FR2463766A1 - NEWS 1 (2H) -ISOQUINOLONES, USEFUL AS ANALGESICS - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS NEW 1 (2H) -ISOQUINOLONES OF GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH REPRESENTS HYDROGEN OR CHLORINE OR A METHOXY GROUP, Z REPRESENTS A DIVALENT REMAINDER OF ALIPHATIC HYDROCARBIDE SAT SAT. STRAIGHT OR BRANCHED CHAIN IN CC, R REPRESENTS A CYANO GROUP, LOWER ALCOXYCARBONYL, CARBAMOYL, N-SUBSTITUTE CARBAMOYL, PHENYL OR PHENYL SUBSTITUTE, R REPRESENTS HYDROGEN OR A LOWER ALKYCARBONYL, OR ALKYL GROUP R R, TAKEN TOGETHER WITH THE NITROGEN ATOM TO WHICH THEY ARE BOUND, MAY FORM A HETEROCYCLIC GROUP, AND THEIR ADDITIONAL SALTS OF ACIDS. APPLICATIONS: AS ANALGESICS, ANTIDEPRESSANTS, ANTIHISTAMINICS, ANTICHOLINERGICS, GASTRIC SECRETION INHIBITORS AND ANTI-ULCER, ESPECIALLY IN TABLETS, CAPSULES, GRANULES, POWDERS, INJECTIONS, SUPPOSITORIES, DOSE OF POMMADES 0.5 MG DAY 50 MG, A IN ADULT MEN, IN 1 TO 3 TAKES.

Description

The present invention relates to novel 1 (2H) -

  isoquinolones and their acid addition salts which have

  analgesic, inhibitory, gastric secretion, anti-

  depressive, antihistamine, anticholinergic and antiulcer.

  The present invention therefore proposes novel 1 (2H) -isoquinolones of general formula (I) below and their salts

  addition of acids which are useful as pharmaceutical agents.

  The invention will be better understood on reading the

  description which will follow with reference to the accompanying drawings, in

  which: - Figures 1 (a) and 1 (b) graphically represent the effect of known compounds and compound C of the invention on the decrease in body temperature induced by reserpine administration;

  FIGS. 2 (a) and 2 (b) represent graphically

  the antihistaminic activity and the anticholinergic activity of the compound A of the invention;

  FIGS. 3 (a) and 3 (b) represent graphically

  the antihistaminic activity and the anticholinergic activity of the compound B of the invention; and

  FIGS. 4 (a) and 4 (b) represent graphically

  antihistamine activity and anticholinergic activity

compound C of the invention.

  The 1 (2H) -isoquinolones of the invention are represented by

sensed by the formula

3 N_N /

  wherein Y is hydrogen or chlorine or methoxy, Z is divalent straight or branched chain C2-C4 saturated aliphatic hydrocarbon radical, R1 is cyano, lower alkoxycarbonyl, carbamoyl; , N-substituted carbamoyl, phenyl or substituted phenyl, 2 represents hydrogen or a lower alkyl group, R3 represents a lower alkyl group, or R2 and R11 together with the nitrogen atom to which they are attached, may form a heterocyclic group, and their acid addition salts. The term "divalent residue of straight or branched chain saturated aliphatic hydrocarbon" means a C 2 -C 4 alkylene group which may be substituted by a C 1 -C 4 alkyl group, for example ethylene, trimethylene, methylethylene , methyltrimethylene, etc. The term "lower alkoxycarbonyl group" refers to an alkoxycarbonyl group containing a C1-C4 alkoxy group, such as methoxycarboxyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like. The term "N-substituted carbamoyl group" refers to an N-alkylcarbamoyl, N, N-dialkylcarbamoyl group,

  containing C1-C4 alkyl groups, a 4-methylpiperazinyl group,

  carbonyl, morpholinocarbonyl, etc. The term "substituted phenyl group" means

  a halophenyl group, such as p-chlorophenyl, or alkoxy-

  phenyl containing a C1-C4 alkoxy group, for example p-methoxy-

  phenyl. The term "lower alkyl group" refers to a straight or branched chain C1-C14 alkyl group such as meth4e, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc. As examples of heterocyclic groups formed by R 2 and R 3 with the nitrogen atom to which they are attached, there may be mentioned pyrrolidino, piperidino, 4-methylpiperazino, 4-hydroxyethylpiperazino, morpholino, etc. groups. The term "acid addition salt" refers to the salts of the compounds of formula (I) formed with pharmaceutically acceptable inorganic or organic acids; mention may be made, for example, of hydrochlorides, sulphates, hydrobromides, methanesulphonates, maleates, tartrates, citrates,

lactatesetc.

  I (2H) -isoquinolones can be prepared by

  mule (I) by reaction of a substituted 1 (2H) -isoquinolone of formula R

4 - (II)

N. H

o

  in which Y and R 1 are as defined above, with a halo

  substituted aminoalkyl genius of formula R

X-Z-N (III)

  in which X represents a halogen atom such as chlorine,

  bromine, etc. and Z, R2 and R3 are as defined above, in

presence of a basic catalyst.

  More particularly, the above reaction between the compounds of formulas (II) and (III) can be advantageously carried out by dissolving the substituted 1 (2H) -isoquinolone of formula (II) in an organic solvent such as dimethylformamide, dimethylsulfoxide, toluene, ethanol, etc., addition of a basic catalyst, for example an alkali metal carbonate such as potassium or sodium carbonate, sodium hydride, sodium amide, alkali metal alkoxides such as methylate sodium, sodium ethoxide, sodium t-butoxide, etc., then optional heating; and then adding to the reaction mixture resulting from the aminoalkyl halide of formula (III) and heating the mixture at about 80 ° to 140 ° C for about 1 to 5 hours. In the above reaction, the basic catalyst

  and the substituted aminoalkyl halide can be used in

  at least equimolar to the 1 (2H) -isoquinolone subs-

  with formula (II). Also, the substituted aminoalkyl halide (III) can be used in the form of a salt with an inorganic acid such as hydrochloride, etc. and in this case the base is preferably used in excess of the equimolar amount by

relative to the compound (II).

  Most of the substituted aminoalkyl halides 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 1 (2H). substituted isoquinolones of formula (II) by another route

  using an amine, according to the following procedures.

  In other words, the compounds of formula (I) can be prepared

  by reaction of the compound of formula (II) with a hydroxyalkyl halide

alkyl of formula

X-Z-OH

  (Iv) wherein X and Z are as defined above, to produce 2- (hydroxyalkyl) -1 (2H) -isoquinolone of formula R1

I N-Z-OH (V)

  wherein Y, Z and R are as defined above, reacting the compound of formula (V) with a halogenating agent to produce a 2 (haloalkyl) -1 (2H) -isoquinolone of formula (VI) wherein Y , Z, R1 and X are such reaction of the compound of formula (VI) with / R2

S - 2

R

  as defined above and an amine of formula (VII)

  wherein R2 and R3 are as defined above.

  In the procedure of the above variant, the reaction between the compounds of formulas (II) can be carried out

  and (IV) using about 1 to 1.5 moles of the hydroxyalkyl halide

  alkyl of formula (IV) per mole of the compound of formula (II) in an organic solvent such as dimethylformamide, toluene, etc. in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, etc. in an amount of at least about 2 moles per mole of the compound of formula (II) at about 80 to about 1 to about 5 hours. The reaction of 2-hydroxyalkyl-1 (2H) -isoquinolone

  of formula (V) thus obtained with a halogenating agent can be carried out

  killed by refluxing, in the presence or absence of organic solvent, for about 30 minutes to 2 hours. Appropriate examples

  halogenating agents are thionyl chloride,

  lyl, phosphorus oxychloride, phosphorus oxybromide, etc. These halogenating agents may be used in molar excess so as to serve as a solvent and, in this case, an organic solvent may not be used. Suitable examples of organic solvents are benzene, carbon tetrachloride and the like.

  The subsequent reaction of 2- (haloalkyl) -1-

  (2H) -isoquinolone of formula (VI) thus obtained with an amine of formula (VII) can be carried out with refluxing for about 1 b 6 h, optionally in the presence of an inorganic base as previously illustrated for the reaction of the compounds of formulas (II) and (III). The reaction can be advantageously

  performed 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 reaches a relatively low boiling point, the reaction is advantageously

  carried out in a closed reaction vessel.

  The compounds of formula (I) having in the 4-position a substituted carbamoyl group may also be prepared by the hot reaction of a ester of the formula ## STR1 ## wherein R 1 is a lower alkoxycarbonyl group. and Y, Z,

  R2 and R3 are as defined above, with an amine of

  mule (VII), in an alcohol as a solvent.

