AU476552B2 - Tetrahydro isoquinolyl carboxylic acid amides - Google Patents

Description

The present invention relates to new 2-[1,2,3,4-

tetrahydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-(2)]-

carboxylic acid amides having interesting pharmacological

properties.

According to one feature of the present invention

there are provided compounds of the general formula

CH3 CH3

0 /R2 (1) N--CH -CO N

IRI R3

(wherein Ri to R3, which may be the same of different,

each represents a hydrogen atom or an alkyl group with

from 1 to 3 carbon atoms).

The compounds of general formula I have interesting

pharmacological properties. In particular the compolnds

according to the invention a muscle relaxing,

sedative, antiarrhythmic and /or anticonvulsive activity.

The compounds according to the invention which have

476,552

58.735n

been tested as hereinafter described have been shown to

all four activities.

Preferred compounds according to the invention.

by virtue of their particularly favourable pharmacological

properties are the following:-

2-[l,2 ,3,4-Tetrahvdro-4,4-dimethyi.-l,3-dioxo-isoquinolyl-

1-acetamide,

2-[l,2 ,3,4-Tetrahydro-4,4-ditnethyl-l,3-dioxo-isoquinolyl-

(2)1-acetic acid methylarnide,

2-[l,2 ,3,4-Th.trahydro-4,4-dimethyl-l,3-dLoxo-isoquinolyl-

J-propionamide,

2-El ,2,3,4-'Tetrahydro-4,4-dimethyl-1,3-diLxo-isoquiniolyl-

(2)1-acetic acid ethylamide,

2- [1,2 ,3,4-Tetrahydro-4 ,4-dimethyl-l ,3-dioxo-isoquinolyl-

(2)1-acetic acid propylarnide,

2-El ,2,3,4-Tetrahydro-i ,4-dinethyl-l;3-dioxo-isoquinolyl- (2)1-acetic acid isopropylamide, and

2- [1,2 ,3,4-Tetrahydro-4 ,4-dimethyl-l ,3-dioxo-isoquinolyl-

(2)]-acetic acid dimethylaxnide,

3 476,552

58,73 5 n3

The compounds of general formula I may, for example,

be prepared by one of the following processes a) to f),

which processes constitute further features of the

present invention:-

a) Reaction of the imide of formula

CH 3

(II)

or of an alkali metal salt thereof with a halogeno-

carboxylic acid amide of formula

2 Hal CH CO -N (III)

RR113

(wherein R1 to R3 are as hereinbefore defined and Hal.

represents a chlorine, bromine or iodine atom).

476,552

58,7 3 5 n3

The reaction using the imide is preferably effected

in the presence of a base, for example potassium tert.-

butoxide, sodium isopropoxide or sodium hydroxide, advan-

tageously in the presence of a solvent, e.g. methanol,

isopropanol or dimethylformamide, and desirably at temper-

atures from 0° to the boiling temperature of the solvent

used, e.g. at temperaturez from 70 to 250 0 C. The. reaction using an alkali metal salt of the imide of

formula II may be effected in the absence of a base.

b) Reaction of a compound of general formula

CH3 CH3

0

(IV) N CH COA

0 1 (wherein R (wherein R1 is as hereinbefore defined and A represents a

hydroxy group or a replaceable radical) with an amine of

formula R^ H -N R (v) 3

R 4 552

476,552

58,735 n3

(wherein R 2 and R 3 are as hereinbefore defined) or, if A

in the compound of formula IV represents a hydroxy group,

with a urea of fomnula

R R2 R

CO (Va)

3 3

(wherein R 2 and R 3 are as hereinbefor3 defined).

Where A in the compound of formula IV represents

a replaceable radical, it may, for example represent a

halogen atom, an imidazolyl group, or an alkoxy, aryloxy,

alkylthio, aryltl'io, acyloxy or optionally substituted

amino group. The compound of formula IV wherein A

represents a replaceable radical may optionally be formed

in situ.

The reaction is optionally carried out in the

presence of a solvent, e.g. in methanol, ether, tetra-

hydrofuran, dimethylformamide or benzene, and advantage-

ously at temperatures from -50 to 250 0 C.

6 476,552

58 7 3 5 n3

If, for example, A represents'the hydroxyl group,

the reaction is preferably carried out in the melt at

temperatures from 200 to 250°C, or in the presence of a

dehydrating agent, e.g. in the presence of cyclohexyl-

carbodiimide, thionyl chloride or phosphorus oxychloride,

and in the presence of a solvent at temperatures from

to 100 0 C.

c) Methylation of a compound of formula

R2 (VI) CO N CH

(wherein R to R3 are as hereinbefore defined).

The reaction is effected with a methylation agent,

for example methyl iodide,preferably in the presence of

a solvent, e.g. methanol or dimethylformamidc, and

desirably in the presence of a base, e.g. sodium methoxide,

sodium hydroxide or sodium carbonate, at temperatures

from -30° to 200'C. The reaction may, however, also be

7 476,552

58, 7 3 5 n73

carried out in the absence, of a s*olvent. d) Reaction of a Compound Of formula

CH3 CH 3

B 0(VII) 0

(wherein B represents an Oxygen atom or an imino group) or of a dicarboxylic. acid Of-formula CH 3 S-COOH

Co CH (VIa)

with a compiound Of formula

H N CH CO N(VIII)

476,552

58,735 3

(wherein R I to R3 are as hereinbefore defined) or with an

acid addition salt thereof.

The reaction is advantageously carried out in the

presence of a solvent, for example glycol, or in the melt, 0 preferably at temperatures from 50 to 250 C and optionally

in the presence of a base,for example potassium tert.-

butoxide. The presence of a base is preferred if an acid

addition salt of the compound of formula VIII is used.

e) For the preparation of compounds of general formula I,

wherein R 2 and R 3 represent hydrogen atoms: Partial

hydrolysis of a compound of formula

CH CH3

S CH CN (IX)

R1

(wherein R I is as hereinbefore defined).

