DE2916577A1 - NEW DERIVATIVES OF ISOCHINOLINE, THEIR MANUFACTURING AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

SC 4645/4666
10 / bs

RHONE-POULENC INDUSTRIES, Paris / France

The invention relates to new derivatives of isoquinoline in general Pormel I

their preparation, their addition salts with acids and those containing them pharmaceutical compositions.

In the general formula I ″, R ₁ denotes a hydrogen atom or a hydroxyalkyl radical having 1 to 4 carbon atoms in the alkyl part, with the ylmidazolin-2-yl-amino group _{bearing the radical R 1} in 4-, 5-, 6-, 7th - or 8-position of the isoquinoline and the symbols R ₂ and R ,, which can be identical or different from one another, are in the remaining positions of the isoquinoline nucleus and each denotes a hydrogen or halogen atom or an alkyl radical with 1 to 4 carbon atoms, alkoxy radical with 1 to 4 carbon atoms in the alkyl part, alkoxyalkyl radical with 1 to 4 carbon atoms in each alkyl part, alkylthio radical with 1 to 4 carbon atoms in the alkyl part or dialkylamino radical with 1 to 4 carbon atoms each iSTE

According to the invention, the new compounds of the general Formula I are produced by the action of an ethylene diamine of the general formula II

S - CH ₂ CHp - NH - R ₁ II

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983

wherein R ^ is defined as given above, to a derivative of Isoquinolines of the general formula III

III

where R ₂ and R ₅ are defined as indicated above and Z, which is in the 4-, 5-, 6-, 7- or 8-position, denotes a 2-alkylisothioureido radical of the general formula IY

or an alkylthiothiocarbonylamino radical of the general formula Y

- NH -

or an isothiocyanate radical.

In the general formulas W and Y, R ¹ denotes an alkyl group having 1 to 4 carbon atoms.

If in the general formula III Z denotes a 2-alkylisothioureido radical of the general formula IY, the reaction is generally carried out using an excess of ethylenediamine of the general formula II, preferably 3 moles per mole of the product of the general formula III, and in one inert solvent such as a lower alcohol, such as methanol, ethanol or butanol, is carried out at a temperature between 4O ⁰ C and the reflux temperature of the reaction mixture for a period of between 1 hour and 48 hours, depending on the reactivity of the products used. The product of general formula III is preferably in the form of a salt

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with a mineral acid or organic acid such as hydrochloride, hydrobromide, hydroiodide or sulfate, used.

The (2-alkylisothioureido) isoquinolines of the general formula HE can be made in three phases from the corresponding aminoisoquinolines by analogy with that of B. Rouot et al., J. Med. Chem. 19, 1049 (1976) described method are obtained according to the following scheme:

III

C ,, H ₁ -CON = C = S o ->

C, H_ CO NH ο

R »shark

VIII

¥ enn in the general formula III Z an alkylthiothiocarbonylamino radical of the general formula V, the reaction is generally carried out in an organic solvent such as Ethanol at the reflux temperature of the reaction mixture and advantageously in the presence of a mercury derivative such as mercury dioxide carried out.

The dithiocarbamate of the general formula III can by action an alkylating agent such as an alkyl halide, e.g. methyl iodide, or an alkyl sulfate, e.g. dimethyl sulfate, to a salt of dithiocarbamic acid of the general formula IX

, HS-CS-NH

IX

909844/0963

are obtained in which R ₂ and R- are as defined above and R "denotes an alkyl radical having 1 to 4 carbon atoms, preferably the ethyl radical.

The reaction is generally carried out in an organic solvent such as acetonitrile at a! Temperature between 20 and 50 ⁰ C.

The dithiocarbamic acid salt of the general formula IX can be obtained are caused by the action of carbon disulfide on a Aminoisoquinoline of the general formula VI in the presence of a tertiary amine of the general formula N (R ") ,, wherein R" is as is defined above, where work is carried out in an organic solvent such as acetonitrile at a temperature of about 20.degree will.

¥ enn in the general formula III Z an isothiocyanate radical means so the reaction is carried out by adding in an organic Solvents such as tetrahydrofuran or ethanol or a mixture of organic solvents at the boiling point of the reaction mixture, and advantageously in the presence of a mercury derivative how mercury dioxide is worked.

To carry out this process, it is possible to use a thioureidoisobhinoline of the general formula X

R ₁ -NH CH ₂ GH ₂ -NH-CS-NH -f- || | X

wherein Rj, R ₂ and R are defined as specified above. as an intermediate product, whereby an ethylenediamine of the general formula II with an isothiocyanatoisoquinoline of the general formula III in an organic solvent such as ethanol, acetonitrile or methylene chloride at a temperature of about 20 ^° C reacted and the product of the general formula X is then cyclized by in an organic solution

8Q9844 / Q963

medium such as to obtain ethanol at a l'eraperatur between 20 ⁰ C and the Rüekflußtemperatiir of Rsaktionsraediums, preferably in the presence of a Hercuriderivato as Mercurioxid is worked to the product of general P or I rs el.

The Isothiocyanatoisochinolin the general I ¹ I or me III can -Be ihiocarbonyldiiinidazol obtained by the action of a Amlnoisochinolin the general formula YI, by operating in an organic solvent such as methylene chloride or acetonitrile at a temperature between 0 and 40 ⁰ C.

The aminoisoquinoline of the general formula VI can be obtained by analogy to that of F.A. French et al., J. Med. Chem., 13 (6) 117 (1970) or by E. Brown, J. Org. Chem., 4j2, 3208 (1977) is used.

The products of the general formula I in which R. is a hydrogen atom or a hydroxyalkyl radical having 1 to 4 carbon atoms, the imidazolin-2-yl-amino group _{bearing the substituent R 1} being in 4-, 5-, 6-, 7th - Or 8-position of the isoquinoline and where one of the symbols R ₂ or R is a halogen atom, preferably a chlorine or bromine atom and the other symbol is a hydrogen or halogen atom or an alkyl radical with 1 to 4 carbon atoms, alkoxy radical with 1 to 4 carbon atoms in the alkyl part, alkoxyalkyl radical with 1 to 4 carbon atoms in each alkyl part, alkylthio radical with 1 to 4 carbon atoms in the alkyl part or dialkylamino radical with 1 to 4 carbon atoms in each alkyl part can be obtained by the action of a halogenating agent on a product of the general formula I, in which R .. is defined as indicated above, one of the symbols Rp or R ^ a hydrogen atom and the other a hydrogen or halogen atom m or an alkyl radical with 1 to 4 carbon atoms, alkoxy radical with 1 to 4 carbon atoms in the alkyl part, alkoxyalkyl radical with 1 to 4 carbon atoms in each alkyl part, alkylthio radical with 1 to 4 carbon atoms in the alkyl part or dialkylamino radical with 1 to 4 carbon atoms in each alkyl part , where - if the symbols R ₀ and R each represent a hydrogen atom ^{- two halogen 3} 909844/0963 .. ^{at <Me}

ORiQSNAL INSPECTED

can fix on the isoquinoline residue.

The halogenating agent used is preferably chlorine or bromine in an organic solvent such as acetic acid _/ or an alkali metal hypochlorite in concentrated acid (for example hydrochloric acid) in the presence of zinc chloride at a temperature between 0 and 40 ^° C.

The fixation of the halogen atom or atoms is preferably carried out in the electrophilic positions of the isoquinoline nucleus and in particular in ortho or para position to the imidazolin-2-yl-amino group.

When the reaction results in a mixture of halogenated products

aer

this can be checked later for this type of product applicable fractionation methods, in particular by fractional crystallization or chromatography.

The new compounds of the general formula I according to the invention can optionally by physical methods such as crystallization or chromatography or chemical methods such as salt formation, Crystallization of the same and then decomposition are purified in an alkaline medium; in these operations is the Nature of the anion of the salt indifferent, it is only important that the salt is well defined and easily crystallizable.

The new compounds prepared according to the invention can be converted into addition salts with acids.

The addition salts can be prepared by the action of the new compounds on acids in suitable solvents; the organic solvent used is, for example, alcohol. Ie, ethers, ketones or chlorinated solvents; the educated Salt precipitates out of its solution after possible concentration; it is separated off by filtering or decanting.