  4-carbamoyl compounds can also be obtained

  of formula (I ') above by hydrolysis of 2- (hydroxyalkyl) -1 (2H) -

  isoquinolone of the formula ## STR1 ## in which R 1 represents a lower alkoxycarbonyl group and Y and Z are as defined above, dissolved in an alkaline alcohol, to the corresponding 4-carboxylated compound of formula COOH 3 / NCV 2 O (III)

0

  in which Y and Z are as defined above, reaction of the 4-carboxylated compound thus obtained with a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc., in the presence of an organic solvent such as benzene or carbon tetrachloride or in the absence of an organic solvent for about 1 to 3 hours, to obtain the corresponding 1 (2H) -isoquinol-4-carbonyl halide of formula COX 4-2-X ( Wherein X, Y and Z are as defined above, reacting the thus obtained acid halide (IX) with an amine of formula (VII) in an amount of at least about 2 moles per mole. of the acid halide in an organic solvent such as benzene, chloroform, ethyl ether, at room temperature (about 15-30 ° C), for about 1 to 5 hours, to obtain the corresponding 4-carbamoyl compound of formula R 2 I-X (x) wherein X, Y, Z. R2 and R3 are as defined above, and reacti of the resulting carbamoyl compound 4 of formula (X) with an amine of formula (VII) in a organic solvent such as acetone, benzene, toluene, at about 90 to 150 ° C for about 1 to 6 hours for

  obtain the desired compound of formula (I ').

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

(X) and amine (VII).

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

high temperature.

  Starting materials of formula (II) in which

  R 1 represents a cyano or lower alkoxycarbonyl group and Y represents

  A chlorine atom or a methoxy group are novel compounds and can be obtained according to the following reaction scheme:

H -R R -CH-CHO

(XI) y (XII)

R1 R1

O O

I2H5 (II)

C2H5

(XIII)

  in which Y is Cl or -OCH and R1 is -CN or -COOR (R = CH3, C2H5, C3% 7 or C4.9 Plus.particularly, mixed in ether

  ethyl mole of a lower alkyl phenylacetate (or phenyl-

  p-substituted acetonitrile of formula (XI), about 1 to 1.5 moles of sodium alkoxide and about 1.5 to 3 moles of ethyl formate

  and the mixture is reacted for about 10 to 24 hours at room temperature.

  ambient, to obtain the formyl compound of formula (XII).

  The resulting formyl compound and an equimolar amount of urethane are heated under reflux in the presence of concentrated sulfuric acid in toluene to give the ethoxycarbonylamino compound of formula (XIII), which is then heated under reflux in the oxide of

  diphenyl to obtain the starting material of formula (II).

  The starting material of formula (II) having in the 4-position a (C 1 -C 4) alkoxycarbonyl group is novel, regardless of the type of the substituent at the 7-position, and these compounds can be easily prepared by esterification of 4-carboxyl compounds or transesterification of methoxy- or ethoxy-carbonyl compounds. These reactions can be carried out using a desired alcohol in the presence of concentrated sulfuric acid by refluxing for about 10 to 20 hours. The compounds of formula (I) thus obtained have excellent analgesic, antireserpine (antidepressant), antihistamine, anticholinergic, gastric secretion inhibitory and anti-ulcer activities and are therefore useful as pharmaceutical agents. The dose of the compounds of the invention as pharmaceutical agents varies according to the severity of the conditions to be treated, the age of the patients, the type of disease or other factors, but it generally varies from 0.5 to 50 mg / kg. body weight and day in adult men, in single or multiple doses (two to three doses). The compounds of the invention may be administered orally, parenterally, or intrarectally in various dosage forms such as tablets, capsules, granules, powders, injections, suppositories, ointments, etc. The above preparations are put into the form of compositions comprising suitable carriers or excipients, by the procedure generally used in the preparation of the preparations.

pharmaceutical compositions.

  Tablets, capsules, granules, powders, etc.

  for oral administration may be prepared from excitatory

  generally used in the art, for example carbon

  calcium nate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, gelatin, polyvinylpyrrolidone, gum arabic, sorbitol, crystalline cellulose, polyethylene glycol, carboxymethylcellulose, silica, etc. Also, the tablets and granules can be provided with a coating according to the method

well known in the art.

  Injection preparations may be

  suspensions or aqueous or oily solutions or powders containing

  naked in ampoules or freeze-dried preparations which are instantly dissolved in a liquid medium just before use and these preparations may be prepared according to the procedure

well known in the art.

  Suppositories may contain well known carriers, for example polyethylene glycol, lanolin, cocoa butter, triglycerides of fatty acids, etc. The ointments can be prepared from conventional bases for ointments by the well-known procedure

in the art.

  The following examples illustrate the invention without, however, limiting its scope. In these examples, parts, percentages, ratios and the like are by weight unless

otherwise stated.

EXAMPLE 1

  22 g of 4-phenyl-1 (2H) -isoquinolone and anhydrous potassium carbonate are added to 100 ml of dimethylformamide and the mixture is stirred for 2 hours at 120 ° C. To the solution is added 18 g of chloroform. - (N, N-dimethylamino) propyl and the mixture is stirred for 3 h at 100 ° C. After the end of the reaction, the solvent is distilled off and water is added to the residue, followed by dichloromethane, and the mixture is stirred vigorously. . The dichloromethane layer is separated, washed with water and dried over anhydrous sodium sulphate. The solvent is evaporated by distillation and

  recrystallizes the residue in the ligrolne to obtain 23 g of 2- [3-

  (N, N-Dimethylamino) propyl] -4-plinyl-1 (2H) -isoquinolone in the form of

colorless prisms; F. 95 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C20I22N2O 78.40 7.24 9, 14

(MW = 306 ,411)

Found 78.36 7.32 8.97

  80 ml of a solution of 16 g of 2- [3-

  (N, N-dimethylamino) propyl] -4-phenyl-1 (2H) -isoquinolone in acetone

  ethyl acetate and 100 ml of a solution of 8 g of tartaric acid in ethyl acetate and the resulting mixture is heated with stirring for a moment. After the mixture was allowed to cool, the precipitated crystals were filtered and recrystallized from a mixture of ethyl alcohol and petroleum ether to give 18 g of 2- [3- (N, N-dimethylamino) propyl] tartrate. 4-phenyl-1 (21H) -isoquinolone under

  form of colorless needles; F. 114 C.

  Elemental analysis: C (%) H (%) N (M) Calcd for C20 22N2O, C4I606 63.15 6, 18 6.14

(MW = 456,500)

Found 63.29 6.23 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 dimethylformamide is stirred for 2 hours at 100 ° C. 11 g of 3-chloropropanol are then added to the resulting solution and the mixture is stirred at C for 5 h. When the reaction is over, the

  solvent by distillation and the residue is dissolved in the dichloro-

  methane. Water was added to the resulting solution and, after vigorous 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 give 23 g of 2- (3hydroxypropyl) -4-phenyl-1 (2H) -isoquinolone in the form of of

colorless prisms; F. 84 C.

  Elemental analysis: C () H (%) N (%) Calc'd for C18H17NO2 77.40 6.13 5.01

(PM 279,342)

Found 77.47 6.09 5.11

  Then 23 g of 2- (3-hydroxypropyl) -4-

  phenyl-1 (2U) -isoquinolone to a mixture of 60 ml of benzene and 25 ml of thionyl chloride and the mixture is refluxed for 1 hour. The solvent is distilled off and the residue is dissolved in dichloromethane. The solution is washed with water and dried, and the solvent is distilled off. The resulting crystals are recrystallized from a mixture of ethyl acetate and ether

  of oil to obtain 23.3 g of 2- (3-chloropropyl) -4-phenyl-1 (2H) -

  isoquinolone in the form of colorless prisms; F. 138 C.

  Elemental analysis: Calculated for C18H16ClNO

(MW = 297.787)

  C (%) 72.60 H (%), 42 N (%) 4.70 Found 72.64 5.40 4.77 14.9 g of 2- (3-chloropropyl) -4-phenyl- 1 (2H) -isoquinolone, 7 g of anhydrous potassium carbonate and 1 ml of piperidine and heated under reflux for 5 hours. The excess piperidine is distilled off and the residue is dissolved in dichloromethane. The solution is washed with water, dried and the solvent is distilled off. The resulting crystals are recrystallized from a mixture of ethyl ether and ether

  of oil, to obtain 15.6 g of 2- (3-piperidinopropyl) -4-phenyl-

  1 (2H) -isoquinolone in the form of colorless prisms; F. 117.5 ° C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C23H26N2O 79.73 7.56 8.09

2326 2

(MW = 346.476)

  Found 79.85 7.55 8.00 __. , __., __ _, v

  Then 10, 4 of 2- (3-piperidinopropyl) -4 is dissolved.

  phenyl-1 (2H) -isoquinolone in 80 ml of ethyl acetate and

  add 4 g of maleic acid to the solution, then shake

  ghost. After cooling, the precipitated crystals are filtered off and recrystallized from a mixture of ethyl ether and ether.

  of oil to obtain 12.2 g of 2- (3-piperidinopropyl) maleate

  4-phenyl-1 (2H) -isoquinolone as colorless prisms;

F. 160o, 5C.

  Elemental Analysis C (%) H (%) N (%) Calcd for C23H26N2O, C4H4O4 70.11, 6.06 54.06

(MW = 462.551)

  Found 70.05 6.58 6.02 The corresponding hydrobromide is obtained as follows:

  10.4 g of 2- (3-piperidinopropyl) -4-phenyl-

  (2H) -isoquinolone in 50 ml of acetone and add 10 ml of

  47% aqueous solution of hydrobromic acid and the mixture is heated.

  After cooling, the precipitated crystals are filtered and recrystallized from a mixture of methanol and petroleum ether

  to obtain 11.6 g of 2- (3-piperidinopropyl) hydrobromide

  phenyl-1 (2H) -isoquinolone in the form of colorless needles; F. 300 C.