The partial hydrolysis can be effected under acidic

or alkaline conditions, preferably at temperatures from

476.552

58, 73 5 n3

0 to 200°C, and optionally in a pressure vessel. The

acidic saponification may, for example, be carried out

with alcoholic hydrochloric acid, e.g. ethanolic hydro-

chloric acid, the imidoester obtained as intermediate,

being subsequently decomposed with water, or with

concentrated sulphuric acid. The alkaline saponification'

may, for example, be effected with sodium hydroxide in the

presence of hydrogen peroxide.

f) Desulfurization of a compound of formula CH 3 CH 3

SR4 N C R (X) CH-

R 0

(wherein R I to R 3 are as hereinbefore defined, R represents

a hydrogen atom or an alkyl, aryl or aralkyl group, and

X represents an anion of an acid) or of the corresponding

base if one of the radicals R 2 to R represents a hydrogen

atom.

476.552

58, 7 3 5 n3

In the tests which follow it ha-s been shown that

in general tile new compounds of general formula I which

have been tested show muscle relaxing, sedative, anti-

arrhythmic and anticonvulsive activities of long duration.

The following compounds have been tested to determine

their biological activity:

A 2-[1,2 ,3,4-tetrahydro44dimthyl1,3dioxo-isoquin-

olyl-(2)]-acetamtide,

B 2-El ,2,3 ,4-tetrahydro4,4dimethyl1,3dioxo-isoqui-n

olyl-(2Y1j-acetic acid methylamide,

C 2-[1,2 ,3,4-tetrahydro4,4dimethyl,3-dioxoisoquini

olyl- ]-propionamide,

D =2-El ,2,3,4-tetrahydro4,4dimethyl1,3dioxo-isoquin-

olyl-(2)]-acetic acid ethylamide,

E 2-El ,2,3,4-tetrahydro4,4dimethyl1,3dioxo-isoquin-

olyl-(2)]-acetic acid propylamide,

F 2-[l,2,34ttayr-,-iety-,-ix-sqi-

olyl-(2)]-acetic acid-isopropylamide and

I I 11476.552

58,7 3 5 /73

G 2-[1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquin-

2 olyl-( )]-acetic acid dimethylamide.

1. Muscle relaxing and sedative activity in mice:

The muscle relaxing and sedative activity was tested

according to the method of Young and Lewis (Science 105,

368 (1947)) with female NMRI-mice of a specific breed

having a body weight of from 20 to 26 g. The test

apparatus comprises slowly turning wire cylinders, sloped

for 30° against the vertical line (length: 43 cm; diameter:

22 cm; mesh-size of the wire netting: cm). After

peroral administration of a suspension of the substance

under test in 1% tylose solution to group: of 10 mice

their bearing in the slowly rotating cylinders (2 rota-

tions/minute) was observed and was compared with a

control group. The dose (ED 5 0 which caused 50% of the

animals to fall out after certain test times was determined

graphically:

12 47 6552

58, 73573

Substance ED5 0 mg/kg p.o.

30-60 120-150 210-240 270-300 minutes

A 40 34 52 32

B 48 71 100

D 70 110 E 95 140

F 75 110 G 34 67 71 100

Anticonvulsive activity in mice:

The anticonvulsive activity was tested as protective

activity in male NMRI-mice of a specific breed and having

a body weight of from 20 to 26 g to the maximum electro-

shock-spasm according to the method of Swinyard, Brown and

Goodman Pharmacol. exp. Therap. 106, 319 (1952))..

The animals were exposed to an alternating current of

Hz and 50 mA (duration of stimulation 0.2 seconds),

whereby the occurence of the tonic extensor spasm was

valued as positive. After peroral application of a

13 476,552

58,.7 3 5 73

suspension of the substance under test in 1% tylose

solution the dose (ED 5 0 providing protection in 50% of

the animals to the tonic extensor component of the back

extremities for various testing times was determined

graphically:

Substance ED 5 0 mg/kg p.o.

150 300 minutes !-T

21

32

69

42

52

Antiarrhythmic activity in rguinea m pigs:

The antiarrhythmic activity was tested as antagonism

to arrhythmics caused by digitalis:

14 476.552

58, 73 5 m

digoxin and injection of A catheter for infusion of the vena cava superior of 11 substance A was bound into g/kg i.p. urethane) with a narcotized guinea pigs (1.5

g. Digoxin was infused intrav- body weight of 335 to 385 arrhythmics enously at 20Y/min. until ventriculous A (a solution of A in occurred. 40 mg/kg of substance to 5 animals polydiol) were then administered

intraveneously over 1 to 2 minutes.

Result: glycoside lasted for The arrhythmics caused by the

after digoxin infusion was a further 13 to 20 minutes (6 animals), while they completed in the control group injection of substance A were removed immediately after

in the test group (5 animals). I which have been.. The compounds of general formula

tested show a low acute toxicity. For example the LD 5 0

to be 1136,mg/kg. for compound A in the mouse was estimated

days). p.o. (observation time: 14

447 6.552

58,735/73

According to yet a further feature of the present

invention there are provided pharmaceutical compositions

comprising as active ingredient a compound of formula I

as hereinbefore defined in association with a pharmaceutical

carrier or excipient.

The compositions according to the invention may be

in a form suitable for oral, rectal or parenteral admin-

istration. Suitable forms of administra-:ion include, for

example, tablets, coated tablets,suppositories and

suspensions.

