intraperitoneally at a dose o~ 0. 35 ml per mouse and the stretching of the mice was obscrvcd l0 minutes after the administration of the acetic acid soiution ~or a ~eriod o~ l0 minutes, alld the percent inhibition was calculated.
The results obta;ned are shown in T~ble l below.
These results clearly indicate that Compound A inhibited the pain reaction induced by ~cetic acid injection, at the dose of 50 and l00 mg/Xg of Compound ~ depending on the dose lcvel.

Table 1 Analgesic ~ctivity ~ose Number of Number of Percent Compound ~mg/kg) ~nimals Stretching Inhibition Control 8 36.5~6.5 - Compound A 25 8 33.8+~.2 Compound A 50 8 16.9+4.8 53.7 Compound A 100 8 10.0~2.8** 72.6 * p<0.05 ** p<O. 01 Anti-~eserpine 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 ~gain a~ministerccl su~cutaneously at a dose of 2 mg/kg. Five hours after the second administration o reserpine, the mice which indicated a constant decrease in body temperature were selected and administered orally with the test compound (Compound C), followed by measuring the rectal temperature of the mice at one hour intervals.
The results obtained are shown in Figure l(a) and Figure l(b). These results indicate that Compound C
increases at a dose of 50 and 100 mg/kg significantly the rectal temperature which has been decreased by the pre-treatment with reserpine.

5`~J~3 1 In this experi.men~, Im.ipramine (lO,ll-dlhydro-N,N-di-methyl-511-dibenz[b,f]azepine-5-propanamine) ana Ami~riptyline ~3-~lO,ll-dihydro-5H-dibenzo[a,dJ-cyclohyp-ten-5-ylidene)-N,N-di-methyl-l-propanamine) were used as typical examples of known compounds for comparison and the results obtained with these com-pounds are also shown in Figure l(a).

-5.la-i 37~3 An-ti-histamine and Anti-chlorinergic 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 31C and the inhibitory activity of the test compounds on the contraction indued by administration of histamine or acetylcholine was determined. The trea~ment 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 ~, 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 histamine-induced contraction curve determined in gui~ea pig ileum to the rigllt direction on th~ igures in parallel. This indicates that Compounds ~, B and C
possess a specific anti-histamine activity. Also9 Compounds ~ and B were found to have a non-specific anti-cholinergic 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 extrac~ed and gastric juice was collected and centrifuged at 3,000 r,p.m. for 15 minutes~

~ . ~h ~ 7 ~ 3 The volume of gastric juice, tlle p~l value and the degree o 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 p}l value.

3 - ~

- 5'1 -O ~_ ~ * k *
~ ~ O
O O I~ Ln L
~) ~) ~i ~ + I+ I
O U
C~; oo ~ t~ Lr) r-t d o u ~-1 O O O O
r-l +l +~ ~+l ,.
~d ~1 ~o oo t` o oo :~
~1 , ,~ ~
U ~ It k ~ t~ ~ O
O r O O O O
H ~1 E~ ~- +l +l ~-~ ~ ~-t t'l Ll~ O
~ ~ li ~ ", "~ oo ~
n ~ ~' ~ o ~ o ~d O
E-~ ~

~ h ar o o ca -U ~' ~ r~/ r-1 0 0 ~d *

o~ c o ~

~:

~ o o ~ p~ ~ o E3 ~ h O O O O ~
U U C~ C~ ¢

7~i3 Anti-ulcer Activity i) Stress Ulcer The test compound was administered orally to l~ister male ra~s (body ~eig}lt, 200 to 230 g} and then the rats weTe ticd up with a steel wire and dipped in water at 23C in a tank to the level of the xiphis-ternum ofrats .
After allowing the rats to stand for 7 hours in water, the rats were sacrificed and the stomach was extracted. lO ml of a 1% formalin solution was injected into the stomach cavity and the stomach was dipped in a 1% formalin solution for 15 minutes to semi-harden the stomach. The stomach was excised along the greater curvature thereof ancl the ulcer generated in the portion of corpus ventriculi was observcd. The results obtaitled are shown in Table 3 below.
As ls 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.