The new compounds according to the invention and their salts have interesting pharmacological properties. They have

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themselves, particularly effective as regulators of the cardiovascular Systems proved. Decrease orally in doses between 0.01 and 5 mg / kg they the arterial pressure: with the epcntan iryaertens'iertfcE Rat (S.E.R;), 'Qkamoto-Qaki strain. The use of the spontaneously hypertensioned rat to study antihypertensive compounds is described by J.L. Roba, Lab. Anim. Sci.,, 26, 305 (1976).

ckeine ^

In addition, the products according to the invention have sedative effects at dosages where "they are used as antihypertensive agents are active, especially in the technique of potentialization the Barkoae with pentobarbital in the rat.

In addition, the products according to the invention have a relatively low toxicity. The lethal dose 50 $ (Ek ₅₀ ) is generally higher than 150 to 200 mg / kg orally in the mouse.

For medical use, the new compounds are either as bases or in the form of the pharmaceutically acceptable addition salts, i.e. non-toxic at the application doses, used.

Examples of pharmaceutically acceptable addition salts are the salts of mineral acids (such as the hydro- ' chlorides, sulfates, nitrates, phosphates) or organic acids (such as acetates, propionates, succinates, benzoates, fumarates, Maleates, tartrates, theophylline acetates, salicylates, phenolphthalinates, Methylene-bis-ß-oxynaphthoate) or substitution derivatives of these acids.

Of particular interest are the products of the general formula I in which R ₁ denotes a hydrogen atom, the imidazolin-2-yl-amino radical is in the 4-, 5-, 6-, 7- or 8-position of the isoquinoline nucleus and the symbols R ₂ and R ,, which can be identical or different from one another, represent a hydrogen or halogen atom or an alkyl radical having 1 to 4 carbon atoms or an alkoxy radical having 1 to 4 carbon atoms in the alkyl part. The connections of the

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general formula I, wherein the imidazolin-2-yl-amino radical in 4- »5- or 8-position of the isoquinoline nucleus.

The following examples are intended to explain the invention in more detail. If a temperature is not specified, the corresponding operation is carried out ^{at about 20 ° C.}

example 1

A mixture of 34.5 g of 4- (2-methyl isothioureido) isoquinoline hydroiodide and 27.0 g of ethylenediamine in 250 ml of ethanol is refluxed for 7 hours. After concentrating the suspension obtained under reduced pressure (20 mm Hg), it takes up in 100 ecm N-sodium hydroxide and 100 ecm chloroform. The suspension obtained is filtered, the cake is washed with 100 ml of distilled water and dried under reduced pressure (0.1 mm Hg). The solid obtained is dissolved in 175 ecm of dimethylformamide at the boiling point. The hot solution is filtered off and the filtrate is then cooled to a temperature of about 0 ^° C. and held at this temperature for one hour. The crystals are separated off by filtration. After drying under reduced pressure (0.1 mm Hg) at 20 ⁰ C for 15 hours and then for one hour under the same Takuum at 50 * 0, one obtains 13.4 g of 4- (4,5-dihydro-imidazole 2-yl) -amino-isoquinoline of m.p. = 247 to 248 ° C.

The 4- (2-methyl-isothioureido) -isoquinoline-hydro;} odid can on can be produced in the following way:

A suspension of 56 ^: g of 4-thioureido-isoquinoline and 41.2 g of methylodide in 750 ecm of methanol is refluxed for 45 minutes. After the resulting solution has been concentrated under reduced pressure (20 mm Hg), the residue is crystallized from 250 ecm of acetone. The crystals are separated off by filtration, washed with 50 ecm of acetone and added for 15 hours under reduced pressure (0.2 mm Hg) 20 ⁰ C dried. Are thus obtained 76.8 g of 4- (2-Methyl-isothioureido) -isoquinoline hydroiodide, mp = 184-186 ⁰ C.

Pas 4-thioureido-isoquinoline can be obtained in the following manner will:

93.5 g of 4- (3-benzoyl-thioureido) -isoquinoline are refluxed in 700 ecm of ethanol and 91 ecm of 10 N sodium hydroxide solution for 15 minutes. After cooling, the crystals are separated off by filtration and washed with 300 ecm of ice-cold ethanol. The filtrate is concentrated under reduced pressure (20 mm Hg), the residue is dissolved in 500 ml of distilled water and the resulting solution is acidified to pH 5-6 by adding acetic acid. The crystals are separated by filtration, washed with distilled water and 300 com for 15 hours under reduced pressure (0.2 mm Hg) at 20 ⁰ G dried. 53.7 g of 4-thioureido-isoquinoline with a melting point of 235 ° to 236 ° C. are thus obtained.

The 4- (3-benzoyl-thioureido) -isoehinolin can in the following way getting produced:

Priority over 10 minutes 53.6 g of benzoyl chloride to a solution of 100 cc of acetone and 29.2 g of ammonium thiocyanate, which was previously heated to 45 ⁰ C, then is brought to boiling for 10 minutes under reflux. A solution of 55.2 g of 4-amino-isoquinoline in 150 ml of acetone is added to the refluxing suspension over the course of 10 minutes, and the reflux is then maintained for 1 hour 30 minutes. The suspension is cooled, 750 ecm of distilled water are added, the crystals are separated off by filtration and washed with 300 ecm of distilled water. After drying for 45 hours under reduced pressure (0.2 mm Hg) at 20 ⁰ C to obtain 93.6 g of 4- (3-benzoyl-thioureido) 4sochinolin mp = 210-211 ⁰ C.

The 4-aminoisoquinoline used as the starting material can be used according to that of I.G. Hinton, J. Chem. Soc. 599 (1959) described method getting produced.

Example 2

A mixture of 1Ί, 7 g of 5- (2-methyl-ieothioureido) -

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isoquinoline and 6.1 g of ethylenediamine in 85 oom of ethanol during 15 hours to reflux, after concentrating the resulting solution under reduced pressure (20 mm Hg) is taken in 120 ecm N-Na-

cunsL »
trium hydroxide solution extracted with 500 com chloroform. After drying over sodium sulphate, the chloroform solution is concentrated under reduced pressure (20 mm Hg), the residue is then taken up in 1200 ecm of boiling cyclohexane, filtered in the heat and the insoluble product is dried under reduced pressure (0.1 mm Hg) . This product is dissolved in 70 cc of an aqueous N-hydrochloric acid solution and 40 com distilled water, the solution decolorized with 0.2 g! Animal charcoal, filtered, and makes at a temperature of about 0 ⁰ C by the addition of 70 cc of N-sodium hydroxide solution alkaline, the fixed. Material is separated by filtration, washed with 60 cc of distilled water and under reduced pressure (0.1 mm Hg) for 22 hours at 20 ⁰ C dried. 5.0 g of 5- (4,5-dihydro-imidazol-2-yl) -amino-isoquinoline with a melting point of 191-192 ° C. are obtained in this way.

The starting materials can be prepared analogously to the procedure described in Example 1. This is how you get:

-19g 5- (2-methyl-isothioureido) -isoquinoline-hydroiodide vom

M.p. = 240 - 245 ° C with decomposition _; by heating 18.3 g

5-thioureido- ^ isoquinoline and 41.0 g of methyl iodide in 180 ecm

Acetone;
-45.1 g of 5-thioureido-isoquinoline, mp = 262-264 ⁰ C by hydrolysis of 127.5 g of 5- (3-benzoyl-thioureido) -isoquinoline

in 1245 ecm ethanol and 124.5 ecm 10 N sodium hydroxide solution; - 128.3 g of 5- (3-benzoyl-thioureido) -isoquinoline, mp = 233-234 ⁰ C of 72.1 g of 5-Aminoisoohinolin, 70.3 g of benzoyl chloride and 38.1 g of ammonium thiocyanate in 475 cc acetone.

The 5-aminoisoquinoline starting product can be prepared according to the method described by F.Misani, J. Org. Formerly ^ 0, 347 (1945) described method will.

Example 3

35.9 g of 3-methyl-5- (2-methyl-isothioureido) -isoquinoline hydroiodide are heated and 18.0 g of ethylenediamine in 250 ecm of ethanol during

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7 hours to reflux. After concentration under reduced pressure (20 mm Hg), the residue is taken up in 100 ecm of distilled water. The crystals are separated by filtration, washed with 100 com of water and dried under reduced pressure (0.2 mm Hg). The product obtained is dissolved in 250 ecm of isopropanol under reflux, clarified with 1 g of animal charcoal and filtered in the heat. The solution obtained is cooled to a temperature of about 0 ⁰ G in an ice bath for one hour from the crystals is separated off by filtration and washed with 100 cc of isopropanol. Subject to drying under reduced pressure (0.2 mm Hg) at 20 ⁰ G for 15 hours and then at 45 ° C for 2 hours, 13.2 g of 5- (4,5-dihydro-imidazol-2-yl) are obtained amino-3-methyl-isoquinoline, mp = 202 to 2O4 ° C.