The compositions according to the invention may

advantageously be administered in the form of dosage

units, each dosage unit containing from 50 to 300 mg,

preferably from 50 to 200 mg, of active ingredient.

The following Examples serve to illustrate the

preparation of compounds of general formula I according

to the invention and pharmaceutical compositions

containing them.

16 476,552

58, 73 5 n3

Example 1 3 -dioxo- 2 -[l,2,3,4Tetrahydro-4,4dimethll1,

isoguinolyl-(2) acetamide

g of 1 2 3 4 -dihydro-4,4-dimethyl-.soquinolin-dione

10 g of potassium tert.-butoxide and 8 g of

chioroacetamide were stirred1 for 6 hours at 801C in

ml of dimcthylformamide. Subsequently, the solvent

was removed1 and the residue was treated with water.

The precipitated crude product was suction filtered

and recrystallized first from methanol and then from

toluene. 182 to 184'C, Yield: 16.5 g (81 of

theory)

Example 2

2-[l,2,3,4-Tetrahydro-4,4dimethyll,3dioxo-

isoguinoiyl-(2) -acetamide

18.8 g of i,,,-erhdo44dmty-sounln

dione-(l,3) werc added in small amounts to a solution

of 2.6 g of sodium in 100 ml of isopropanol. The

mnixture was ref luxed with stirring and a solution of 10 g

of chloroacetamide in 50 ml of isopropanol was slowly

17 476,552

58, 73 5 n3

added dropwise. Subsequently, the mixture was ref luxed

for a further 2 hours, and then TChe solvent was removed

and the residue was washed several times with water.

182 to 1841C (from isopropanol)-,

Yield: 19.1 g (77.5 of theory)

Example 3

2-[l,2,3,'!.-Tetrahydro-4,4-dimethyl-l,3-dioxo-

isoguinolyl-(2))-acetarnide

a) 95 g of 3,4-dihydro-4,4-dimethyl-isochroman-dione-

and 37.5 g of glycine were melted together with

stirring as the bath temperature was slowly raised to

l8 0 The water which was produced during the

reaction was distilled off. After 7 hours of reaction

time the mixture was cooled, and dissolved while still

warm in glacial acetic acid. On cooling 2-[1,2,3,4-

tetrahydro-4,4- dimethyl-1,3-dioxo-isoquinolyl--(2)J-acetic

acid precipitated out and was suction filtered.

152 to 154 0 C, Yield: 92.7 g (75 of theory).

b) 5 g of 2-[l,2,3,4-tetrahydro-4,4-diinethyl-l,3-dioxo-

isoquinolyl-(2)]-acetic acid prepared as above were

is 18 476.5 52

58,735

refluxed for one hour with 50 ml of distilled

thionyl chloride. The excess of thionyl chloride was

removed in vacuo,and the residue remaining was dissolved

in 100 ml of ether. This solution was saturated with

ammonia whilst stirring and cooling. After standing

overnight, the solution was reacted with water and

extracted with chloroform. The organic layers were

combined, dried and the solvent was removed. The

residue was recrystallized from methanol. 0 182 to 184 C, Yield: 3.8 g (77 7. of theory)

Example 4

a) 2-[l,2,3,4-Tetrahydro-l,3-dioxo-isocuinolyl-(2)]-

acetic acid

18.0 g of homophthalic acid and 8.0 g of glycine were 0 melted together at 180 C, heated at 180 to 190°C for

hours whilst stirring and the water formed during the

reaction was distilled off over a bridg-. After

recrystallizing from ethanol, yellow crystals were

obtained 253 to 2550C).

19 47 6,552

58, 7 3 5 n3

b) 2-[1,2,3,4-Tetrahydro-l,3-dioxo-isoquinolyl-

]-acetamide

22 g of 2-.[,2,3,4Tetrahydro1,3dioxo-isoqifolyl1(2)1>

acetic acid prepared as above were ref luxed for one

hour with 100. ml of acetic anhydride. The solution

obtained was subsequently cooled with ice. The

precipitate which formed was suction filtered and was

added in small amounts to 100 ml of conccntrated

ammonia without further purification. The solution

was stirred for a further 1/2 hour, and acidified whilst

cooling with 50% concentrated hydrochloric acid. The

precipitated reaz-tion product was washed several times

with water and recrystallized from dimethylformamide

M..)2751C (decomp.).

b) 2-[1,2,3,4-Tetrahydro-4,4-dimthyl-1,3-dioxo-

isoauinolyl- 1-acetamide

2.2 g of 2-[1,2,3,4-tetrahydro-1,3dioxo-isoquinolyl-

(2)11-acetainide and 3 g of methyl iodide were ref luxed for

3 hours in a solution of 460 mg of sodium in 20 ml of

20476,552

58,7353

methanol. Subsequently the solvent was removed, the

residue was reacted with water, and the precipitated

crude product was-suction filtered and recrystallized

from methanol.

182 to 184 0 C.

Example

a) (2-Carboxy-phenyl)-dimethyl-acetic acid

g of 3,4-dihydro-4,4-dimethyl-isochroman-dionc-(l,3)

were heated for one hour on a steam bath with

potassium hydroxide solution. The solution obtained

was extracted with ether. The aqueous layer was

acidified with ice-cooling with concentrated

hydrochloric acid (pH The solution was again

extracted several times with ether. The ethereal

solutions were dried over calcium chloride and the

solvent was removed in vacuo. The residue consisted of

colorless crystals, which were soluble in aqueous sodium

hydrogen carbonate solution.

115 to 118 0 C.