  Elemental analysis: C (%) H (%) N (M) Calcd for C 23 H 26 N 20 HBr 64.64 6.37 6.55

(MW = 427.393)

Found 64.75 6.37 6.46

EXAMPLE 3

  22 g of 7-chloro-4-ethoxycarbonyl-1 (2H) -

  isoquinolone and 0.5 g of sodium hydride in 100 ml of toluene and the mixture is heated under reflux. Then 3- (N, N-dimethylamino) -propyl chloride is added to the reaction mixture, followed by stirring.

  for 2 hours at 100oC. The reaction mixture is then treated with

  same way as described in Example 1 and recrystallize the crystals

  resulting in petroleum ether to obtain 22.3 g of 7-chloro

  2- [3- (N, N-dimethylamino) -propyl] -4-ethoxycarbonyl-l (2H) -isoquinolone

  in the form of colorless needles; F. 60C.

  Elemental analysis: C (%) H (%) N (%) Calc'd for C17H21ClN2O3

21 2 3 60.62 6.28 8.32

(MW = 336.822)

Found 60.55 6.32 8.21

  7-Chloro-2- [3- (N, N-dimethyl) is then reacted.

  amino) -propyl] -4-ethoxycarbonyl-l (2)} - isoquinolone with the acid

  in the same manner as described in Example 2 and recreates

  crystallizes the resulting crystals in a mixture of ethanol and ether

  of oil to give 7-chloro-2- [3- (N, N-dimethyl) maleate

  amino) -propyl] -4-ethoxycarbonyl-1 (2H) -isoquinolone hemihydrate

  in the form of colorless needles; Mp 146.5 ° C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C C H N 2 O 2 O 4 C 4 H 4 O 4/54 54 6

17 21 2 3'4 4 '2> 61 5.67 6.06

(MW = 461.904)

Found 54.78 5.53 5.95

EXAMPLE 4

  25 g of 7-chloro-4-ethoxycarbonyl-1 (2H) - are dissolved

  isoquinolone in 100 ml of dimethylformamide with heating and 27 g of anhydrous potassium carbonate are added to the solution, followed by

  stirred for 2 hours at 110 ° C. 14 g of 3-chloro

  propanol and stirring is continued for 5 hours at 110 ° C.

  solvent by distillation and the residue is dissolved in the dichloro-

  methane. The solution is washed with water, dried and the solvent is distilled off. The resulting crystals were recrystallized from a mixture of ethanol and petroleum ether to give 20.1 g of 7chloro-4-ethoxycarbonyl-2- (3-hydroxypropyl) -1 (2H) -isoquinolone.

  in the form of colorless prisms; F. 193 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C15H16ClNO4 58.16 5.21 4.52

(MW = 309.752)

Found 58.29 5.26 4.53

  Then 20.1 g of 7-chloro-4-ethoxy-

  carbonyl-2- (3-hydroxypropyl) -1 (2H) -isoquinolone in 50 ml of ethanol

  and 100 ml of an ethanolic solution are added to the resulting solution.

  5.5 g of potassium hydroxide are added, followed by vigorous stirring.

  The resulting solution is then poured into ice water and

filter the mixture.

  The filtrate is neutralized with dilute acetic acid and the precipitated crystals are filtered and washed with water. Recrystallization from a mixture of ethanol and petroleum ether

  gives 16.4 g of 4-carboxy-7-chloro-2- (3-hydroxypropyl) -1 (2H) -isoquinoline.

  nolone in the form of colorless prisms; Y. 193 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C13R12ClNO4 55.43 4.29 4.97

(MW = $ 281.69)

Found 55.40 4.38 4. & 6

  16.4 g of 4-carboxy-7-chloro-2- are suspended

  (3-hydroxypropyl) -1 (2H) -isoquinolone in 100 ml of benzene and 25 g of thionyl chloride are added to the suspension. The resulting mixture is refluxed for 3 hours and the solvent is distilled off. The residue is dissolved in dichloromethane, the solution is washed with water and dried. The solvent is distilled off and the resulting crystals are recrystallized from a mixture of ethyl acetate and petroleum ether to give 15.6 g of 7-chloro-4-chlorocarbonyl-2 (3-chloropropyl) -1 (2H) -isoquinonolone

  in the form of colorless prisms; F. 1250C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C13HloCl3NO2 49.01 3.16 4.40

(MW = 318.589)

  Found 49.20 3.10 4.26 The mixture is heated in an autoclave at 90 ° C. for 6 hours.

  mixture of 3.2 g of 7-chloro-4-chlorocarbonyl-2- (3-chloropropyl) -

  1 (2H) -isoquinolone, 100 ml of a 20% solution of dimethylamine in acetone and 2.5 g of anhydrous potassium carbonate. Hunting

  the solvent by distillation and the residue is dissolved in dichloromethane

  methane. The solution is washed with water, dried and the solvent is distilled off. The resulting crystals were recrystallized from a mixture of ethanol and petroleum ether to give 2.5 g of 7-chloro-2- [3- (N, N-dimethylamino) -propyl] -4- (N, N-dimethylcarbamoyl).

  l (2H) -isoquinolone in the form of colorless prisms; F. 145 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C17H22ClN2O 60.80 6.60 12.51

(PU = 335.837)

Found 60.92 6.63 12.41

EXAMPLE 5

  A mixture of 21.6 g is heated for 2 hours at 100 ° C.

  of 4-ethoxycarbonyl-1 (2H) -isoquinolone, 25 g of potassium carbonate

  anhydrous sium and 100 ml of dimethylformamide. 14 ml is then added

  3-chloropropanol and the mixture is heated for 4 hours at 110.degree.

  The solvent is distilled off and the residue is extracted with dichloromethane. The extract is washed with water, dried and the solvent is distilled off. 120 ml of an ethanolic solution of 5.5 g of potassium hydroxide are added to the residue and the mixture is heated. After cooling, the reaction mixture is poured into ice water and filtered. The filtrate is neutralized with dilute acetic acid, the precipitated crystals are filtered and recrystallized from a mixture of ethanol and petroleum ether.

  to obtain 12.5 g of 4-carboxy-2- (3-hydroxypropyl) -1 (2H) -iso-

  nolone in the form of colorless prisms; F. 205 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C13H13NO4 63.15 5.30 5, 66

(MW = 247,253)

Found 63.23 5.36 5.54

-Z463766

  12.5 g of 4-carboxy-2- (3-hydroxypropyl) -

  1 (2H) -isoquinolone to a mixture of 50 ml of carbon tetrachloride and 25 ml of thionyl chloride and the resulting mixture was refluxed for 2 h. The solvent is distilled off and the residue is dissolved in dichloromethane. The solution is washed with water, dried and the solvent is distilled off. The resulting crystals are recrystallized from an acetate mixture

  of ethyl and petroleum ether to obtain 12.8 g of 4-chloro

  carbonyl-2- (3-chloropropyl) -1 (2H) -isoquinolone SO in the form of prisms

* colorless; F. 101 C.

  Elemental analysis C (%) H (%) N (%) Calculated for C13H11Cl2NO2 54'95 3.90 4, 93

(MW = 284.144)

Found 54.83 3.92 4.86

  12.8 g of 4-chlorocarbonyl-2- (3-chloro)

  propyl) -1 (2U) -isoquinolone in 150 ml of chloroform and a mixture of 6.6 g of n-butylamine and 20 ml of triethylamine is added with stirring.

  amine. After 5 h, the reaction mixture is washed with water and dried. The solvent is distilled off and the resulting crystals are recrystallized from a mixture of ethyl acetate and diethyl ether.

  oil to obtain 10 g of 4- [N- (n-butylcarbamoyl) -2- (3-chloropropyl) -

  l (2H) -isoqu.ltnolone in the form of colorless prisms; F. 149 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C17H21 CN202 63.65 6.60 8.73

(MW = 320.822)

Found 63.79 6.53 8.70

  10 g of 4- [N- (n-butyl) carbonate are placed in an autoclave.

  bamoyl] -2- (3-chloro-propyl) -1 (2H) -isoquinolone, 9.5 g of anhydrous potassium carbonate and 200 ml of a 20% solution of dimethylamine in acetone and the mixture is heated to 90.degree. C for 5 h. The reaction mixture is then filtered and the solvent is removed from the filtrate by distillation. The resulting oily substance is reacted with oxalic acid in the same manner as described in Example 1 for the preparation of the tartrate. The resulting crystals are recrystallized from a mixture of methanol and ethyl ether to give

  obtain 7.5 g of 4- [N-butyl)% rbamoyl] -2- [3- (N, N-dimethyl) oxalate;

  amino) -propyl-1 (2H) -isoquinolone in the form of colorless prisms;

F. 211 C (decomposition).

  Elemental analysis: C (%) H (%) N (%) Calcd for C19 H27 N302C2H2O4 60.13 6.97 1002

(MW = 419.482)

  Found 60.29 6.90 10.08 The following compounds are prepared

  as described in Examples 1 to 5.

EXAMPLE 6

in the same way

  2- [2- (N, N-Dimethylamino) ethyl] -4-phenyl-l (2H) -isoqui-

  nolone. Recrystallized from a mixture of ethyl ether and ether

  of oil. Colorless prisms; F. 89 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C19H20 - 78.05 6.89 9, 58

(MW = 292.384)

Found 78.09 6.79 9.63

  2- [2- (N, N-Dimethylamino) ethyl] hydrochloride

  phenyl-l (2H) -isoquinolone. Recrystallized in a mixture of ethanol

  and petroleum ether. Colorless needles; M.p. 258.50C.