The starting materials can be prepared 'by analogously

Example 1 is worked. One obtains: ι

-sfch y dr ο i n rl i rl j

- 60.5 g of 3-methyl-5- (2-methyl-isothioureido) -isoehinolTry das

melts with decomposition at 240-242 ⁰ C, ecm by heating 39 g of 3-methyl-5-thioureido-isoquinoline and 28.4 g in 700 Methyljjodid methanol;

- 39 g of 3-methyl-5-thioureido-isoquinoline, which melts at about 280 ⁰ C, by hydrolysis of 65 g of 5- (3-benzoyl-thioureido) -3-methyl-isoquinoline with 60 cc of 10 N-in 650 lfatronlaugelÖBung ecm ethanol;

- 65 g of 5- (3-benzoyl-thioureid ₁ o) -3-methyl-isoquinoline from

Ϊ ¹ . = 203 to 204 ⁰ C from 35 g S-amino-S-mettayl-isoohinolin, 31 g benzoyl chloride and 16.8 g ammonium thiocyanate in ^ 65 ecm acetone.

The 5-amino-3-methyl-isoquinoline can be prepared according to the IT.P. Buu Hol, J. Che ^. Soc. 3924 ( 1964 ) described method.

Example 4

20.7 g of 5- (2-methyl-isothioureido) -isoquinoline-hydroiodide are heated and 18.8 g of 2- (2-hydroxyethyl) -amino-ethylamine in 240 ecm of ethanol for 24 hours under reflux. The solvent is chased away under reduced pressure (20 mm Hg), then the residue is extracted with 600 ecm chloroform and 100 ecm potassium sodium hydroxide solution

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solution. The chloroform extract is washed with 600 ecm of distilled water, dried over sodium sulfate, filtered and then concentrated under reduced pressure (20 mm Hg). The residue obtained is dissolved in 200 ecm of ethanol, the solution is clarified with 0.2 g of animal charcoal and filtered. 40 ecm emsr 3,6 solution of gaseous hydrogen chloride in ether are added to the filtrate. The mixture is stirred for 5 hours at 20 ⁰ G, the crystals separated by filtration and washed with 85 cc of ethanol. After drying under reduced pressure (20 mm Hg) at 20 ⁰ G for 20 hours is obtained 15.2 g of 5- / V (2-hydroxyethyl) -4,5-dihydroimidazole-2-yl / - aminoisoquinolin in the form of Dihydrochloride, which melts at 250 to 255 ° C with decomposition.

The 2- (2-hydroxyethyl) -amino-ethylamine can according to the method by Knorr R., Ber. 35, 4470 (1902).

Example 5

8.6 g of 3,4-dimethyl-5- (2-methyl-isothioureido) -isoquinoline-hydroiodide and 5.6 g of ethylenediamine are refluxed in 80 ecm of ethanol for 38 hours. After concentration under reduced pressure (20 mm Hg), the residue is taken up in 50 ecm of distilled water. The crystals are separated off by filtration, washed with 60 ml of distilled water and dried under reduced pressure (0.2 mm Hg). The solid obtained is dissolved in 320 ecm of acetonitrile under reflux, clarified with 1 g of animal charcoal and filtered while hot. The resulting solution is cooled in an ice bath for 1 hour, the crystals formed are separated off by filtration and washed with 60 ecm acetonitrile. After drying under reduced pressure (0.2 mm Hg) for 15 hours at 20 ^° C. and then for 2 hours at 50 ^° C., 3.3 g of 5- (4,5-dihydro-imidazol-2-yl) - amino-3,4-dimethylisoquinoline. from F. = 220 to 221 ⁰ G.

The starting materials can be obtained by analogously to Example 1 is being worked on. This is how you get:

- 8.6 g of 3,4-dimethyl-5- (2-methyl-isothioureido) -isoquinoline hydroiodide from the temperature = 174 - 176 ° C by heating 8.8 g of I ^ -dimethyl-S-thioureido-isoquinoline and 6.6 g of methyl iodide in 175 ecm of methanol;

- 8.8 g of 3,4-dimethyl-5-thioureido-isoquinoline with a melting point of 248-25O ° C by hydrolysis of 14.4 g of 5- (3-benzoyl-thioureido) -3,4-dimethyl-isoquinoline with 13.7 ecm 10 IT sodium hydroxide solution in 170 ecm ethanol; ..

- 14 »4 g of 5- (3-benzoyl-thioureido) -3,4-dimethyl-isoquinoline vom F. = 203 - 2O4 ° C from 8.6 g of 5-amino ~ 3,4-dimethyl-isoquinoline, 7.7 g benzoyl chloride and 4.2 g ammonium thiocyanate in 130 ecm Acetone.

The 5-amino-3 "i4-diii3ethyl-isoquinoline can be produced in a manner analogous to the 5-amino-3-p-socoinoline from the 3,4-dimethyl-isoquinoline by nitration and then reduction according to the method of NP Buu Hoi J. Chem. Soc. 3924 ( 1964 ).

Example 6

38.5 g of 7- (2-methyl-isothioureido) ~ isoquinoline-hydroiodide and 33.1 g of ethylenediamine are refluxed in 250 ecm of ethanol for 2 hours. After cooling, 25 ecm 5 N sodium hydroxide solution is added, the mixture is cooled in an ice bath for 30 minutes, the crystals formed are separated off by filtration and washed with 30 ecm 90% ethanol. The product obtained is dissolved in 250 cc of dimethylformamide at 100 ⁰ C, the solution was clarified with 0.1 g charcoal, filtered in the heat and cools the filtrate through a water bath at about 20 ⁰ C., then with an ice bath to a temperature of about 0 ° C and maintains this temperature for one hour. The crystals formed are separated by filtration, washed with 30 cc of dimethylformamide, and under reduced pressure (0.2 mm Hg) at 20 ⁰ C for 15 hours and then under the same vacuum at 50 ⁰ C for one hour. Are thus obtained 9.9 g of 7- (4,5-dihydro-imidazol-2-yl) -aminoisochinolin mp = 262-263 ⁰ C. ·;; ** -.

The starting materials can be obtained by working in a manner analogous to that in Example 1. This is how you get:

- 38.6 g of 7- (2-methyl-isothioureido) -isoquinoline-hydroiodide vom F. = 198-200 ° C by heating 44.1 g of 7-thioureido-isoquinoline and 34.0 g of methyl iodide in 620 ecm of methanol;

- 44.2 g of 7-thioureido-isoquinoline with a temperature of 258 - 259 ° C Hydrolysis of 68.1 g of 7- (3-benzoyl-thioureido) -isoquinoline in

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500 ecm ethanol and 67 ecm 10 N-E sodium hydroxide solution;

- 68.2 g of 7- (3-benzoyl-thioureido) -isoquinoline from P. = 222-223 ° 0 from 42.2 g of 7-amino-isoquinoline, 41.2 g of benzoyl chloride and 22.3 g ammonium thiocyanate in 200 ecm acetone and 50 ecm dimethylformamide.

The 7-amino-isoquinoline used as starting material can after that of R. Robinson, J. Am. Chem. Soc, j59, 1939 (1947) Method.

Example 7

A mixture of 34.5 g of 8- (2-methyl-isothioureido) -isoquinoline-hydroiodide and 28.8 g of ethylenediamine in 250 ecm of methanol is refluxed for 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg) and the residue is extracted with 700 ecm of chloroform and 250 ecm of hydrochloric acid solution. The solvent is evaporated again under reduced pressure (20 mm Eg), the residue is dissolved in 90 cc of chloroform at the boiling point, clarified with 0.1 g charcoal, filtered while hot, the mixture is cooled to a Piltrat! Temperature of about 0 ⁰ C and maintains this temperature for 2 hours. The crystals which have appeared are separated off by filtration, washed with 50 ml of isopropyl ether and dried under reduced pressure (0.2 mm Hg). The solid obtained is dissolved in 200 com acetonitrile at the boiling point and then cooled to a temperature of about 0 ^° C. and this temperature is maintained for 3 hours. Filter the resulting suspension, the crystals washed with 30 cc of acetonitrile and dried under reduced pressure (0.2 mm Hg) at 20 ⁰ C for 15 hours and then at 50 ⁰ C for one hour. 4.9 g of 8- (4,5-dihydrorimidazol-2-yl) -amino-isoquinoline with a P * = 225-226 ° C. are obtained in this way.