21 4 7 6,5 52

58, 7 35 n3

b) 2- [1,2,3,4-.Tetraiydro-4,4-dimethylI-1, 3-dioxo-

isoguinolyl-(2) ]-acetamide

2 g of (2 -carbox-yphenyl1) -dimethyI- acetic acid, 1. 1. g

of glycine amide hydrochloride and 1.2 g of potassium

tert. -butoxide were heated fcr 3 hoUl 3 in glycol at

180'C. After removing the solvent under high vacuum,

the mixture was reacted with water and the precipitate.d

crude product was recrystallized twice from iso propanol.

182 to 1841C

Example 6

a) 2-[l,2,3,4-Tetrahydro-4,4-diniethyl-l,3-dioxo-

28.4 g of 1,2,3,4-tetrahydro.-4,4-dimethyl-isoquinolin-

dione-(l,3) and 16.9 g of potassium tert.-butoxide

were dissolved in 200 ml of dimethylformamide. 11.3 g

of chloroacetonitrile dissolved in 56 ml of

dimethylformamide, were added dropwise whilst stirring

over 30 minutes. Subsequently the mixture was heated

for 14 hours at 60'C and then reacted with 1 litre of

water. The precipitated crude product was isolated,

22 476,5 52

58,.7 35 n73

dried and recrystallized from ethanol with the

addition of charcoal.

154'C 3 -dioxo- b) 2 2 ,3,4-TetIahydro4,4dimethyll,

isoguinoly-) ]-acetamide of water A solution of 1.6 g of sodium hydroxide in 5 ml

was added to a solution of 2.3 g of 2-[l,2,3,4-tetra-

hydro-4,4-dimfethy1,3dioxo-isoquinolyl ('2)1-acetonitrile

in 40 ml of ethanol and 4 ml of 30% hydrogen peroxide..

The reaction mixture was held for 3 hours at

temperatures from 50 to 551C. Subsequently the

and the mixture was acidified, the solvent was removed,

residue was reacted with water. The precipitated crude

product was recrystallized twice from isopropanol.

.182 to 1841C

Example 7

2 1 2 ,3,4 Tetraydro-4,4dimethyl-1,3dioxo-isoquinolyl-

1-acetamide 3 ,3,4tetrahydro-4,4dimethyl1 -dioxo- 2 g of 2 2

5 ml of isoquinolyl-(2)>-acetonitrile were dissolved in

23 23 476.55.2

8,7 3

0 The concentrated sulfuric acid at 100 C.

solution was left standing overnight arnd was then

extracted several times witb chloroform. The solvent

from was removed and the residue recrystallized twice

i sopropal.

M.p. :182 to 184'C

Example 8 3 ioxo a) 2 2,3,47 trahydro-4,4dim thyll

isoguinolyl-(2) ]-thioacctamide

Hydrogen sulphide was bubbled into a stirred solution 3 of 10 g of 2 -[l,2,3,4-tetrahydro-4,4-dimethyl-,

isoquinolyl.(2)]-acetoflitrile in 12 ml of pyridine hour. and 5 ml of triethylamine over a period of one was Water was then added and the precipitated product

suction tiltered and recrystallized first from methanol

and then from glacial acetic acid. 3 b) 2 -[l,2,3,4-Tetrahydro-4,4dimethyll1, -dioxo-

isoguinolyl- 1-acetamide 3 g of -[1,2,3,4tetrahydro-4,4dimethyl1, -dioxo- 2

24 24 47 6,552

58, 7 3 5 n73

isoquinolyl-(2)L-thioacetamide dissolvad in glacial

acetic acid were reacted with 0.5 ml of a 30% hydrogen

peroxide solution. After standing overnight the

solvent was removed and the residue was recrystallized

from isopropanol.

182 to 184'C

Example 9 3 a) -[1,2,3,4Tetrahydro-4,4dimeth~yl-, -dioxo- 2

isoquinolyl-( 2)]-acetimidic acid thiomethylester

hydroiodide_____ 3 -dioxo- 1 g of 2 -[1,2,3,4-tetrahydro4,4dimethyl1,

isoquinolyl-(2)]-thioacetamide were ref laxed for 3 hours

ml of acetone and I ml of methyl iodide. 100 ml

of ether were subsequently addcd and after ice-cooling

the precipitated crystals were suction filtered.

from 185'C (decomp.)

2-1234Ttayr-,4dmty-L3do

isoguinolyl-(2) ]-acetamide

Prepared from 0.5 g of 2-[1,2,3,4-tpl.rah-ydro-4,4-dimethyl-

47 6,552

58R7 3 5 in,

l,3-dioxo-isoqui*nolyl-(2)]-acetimidic acid

thiomethylester hydroiodide and 30% h.ydrogen peroxide

in glacial acetic acid analogously to Example 8b.

182 to 1841C

Example

2-[1,2,3,4-Tetrahydro-4,4--dimethyl-l,3-dioxo-isoquinolyl-'

1-acetamide

1 g of 2-[l,2,3,4-tetrahydro-4,4-dimeth-y.-l,3-dioxo-

isoquinolyl-(2) ]-acetirnidic acid thiornethylester hydro-

iodide were boi!ted for 2 minutes in saturated aqueous

potassium carbonate solution. The solution was then

extracted with chloroform and after removing the solvent,

the residue was recrystallized from isopropanol.

182 to 1841C

Example 11

2-[1,2,3,4-'Letrahydro-4,4-dimetlhyl-1,3-dioxo-i3oquinolyl-

1-adetamide

1.9 g of l,2,3,4-tetrahydro-4,4-dimethyl-isochroman-

dione-(i,3), 1.65 g of glycine amide hydrochloride and

1.68 g of potass ium tert. -butoxide were added to 30 ml of

26 476,552

58. 735 3

at 1500C. ethylene glycol and heated for 12 minutes and the The mixture was poured onto an ice-water mixture

precipitate was suction filtered and recrystallized

from isopropanol.