  Elemental analysis: 0 (%) H (%) N (%) Calcd for C19H20N2O, HCl 69.40 6.44 8.52

(MW = 328.845)

Found 69.49 6.46 8.53

EXAMPLE 7

  2- [3- (N, N-diethylamino) propyl] -4-phenyl-1 (2H) -

  isoquinolone. Recrystallized in petroleum ether. Colorless needles; F. 410C Elemental Analysis: C (%) H (%) N (Calc'd for C22H2NO2 79.01, 7.88,

(MW = 334,465)

Found 78.95 7.91 8 .: Y)

  2- [3- (N, N-Diethylamino) propyl] maleate

  phenyl-l (21) -isoquinolone. Recrystalled in a mixture of ethanol

  and ethyl ether. Colorless prisms; F. 140 ° C.

  k5 Elemental analysis C (%) H (%) N (%) Calcd for C22H2N2OCHO4 6931 6.22

(MW = 4-50,539)

  Found 69.42 6.73 6.09 2- [3- (N, N-Diethylamino) propyl) -4-phenyl-1 (21) -isoquinolone hydrobromide. Recrystallized from a mixture of methanol and

  of petroleum ether. Colorless prisms; Mp 146, 35C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H26N2O, HBr 63.62 6.55 6.74

(MW = 415.382)

Found 63.75 6.46 6.69

EXAMPLE 8

  4-Phenyl-2- (3-pyrrolidinopropyl) -1 (2H) -isoquinolone.

  Recrystallized from ethyl ether and petroleum ether. prisms

colorless; F. 115 C.

  Elemental analysis: C (%) HM) N%) Calcd for H79.48 7N28 8.43

(MW = 332.449)

Found 79.59 7.33 8.40

  4-Phenyl-2- (3-pyrrolidinopropyl) -1 (2H) hydrobromide

  isoquinolone. Recrystallized in a methanol-ethanol and ether solution

  of oil. Colorless needles; F. 2770C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H2N2ORBr 63.93 6.10 6, 78

(MW = 413,366)

Found 63,85 6,16 6> 70

EXAMPLE 9

  2- (3-Morpholinopropyl) -4-phenyl-1 (2H) -isoquinolone.

  Recrystallized from a mixture of diethyl ether and diethyl ether

  oil. Colorless prisms; F. 101 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H24NfO2 75.83 6.94

24 2 75 83 6.94 8.04

(MW = 348,449)

Found 75.95 6.99 7.95

  2- (3-Morpholinopropyl) -4-phenyl (1 (2H) maleate -

  isoquinolone. Recrystallized in a mixture of ethanol and ether

  ethyl. Colorless flakes; F. 192 C.

  Elemental Analysis: C (%) H (%) N (%) Calcd for C22H24N2O2, C4H4O4 67.23 6.08 6.03

(MW = 464.523)

Found 67.41 6.15 5.90

  2- (3-Morpholinopropyl) -4-phenyl-1 (2H) hydrobromide

  isoquinolone. Recrystallized in a mixture of methanol and ether

  of oil. Colorless needles; F.> 290 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H24202, HBr 61.54 5.87, 6.52

(MW = 429,366)

Found 61.63 5.89 6.44

EXAMPLE 10

  2- [3- (4-methylpiperazino) -propyl] -4-phenyl-1l (2H) -

  isoquinoline. Recrystallized from a mixture of diethyl ether and

  of petroleum ether. Colorless prisms; F. 1160C.

  Elemental analysis: C (%) H () N (%) Calcd for C23H27N3O 76.42 7.53 11, 62

(P4M 361,491)

Found 76.49 7.50 11.63

EXAMPLE 11

  2 - [[4- (2-hydroxyethyl) piperazino] propyl} -4-phenyl-

  l (2H) -isoquinoline. Recrystallized in a mixture of ethyl acetate

  and petroleum ether. Prismas colorless; F. 131 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C24H29N3O2 76.63 7.47 10, 73

(MW = 391.518)

Found 73.56 7.49 10.72

  2-t3- [4- (2-hydroxyethyl) piperazino] dimaleate

  propyl} -4-phenyl-l (2H) -isoquinolone. Recrystallized in ethanol.

  Colorless prisms; F. 192 C, Elemental Analysis: C (%) H (%) N (%) Calcd for C2429302 2C4H4O4 61.63 5.98 6.74

(MW = 623.666)

Found 61.83 6.02 6.63

EXAMPLE 12

  2- [3- (4-Isopropylamino) propyl] hydrobromide

  phenyl-l (2H) -isoquinolone. Recrystallized in a mixture of ethanol

  and petroleum ether. Colorless needles; F. 139 C.

  Elemental analysis: C (%) H (%) N (.) Calculated for C21H2N2O, HBr 62.85 6 28 6.98

(MW = 401.355)

Found 62.89 6.35 6.96

EXAMPLE 13

  2- [2- (NN-Dimethylamino) propyl] -4-phenyl-l (2H) -iso-

  quinolone. Recrystallized from a mixture of ethanol and n-hexane.

Colorless scales. F. 107 C.

  Elemental analysis C (%) a (%) N (%) Calcd for C20H22N2O 78 ', 40 7.24 9, 14

(MW = 306 ,411)

Found 78.51 7.30 9.00

  2- [2- (N, N-dimethylamino) propyl] maleate

  phenyl-l (21) -isoquinolone. Recrystallized in a mixture of ethanol

  and diethyl ether. Colorless needles; F. 139 C.

  Elemental analysis C (%) H (M) N (.) Calculated for C20H22N2O, C4H4O4 68.23 6, 6.63

(MW = 422.485)

Found 6B, 35 6.26 6.69

EXAMPLE 14

  2- [3- (N, N-Dimethylamino) -2-methylpropyl] maleate

  phenyl-1 (211-isoquinolone) Recrystallized from methanol

  and diethyl ether. Colorless prisms; F. 174 C.

  Elemental analysis: C () HM ()%) Calc'd for C21 H24N 2 O4H4 O4 6879 647 642

(PM - 436,512)

Found 68.74 6.56 6.29

EXAMPLE 15

  2- [3- (N, N-Dimethylamino) propyl] -7-methoxy-4- (p-

  methoxyphenyl) -l (2H) -isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless needles;

F. 74 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H26N2O3 72.11 7.15 7, 64

(MW = 366.464)

  Found 72.25, 7.54 2- [3- (N, N-dimethylamino) propyl] -7-methoxy-4- (p-methoxyphenyl) -1 (2H) -isoquinolone maleate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms;

F. 146 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H26N2O31Cl4H4O4 64.72 6.27 5.81

(MW = 482.538)

Found 64.86 6.15 5.90

EXAMPLE 16

  4-Cyano-2- [2- (N, N-diethylamino) -ethyl] -1 (2H) * iso

  quinolone. Recrystallized in the alpine. Colorless prisms;

F. 90 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C16H19N3O 71.35 7.11 15, 60

(MW = 269,349)

Found 71.29 7.16 15.52

  4-Cyano-2- [2- (N, N-diethylamino) -ethyl] maleate

  l (2H) -isoquinolone. Recrystallized in a mixture of ethanol and ether

  diethyl. Colorless needles; F. 145 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C16H19N3O, C4H4O4 62.33 6.02 10.90

(MW = 385.423)

Found 62.20 5.89 10.85

EXAMPLE 17

  4-cyano-2- [3- (N, N-dimethylamino) propyl] monohydrate

  l (2H) -isoquinolone. Recrystallized in petroleum ether. Colorless needles; F. 60 C, Elemental Analysis: C (%) H (%) N (%) Calculated for C15H 17N3OH20 65.91 7.01 15.37

(MW = 273.338)

Found 65.84 6.85 15.35

  4-cyano-2- [3- (N, N-dimethylamino) propyl] -train tartrate

  1 (2H) -isoquinolone hemihydrate. Recrystallized in a mixture of

  methanol and petroleum ether. Colorless prisms; F. 178 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C15H17N3O C4H606 11 / 2H20 55.07 5.83 10.14

(MW = 414.416)

Found 55.16 5.66 9.97

EXAMPLE 18

  4-Cyano-2- [3- (N, N-dimethylamino) propyl] -7-methoxy-

  l (2H) -isoquinolone. Recrystallized in the ligrinne. Colorless prisms;

F. 116 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C16HN302 67.35 6.71 14, 73

(MW = 285,349)

Found 67.43 6.75 14.60

  4-cyano-2- [3- (N, N-dimethylamino) propyl] maleate

  7-methoxy-l (2H) -isoquinolone. Recrystallized in a mixture of ethanol

  and diethyl ether. Colorless prisms; F. 174 C.