The starting materials can be obtained by analogously to Example 1 is being worked on. You get so

- 31.2 g of 8- (2-methyl-isothioureido) -isoquinoline-hydroiodide vom

P. = 227-228 ° C by heating 32 g of 8-thioureido-isoquinoline and 24.6 g of methyl iodide in 350 ecm of methanol;

- 32.1 g of 8-thioureido-isoquinoline from Fs 263-265 ^e C through. Eydro

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lysis of 54.2 g of 8- (3-benzoyl-thioureido) -isoquinoline in 400 ecm Ethanol and 53 ecm 10 N sodium hydroxide solution;

54.3 g of 8- (3-benzoyl-thioureido) -isoquinoline with a melting point of 239-24O ° C from 30 g of 8-aminoisoquinoline, 29.3 g of benzoyl chloride and 15.9 g Ammonium thiocyanate in 350 ecm acetone.

The 8-aminoisoquinoline used as starting material can be prepared according to the method described by Y. Ahmad, J. Chem. Soc. 3882 ( 1961 ) described method.

Example 8

A mixture of 9.0 g of 6- (2-methyl-isothioureido) -isoquinoline-hydroiodide and 6.6 g of ethylenediamine in 90 ecm of ethanol is refluxed for 7 hours. The solvent is evaporated under reduced pressure (20 mm Hg), the residue is taken up in 100 cc of distilled water and cooled to about 0 ⁰ C. This temperature is maintained for 2 hours. The crystals which have appeared are separated off by filtration, washed with 75 ecm of distilled water and dried under reduced pressure (0.2 mm Hg) for 15 hours. The solid obtained is dissolved in 100 ecm of isopropanol under reflux, the solution is clarified with 0.5 g of animal charcoal, filtered in the heat, the solution obtained is cooled to a temperature of about 0 ^° C. and this temperature is maintained for one hour. The appeared crystals are separated by filtration, washed with 15 cc of isopropanol, and under reduced pressure (0.2 mm Hg) for 15 hours at 20 ^e C and then under the same vacuum at 50 ⁰ C for 2 hours. 1.85 g of 6- (4,5-dihydro-imidazol-2-yl) -amino-isoquinoline with a melting point of 245 ° -246 ° C. are obtained.

The starting materials can be obtained by working analogously to Example 1. This is how you get:

- 9.1 g of 6- (2-methyl-isothioureido) -isoquinoline-hydro; iodide, which ^{melts at about 200 0} C, by heating 6.0 g of 6-thioureido-isoquinoline with 5 g of methyl iodide in 140 com methanol?

- 6.1 g of 6-thioureido-isoquinoline, mp = 260-262 ⁰ C by hydrolysis of 14 g of 6- (3-benzoyl-thioureido) -isoquinoline in 170 cc and 13.7 cc Ithanol 10 Ii-sodium hydroxide solution;

909844/0963.

- ¹ 9 - 291657?

- 18 g of 6 ~ (3-benzoyl-thioureido) -isoquinoline with a melting point of 208-210 ° C

from 17.3 g of 6-aminoisoquinoline - 18.3 g of benzoyl chloride and 9.9 g Ammonium thiocyanate in 70 ecm acetone.

The 6-aminoisoquinoline used as starting material can after that of R. Manske, J. Am. Chem. Soc. 72 ,, 4997 (1950) Method can be obtained.

Example 9

A mixture of 22.7 g of 6-chloro-5- (2-methyl-isothioureido) -isoquinoline hydroiodide and 15 g of ethylenediamine in 230 ecm of ethanol is refluxed for 20 hours. The solvent is evaporated off under reduced pressure (20 mm Hg), then the residue is extracted with 350 ecm chloroform and 450 ecm water. The organic extracts are washed with 300 ml of distilled water, clarified with 1 g of animal charcoal, dried over 30 g of sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The residue is dissolved in 250 cc of trichlorethylene in. The boiling point, clarified with 1 g! Animal charcoal, the solution filtered and cooled to 1 hour at a temperature of about 0 ⁰ C. The appeared crystals are separated by filtration, washed with 45 cc of trichlorethylene and dried under reduced pressure (0.2 mm Hg) at 20 ^° C. for 15 hours. The solid obtained is extracted with 25 ecm of distilled water, 25 ecm of an N hydrochloric acid solution and 90 ecm of ether. Are added to the aqueous extract 1 g of animal charcoal, filtered, cooled to a temperature of about 0 ⁰ C and makes the cold hydrochloride solution by the addition of 2.6 cc of 10 H-sodium hydroxide solution alkaline. The crystals formed are separated by filtration, washed with 50 cc of water and under reduced pressure (0.2 mm Hg) at 20 ⁰ C for 15 hours and then under the same vacuum for 3 hours at 50 ⁰ C. 2.2 g of 6-chloro-5- (4,5-dihydro-imidazol-2-yl) -aminoisoquinoline with a melting point of 156-158 ° C. are obtained in this way.

The starting materials can be obtained by analogously to Example 1 is being worked on. This is how you get:

- 44.0 g of 6-chloro-5 - (2-methyl-isothioureido) -isoquinoline hydroiodide which melts at about 220 ⁰ C, by heating 41.3 g

909844/0963.

ö-chloro-S-thioureido-isoquinoline with 27 g of methyl iodide in 700 ecm of methanol;

- 41.4 g of e-chloro-S-thioureido-isoquinoline of F. = 170-172 ⁰ C by hydrolysis of 55.7 g of 5- (3-benzoyl-thioureido) -6-chloroisoquinoline in 650 com ethanol and 52 ecm 10 N sodium hydroxide solution;

55j8 g of 5- (3-benzoyl-thioureido) -6-chloro-isoquinoline from

Mp = 206-208 ⁰ C of 30.5 g of S-amino-ö-chloroisoquinoline, 26.7 g of benzoyl chloride and 14.5 g of ammonium thiocyanate in 470 cc of acetone;

- 29.0 g of 5-amino-O-ChIOrISOChInOHn mp = 118-120 ⁰ C by reduction of 42 g of 6-chloro-5-nitroisoquinoline with 48.3 g iron powder in 525 cc of water;

- 42.1 g of 6-chloro-5-nitro-isoquinoline with a temperature of 135-136 ° C Nitrate 34 g of 6-chloroisoquinoline with 46.2 g of potassium nitrate in 140 ecm concentrated sulfuric acid.

The 6-chloroisoquinoline can be prepared according to that of G. Favini, Gazz. Chin. Ital. 89, 2222 (1959) described method can be obtained.

Example 10

6.9 g of 6-methozy-5- (2-methyl-isothioureido) -isoquinoline-hydroiodide are heated and 4.3 g of ethylenediamine in 70 ecm of ethanol for 17 hours to reflux.

After cooling (20 mm Hg) the solution is concentrated under reduced pressure at 20 ⁰ C and the residue is taken up in 80 cc of distilled water by stirring for 2 hours at 0 ⁰ C. After filtering the insolubles with 85 cc of distilled water is washed and then under reduced pressure (0.1 mm Hg) at 20 ⁰ C dried. The pesticide obtained is dissolved in 110 com acetonitrile at the boiling point in the presence of 0.6 g decolorizing charcoal. After filtering in the heat, the filtrate is cooled ^{to 0 ° C. for one hour.} The precipitated product is separated by filtration, washed with 25 cc of acetonitrile, and then under reduced pressure (0.1 mm Hg) at 20 ⁰ C for 20 hours.

The pesticide obtained (1.05 g) is dissolved in 80 ecm acetonitrile in

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the boiling point dissolved in the presence of 0.2 g decolorizing carbon. After filtering in the heat, the filtrate is cooled ^{at 20 ° C. for two periods.} The product which precipitates is separated by filtration, washed with 15 cc of acetonitrile, and then under reduced pressure (0.2 mm Hg) at 20 ⁰ C dried. Are thus obtained 0.85 g of 5- (4,5-dihydro-imidazol-2-yl) amino-6-methoxy-isoquinoline, mp = 204-205 ⁰ C.