182 to 184°C

Example 12

2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-

isoquinolyl-(2)'-acetamide

0.04 g of 1,2,3,4-tetrahydro-4,4-dimethyl-isochroman-

dione-(l,3) were mixed with 0.03 g of glycine amide

hydrochloride and 0.03 g of potassium tert.-butoxide

and heated together to form a melt. After cooling, the

mixture was poured into water and extracted with ethyl

acetate. The ethyl acetate extracts were evaporated

and the residue was recrystallized from isoropanol.

182 to 1841C

Example 13

2-[l,2,3,4-Tetrahydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-

(2)]-acetamide

0.04 g of 1,2,3,4-tetrahydro-2,4-trimethyl-isoquinoline-

27 476,552

58,7 3 5 n3

dione-(1,3) were melted with 0.04 g of glycine amide

hydrochloride and 0.04 g of potassium tert.-butoxide.

After 2 minutes the mixture was reacted with water and

extracted with ethyl acetate. The evaporation residue

was recrystallized from isopropanol.

182 to 18400

Example 14

2-[l,2,3,4-Tetrahydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-

(2)]-acetamide 3 3.4 g of l,.2, ,4-tetrahydro-4,4-dimethyl-isoquinolin-

dione-(l,3) were dissolved in 50 ml of absolute

dimethylformamide. This solution was reacted in small

amounts with 1.0 g of sodium hydride(80% suspension in

oil) and the mixture was stirred for a further half

hour at room temperature. 5.3 g of echyl bromo-acetate

were added and the solution was stirred for a further

6 hours at room temperature. The solution was poured

onto an ice-water mixture, acidified and extracted with

ethyl acetate. The ethyl acetate extracts were washed

with water and the solvent was evaporated, whereby

28 476,552

58,735 m

crude 2-[l,2,3,4-tetrahydro-4,4-di nethyl-l,3-isoquinclyl-

(2)]-acetic acid ethyl ester was obtained as an oil.

1.4 g of this ester were dissolved in 15 ml of

saturated methanolic ammonia and heated for 2 hours 0 in an autoclave at 150 C. The solution was then

evaporated and the residue was recrystallized from

isopropanol.

182 to 184 0C

Example

2-[1,2,3,4-Tetr.hydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-

(2)]-acetamide

1.25 g of 2-[l,2,3,4-tetrahydro-4,4-dimethyl-l,3-dioxo-

isoquiiiolyl-(2)]-acetic acid were refluxed for 2 1/2

hours with a mixture of 10 ml of chloroform and 5 ml of

thionyl chloride whereby the acid chloride was produced.

After removal of the solvent this acid chloride was

absorbed in 10 .i of benzene. 5 ml of the resulting

solution were dropped into a suspension of.0.33 g of

potassium phenolate in 15 ml of tetrahydrofuran and the

29 476,552

8,7 3 5 n~3

solution was left to stand for 2 hours at room

temperature. The solution was then reacted with 20 ml

of ethyl acetate and washed with sodium carbonate

solution, water, dilute hydrochloric acid and again with

water and evaporated, whereby crude 2-[l,2,3,4-tetra-

hydro-4,14-dimethyl-l ,3-dioxci-isoquinolyl-(2) ]-acetic

acid phenyl ester was obtained as an oil. The ester was absorbed in 100 ml of benzene and reacted with 25 ml

of saturated methanolic ammonia and left standing for

2 hours at room temperature. The soluLion was ev'aporated and the residue recrystallized from

isopropano 1.

182 to 184*C

Example 16

2-[1,2,3,4-Tetrahydro4,4-dimethyl..l3..ioxo-.isoquinolyl-

]-acetamide

nil of a solution of 2-[1,2,3,4-tetrahydro-4,4-dimethyl.

l,3 -dioxo-isoquinolyl-(2)]-acetyl chloride in benzene

p repared According to Example 15 were dropped into a solution of 0.27 g of thiophenol and 0.3 g of

30 476,552

58:735

triethylamine in 10 ml of benzene. After standing for

2 hours at room temperature, a further 10 ml of benzene

was added and the solution was washed successively with

dilute hydrochloric acid, diute sodium chloride solution

and water and dried.

This solution of the 2-[l,2,3,4-tetrahydro-4,4-dimethy.l-

1,3-dioxo-isoquinolyl-(2)]-acetic acid thiophenyl ester

in benzene was immediately reacted with 40 ml of

saturated methanolic ammonia and left to stand for 2

hours at room temperature. Then the solution was

evaporated and the residue obtained was recrystallized

from isopropanol.

182 to 184 0 C

Example 17

2-[l,2,3,4-Tetrahydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-

(2)]-acetamide

0.31 g of 2-[l,2,3,4-tetrahydro-4,4-dimethyl-l,3-dioxo-

isoquinolyl (2)]-acetic acid were converted into the acid

chloride by refluxing with 2 ml of thionyl chloride in

6 ml of benzene. After the evaporation of the solvent,

31 -47 6.5 52

58, 73 5n/3

thc acid chloride remaining was absorbed in 3 ml of

tetrahycirofuran and added dropwise to~ a solution of

0.18 g of imidazole in 5 ml of tetrahydrofuran. After minutes the precipitated imidazole hydrochloride

was suction filtered. The solution of 2-flt,2,3,4- tetrahydro-4, 4-dimethyl- 1,3 -dioxo-isoqU4nolyl-(2) 1-acetic

acid imidazolide thus obtained was immediately reacted

with 10 ml of saturated methanolic ammonia and left to

stand for I hour at room temperature. After the evaporation of the solvent, the residue was dissolved

in ethyl acetate, and washed with dilute-

hydrochloric acid and water. The organic layer was then

evaporated and the residue was recrystallized from

isopropanol.