  Elemental analysis: - C (%) H (%) N (%) Calcd for C16H19N3O2, V4H4O4 59, 84 5.78 10.47

(MW = 401.423)

Found 59.73 5.76 10.55

EXAMPLE 19

  2- [3- (N, N-Dimethylamino) -propyl] -4-ethoxy-tartaric acid tartrate

  carbonyl-1 (2I) -isoquinolone hemihydrate. Recrystallized from a mixture of ethanol and diethyl ether. Colorless needles;

F. 184 C (decomposition).

  - Elemental analysis; C (%) H (%) N (%) Calcd for C17H22N2O3, C4H606.1 / 2H2 54.42 6.31 6.04

(MW = 463,473)

Found 54.60 6.25 6.23

EXAMPLE 20

  2- [3- (N, N-Dimethylamino) propyl] -4-ethoxycarbonyl-7-

  methoxy-l (21H) -isoquinolone. Recrystallized in a mixture of ether

  of oil. Colorless needles; F. 50 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C18H24N2O4 65.04 7.28 8, 43

(MW = 332.403)

  Found 65.10 7.22 8.43 Malgate of 2- [3- (N, N-dimethylamino) propyl] -4-

  ethoxycarbonyl-7-methoxy-1 (2H) -isoquinolone hemihydrate. Recristal-

  in a mixture of ethanol and diethyl ether. Scales

colorless; F. 121 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C 18H 24N 2 4, C 4 O 40 1/2 H 2 O 57.76 6.39 6.12

(MW = 456.485)

Found 57.73 6.21 6.19

EXAMPLE 21

  7-Chloro-4- (p-chlorophenyl) -2- [3- (N, N-dimdthylamino) -

  propyl] -l (2H) -isoquinolonè. Recrystallized in the ligroIne. prisms

colorless; F. 100 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C20-20C1220 64.01 537 746

C2020C2 ,,, 4

(MW = 375.301)

Found 64.20 5.31 7.47

  7-Chloro-4- (p-chlorophenyl) -2- [3- (N, N-)) tartarate

  dimethylamino) -propyl] -1 (2H) -isoquinolone. Recrystallized from a mixture of ethanol and diethyl ether. Colorless crystalline powder;

F. 192 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C 2 R 0 O 2 Cl 2 NOC 4 O 6 54.87 4.99 5.33

(MW = 525,390)

Found 54.97 4.96 5.46

EXAMPLE 22

  7-Chloro-2- [3- (N, N-dimethylamino) propyl] oxalate

  4- (N, N-Dimethylcarbamoyl) -1 (2H) -isoquinolone. Recrystallized from a mixture of ethanol and diethylketo ether Colorless needles;

F. 223 C.

  Elemental Analysis C (%) H (R) N (%) Calcd for C17H22ClN3O2, C 2 H 2 O 4 53.59 5.68 9.87

(MW = 425.873)

Found 53.46 5.62 9 s88

- - at - -

- y -

EXAMPLE 23

  7-Chloro-4- (4-méthylpipérazinocarbonyl) -2- [3- (4-

  methylpiperazino) -propyl] -1 (2R) -isoquinolone. Recrystallized from a mixture of diethyl ether and petroleum ether. Colorless prisms; F. 128 C. Elemental analysis: C (%) H (%) N

  Calc'd for C23H32C N502 61.94 7.23 1.

(MW = 445.997)

(7.), 70 Found 62.06 '7.36 15.61

  7-Chloro-4- (4-methylpiperazinocarbonyl) trimetate

  2- [3- (4-methylpiperazino) propyl] -1 (2H) -isoquinolone. recrystallized

  in a mixture of methanol and diethyl ether. Crystal powder

white line; F. 146 C.

  Elemental analysis: C () H (%) N (%) Calcd for C23H32ClN5O2.3C4H4O4 52.93 5.58 8.82

(MW = 794.219)

Found 52.86 5.66 8.70

EXAMPLE 24

  7-Chloro-4-morpholinocarbonyl-2- (3-morpholinopropyl) -

  l (2H) -isoquinolone. Recrystallized in a mixture of ethyl acetate

  and petroleum ether. Colorless prisms; F. 178 C.

  Elemental analysis: C (%) H (x) N (%) Calcd for C21H26ClN3O4 60.07 6.24 10.01

(MW = 419.912)

Found 60.16 6.22 9.8:

  7-Chloro-4-morpholinocarbonyl-2- (3-

  morpholinQpropyl) -l (2H) -isoquinolone. Recrystallized in a mixture

  ethanol and diethyl ether. Colorless needles; F. 178 C.

  Elemental Analysis: C (%) H (7) N (% Calculated for C21H26ClN3O4, C4H4O4 56, O2 5.64 7.84

(MW = 535.986)

  Find. 6 le 5? 7 1R:) S_, _ ", v" R 1 -

* EXAMPLE 25

  4-Carbamoyl-2- [3- (N, N-dimethylamino) -propyl] -1i (2H) -

  isoquinolone monohydrate. Recrystallized from a mixture of ethanol and petroleum ether. Colorless crystalline powder; 159 C (decomposition). Elemental analysis: C (%) H (%) N (%) Calcd for C15H19N3O2H2O 61.84 7, 27 14.4

(MW = 291.353)

Found 61.79 7.30 14,

  4-Carbamoyl-2- [3- (N, N-dimethylamino) oxalate

  propyl] -l (2H) -isoquinolone. Recrystallized in a mixture of ethanol

  and petroleum ether. Colorless crystalline powder; F. 156 C.

  Elemental analysis: C (%) H (%) N (% Calculated for C 15 H 19 N 3 O 2, C 2 R 2 O 4 56.19 5, 83 11,

(MW = 363,373)

Found 56.32 5.72 11,

EXAMPLE 26

) 56

  2- [3- (N, N-diethylamino) -propyl] -4- (N, N-) oxalate

  diethylcarbamoyl) -l (2H) -isoquinolone. Recristallisú in a mixture

  of methanol and diethyl ether. Colorless prisms; F. 168 C.

  Elemental analysis: - C (%) H (%) N (%) Calculated for C 21 H 31 N 3 O 2, C 2 H 2 O 4 61, 73 7.43 9.39

(MW = 447.536)

Found 61.65 7.49 9.30

EXAMPLE 27

  4- (n-Butoxycarbonyl) -2- [3- (N, N-dimethyl) maleate

  amino) -propyl] -1 (2H) -isoquinolone. Recrystallized in a mixture

  ethanol and diethyl ether. Colorless prisms; F. 142 C.

  Elemental analysis: C (%) H (%) Calculated for ClgH26N2O3, C4H4R4 61.87 6.77 6.2

(MW = 446.505)

Found 61.99 6 76 6 9L

- 1J -

) c & ^ 1.

EXAMPLE 28

  2- [2- (N, N-diethylamino) ethyl] -4-phenyl maleate

  l (2H) -isoquinolone. Recrystallized in a mixture of ethanol and

  diethyl ether. Colorless needles; F. 197.5 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C21 24N2O, C4 46 68.79 6, 47 6.42

(MW = 436.512)

Found 68.93 6.55 6.39

EXAMPLE 29

  4-Phenyl-2 (2-pyrrolidinoéthyl) -l (21) -isoquinolone.

  Recrystallized from a mixture of ethyl acetate and diethyl ether

  oil. Colorless prisms; F. 131.5 C.

  Elemental analysis: - C (%) H (%) N (Calcd for C21H22N2O 79.21 6.96 8,

(MW = 318.422)

Found 79.16 7.04 8

  4-phenyl-2- (2-pyrrolidinoethyl) -1 (2H) maleate

  isoquinolone. Recrystallized in a mixture of ethanol and ether

  diethyl. Colorless needles; F. 176.5 C.

  Elemental analysis: C (%) H (%) Ni Calcd for C21H22N2O, C444 69.11 6.03 6

(MW = 434,496)

Found 69.29 5.91 6

EXAMPLE 30

  2- [2- (N, N-diethylamino) propyl] -4-phenyl-l (2H) -

  isoquinolone. Recrystallized from a mixture of diethyl ether

  and petroleum ether. Colorless prisms; F. 920C.

  Elemental analysis: C (%) H (%) Calcd for C22H26N2O 79.01 7.84

(MW = 334.465).

  Found 79.00 7.69%) (%) N (%) 38.38

  2- [2- (N, N-diethylamino) -propyl] hydrochloride

  phenyl-l (2H) -isoquinolone. Recrystallized in a mixture of methanol

  and diethyl ether. Colorless needles; F. 203 C.

  8.45 Elemental Analysis: C (%) H (%) N (%) Calcd for C22H26020, HCl 71.24 7.34 7.55

(MW = 370.926)

  Found 71.32 7.31 7.38 2- [2- (N, N-Diethylamino) -propyl] -4-phenyl-1 (2H) -isoquinolone maleate. Recrystallized from a mixture of methanol and

  diethyl ether. Colorless prisms; F. 142 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H262 ', C4O404 69.31 6, 71 6.22

(MW = 450.539)

Found 69.51 6.78 6.25

EXAMPLE 31

  2- [2- (4-methylpiperazino) -ethyl] -4-phenyl-l (2H) -

  isoquinolone. Recrystallized from a mixture of ethyl acetate and

  of petroleum ether. Colorless prisms; F. 103.5 C.