6-Methoxy-5- (2-methyl-isothioureido) -isoquinoline-hydro3odide can be obtained from 6-methoxyisoquinoline. For this purpose one prepares:

-7g 6-methoxy-5- (2-methyl-isothioureido) -isoquinoline-hydroiodide of m.p. = 240 ° C (with decomposition) by heating 22 g 6-methoxy-5-thioureido-isoquinoline and 15.6 g of methyl iodide in 400 ecm of methanol;

- 22 g ö-methoxy - ^ - thioureido-isoquinoline from F. = 170-172 ⁰ C by heating 36.8 g 5- (3-benzoyl-thioureido) -6-methoxyisoquinoline in 410 ecm ethanol and 33 ecm 10 U -lfetron liquor solution;

36.8 g of 5- (3-benzoyl-thioureido) -6-methoxy-isoquinoline from P. = 200-202 ⁰ C by heating 23.5 g of 5-amino-6-methoxyisoquinoline, 21.1 g of benzoyl chloride and 11.5 g of ammonium thiocyanate in 360 ecm of acetone;

- 22.1 g of S-amino-ö-methoxy-isoquinoline, mp = 121-123 ⁰ C by the reduction of 36 g of 6-Mpthoxy-5-nitroisoquinoline in 450 cc of water with 42 g of iron powder;

- 38.8 g ö-methoxy ^ -nitroisochinolin from P. - 135-137 ⁰ C by nitriding of 34.2 g of 6-methoxy-isoquinolin in 137 cc of concentrated sulfuric acid with 46.7 g Ealiumnitrat.

The 6-methoxyisoquinoline can be prepared according to the method described by R. Robinson, J. Am. Chem. Soc. j> 9, 1939 (1947) described method will.

Example 11

To 10 g of ethylenediamine in solution in 250 cc of ethanol are added 28 g of 8-isothiocyanato-i-methyiisochinolin in solution in 250 cc of ethanol at 20 ⁰ C.

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A solid white precipitate appears for a few minutes. Stirring is maintained for 18 hours at 20 ⁰ C, then the white solid is separated by filtration and washed with 40 cc of ethanol.

20 ecm of yellow mercury dioxide are added to the combined ethanolic solutions and the suspension is refluxed for 3 hours. The mercury sulfide formed is separated off by filtration and then washed with 40 ecm of ethanol. The filtrate is concentrated to 20 ecm. The resulting precipitate is separated by filtration, washed with 40 cc of isopropyl ether and concentrated under reduced pressure (20 mm Hg) at 20 ⁰ C.

The product thus obtained is dissolved in 180 ecm acetonitrile at the boiling point. After filtering on the heat, the solution is ^{cooled to a temperature of about 0 °} C. for 2 hours. The resulting precipitate is separated by filtration, washed with 10 cc of acetonitrile and dried under reduced pressure (0.1 mm Hg) at 20 ⁰ C for 15 hours and then at 60 ⁰ C under the same pressure for 2 hours. 7.9 g of 8- (4,5-dihydro-imidazol-2-yl) -amino-1-methyl-isoquinoline with a melting point of 188 ° C. are obtained. The S-isothiocyanato- 1-methyl-isoquinoline can be prepared in the following way:

45.4 g Ν, Ν'-thiocarbonyldiimidazole in solution in 500 cc of methylene chloride are added at 20 ⁰ C 33.7 g of 8-amino-i-methyl-isoquinoline. The solution is stirred for 20 hours at 20 ^° C. After concentration, it is purified by chromatographic filtration on a column (height: 53 cm, diameter: 5.8 cm) which contains 700 g of silicon dioxide, eluting with methylene chloride. Concentrate the elution fractions containing the purified product, and drying the resulting solid under reduced pressure (20 mm Hg) at 20 ⁰ C. are thus obtained 28 g of 8-isothiocyanato-1-methyl-isoquinoline, mp = 50 ⁰ C.

The 8-amino-i-methylisoquinoline can be prepared according to the method of F.A.French and Mitarb., J. Med. Chem. 13 (6), 1117 (1970) can be obtained.

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Example 12

To a solution of 24.3 g of ethylenediamine in 360 ecm of ethanol 36 g of yellow mercury dioxide are refluxed and then 20 g of S-isothiocyanato-T-methyl-isoquinoline are added dropwise over 30 minutes in solution in 50 ecm of tetrahydrofuran.

The reflux is maintained for 1 1/2 hours. The mercury salts are separated off by filtering in the heat. The filtrate is concentrated until a yellow pasty residue is obtained, which is dissolved in 200 ecm boiling acetonitrile. 0.5 g of decolorizing charcoal is added and the mixture is filtered while hot. A product crystallizes out in the filtrate on cooling. The crystals are separated off by filtration and dried under reduced pressure (20 mm Hg at 20 ^° C., then 0.1 mm Hg at 60 ^° C.). One obtains H, 9 g of 8- (4,5-dihydro-imidazol-2-yl) amino-7-methyl-isoquinoline, mp = 168 ⁰ C.

The S-isothiocyanato-T-methylisoquinoline can in the following manner getting produced:

58.8 g of S-amino-T-methylisoquinoline are added to 82 g of NjlT'-thiocarbonyldiimidazole in solution in 530 ecm of methylene chloride. The mixture is stirred for 20 hours at 20 ^° C. It is purified by chromatography on a column (height: 75 cm, diameter: 5.8 cm) which contains 1 kg of silicon dioxide by eluting with methylene chloride. The fractions which contain the purified product are concentrated under reduced pressure (20 mm Hg) at 20 ^° C. Dry the resulting solid under reduced pressure (20 mm Hg) at 20 ⁰ C.-Man is thus obtained 63.2 g of S-isothiocyanato-T-methyl-isoquinoline, mp = 72 ⁰ C.

The 8-amino-7-methylisoquinoline can be prepared according to the method described by E. Brown, J. Org. Chem. 4_2, 3208 (1977) described method will.

Example 13

At 20 ⁰ C is stirred a solution of 9.5 g of 5-isothiocyanato-ir methoxy-isoquinoline and 13.2 g of ethylenediamine in 200 cc of methylene chloride for 11/2 hours. After narrowing under reduced

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This pressure (20 mm Hg) is added to the residue 200 ecm of ethanol and 8 g of mercury dioxide. The suspension is refluxed for 45 minutes. Each filtering in the heat, the insolubles are washed with 45 ecm boiling oil. After cooling, the combined ethanolic solutions at 20 ⁰ C for 12 hours that occurred crystals are separated by filtration, washed with 40 cc of ethanol and then with 60 cc of distilled water and under reduced pressure (0.2 mm Hg)

dried at 20 ^° C. and then at 50 ^° C. for a total of 2 hours ^ This gives 7.1 g of 5- (4-5-dihydroimidazol-2-yl) -amino-1-methoxy-isoquinoline with a melting point of 214-215 * 0.

The 5-isothiocyanato-i-methoxy-isoquinoline can have the following V / can be produced:

The mixture is stirred a solution of 14.3 g of 5-amino-i-methoxy-isoquinoline and 17.5 g !!! ', IT' thiocarbonyl diimidazole in 500 cc of methylene chloride for 20 hours at 20 ⁰ C. Stir the solution concentrated under reduced pressure (20 mm Hg), then the residue is chromatographed on a column of 30 g of silicon dioxide (height: 40 cm, diameter: 5 cm), eluting with 2000 ecm of ethylene chloride. The eluate is concentrated under reduced pressure (20 mm Hg). The residue obtained is dried ^{at 40 °} C. under reduced pressure (20 mm Hg). Are thus obtained 9.5 g of S-isothiocyanato-i-methoxy-isoquinoline, mp = 95-100 ⁰ C.

The 5-amino-i-methoxy-isoquinoline can be prepared in the following manner will:

17.3q 1-methoxy-5-nitroisoquinoline is reduced in 300 ecm acetic acid in the presence of 1 g palladium on carbon to 10 $ for 5 hours with hydrogen at 30 to 45 ⁰ C under normal pressure. The catalyst is separated off by filtration and washed with 100 ecm of ethanol. The filtrate is concentrated under reduced pressure (20 mm Hg). The residue obtained is taken up with a solution of 15 g of sodium bicarbonate in 300 ml of distilled water for 15 minutes while stirring. The insolubles are filtered off, washed with 150 ecm of distilled water and dried in air at 20 ° C. for 20 hours. Are thus obtained 14.3 g of 5-amino-i-methoxyisoquinoline, mp = 56-6O ^e C.