182 to 184*C

Example 18

2-[l ,2,3,4-Tetrahydro-4,4--dimethyl-l 3 -d4oxo-isoquinolyl-

(2)]-acetamide

0.06 g of 2-[1,2,3,4-tetrahydro4,4-ime~hyl-,3-dioxo-.

isoquinolyl-(2)]-acetic acid were dissolved in 5 ml of

3-2 476,552

58, 73 5 n3

tc-trahydrofuran and reacted with 0*..04 g of

triethylamine. 0,05 g of isovaleric acid chloride were'

added whilst stirring. After standing for 5 minutes,

the precipitated triethylamine hydrochloride was removed

by suction filtration. The mixed anhydride contained in

the mother liquor, together with 2-[l,2,3,4-tetrahydro-

4,4-direthyl-l,3-dioxo-isoquinolyl-(12)]-acetic acid and

isovaleric acid was not purified, bu the solution was

reacted wit!, ice-cooling with 0.4ml dsaturated rnethanolic

ammonia. After standing for 2 hours at 00 C, the

sohtition was evaporated, the residue dissolved in

ethyl acetate an-! the solution was washed with

saturated bicarbonate solution. After the

evapora.tion of th e ethylacetate layer, the-solution was

recrystallized from isopropanol.

182 to 1841C

Example 19

2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl-

]-acetamide

0.03 g of 2-[1,2,3,4-tetrah-ydro-4,4-dimethyl-1,3-dioxo-

23 33 6,5~47

58,7 35 m'

iscquinolyl-(2)]-acetic acid were mixed with 0.2 g of 0 urea and heated for 2 minutes at 220 C. After cooling,

the mixture was reacted with water and extracted with

ethyl acetate. A precipitate which was insoluble in

both phases, was removed by suction filtration. The

ethyl acetate layer was washed with bicarbonate

solution and evaporated. The residue was

reciystallized from isopropanol.

182 to 184 0 C

Example

2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl-

(2)]-acetamide

The ammonium salt of the 2-[l,2,3,4-tetrahydro-4,4-

dimethyl-1,3-dioxo-isoquinolyl-(2)]-acetic acid was

heated for 10 minutes at temperatures above 250 0 C. After

cooling, the mixture obtained was dissolved in ethyl

acetate and the solution was washed with saturated

hydrogen carbonate solution and evaporated. The residue

was recrystallized from isopropanol.

182 to 184°C

34552 47 6,5 52

58, 7 3 5 n3

Example 21

2-[l,2,3,4-Tetrahydro-4,4--dimethyl1-l,3-dioxo-isoquinolyl-

]-acetamide

2 ml of tetrahydrofuran were poured over 0.025 g of the

ammonium salt of the ,4-tetrahydro-4,L-dimethyl-

l,3-dioxo-isoquinolyl-(2)]-acetic acid which is

partially soluble in tetrahydrofuran. A solution of

0.025 g of dicyclohexylcarbodinide in 2 ml of

tetrahydrofuran was then added dropwise. with stirring

at-room temperature and the solution was again stirred

for 30 minutes. Tlhe precipitated dicyclohexylurea. was

removed by suction filtration and the soluition was

evaporated and the residue recrystallized from

isopropanol.

M. 182 to 1841C

Example 22

a) 2-[l,2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-

isoguinolyl-(2)1-acetimidic acid ethyl ese hydrochloride

2.3 g of 2-[l,2,3,4-tetrahydro-4,4-dimethyl-l,3-dioxo-

isoquinolyl-(2)]-acetonitrile were suspended in a mixture of

-47 6,552

58, 735

ml of absolute ethanol, 40 ml of absolute ether and

ml of absolute benzene and hydrogen chloride was

introduced thereto. After the precipitate had

completely dissolved, hydrogen chloride was passed in

for a further 3 hours. After standing in the

refrigerator overnight, the mixture was evaporated to

dryness, dissolved in 5 ml of ethanol and precipitated

with ether 121°C). A solution of the free

iminoester i~ ether was obtained by suspending 0.25 g

in 5 ml of ether: shaking with 1.5 ml of 4N sodium

hydroxide and isolating the organic layer.

b) 2-[1,2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-

isoquinolyl-(2)]-acetamide

The ethereal solution of the free iminoester prepared above

was reacted with 2 ml of tetrahydrofuran and 2 ml of water

and refluxed for two days. The solution was diluted

with water, and cthyl acetate was added. The organic layer was then separated. After evaporation of the ethyl

acetate, the solution was recrystallized from

isopropanol. 182 to 184'C

36 476.552

58, 7 3 5 n3

Example 23

2-[1,2,3,4-Tetrahydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-

(2)1-acetamide

0.31 g of 2-[l,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-

isoquinolyl-(2)]-acetic acid were converted into the

acid chloride and this was dissolved in 5 ml of benzene.

The solution was added dropwise to a solution of 0.08 g

of ethylmercaptax, and 0.14 g of triethylamine in 20 ml of

benzene. After standing for 2 hours at room temperature,

the solution was successively washed with dilute hydro-

chloric acid, dilute sodium carbonate solution and wacer.

The solution of 2-[1,2,3,4-tetrahydro-4,4-dimethyl-l,3-

dioxo-isoquinolyl-(2)]-acetic acid thioethyl ester in

benzene thus obtained was dried and then immediately

reacted with 20 ml of saturated methanolic ammonia. The

mixture was heated in an autoclave for 2 hours at 100 0C.

It was then evaporated, dissolved in ethyl acetate and

washed with bicarbonate solution. After evaporation of

the ethyl acetate layer, the solution was recrystallized

37 476,552

58,7 3 5 n3

from isopropanol.