  Analysis & Elemention: C (%) R (M) Nt%) Calculated for C22H25N30 76.05 7.25 12, 09

(MW = 347,464)

Found 75.92 7.31 11.95

  2- [2- (4-methylpipdrazino) -ethyl] dimaleate

  phenyl-l (2H) -isoquinolone. Recrystallisd in a mixture of dimethyl

  formamide and methanol. White crystalline powder; F. 207 C (decomposition) Elemental analysis: C (%) H (%) N (%) Calculated for C 22 N02C4H4 62.17. 5.74 725

22R253 4442

(MW = 579.612)

Found - 62.30 5.65 7.10

EXAMPLE 32

  4-Phenyl-2- (2-pyrrolidinopropyl) -1 (2H) -isoquinolone. Recrystallized from a mixture of diethyl ether and diethyl ether

  oil. Colorless prisms; F. 84 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H24N2O 79.48 7.28 8, 43

(MW = 332.449)

Found 79.44 7.25 8.41

  4-phenyl-2- (2-pyrrolidinopropyl) hydrochloride

  l (2H) -isoquinolone. Recrystallized in a mixture of ethanol and

  diethyl ether. Hands-colorless; F. 237 C (decomposition).

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H24N2, HCl 71.63 6.83 7.59

(MW = 368.910)

Found 71.56 6.90 7.66

EXAMPLE 33

  4-Phenyl-2- (2-piperazinopropyl) -1 (2H) hydrochloride

  isoquinolone. Recrystallized from a mixture of ethanol and diethyl ether. White crystalline powder; F. 250 C (decomposition) Elemental analysis: C (7) H (%) N (%) Calcd for C23H26N2O, HCl 72.14, 7.11 7.32

23 to 26

(MW = 382.937)

Found 72.26 7.13 7.20

EXAMPLE 34

  2- [2- (4-methylpiperazino) -propyl] dimaleate

  phenyl-l (21) -isoquinolone. Recrystallized from a mixture of dimethyl

  formamide and ethanol. White crystalline powder; F. 189.5 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C 23 H 27 N 3 O 2 Cl 4 H 4 O 4 62, 72 5.94 7.08

(MW = 593.639)

Found 62.93 5.81 7.15

EXAMPLE 35

  7-Chloro-4- (p-chlorophenyl) -2- [2- (N, N-diethylamino) -

  ethyl] -l (2H) -isoquinolone. Re-crystallized in petroleum ether.

Colorless prisms; F. 90 C.

  Elemental analysis: C (%) H (x) N (%) Calcd for C21H22Cl2N2O 64.79 5.70 7.20

(MW = 389.328)

Found 64.71 5.73 7.14

  7-Chloro-4- (p-chlorophenyl) -2- [2 (N, N-) maleate

  diethylamino) ethyl] -l (2H) -isoquinolone. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms;

F. 134 C.

Z463766

  Elemental analysis: C (%) H (%) N (%) Calcd for C21H22Cl2N2O, CH4404 59, 41 5.19 5.54

(MW = 505.402)

Found 59.27 5.25 5.63

EXAMPLE 36

  7-Chloro-4- (p-chlorophenyl) -2- [2- (N, N-diethylamino) -

  propyl] -1 (2H) -isoquinolone. Recrystallized in petroleum ether.

Colorless prisms; F. 107 ° C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H24Cl2N2O 65.51 6.00 6, 95

(MW = 403.355)

Found 65.68 6.11 6.87

  7-chloro-4- (p-chlorophenyl) -2- [2- hydrochloride]

  (N, N-diethylamino) propyl] -1 (2:11) -isoquinolone. Recrystallized in

  aqueous ethanol. Colorless prisms; F. 195 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H24Cl2N2HCl 60.08 5.73 6.37

(MW = 439.816)

Found 60.18 5.62 6.49

  7-Chloro-4- (p-chlorophenyl) -2- [2- (N, N-) maleate

  diethylamino) propyl] -l (2H) -isoquinolone. Recrystallized from a mixture of ethanol and diethyl ether. White crystalline powder;

F. 112 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H4Cl2N2O4H44 60.12 5, 43 5.39

(MW = 519.429)

Found 60.06 5.55 5.26

EXAMPLE 37

  2- [2- (N, N-diethylamino) -ethyl] -7-methoxy maleate

  4- (p-methoxyphenyl) -l (2H) -isoquinolone. Recrystallized in a mixture

  of methanol and diethyl ether. Colorless prisms; F. 161 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for 238NO03CRH06 Caleulated for C31 -28 2 3'C4 404 65.31 6.50 5.64

(PM - 496,565)

Found 65.48 6.48 5.53

EXAMPLE 38

  2- [2- (N, N-Diethylamino) ethyl] -4-ethoxycarbonyl-7-

  methoxy-l (2H) -isoquinolone. Recrystallized in petroleum ether.

Colorless premiums; F. 47 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C19H26N2O4 65.88 7.56 8, 09

(MW = 346.430)

Found 65.81 7.62 8.06

  2- [2- (N, N-diethylamino) ethyl] -4-ethoxy maleate

  carbonyl-7-methoxy-l (2H) -isoquinolone. Recrystallized in a mixture

  ethanol and diethyl ether. Colorless needles; F. 135 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C1919N2O4, C4H4O4 59.73 6.54 6.06

(MW = 462.504)

Found 59.90 6.50 6.14

EXAMPLE 39

  2- [2- (N, N-diethylamino) -propyl] hydrochloride

  methoxy-4- (p-methoxyphenyl) -l (2:11) -isoquinolone. Recrystallized from a mixture of ethanol and diethyl ether. Colorless prisms;

F. 244C

  Elementary analysis; C (%) H (%) N (%) Calcd for C24H30N2O3 HCl 66.89 7, 25 6.50

(MW = 430.979)

Found 66.76 7.28 6.48

EXAMPLE 40

  2- [2- (N, N-Diethylamino) propyl] -4-ethoxycarbonyl-7-

  methoxy-l (2H) -isoquinolone. Recrystallized in petroleum ether.

Colorless prisms; F. 100 C.

  Elemental analysis: C (%) H () N (%) Calcd for C20H28N2O4 66.64 7.83 7, 77

(MW = 360.457)

Found - 66.78 7.70 7.65

EXAMPLE 41

  2- [2- (N, N-diethylamino) -l-methylethyl] -4-phenyl-

  l (2H) -isoquinolone. Recrystallized from a mixture of diethyl ether

  and petroleum ether. Colorless prisms; F. 95 C.

  Elemental analysis:.) H (%) N (%) Calcd for C22H26N2O 79.01 7.84 8.38

(MW = 334,465)

  Found 79.10 7.90 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; F. 198 C (decomposition). Elemental analysis: C (%) H (%) N (%) Calculated for C22H26N2O, HCl 71.24 7C34 7.55

(MW = 370.926)

Found 71.16 7.45 7.60

EXAMPLE 42

  4-Cyano-2- [2- (N, N-diethylamino) propyl] -l (2H) -iso-

  quinolone. Recrystallized from a mixture of diethyl ether and

  of petroleum ether. Colorless prisms; F. 93 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C17H21N30 72.06 7.47 14, 83

(MW = 283.376)

Found 71.91 7.55 14.79

  4-cyano-2- [2- (N, N-diethylamino) propyl] -aleate

  l (2H) -isoquinolone. Recrystallized in a mixture of methanol and

  diethyl ether. Colorless prisms; F. 148 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C17H21N3O, C4404 63.15. 6.31 10.52

(MW = 399,451)

Found 63.31 6:22 10.44

EXAMPLE 43

  4-Cyano-2p [2- (N, N-dimethylamino) propyl] -l (2H) -iso-

  quinolone. Recrystallized from a mixture of ethyl acetate and

  of petroleum ether. Colorless prisms; F. 141 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C15H17N30 70.56 6.71 16, 46

(MW = 255.322)

Found 70.44 6.71 16.59

  4-cyano-2- [2- (N, N-dimethylamino) propyl] maleate

  l (2H) -isoquinolone. Recrystallized from a mixture of methanol and

  diethyl ether. White crystalline powder; F. 177 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C15H17N3O, C4H4O4 61.45 5, 70 11.31

(MW = 371.396)

Found 61.61 5.78 11.33

EXAMPLE 44

  2- [2- (N, N -diethylamino) -propyl] maleate

  phenyl-7-methoxy-l (2H) -isoquinolone. Recrystallized from a mixture of ethyl acetate and diethyl ether. Colorless needles;

F. 98 ° C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C23H28N2O2, C4H4O4 67.48 6.71 5.83

(MW = 480.560)

Found 67.31 6.66 5.88

EXAMPLE 45

  4- (p-Methoxyphenyl) -2-r2- (N, N-) hydrochloride

  diethylamino) -ethyl] -1 (2H) -isoquinolone hemihydrate. Recrystallisi in a mixture of ethanol and diethyl ether. White needles;

F. 193 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C22H26N2O2, HCl.1 / 2H2O 66, 74 7.13 7.07

(MW = 395.933)

Found 66.74 6.91 7.18

EXAMPLE 44

  4- (p-Chlorophenyl) -2- [2- (N, N-) hydrochloride

  diethylamino) ethyl] -1 (2H) -isoquinolone. Recrystallized from a mixture of methanol and diethyl ether. Crystalline powder

white; F. 1940C.

  Elemental analysis C (%) H (%) N (%) Calcd. For 2H23ClN2O2HCl / 2H2O 6300 6, 29 7.00 21l23 2> 0 '

(MW = 400.3% 3)

  Found 62.97 6.17 7.30 The following examples illustrate the pharmacological activities, the acute toxicity and the pharmaceutical preparations of characteristic compounds of formula (I) according to the invention, in

  comparison with known compounds.