7~`3 Table 3 Anti-ulcer Activi~y ~Stress~

Dose Number Ulcerous - Percent Compound (mg/kg) of Rats Index (mm) Inhibition (%) Control 6 75.8 Compound A25 6 58.0 23.5 - Compound A50 6 48.2 36.4 Compound A100 ~ 25.3 66.0 Sulpiride*100 6 71.0 Atropine 5 6 5.3 93.0 *Sulpiride = 5-(aminosul~onyl~-N-~(l-ethyl-2-Pyrrolidinyl)methy:
2-methoxy-benzamide.
ii) Indomethacin Ulcer ~ suspension of indomethacin in 0.25% CMC was admini~ter~
subcutaneously at a dose of 20 mg/kg to Wister male rats (body weightl 125 - 150 g) fasted for 24 hours. The test Compound was administered ora~ly 30 minutes before the administration of indomethacin. Seven hours after the administration of indomethancin, the rats 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--~nduced ulcer at a dose oE 50 mg/kg.

.h5 37~i 3 _ ble 4 Anti-ulcer Activity (Indomethacin) Dose Number Ulcer~us Percent Compound ~mg/kg) of Rats Index(mm) Inhibi~ion (~
Control 8 15.4 Compound B 50 8 6.0 61.0 Compound D 50 8 4.1 73.0 --, Scralphate* 300 8 2.9 81.1 *Scralphate = basic aluminum sucrose sulfate.

Acute Toxicity The test compound was administered to ddy male mice (body weight, 20 to 25 g) asted o~ernight before admini-stration. ~fter administration, general conditions of mice were observed for 7 days and 50% lethal dose LD50 tmg/kg) was determined. The results ob~ined are shown in Table 5 below.
Table 5 Acute Toxicity Compound LI)50 (mg/kg) Compound ~ 662 Compound B 195 Compound C 699 Compound ~ 505 ~ ?~ 3 Pre~aration Examples 1. Granules Compound A 200 mg Lactose 500 mg Corn Starch 280 mg Hydroxypropylcellulosc20 mg l,000 mg per pack The granule preparation was prepared in a conventional manner using the a~ove formulation.
2. Tablets Compound ~ 100 mg Lactose 85 mg Crystalline Cellulose50 mg Hydroxypropylcellulose30 mg Talc 4 mg Magnesium Stearate 1 mg 270 mg per tablet The tablet preparation was prepared in a conventional manner using the above ormulation.
3. Capsules Compound C 200 mg Lactose 100 mg Crystalline Cellulose18 mg s. i,7~ 3 Magnesium Stearate 2 mg 400 mg per capsule The tablct preparation w~s prepared i.n a convention~l m~nner using the above formulation.