182 184 0 C

Example 24

2-[1,2,3,4-Tetrahydro-4,4-dimethyl-l,3-dioxo-isoquinolyl-

(2)]-propionamide

47.5 g of 3,4-dihydro-4,4-dimethyl-isochroman-dione(l,3)

and 22.3 g of L-alanine were melted together with stirring

at temperatures slowly reaching 180 0 C. The water formed

during the reaction was distilled off over a bridge

(reaction nime: 5 hours). After cooling, the mixture

was dissolved in 100 ml of acetone, reacted with 500 ml

of saturated sodium hydrogen carbonate solution and

extracted with chloroform.. The aqueous layer was

strongly acidified with 2N hydrochloric acid and the

precipitated oily product extracted several times with

chloroform. After drying and removing the solvent, an

oil remained which slowly crystallized. By recrystalli-

zation from toluene, 31.4 g (48% of theory) of 2-[1,2,3,4-

tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl-(2)]-propionic

386,552 47 6,5 52

58, 73~ 5 n3~

acid were obtained as colorless crystals of m.p. 143 to

145 0 C.

The 2-El ,2,3,4-tetrahydro-4,4-dirnethyl-l ,3-dioxo-isoquinolyl-

(2)]-propionic acid prepared above was converted into the

amide analogously to.Example 2.

184 to 186*C

Example

2-[l,2 ,3,4-Tetrahydro-4,4-dimethyl-isoauinolyl-(2)]-

acetic acid methylamide

15.5 g of the acid chloride, prepared from

tetrahydro-4,4-dimethyl-l ,3-dioxo-isoquino'Lyl-(2) )-acetic

acid and thi-onyl chloride analogously to Example 2, were

dissolved in 400 ml of ether. Methylami-ae was introduced

until the solution was saturated. Subsequently, the

solution was ref luxed for a further 2 hours, the solvent

was removed and the residue was washed with wiater.-

M 182 to 18400' (from isopropanol)

39 476.552

58. 735 n3

Example 26

2-Li ,2,3 ,4-Tetrah-ydro-4 ,4-dimethiyi-isoquinolyl- (2)1-

acetic acid dimethylarnide

Prepared analogously to Example 25, but using dimethyl-

amine as the amine component.

183 to. 185 0 C (from methanol).

Example 27

2- [1,2,3 ,4-Tetrahydro-4,4-dimethyl-isoquim~olyl-(2) 1- acetic acid ethylamide

Prepared analogously to Example 25, bitusing dthylamine

as the amine component.

143 to 145'C (from ethyl acetate)

Example 28

2- [1,2 ,-i,4-Tetrahydro-4,4-di*methyl-isoq-Linolyl-(2) ]-acetic.

acid propvrlamide

Prepared analogously to Example 25, but using n-propylamine

as the amine component.

116 to 118'C (from ethyl acetate)

476,552

58, 73 5M1

Example 29

2-[1,2,3 ,4-Tetrahyciro-4 ,4-dimethyl-isoquinoly1-

acetic acid isopropylamide

Prepared analogously to Example 25, but using isopropyl-

amine as the amine component.

125 to 12800 (from ethyl acetate).

Example

Tablets containiig 100 mg of'2-[l,2,3,4-tetrahydro-4,4-.

dimethyl-1.3-dioxo-isoguinolyl-(2) 1-acetamide

Composition:

Active ingredient 100.-0 mg lactrose 50.0 mg polyvinyl pyrrolidone 5.0 mg carboxymethylcelluluse 19.0 mg magnesium stearate 1.0 mg

175.0 mg

The active ingredient and lactose were homoge neously

moistened with aqueous-PVP solution, granulated through a

screen of 1.5 mun, dried at 50*C in acirculating drier and

passed through a screen of 1.0 mm.

41 476.552

58. 73 5 n3

The dry graiulate was admixed with the remaining auxiliary

products and pressed into tablets.

Weight of tablets: 175 g

Punch: 8 mm

Example 31

Coated tablets containing 50 mg cf 2-[1,2,3,4-tetrahydro-4,

4-dimethyl- ,3-dioxo-isoquinolyl-(2) 1-acetamide

1 coated tablet core contains:

Active ingredient 50.0 mg corn starch dried 20.0 mg soluble starch 2.0 mg carboxymethylcellulose 7.0 mg magnesium stearate 1.0 mg

80.0 mg

The active ingredient and corn starch were homogeneously

moistened with the aqueous solution of the soluble starch,

granulated through a screen of 1.0 mm mesh size, dried

at 500 C in a circulating drier and passed through a

screen of 1.0 mm again. The granulate and the remaining

auxiliary products were mixed and pressed to form coated

42 47 6,552

58,735

tablet cores.

Weight of core: 80 rag

Punch: 6 mm, arched

The finished cores were covered with a coat consisting'

essentially of sugar and talcum in conventional manner.

The finished coated tablets were polished with beeswax.

Weight of the coated tablet: 120 mg

Example 32.

Suppositories containing 200 mg of [,2,3,4-tetrahydro-

4,4-dimethyl-l ,3-dioxo-isoquinolyl-C2)]-acetamide

1 suppository contains: Active ingredient 200.0 mg suppository mass, (e.g..Witepsl H 19 and Witepsol W 45)Z 1 500.0 mg

1 700.0 mg

Method of preparation:

The suppository mass was melted. At 38 0 C the pulverized

active ingredient was homogenously dispersed in the melt.