  Compounds tested Compound A: Compound B: Compound C: Compound D:

  2- [3- (N, N-dimethylamino)) tartrate

  propyl] -4-phenyl-1 (2H) -isoquinolone (prepared in Example 1)

  2- [2- (N, N-dimethylamino) hydrochloride

  ethyl] -4-phenyl-1 (2H) -isoquinolone (prepared in Example 6)

  4-cyano-2- [3- (N, N-dimethyl) tartarate

  amino) -propyl] -1 (2H) -isoquinolone hemi

hydrated (prepared in Example 17)

  2- [2- (N, N-dimethylamino) maleate

  propyl] -4-phenyl-1 (2H) -isoquinolone (prepared in Example 13) Analgesic activity According to the method of acetic acid convulsions described by Koster et al. [Fed. Pro., 18, 412 (1959)], Compound A is administered orally to male mice ddy (25 g body weight) which have been incubated overnight prior to testing. 1 hour later

  administration of Compound A is administered intraperitoneally

  A 0.6% aqueous solution of acetic acid was added at a dose of 0.35 ml per mouse and the convulsions of the mice were observed 10 min after the administration of the acetic acid solution for a period of one hour.

  duration of 10 min and the percent inhibition is calculated.

  The results obtained are shown in Table I below. These results clearly indicate that compound A inhibits the injection-induced pain response

  of acetic acid at doses of 50 and 100 mg / kg, depending on the dose.

  Antireserpine activity (antidepressant activity) Reserpine was administered to male mice ddy (body weight 25 to 30 g) at a dose of 2 mg / kg and, after fasting for 18 h, the reserpine was again administered by subcutaneously at a dose of 2 mg / kg. Five hours after the second reserpine administration, the mice were selected to show a constant decrease in body temperature and orally administered the test compound (Compound C), and the rectal temperature of the mice was measured at 1 hour intervals. The results obtained are shown in FIGS. 1 (a) and 1 (b). In Figure 1 (a), the -0-XY curve corresponds to the control animals, the -UKF curve corresponds to the administration of mg / kg po of imipramine and the -OD- curve to the administration of 50 mg / kg in amitriptyline. In FIG. 1 (b), the -CH- curve corresponds to the control animals, the -4-A- curve corresponds to

  the administration of 50 mg / kg p.o. of the compound C and the curve -A-A-

  corresponds to 100 mg / kg p.o. of the compound C. In Figures 1 (a) and 1 (b), the points of the curves

* marked * correspond to p <-0.05 and the points marked ** correspond to

lay at p <0.01.

  These results indicate that compound C increases significantly at doses of 50 and 100 mg / kg

  rectal which has been lowered by reserpine pre-treatment.

  In this experiment, imipramine or 10,11-dihydro-N, N-dimethyl-5H-dibenzofbf] azepine-5-propanamine is used and

  amitriptyline or 3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-

  ylidene) -N, N-dimethyl-1-propanamine as typical examples of known comparative compounds and the results obtained with these

  compounds are also shown in Figure l (a).

  Antihistamine and anticholinergic activities Extracted ileum from a guinea pig (body weight 300

  at 400 g) and suspended in a tube of Magnus containing a solution

  Tyrode (saturated with oxygen) at 31 ° C and the

  inhibitory effect of the compounds tested on the contraction induced by the administration of histamine or acetylcholine. The treatment with the test compounds is carried out 30 seconds before the contraction induction. The results obtained are shown in FIGS. 2 (a) and 2 (b) for compound A, FIGS. 3 (a) and 3 (b) for compound B and FIGS. 4 (a) and 4 (b) for In these figures, the curve a- corresponds to the control animals. The 1.0 value of contraction of ileum corresponds to histamine in Figures 2 (a), 3 (a) and 4 (a) and acetylcholine in Figures 2 (b), 3 (b). )

  and 4 (b). In addition, the curves - "--- correspond to a concentration

  10 6 mol / l: the curves --- to --- at a concentration of 5. 10'6 mol / l. In Figures 2 (b), 3 (a) and 3 (b), the curves -. -correspond to a concentration of 10-5 mol / l and the -5-

  curves --- O ---- correspond to a concentration of 5.10'5 mol / l.

  In Figures 4 (a) and 4 (b), the curves --- A --- correspond to a concentration of 5.105 mol / l and the curve --- - corresponds to a concentration of 104 mol / l. As can be seen from these figures, compounds A, B and C move parallel to the right

  histamine-induced contraction curve of guinea pig ileum.

  This indicates that compounds A, B and C possess specific antihistaminic activity. It is also found that the compounds

  A and B have non-specific anticholinergic activity.

  Inhibitory activity of gastric secretion In male Wistar rats (body weight 180 to

  200 g) having been fed for 24 hours, the pylorus is ligated under anesthesia.

  ether thesis and administered immediately after the test compound in the duodenum. 4 hours after administration, the stomach is extracted and the gastric juice is collected and centrifuged at 3000 rpm for 15 minutes. The supernatant liquor is then determined by the volume of gastric juice, the pH and the degree of

secretion of acid.

  The results obtained are shown in Table II below. As these results show, compounds A and C reduce gastric juice volume and acid secretion and

increase the pH.

  Anti-ulcer activity i) stress ulcer

________________

  The test compound is orally administered to male Wistar rats (body weight 200 to 270 g) and then the rats are attached with steel wire and immersed in water at 23 ° C.

  in a reservoir up to the level of the xiphisternum of the rats.

  After allowing the rats to stand for 7 hours in water, the rats are sacrificed and the stomach is extracted. 10 ml of a 1% solution of formaldehyde is injected into the stomach cavity and the stomach is immersed in a 1% formaldehyde solution for 15 minutes for the stomach to be semi-hardened. The stomach is excised along its largest line of curvature and the ulcers produced in the portion of the ventriculi corpus are observed. The results obtained are shown in Table III below. As is apparent from these results, Compound A inhibits ulcer production by water immersion stress at a dose of 25, 50 and 100 mg, depending on the dose. ii) ulcer! Indomethacin A suspension of indomethacin in 0.25% carboxymethylcellulose was administered subcutaneously at a dose of mg / kg to Wistar male rats (body weight 125150 g) fasting for 24 hours. The test compound is administered orally

  min before administration of indomethacin. 7 hours after the administration

  Indomethacin is administered, the sacts are sacrificed by dislocation of the neck, and the stomach is extracted. 7.5 ml of 1% formaldehyde solution are injected into the stomach cavity and the stomach is hardened. Linear-type ulcers produced on the membrane are then observed

mucous membrane of the stomach.

  The results obtained are shown in Table IV below. As it appears from these results, compounds B and D inhibit indomethacin-induced ulcers.

at a dose of 50 mg / kg.

  Acute Toxicity The test compound was administered to male mice ddy (20-25 g body weight) fasting overnight prior to administration. After administration, the general condition of the mice is observed for 7 days and the LD50 lethal dose (mg / kg) is determined.

  The results obtained are shown in Table V below.

  The following examples illustrate preparations

  pharmaceutical compounds containing the compounds of the invention.

  Examples of preparations 1. Granules Compound A 200 mg Lactose 500 mg Starch 280 mg Hydroxypropylcellulose 20 mg 1.000 mg per sachet The preparation of granules is prepared in a

  classic using the above formulation.

2. Tablets

  Compound B Lactose Crystalline Cellulose Hydroxypropylcellulose Talc Magnesium Stdarate The preparation for conventional preparation is prepared using the above formulation mg mg mg mg 4 mg 1 mg 270 mg per tablet tablets so S. 3. capsules Compound C Lactose Microcrystalline Cellulose Stearate magnesium mg mg 18 mg -2 mg 400 mg per capsule The preparation for tablets is prepared

  classic using the above formulation.

  As previously described, some of the starting materials of formula (II) are novel compounds. The following examples describe the preparation of novel products. Reference Example 1 20 g of ethyl p-chlorophenylacetate, g of sodium ethoxide and 15 g of ethyl formate, in this order, are added to 200 ml of ethyl ether and the mixture is stirred for 16 hours. At room temperature, an equal amount of water is then added to the reaction mixture and, after shaking vigorously, the aqueous layer is separated. The aqueous layer is neutralized with 2N hydrochloric acid and the oily substance released is extracted with dichloromethane. The extract is washed with water and the

  solvent by distillation to obtain 14.2 g of p-chlorophenyl-

  α- (Formyl) ethyl acetate, m.p.

  14.2 g of p-chlorophenyl -formyl are then added.

  ethyl acetate and 6.5 g of urethane to 50 ml of toluene containing 0.3 ml of concentrated sulfuric acid, and the mixture is refluxed by distilling off the water which forms during the reaction until the reaction is complete. The solvent is distilled off and the residue is extracted with hot ethyl ether. The solvent is removed from the extract by distillation

  to obtain 13.7 g of p-chlorophenyl- (α-ethoxycarbonylaminomethylene) -

ethyl acetate, F. 720C.

  13.7 g of p-chlorophenyl- (α-ethoxycarbonyl)

  aminomethylene) -ethyl acetate to 50 ml of diphenyl ether and the mixture is refluxed for 3 hours. After cooling, benzene and petroleum ether are added to the reaction mixture, the precipitated crystals are filtered and recrystallized from a mixture of dimethylformamide and ethanol to give 7 g of 7-chloro-4-ethoxycarbonyl-1 ( 2H) -isoquinolone in the form of prisms

colorless, F. 243 C.