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The 1-methoxy-5-nitroisoquinoline can be prepared in the following manner will:

A suspension of 20.8 g of i-chloro-5-nitroisoquinoline and 12 g of sodium methylate in 500 ecm of methanol is refluxed for 1 1/2 hours. After cooling, the re-strike is separated by filtration, washed with 50 cc of methanol and then with 150 cc of distilled water and then is dried for 20 hours at 20 ⁰ C in air. This gives 17.3 g of i-methoxy-S-nitroisoquinoline with a melting point of 135-136 ° O. "

The i-Ohlor-5-nitroisoquinoline can be prepared according to the method described by B. Elpern, J.Am. Chem. Soc. j> 8, 1436 (1946) described method will.

Example 14

To 17.7 g of ethylenediamine, dissolved in 500 ecm of methylene chloride, are added 19.7 g of 8-isothiocyanato-S-diethylisoquinoline are obtained. One stirs during 20 hours at 20 ° 0. After evaporation of the solvent, the yellow oil obtained is aufgenou..aen in 500 ecm of ethanol. Chew heated to reflux and then added 20 g of yellow kercurioxide.

Each hour of refluxing, the mercury salts are separated off by filtration and washed with 50 ecm of boiling ethanol. The combined ethanolic solutions are evaporated. The yellow solid obtained is taken up in 100 ecm of distilled water. After filtering and washing with 20 can of distilled water, the insoluble matter is dried ^{at 20 ° C. under reduced pressure (20 mm Hg).} This product is taken up in 200 ecm isopropanol containing 5 $ water at the boiling point. After filtering in the heat, the product remaining on the filter is washed with 50 com isopropanol with 5% water and then dissolved in 20 ecm 1 IT hydrochloric acid. After filtering on a glass frit, the solution is neutralized by adding 20 ecm of 1N sodium hydroxide solution. The resulting precipitate is separated by filtration, washed with 20 cc water and then under reduced pressure (20 mm Hg at 20 ⁰ G and then 0.1 mm Hg at 60 ⁰ C).

This gives 2 ₉ 4 g of 8- (4j, 5-dihydro-imidazol-2-jl) -amino-5-methyl-

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isoquinoline from F. = 261 ^e C.

The S-isothiocyanato-S-methyl "- isoquinoline can have the following Way to be made:

32.4 g N ^ N'-thiocarbonyldiimidazole, dissolved in 450 cc of methylene chloride -Is 27 g of 8-amino-5-methylisoquinoline at 20 ⁰ C. The mixture is stirred for 20 hours at 20 ⁰ C. The mixture is concentrated and the solution is the residue is then purified by chromatographic filtration on a column (height: 51 cm, diameter: 5 cm) containing 500 g of silicon dioxide by eluting with 1 l of methylene chloride. Concentrate the elution fractions containing the purified product, and drying the resulting solid under reduced pressure (20 mm Hg) at 20 ⁰ C. are thus obtained 19.7 g of S-isothiocyanato-S-methylisoquinoline, m.p. = 58 ° C.

The 8-amino-5-methylisoquinoline can be prepared in the following manner will:

33 g of 5-methyl-8-nitroisoquinoline are added to 2 g of 10 ^ palladium on carbon, suspended in 400 ecm of acetic acid, and a stream of hydrogen is allowed to pass for 5 hours. After filtering on a glass frit equipped with a filter medium and washing with 100 ecm of distilled water, the solution is concentrated and then the residue is taken up in 100 ecm of water. The solution is neutralized by adding 1 IT sodium hydroxide solution. The precipitated solid is separated by filtration, ECM 20 with distilled water, washed and then under reduced pressure (20 mm Hg) at 20 ⁰ C dried. 26.6 g of S-amino-S-methylisoquinoline with a melting point of 136 ° C. are thus obtained.

The S-methyl-e-nitroisoquinoline can be prepared in the following manner will:

24.8 g of 5-methylisoquinoline are added in proportions to 135 ecm sulfuric acid (d = 1.83), which is cooled to 0 ° C. To the resulting solution, which is kept at 0 ^° C., 19.2 g of potassium nitrate are added in portions over 11/2 hours. The stirring is maintained for 30 minutes at 5 ^° C. and then for 1 1/2 hours at 20 ^° C.

It is poured onto 600 g of ice while stirring. One neutralizes through

9098U / 0963

Addition of ammonia (d = 0.92) with cooling to 0 ⁰ C. This gives a precipitate which is separated by filtration, washed with 25O cc of water and then, under reduced pressure (20 mm Hg) at 20 ⁰ C is dried . 33 g of 5-methyl-8-nitroisoquinoline with a melting point of 78 ° C. are thus obtained.

The 5-Methylisoehinolin can according to the TMRodionov, Zhur. Obshchei Khim. 27, 734 (1957) / Chem. Abstr. 5 ±, 16475 g (1957) 7 method described.

Example 15

At 20 ⁰ C is stirred a solution of 10 g of 5-isothiocyanato-1-dimethylaminoisochinolin and 7.8 g ethylenediamine in 200 cc of methylene chloride for 20 hours. The mixture is concentrated under reduced pressure (20 mm Hg), then the residue obtained is refluxed in 200 cc of ethanol in the presence of 10 g of yellow mercury dioxide for 1 1/2 hours. Mercury sulfide is filtered off in the heat and the filtrate is allowed to cool ^{to 20 ° C.} The crystals obtained are separated off by filtration and washed with 40 ecm of ethanol and then with 60 ecm of distilled water. These crystals are dissolved in 50 ecm 2 N hydrochloric acid and 0.1 g decolorizing carbon is added. After filtering, the solution is made alkaline by adding 25 ecm 4 N sodium hydroxide solution. After one hour of cooling to 0 ⁰ C, the precipitate is separated by filtration, washed with 60 cc of distilled water and then under reduced pressure (0.2 mm Hg) at 20 ⁰ C for 20 hours. This gives 4.9 g of 5- (4,5-dihydro-imidazol-2-yl) -amino-1-dimethylaminoisoquinoline with a melting point of 215-216 ° C.

The S-isothiocyanato-i-dimethylaminoisoquinoline can be obtained from 1-chloro-5-nitroisoquinoline can be obtained. For this purpose one prepares:

- 10.2 g of 5-isothiocyanato-i-dimethylaminoisoquinoline from F. =

53-55 ° C. from 9.3 g of S-amino-i-dimethylaminoisoquinoline and ^{11 g of N, N f} -thiocarbonyl-diimidazole in 200 ecm of methylene chloride;

- 9.3 g of S-amino-i-dimethylaminoisoquinoline in the form of an oil by reducing 12.5 g of i-dimethylamino-5-nitroisoquinoline in 250 ecm acetic acid using hydrogen in the presence of 1 g

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ίθ ^ -igeoi palladium on carbon;

- 12.5 g of 1-dimethylamino-5-thiitroio-ol; iinoline of ".?" = 120 ° C Heating 13 g of i-chloro-S-nitroisochiuolin with 17 g of dimethylamine in 180 ecm acetonitrile.

The i-ghlor-5-nitroisoquinoline can be prepared according to the method described by B.Elpern, J.Am. Chem. Soc. (58_, 1436 (1946) described method will. , "

Example 16

The mixture is stirred a solution of 7.2 g of S-isothiocyanato-i-methoxyoiethylisochinolin und.5,6 g of ethylenediamine in 150 cc of methylene chloride for 15 hours at 20 ⁰ C. compartment the Einenget) are added to the residue 100 cc of ethanol and 7, 5 g of mercury dioxide. The mixture is stirred for 2 hours at 20 ⁰ C and then heated to reflux, filtered while hot and the filtrate concentrated under reduced pressure (20 mm Hg). The residue is taken up in 50 ecm of distilled water, filtered and the filtrate is concentrated under reduced pressure (20 mm Hg) to a volume of 5 ecm. The pesticide formed is separated off by filtration and the cake is washed with 4 ecm of water. The cake is dissolved in 40 ecm 1N hydrochloric acid solution. The cloudy solution is filtered and the filtrate is made alkaline with 40 ecm 1 N sodium hydroxide solution. Extraction is carried out with 80 ecm of chloroform. After drying over 10 g of magnesium sulfate and filtering, the chloroform extract is concentrated ^{at 20 ° C. under reduced pressure (20 mm Hg).} The residue is taken up in 160 ecm boiling acetonitrile. Filter in the heat. After cooling to 20 ⁰ C the formed crystals are separated by filtration, washed with 20 cc of the acetonitrile and dried under reduced pressure (0.1 mm Hg) at 40 ⁰ C for 2 hours. Are thus obtained 2.45 g of 8- (4,5-dihydro-imidazol-2-yl) amino-1-methoxymethylisoGhinolin from Έ = 188-190 ⁰ C (with decomposition).