The suppository mass was cooled to 35°C and poured into

pre-cooled moulds. Weight of suppository: 1.7 g

43 476,552

Example 33

Suspension containing 250 mg of 2-[l,2,3,4-tetrahydro- 4 4 -dimethyl-l,3-dioxo-isoquinolyl(2)-acetamide per

ml

100 ml of suspension contain:

Active ingredient 5.0 g carboxyrnethylceih ulose 0.1 g methyl p-hydroxybenazoate 0.05 g propyl p-hydroxybenzoate 0.01 g, cane sugar 10.0 g glycerine 5.0 g sorbit solution 70 20.0 g aroma 0.3 g distilled water ad 100.0 ml

Method of preparation:

The distilled water was heated to 700 C and the

476,552

58.73 5 m

methyl and propyl p-hydroxybenzoates, the glycerine

and carboxymethylcellulose were dissolved therein

whilst stirring. The solution was cooled to room

temperature and the active ingredient was added whilst

stirring. The solution was then made homogeneous.

After addition of the sugar, sorbit solution and aroma,

the suspension was evacuated for de-aeration whilst

stirring.

ml of the suspension contain 250 mg.

of .2-[1,2,.3,4-tetrahudro-4,4-dimethyl-l,3-

dioxo-isoquinolyl-(2)]-acetamide

476.552

Claims (1)

1. 58,7 35 nm

   The claims defining the invention are as follows:- 1.Compounds of general formula

   CH 3 3

   6 N~-CH CO N

   (wherein R1to R $which may be the same or different,

   each rcpresents a hydrogen atom or an alkyl group with

   from 1 to 3 carbon atoms).

   2. A compound selected from the following

   2-[l,2,3;4 Tetrahiydro-4,4-dimethyl-l,3-dioxo-

   isoquinolyl- -acetamide;

   2-[1,2,3,.L-Tetrahydro-4,4-dimethyl-1.,3-dioxo-.

   isoquinolyl-(2)]-acetic acid methylaiide;

   2-[1 ,2,3,4-Tetrahydro-4,4-dimethyl-1 ,3-dioxo-

   isoquinolyl- 1-propionanide;

   2-[l,'2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-

   isoquinolyl-(2)]. acetic acid ethylamide;

   2-[1,2,3,4-Tetrahydro-4,4-dimethy1,3-dioxo-

   isoquinolyl-(.2) 1-acetic acid propylamide;

   46 46 6.552 ~47

   58,.73 5 M

   3 2-[l,2,3,4-Tetrahydro-4,4-dimethyl-l, -dioxo-

   isoquinolyl-(2)]-acetic acid isopropylamide; and

   2-[l ,2,3,4-Tetrahydro-4,4-dimethvll ,3-dioxo-

   isoquinolyl-(2) 1-acetic acid dimethylanide..

   3. Compounds as claimed in claim.1 other than those

   claimed in claim 2 as herein specifically disclosed.

   4. A process for the preparation of compounds of

   general formula I as defined in claim 1 selected from

   the following

   a) Reaction of an imide of formula CH 3 CH3

   0

   or an alkali metal salt there-of with a halogeno-

   carboxylic, acid amide of formula

   R Hal- H -CO -N

   R R3

   47 76.552

   58, 73 5 n3

   (wherein R 1 to R 3 are as defined il claim 1 and Hal represents a chlorine, bromine or iodine atom);

   b) Reaction of a compound of formula

   CH3 CH3

   N S CH J1(IV)COA R1

   (wherein RI is as defined in claim 1 and A represents

   a hydroxy group or a replaceable radical) with an amine of formula

   R2 H N

   R3 (v)

   (wherein R2 and R3 are as defined in claim 1) or, if A in the compound of formula IV represents a hydroxy

   group, with a urea of formula

   R R \N CO N

   R R3 (Va) R 3

   48 476,5 52

   58, 7 3 5 n73

   1); (wherein R2 and R3are as defined in claimn

   C) Methlation of a compound of formula

   0 CO N (VI) R,. A

   (wherein R1 to R.3are as defined in claim 1);

   d) Reaction of a compound of formula

   CH 3 CHU3

   (VII)

   imino group) (wherein B represents an oxygen atom or an

   o r a dicarboxylic, acid of formul;a

   CH3

   C COOH

   CH 3 (VI Ia) (a COOH

   49 49 476,552

   58,735 n

   with a compomnd of formula

   /R 2 HN CH CO N (VIII) R R3

   (wherein R1 to R 3 are as defined in claim 1) or with an

   acid addition salt thereof;

   e) For the preparation of compounds of general

   formula I wherein R1 is as defined in claim 1 and R 2 and R 3 represent hydrogen atoms: Partial hydrolysis of a

   compound of formula

   CH3 CH3

   N H CN (I) R 0 1

   (wherein R 1 is as defined in claim and

   f) Desulfurization of a compound of formula

   47 6.5 52

   58,7 3

   CH 3 CH 3 S /SR 4

   N CH- C R X

   0 R1 R (X) R3

   (whercin R 1 to R3 are as defined in claim 1, R

   represents a hydrogen atom or an alkyl, aryl or

   aralkyl group, and X represents an anion of an acid)

   or the corresponding base when one of the radicals

   R 2 to R 4 represents a hydrogen atom.

   A process as claimed in claim 4 substantially

   as herein described.

   6. A process for the preparation of compounds

   as claimed in claim 1 substantially as herein described

   in any of Examples 1 to 29.

   7. Compounds as claimed in claim 1 when prepared

   by a process as claimed in any of claims 4 to 6.

   8. Pharmaceutical compositions comprising as active

   476;552

   58,735 n

   ingredient at least one compound of formula I as claimed in

   claim 1 in association with a pharmaceutical carrier

   or excipient.

   9. Pharmaceutical compositions as claimed in claim 8

   substantially as herein described.

   Pharmaceutical compositions substantially as

   herein described in any of Examples 30 to 33.

   D A T E D this 30th day of July, 1973.

   DR. KARL THOMAE GmbH By its Patent Attorneys: )CALLINAN AND NEWTON

   52 47 6,552