As dcscribcd l-cforc, somc of the starting materials having tlle formula (II~ arc novel compounds. The prepara-tions of typical cxam~les of the novel starting materials are described in thc ~ollowing Reference Examples.
S l~ccrence Example 1 20 g of cthyl l)-chloropllenyl acet;l~e, 10 g of sodium ethoxiclc an~l 15 ~ of cthyl Eormatc were a~ded in that order to 200 ~1 o dicthyl cthcr and the mixture was stirred for 16 hours at room temperature. Thereafter, water in an cqual amount to the reaction mixture was added to the rcaction mixture and, after thoroughly shaking~
the a~ueous layer was separatecl. The a~ueous layer was rcndercd ncutral with 2N hydrochloric acid and the liberated oily substance wa~ cxtracte~ with dichloromcthane. The extract was washed wi~h'water and the solvent was dis~illect off to o~tain 14.2 g of ethyl p-chlorophenyl-(~-formyl)-acctate havillg a mclting point oE 50C.
Then, 14.2 g of ethyl p-chlorophenyl-t~-formyl~-acetate and 6.5 g of ure~hane were added .to 50 ml of toluene containing 0.3 ml of concentrated suluric acid~ and the mixture was heatcd at reflux while distilling out water which was formed during the reaction un~il no furtller water was distilled out. Thereafter, the solvent was distilled off, and ~hc residuc was ex~racted with di~thyl ether while hot. The solvcnt was distilled oE-E from the extract to obtain 13.7 g o cthyl p-chlorophenyl-t~-etlloxycarbonyl-amino1ne~hylene)acetate having a melting point of 72C.
Then, 13.7 g of cthyl p-chlorophenyl-(~-ethoxy-carbonylaminomethylcnc)acctate was added to 50 ml of S ~iphenyl cthcr and thc mixturc was heatc~ at reflux for 3 hours. ~ftcr cooling, henzcne and pctrolcum ether were added to the reaction mixture, an~ the precipitated crystals were filtcrcd and recrystallized from a mixture of dimethyl-formamidc and cthanol to obt~in 7 g of 7-chloro-4-etlloxy-carbonyl-1~2ll)-isoquinolotlc ha~ing a melting point of 2~3C
as colorless T~risms.
Elementary Analysis:
C~lcd for C12ll10ClN3 = 251-671 C, 57.27; Il, 4.01; N, 5.57 (%) Found: C, 57.36; Il, 4.05; N, 5.53 (%) Reference Exa~le 2 l`he procedure described in Reference Example l was rcpeatecl but using ethyl p-methoxyphenylacetate as a starting materiaI instead of the ethyl p- chloro phenylacetate, and the resulting crystals were recrystallized from a mixture of dimethylEormamide and ethanol to obtain 4-etlloxycarbonyl-7-methoxy-1(2H)-isoquinolone having a melting point of 191C as colorless prisms. Yield, 64~.
Elementary ~nalysis:
for C13ll13N4 247.253:

h ~ 3 C~ 63.15; Il, 5.30; N, 5.66 (%) Founcl: C~ 63.27; Il, 5.2~; N, 5.72 (~3 Reference Example 3 The procedure described in Reference Example 1 was repeat~d but using p-mct}loxyphenylacetonitrile as a startin~
material instead of the ethyl p- chloxo phenylacetate, and the resulting crystals were recrystaIlized from a mixture of dimethylformamide and ethanol to obtain 4-cyano-7-methoxy-1~2H)-isoquinolone having a melting point of 264C.
Yield, 58~.
Elementary Analysis: -Calcd for C~ 8N22 C, 66.00; ll, 4.03; N~ 13~99 (%) Found: C, 66.16; ll, 4.20; N, 13.88 (%) _ f rence Example 4 - A mixture of 19 g of 4-carboxy-1(2~1)-isoquinolone, 10 ml of concentrated sulfuric acid and 1 liter of n-butanol was hea~ed 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 separatcd by filtration and recrystalli~ed from a mixture of n-butanol and petroleum ether to obtain 17 g of 4-n-butoxycarbonyl-l(2ll)-isoquinolone as colorless ne~dles having a melting point of 170C.

~i3~3 Elementary An~llysis:
Calcd :i~or Cl~ 5N03 2~5. 281:
C, 68.56; Il, 6.16; N, 5.71 (~i) Found: C, 68.62; Il, 6.11; N, 5.58 ~%)

Claims (32)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds of the general formula (I) (I) wherein Y is selected from the group consisting of hydrogen, chlorine and a methoxy group;
Z represents a straight chain or a branched chain divalent saturated aliphatic hydrocarbon group having 2 to 4 carbon atoms;
R1 is selected from the group consisting of a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, an N-substituted carbamoyl group selected from the group consisting of an N-alkylcarbamoyl group, an N,N-dialkylcarbamoyl group wherein each alkyl group has 1 to 4 carbon atoms, a 4-methyl-piperazinocarbonyl group and a morpholinocarbamoyl group; a phenyl group, and a substituted phenyl group selected from the group consisting of a halophenyl group and an alkoxyphenyl group having 1 to 4 carbon atoms in the alkoxy group;
R2 represents a hydrogen atom or a lower alkyl group;