The S-isothiocyanato-i-methoxymethyl-isoquinoline can have the following Way to be made:

The mixture is stirred a solution of 13 g of 8-amino-i-methoxymethyl-isoquinoline and 15 g Ν, Ν'-thiocarbonyldiimidazole in 130 cc of methylene chloride for 20 hours at 20 ⁰ C. The solution is at a

Column of 250 g of silicon dioxide (height: 27 cm, diameter: 5 cm) chromatographed, eluting with 3000 ecm of methylene chloride. The eluate is concentrated under reduced pressure (20 min Hg). This gives 7.2 g of S-Iöothiocyanato-i-methoxymethyl-isoquinoline from Έ. = 90 ⁰ C.

The 8-amino ~ 1-methoxynieth.yl-isocb.inol in can in the following way getting produced:

58.7 g of hydrazine hydrate are added over a period of 30 minutes to a solution of 28.6 g of 5-bromo-1-methoxymethyl-8-nitroisoquinoline in 570 ecm of refluxing ethanol to which 6 g of Afo-strength palladium on carbon has been added . After the addition is complete, the mixture is refluxed for 2 hours. After filtering the catalyst, the alcoholic solution is concentrated under reduced pressure (20 mm Hg). The residue is extracted with a mixture of 50 ecm water and 100 ecm ether. The organic phase, which is dried in the presence of 15 g of magnesium sulfate and then filtered, is concentrated under reduced pressure (20 mm Hg). Are thus obtained 17 g of 8-amino-i-methoxymethyl-isoquinoline from P. = 72-75 ⁰ C.

The S-bromo-i-methoxymethyl-S-nitroisoquinoline can be used in the following Way to be made:

To a cooled to 0 ⁰ C solution of 26 g of 5-bromo-i-methoxymethylisochinolin in 120 cc of concentrated sulfuric acid are added 11.4 g of potassium nitrate in portions. Hach completion of the addition the temperature is maintained for 30 minutes at 0 ⁰ C and then for 11.2 hours at 20 ⁰ C. It is then poured onto 600 g of crushed ice and neutralized with 400 cc of a 11 U-ammoniacal solution. The precipitate obtained is filtered off, the cake is washed with 400 ecm of distilled water and air-dried for 20 hours. 28.6 g of 5-bromo-1-methoxymethyl-8-nitroisoquinoline with a P. = 136-137 ° C. are obtained in this way

The 5-bromo-1-methoxymethyl-isoohinolin can in the following way will be obtained:

A mixture of 40 g of 5-bromo-i-bromomethyl-isoehinolin is heated and 12 g of sodium methylate in 400 ecm of methanol for 30 minutes to reflux. The solution obtained is concentrated and the

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-30 - 291657?

residue obtained in 100 com of distilled water. The precipitate obtained is filtered, washed the cake with 100 cc of distilled v / ater and dried under reduced pressure (0.2 mm Hg) at 20 ⁰ C. are thus obtained 26.2 g of 5-bromo-1-methoxymethyl-isoquinoline from F. = 72 ⁰ C.

The 5-broin-i-bromomethyl-isoehinolin can in the following way getting produced:

A mixture of 89 g of 5-bromo-1-methylisoquinoline, 125 g of N-bromosuccinimide and 4> 5 g of benzoyl peroxide in 2200 ecm of carbon tetrachloride is refluxed for 16 hours. The suspension obtained is filtered and the cake is washed with 400 ecm carbon tetrachloride. The filtrate is poured into a column of 1000 g of silicon dioxide (diameter: 9.5 cm, height: 32 cm). It is eluted with 1600 ecm of methylene chloride. The eluate is concentrated under reduced pressure. Are thus obtained 55 g of 5-bromo-i-brommethylisochinolin from P. = 116-117 ⁰ C.

The 5-bromo-i-methylisoquinoline can be prepared in the following manner will:

To 117 g of 1-methylisoquinoline is added in small portions over 30 minutes 226 g of anhydrous aluminum chloride, the temperature of the reaction medium from 30 to 120 ⁰ C varied. After cooling to a temperature of about 80 ⁰ C are added over 2 1/2 hours, 28.7 cc of bromine and then keeps still for 2 hours at this temperature. After cooling to a temperature of about 20 ^° C., the reaction medium is poured onto 2.5 kg of crushed ice. 900 ecm of a 10 N sodium hydroxide solution are then added. The product, which partially precipitates, is extracted with 1.5 liters and then twice with 500 ecm of ethyl ether. The combined organic layers are dried over magnesium sulfate. After filtering and concentrating to dryness, the residue on the filter is washed with 500 ecm and then five times with 100 ecm hexane and dried under reduced pressure. This gives 86.5 g of 5-bromo-i-methylisoquinoline with a melting point of 98 ° C.

The wasohwaters are concentrated to dryness and the residue is taken up in 100 ecm hexane. The insoluble becomes through

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_ ₃₁ _ 291657?

Separated by filtration, washed three times with 50 com petroleum ether and dried. Are thus obtained 21g 5 ~ bromo ~ 1-niethylisoehinolin from P. = 94 ⁰ C.

At game 17

To 10 g of ethylenedi-amine in 350 ecm of anhydrous ethanol is added 20.7 g of yellow mercury dioxide. The mixture is heated to reflux and added 6.2 g of 8-isothiocyanato ~ 1,5 ~ dimethylisoehinoline in solution in 60 ecm [tetrahydrofuran to. It is held for 11/2 hours at reflux. Filter in the heat to remove the queek silver salts separate and wash them with 50 ecm boiling ethanol. The ethanolic solutions are concentrated and the residue is taken up in 200 ecm distilled water.

The insoluble product is separated off by filtration and washed it with 50 ecm of water. The filtrate is reduced to pH 3 with 11 N hydrochloric acid acidified and then treated with decolorizing charcoal. That By adding a 10N sodium hydroxide solution, Piltrat is brought to about pH 9, extracted with 500 ecm of methylene chloride. The methylene chloride extract is dried over sodium sulfate and then narrowed.

The yellow solid obtained is chromatographed on a column (height: 13 cm, diameter 1.5 cm) containing 20 g of aluminum oxide and eluted with methylene chloride. The elution fractions containing the product are concentrated to dryness. It is taken up with a minimal amount of boiling isopropanol. A solution is obtained which is treated with decolorizing charcoal. After filtering, the filtrate is allowed to cool and crystallization is initiated by scratching. After several hours of standing at 0 ⁰ C, the crystals are separated by filtration, washed with 5 cc of ethyl ether and dried under reduced pressure. The crystals are taken up in 20 ecm boiling acetonitrile and the solution is treated with decolorizing charcoal and then filtered while hot. The FiItrat is cooled to about 20 ⁰ C and it initiates the crystallization. After standing for several hours at 20 ⁰ C, the crystals are separated by FiItrieren and then washed with 2 cc of acetonitrile. That

4 4/0963

The product obtained is dried under reduced pressure (20 "Hg" at 20 ^° C., then 0.5 mm Hg at 60 ^° C.). This gives 0.7 g of 8- (4,5-dihydroimidazol-2-yl) - amino-1,5-dimethylisoquinoline, mp = 182 ° C.

The 8-isothiocyanato-i, 5-dimethylisoquinoline can have the following Way to be made:

8 g of U, 1T'-thiocarbonyldiimidazole are added to 6.4 g of 8-amino-1,5-dimethylisoquinoline in 100 ecm of methylene chloride. The mixture is stirred for 20 hours at 20 ^° C. The reaction mixture is concentrated to dryness and the residue is chromatographed on a column (height: 24.5 cm, diameter 2.7 cm) containing 70 g of silicon dioxide, with is eluted with methylene chloride. The fractions containing the purified product are concentrated. Dry the resulting solid under reduced pressure (20 mm Hg) at 20 ⁰ C. are thus obtained 6.2 g of 8-isothiocyanato-1,5-dimethylisoquinoline, mp = 124 ° C.