  Elemental analysis: C (%) H (%) N (%) Calculated for C12H10 lONO3 57.27 4.01 5.57

(MW = 251.671)

  Found: 57.36 4.05 5.53 Reference Example 2 The procedure described in Reference Example 1 was repeated, but using ethyl methoxyphenylacetate as starting material instead of ethyl pchlorophenylacetate and

  the resulting crystals are recrystallized from a dimethyl

  formamide and ethanol to give 4-ethoxycarbonyl-7-methoxy-

  1 (2H) -isoquinolone as colorless prisms, F. 191 C,

yield 64%.

  Elemental analysis: C (%) H (%) N (%) Calcd for C13H13NO4 63.15 5.30 5, 66

(PH = 247.253)

  Found 63.27 5.28 5.72 Reference Example 3 The procedure described in Reference Example 2 was repeated, but using pmethoxyphenylacetonitrile as starting material instead of ethyl pchlorophenylacetate, and

  recrystallizes the resulting crystals in a mixture of dimethyl

  formamide and ethanol to give 4-cyano-7-methoxy-1 (2H) -iso-

quinolone, mp 264 ° C., yield 58%.

  Elemental analysis: C (%) H (%) N (%) Calculated for C₁₁H₁NN₂O 66 66.00 4.03 13.99 (pH = 200.199) Found 66.16 4.20 13.88 Reference Example 4 refluxing for 20 hours a mixture of 19 g of 4-carboxy-1 (2H) isoquinolone, 10 ml of concentrated sulfuric acid and 1 liter of n-butanol. The solvent is distilled off and petroleum ether is added to the residue and the mixture is allowed to stand. The solidified material is filtered off and recrystallized from a mixture of n-butanol and petroleum ether to give 17 g of 4-n-butoxycarbonyl (2H) -isoquinolone in the form of

colorless needles, F. 170 C.

  Elemental analysis: C (%) H (%) N (%) Calcd for C14H15NO3 68.56 6.16 5, 71

(MW = 245.281)

  Found 68.82 6.11 5.58 It is understood that the invention is not limited

  to the preferred embodiments described above as illus-

  tration and that those skilled in the art may make changes

  without departing from the scope of the invention.

Table I

  Analgesic activity Number of convulsions

36.5 + 6.5

33.8 + 8.2

16.9 + 4.8 *

  , 0 ± 2.8 t Inhibition (%) 53.7 72.6 * p <0.05 p <0.01 r> 0% Lm 0% 4> bones. Compose Dose (mg / kg) Number of Animals Control Compound A Compound A. Compound A at

Table II

  Inhibitory activity of gastric secretion Dose Composd (ai / kg) Number of rats Volume of gastric suC (mi)

2.51 + 0.32

0.53 ± 0.12 *

1.85 + 0.35

0.90 - 0.09 *

1.71 + 0.11

3.06 + 0.44 *

1.88 + 0.10

2.22 + 0.25

184 + 27.2

22 + 5.9 and

72 5.3 **

  57 6.0 t * 'p <0.05 * p <, 01' ri 0O sa w on Control Compos4 A Compose C Atropine pH Acid secretion (/ u Eq.) 4s r4

Table III

  Anti-ulcer activity (Stress) Compound Dose Number of ulcer IndexInhibition (mg / kg) rats tion (mm) (%) Control 6 75.8 Compound A 25 6 58.0 23.5 Compound A d 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 * 5-Aminosulfonyl-N - [(1-ethyl-2-pyrrolidinyl) methyl] -2-methoxybenzamide Where:

Table IV

  Anti-ulcer activity (indomdthacin) Dose (lgikg) Compost.

Ulcer index

  (mmin) Inhibition (%) Control 8 Compound B 50 8 Compound D 50 -. Sucralfate * 300 8 * basic aluminum sucrose sulphate Number of rats, 4 6.0 4.1 2.9 61.0 73.0 81.1 raw 0% IM -'J

Table V

  Acute toxicity Compound LD50 (mg / kg) Compound A 662 Compound B 195 Compound C 699 Compound D.505 M 0% 01%

R E V E N D I T I ON

  1. Novel 1 (2H) -isoquinolones, characterized in that they correspond to the general formula R1

- / R2 (I)

  NZN wherein Y is hydrogen or chlorine or methoxy, Z is a divalent straight or branched C 4 -C 4 saturated aliphatic hydrocarbon radical R 1 is cyano, lower alkoxycarbonyl, carbamoyl, N-substituted carbamoyl , phenyl or substituted phenyl, R2 represents hydrogen or a lower alkyl group, 3 represents a lower alkyl group, or R2 and R, taken together with the nitrogen atom to which they are attached, may form a heterocyclic group, and their acid addition salts, 2. Compounds according to claim 1, characterized in

  what it consisted of 2- [3- (N, N-dimethylamino) -propyl] -4-phenyl-

  1 (2H) -isoquinolone and its acid addition salts.

  3. Compounds according to claim 1, characterized in

  they consist of 2- [2- (N, N-dimethylamino) ethyl] -4-phenyl-

  l (2H) -isoquinolone and its acid addition salts.

  4. Compounds according to claim 1, characterized in

  what they consist of 4-cyano-2- [3- (N, N-dimethylamino) -propyl] -

  1 (2H) -isoquinolone and its acid addition salts.

  5. Compounds according to claim 1, characterized in

  what they consist of 2- [2- (N, N-dimethylamino) -propyl] -4-phenyl-

  l (2H) -isoquinolone and its acid addition salts.

  6. Process for the preparation of compounds according to

  Claim 1, characterized in that a 1 (2H) -

  substituted isoquinolone of formula R1 wherein Y and R1 are as defined above, with an aminoalkyl halide of formula / R2

X-Z-N (III)

  wherein X represents a halogen atom and Z, R2 and R3 are as defined above, in the presence of a basic catalyst. 7. Process for the preparation of compounds according to claim 1 bearing a carbamoyl group in the 4-position, characterized in that a 4-ester of general formula R 1 is reacted under heat conditions.

N I N-Z-N (I ')

y R3

0

  in which R is a lower alkoxycarbonyl group and Y, Z, R2 and 3 are as defined above, with an amine of formula (VII), in an alcohol as solvent. "8. Process for the preparation of the compounds according to claim 1, characterized in that the compound of

  formula (II) as defined above with a hydroxy halide

alkyl of formula

X-Z-OH

  (Iv) wherein X and Z are as defined above, to produce 2- (hydroxyalkyl) -1 (21H) -isoquinolone of formula R1

] .N -Z-OH (V)

  wherein Y, Z and R1 are as defined above, the compound of formula (V) is reacted with a halogenating agent to produce a 2 (haloalkyl) -1 (2H) -isoquinolone of formula R1 II NZX y ( VI) in which Y, Z, R1 and X are as defined above and the compound of formula (VI) is reacted with an amine of formula HN "a3 (VII)

  wherein R2 and R3 are as defined above.

  9. Process according to claim 8, characterized in

  the 4-carbamoyl compounds of formula (I ') - hereinafter

  by hydrolysis of the 2- (hydroxyalkyl) -1 (2H) -isoquinolone of the formula

2463? 66

(V)

N-Z-OH

  in which R 1 represents a lower alkoxycarbonyl group and Y and Z are as defined above, dissolved in an alkaline alcohol to the corresponding 4-carboxylated compound of formula

(VIII)

  Wherein Y and Z are as defined above, reaction of the 4-carboxyl compound with a halogenating agent in the presence or absence of an organic solvent for about 1 to 3 hours to obtain the halogenide of the compound. (2H) -isoquinolone-4-carbonyl corresponding formula COX

1 N-Z-X

  in which X, Y and Z are as defined above, reaction of the acid halide (IX) thus obtained with an amine of formula

  (VII) in an amount of at least about 2 moles per mole of the halogen

  acid in an organic solvent at room temperature for about 1 to 5 hours, to obtain the corresponding 4-carbamoyl compound of formula R 2/2 CON 1 R 3 fol (X) NZX O wherein X, Y, Z, R2 and R3 are as defined above and reaction of the resulting compound (X) with an amine of formula (VII) in an organic solvent at about 90 to 150 ° C for about 1 to

  6 h to obtain the desired compound of formula (I ').

  10. Intermediate products necessary for the preparation of the compounds according to claim 1, characterized in that they correspond to the general formula R1

- NH

  Y, 1 in which R 1 represents a cyano group or a group (alkoxy)

  lower) carbonyl and Y is as defined in claim 1.

  he. New drugs, useful especially as an analgesia

  characterized in that they consist of compounds of formula (I) according to claim 1, and their non-acid addition salts.

toxic acceptable in pharmacy.

  12. Therapeutic compositions, characterized in that they contain as active ingredient at least one drug according to claim 11, in combination with a carrier or excipient

appropriate pharmaceutical

  13. Pharmaceutical forms of administration of the compositions according to claim 12, characterized in that they are in particular tablets, capsules, granules, powders, injections, suppositories, ointments, at daily doses of 0.5 to 50 mg / ml. kg

  body weight in adult man, in 1 to 3 shots.