R3 represents a lower alkyl group; or R2 and R3 may form, when taken together with the nitrogen atom to which they are attached, a heterocyclic group Claim 1 continued selected from the group consisting of a pyrrolidine group, a piperidino group, a 4-methylpiperazino group, a 4-hydroxyethylpiperazino group and a morphorlino group;
and the pharmaceutically acceptable acid addition salts thereof;
which comprises selecting a process from the group of processes consisting of:
(a) reacting a substituted -1(2H)-isoquinolone of the general formula (II) (II) wherein Y and R1 are defined hereinbefore, with a substituted-aminoalkyl halide of the general formula (III) (III) wherein Z, R2 and R3 are defined hereinbefore, X is a halogen atom,in the presence of a basic catalyst;
(b) a process comprising the steps of (i) reacting a compound of the general formula (II) as defined hereinbefore with a hydroxyalkyl halide of the formula (IV) X - Z - OH (IV) wherein X and Z are defined hereinbefore, (ii) reacting the thus produced 2-(hydroxyalkyl)-1(2H)-iso-quinolone compound of the formula (V) Claim 1 continued (V) wherein Y, R1 and Z are defined hereinbefore, with a halogenating agent;
(iii) reacting the thus produced 2-(haloalkyl)-1(2H)-isoquinolone compound of the formula (VI) (VI) wherein Y, R1 and Z are defined hereinbefore,with an amine of the formula (VII) (VII) wherein R2, R3 are defined hereinbefore;
(c) for the preparation of the compounds of formula (I) having a substituted group at the 4-position, heat-reacting the 4-ester compound of the formula (I') (I') wherein R1 is a lower alkoxycarbonyl group, Y, Z, R2 and R3 are defined hereinbefore,with an amine of the formula (VII) in an alcohol solvent;
1. Claim 1 continued (d) for the preparation of the 4-carbamoyl compounds of the formula (I'), (i) hydrolyzing the 2-(hydroxyalkyl)-1(2H)-isoquinolone compound of the formula (V) wherein R1 represents a lower alkoxycarbonyl group, dissolved in an alkaline alcohol, (ii) reacting the thus obtained corresponding 4-carboxy compound of the general formula (VIII) (VIII) wherein Y and Z are defined hereinbefore, with a halogenating agent, (iii) reacting the thus obtained 4-acid halide of the formula (IX) (IX) wherein X, Y and Z are defined hereinbefore, with an amine of the formula (VII);
   (iv) reacting the thus produced 4-carbamoyl compound of the formula (X) (X) wherein X, Y, Z, R2 and R3 are defined hereinbefore, with an amine of the formula (VII).
2. 2. A process as claimed in claim 1 wherein 7, represents an alkylene group having 2 to 4 carbon atoms or an alkylene group having 2 to 4 carbon atoms which has been substituted with an alkyl group having 1 to 4 carbon atoms.
3. 3. A process as claimed in claim 1 wherein said salts are selected from the group consisting of hydrochloride, sul-fate, hydrobromide, methanesulfonate, maleate, tartarate, citrate and lactate.
4. 4. A process as claimed in claim 1(a) wherein X
   represents chlorine or bromine.
5. 5. A process as claimed in claim 1(a).
6. 6. A process as claimed in claim 5 which comprises (a) dissolving the compound of formula (II) in an organic solvent selected from the group consisting of dimethylformamide, dimethyl sulfoxide, toluene and ethanol;
   (b) adding thereto a basic catalyst selected from the group consisting of alkali metal carbonates, sodium hydride, sodium amide, alkali metal alkoxides;
   (c) adding thereto the compound of the general formula (III);
   and (d) heating the mixture at a temperature of from about 80°C
   to about 140°C for a period of time from about 1 hour to about 5 hours.
7. 7. A process as claimed in claim 6 further including the steps of heating the mixture of step (b).
8. 8. A process as claimed in claim 1(b).
9. 9. A process as claimed in claim 8 wherein said halogenating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorous oxychloride and phosphorus oxybromide.
10. 10. A process as claimed in claim 1(c).
11. 11. A process as claimed in claim 10 wherein said halogenating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorous oxychloride and phosphorus oxybromide.
12. 12. A process as claimed in claim 1(d) wherein step (ii) is conducted in the presence of an organic solvent selected from the group consisting of benzene or carbon tetra-chloride.
13. 13. A process as claimed in claim 1(d) wherein step (IV) is conducted in an organic solvent selected from the group consisting of acetone, benzene and toluene at a temperature of about 90°C to about 150°C for a period of about 1 hour to about 6 hours.
14. 14. A process as claimed in claim 1(d).
15. 15. A process as claimed in claim 1 further including the step of converting the free bases of the compounds of the formula (I) as defined in claim 1 into the pharmaceutically acceptable acid addition salts.
16. 16. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
17. 17. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 2 or 3 or an obvious chemical equivalent thereof.
18. 18. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 4 or 5 or an obvious chemical equivalent thereof.
19. 19. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 6 or 7 or an obvious chemical equivalent thereof.
20. 20. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 8 or 9 or an obvious chemical equivalent thereof.
21. 21. Compounds of the general formula (I) as defined in claim 1 which have a substituted group at the 4-position, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 10 or 11 or an obvious chemical equivalent thereof.
22. 22. 4-Carbamoyl compounds of the general formula (I') as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 12 or 13.
23. 23. 4-Carbamoyl compounds of the general formula (I') as defined in claim 1 and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 14.
24. 24. Pharmaceutically acceptable acid addition salts of the compounds of the general formula (I) as defined in claim 1 whenever prepared by a process as claimed in claim 15 or an obvious chemical equivalent thereof.
25. 25. A process as claimed in claim 1 for the preparation of 2-(3-N,N-dimethylaminopropyl)-4-phenyl-1(2H)-isoquinolone and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 4-phenyl-1(2H)-isoquinolone with 3-N,N-dimethylaminopropyl chloride.
26. 26. 2-(3-N,N-Dimethylaminopropyl)-4-phenyl-1(2H)-isoquinolone and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. 27. A process as claimed in claim 1 for the preparation of 2-(2-N,N-dimethylaminoethyl)-4-phenyl-1(2H)-isoquinolone and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 4-phenyl-1(2H)-isoquinolone with N, N-dimethylaminoethyl chloride hydrochloride.
28. 28. 2-(2-N,N-Dimethylaminoethyl)-4-phenyl-1(2H)-isoquino-lone and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 27 or an obvious chemical equivalent thereof.
29. 29. A process as claimed in claim 1 for the preparation of 4-cyano-2-(3-N,N-dimethylaminopropyl)-1(2H)-isoquinolone and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 4-cyano-1(2H)-isoquinolone with 3-N, N-dimethylaminopropyl chloride hydrochloride.
30. 30. 4-Cyano-2-(3-N,N-dimethylaminopropyl)-1(2H)-iso-quinolone and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. 31. A process as claimed in claim 1 for the preparation of 2-(2-N,N-dimethylaminopropyl)-4-phenyl-1(2H)-isoquinolone and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting 4-phenyl-1(2H)-isoquinolone with 2-N,N-dimethylaminopropyl chloride.
32. 32. 2-(2-N,N-Dimethylaminopropyl)-4-phenyl-1(2H)-isoquinolone and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 31 or an obvious chemical equivalent thereof.