The 8-amino-1,5-dimethylisoquinoline can be obtained in the following manner getting produced:

2 g of 10 $ palladium on carbon are added to 8.2 g of 1,5-dimethyl-e-nitroisoquinoline, dissolved in 70 ecm acetic acid. After flushing the apparatus with nitrogen, a stream of hydrogen is allowed to flow into the suspension. The mixture is stirred under these conditions for 3 hours. The apparatus is flushed with nitrogen. It is filtered and the filtrate is concentrated to dryness. The residue is taken in 500 cc of ice water and brings by addition of 10 N-ammonia are the pH to about 8. The mixture is allowed during -2 hours at 0 ⁰ C, and then separating the crystals by filtration, and washed with 45 ecm of water. After drying in air and then under reduced pressure (20 mm Hg) at 20 ° C., 6.4 g of 8-amino-1,5-dimethylisoquinoline with a melting point of 158 ° C. are obtained.

The 1, S-dimethyl-e-nitroisoquinoline can in the following way getting produced:

To 28.8 g of 1,5-dimethyl-isoquinoline, dissolved in 140 ecm more concentrated Sulfuric acid, 20.8 g of potassium nitrate are added in small quantities within 3 hours. The mixture is stirred for 2 hours

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291657?

20 ° G. The solution is poured onto 2 kg of crushed ice and neutralized by adding 10 N amnionia. A brown product precipitates, which is separated off by filtration, washed with 400 ecm of distilled water, air-dried and then taken up with 2 liters of ethyl ether. The insolubles are filtered off and the filtrate is concentrated to dryness. The residue is stirred vigorously with 30 ecm diisopropyl ether. The insolubles are separated by filtration and then drying it under reduced pressure (20 mm Hg) at 20 ⁰ C. are thus obtained 18.4 g of 1, S-dimethyl-e-nitroisoquinoline, mp = 120 ⁰ C.

The 1,5-diniethyl-isoquinoline can according to the method of Ernst Späth et al., Ber. 63 B , 134-141 (1930).

Example 18

G to 6.7 S-isothiocyanato-S-methylthioisoquinolin dissolved in 100 cc of methylene chloride is added 6 cc of ethylenediamine and the mixture is stirred for 20 hours at 20 ⁰ C. skilled concentration, the residue is taken up in 100 cc of ethanol. The mixture is heated to reflux, 7 g of yellow Hercurioxid are added and the reflux is continued for 3 minutes. The mixture is stirred for a further 30 minutes, the temperature being allowed to come back ^{to about 20 ° C.} It is heated again to reflux and the mercury salts are filtered off in the heat, which are washed with 20 ecm of ethanol. The ethanol solutions are concentrated. The residue is vigorously stirred with 50 ecm of water. The insolubles are separated off by filtration, washed with 30 ecm of water and then taken up in 250 ecm of boiling acetonitrile. After filtering in the heat and cooling the filtrate, a yellow product crystallizes. The crystals are separated by filtration off, washed with 30 cc of acetonitrile and dried under reduced pressure (20 mm Hg at 20 ° C, then 0.1 mm Hg at 40 ⁰ C). Are thus obtained 3.4 g of 8- (4,5-dihydro-imidazol-2-yl) amino-5-methylthioisoquinolin mp = 212-214 ⁰ C.

The e-Isothiocyanato - ^ - methylisoquinoline can in the following way getting produced:

To 6.5 g of 8-amino-5-methylthio-isoquinoline in solution in 100 ecm of methylene chloride are added 8.2 g of ETJIT'-thiocarbonyldiimidazole and

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_3 * _ 291657?

the mixture is stirred at 20 ° 0 for 20 hours. Do the evaporation of the Solvent the residue on a column (height: 32 cm, Diameter: 3.5 cm) containing 110 g of silicon dioxide, chromatographed. Elute with methylene chloride. The fractions containing the purified product are combined and dried to dry constricted. The product obtained is dried under reduced pressure (20 mm Hg) at 20 ° C. 6.7 g of 8-isothiocyanato-5-methylthioisoquinoline are obtained in this way from P. = 124 ° C.

Example 19

To 1 g of e-isothiocyanato-S ^ -dimethylthio-isoquinoline, dissolved in 50 ecm of methylene chloride, 0.8 ecm of ethylenediamine is added. The mixture is stirred for 20 hours at 20 ⁰ C. skilled concentration, the residue in 50 cc of ethanol is added .. The mixture is heated to reflux, then gives 1 g of yellow Hercurioxid to. The mixture is refluxed for 3 minutes and then stirred for a further 30 minutes, the temperature being allowed to return to about 20.degree. It is heated again to reflux and the mercury salts are filtered off in the heat, which are washed with 10 ecm of ethanol. The ethanol solutions are concentrated to dryness. The residue is taken up in 20 ecm of water. The insolubles are separated by filtration from, it is washed with 30 cc of water, then drying it under reduced pressure (20 mm Hg) at 20 ⁰ C. are thus obtained 0.85 g of 8- (4,5-dihydro-imidazole 2-yl) -amino-5,7-dimethylthio-isoquinoline of F. = 206 ⁰ C.

The e-isothiocyanato-S ^ -dimethylthio-isoquinoline can have the following Way to be made:

G to 2 e-amino-S ^ -dimethylthio-isoquinoline, dissolved in 30 cc Methylenehlorid / are one 1.95 g of N, M ^"! -Thiocarbonyldiimidazol. The mixture is stirred for 20 hours at 20 ⁰ C. After evaporation of the solvent the residue is chromatographed on a column (height: 20 cm, diameter: 3 cm) containing 50 g of silica, eluting with methylene chloride, the fractions containing the purified product are combined and concentrated. The product obtained is under reduced pressure (20 mm Hg) at 20 ⁰ C. is thus obtained 1 g of 8-isothiocyanato-5,7-dimethylthio-isoquinoline, mp =

909844 ^ 9 63

-35 - 29,657?

The 8-amino ~ 5-nieth.ylthio-isochinoline and the 8-AmiTio-5,7-äimetta.ylthio-isoquinoline can be prepared in the following way: One passes at O ⁰ C in 125 ecm of ethanol, the 12, contains 7 g üTatriummethylat, "a methyl mercaptan until saturation. one gives 24.1 g of 5-bromo-8-nitroisoquinoline to. the mixture is stirred for 16 hours at 20 ⁰ C., then heated to reflux for 20 minutes. After evaporation of the Using a solvent, the residue is simultaneously taken up in 200 ml of methylene chloride and 200 ml of distilled water with vigorous stirring, the organic phase is decanted and the aqueous phase is extracted with 200 ml of methylene chloride.

The combined organic layers are washed with 200 ecm of water and dried over magnesium sulfate. After the solvent has been concentrated, the residue is chromatographed on a column (height: 25 cm, diameter: 5 cm) ₍ containing 250 g of silicon dioxide), first with 5 1 of methylene chloride and then with 1 1 of a mixture in fractions of 250 ecm Methylene chloride and methanol are eluted with 2% methanol, these fractions are concentrated to dryness and the product is ^{dried under reduced pressure (20 mm Hg) at 20 °} C. This gives 7.1 g of 8-amino-5,7-dimethylthio -isoquinoline from the temperature = 120 ° u.

If one with 1.5 1 continues the elution of a mixture of methylene chloride and methanol with methanol 4f °, is obtained after the concentration to dryness and drying under reduced pressure (20 mm Hg) at 20 ⁰ C 6.5 g of 8-amino -5-methylthio-isoquinoline with a melting point of 126 ° C.

Example 20

A mixture of 4.68 g of meth.yl-5-isoquinolyl-dithiocarbamate and 3.6 g of ethylenediamine in 100 ecm of ethanol is refluxed for 1 1/2 hours. 5 g of mercury dioxide are then added and the mixture is heated again to reflux for 3 1/2 hours. After filtering on the heat, the filtrate is concentrated under reduced pressure (20 mm Hg). The residue obtained is taken up with stirring in 30 ecm of distilled water for 1 hour. The insoluble matter is separated by filtration, washed with 30 cc of distilled water and then under reduced pressure (0.2 mm Hg) at 20 ⁰ C dried. 2.6 g of 5- (4,5-di-

909844/0963

.36. 291657?

hydro-imidazol ~ 2-yl) -amino-isoquinoline with a temperature of 191-192 ° C.

The 5-inoquinolyl dithiocarbamic acid methyl ester can be as follows getting produced:

A solution of 15.6 g of methyl iodide in 25 ml of acetonitrile is added dropwise to a suspension of 32.1 g of triethylammonium 5-isoquinolyldithiocarbamate in 100 ecm of acetonitrile, a temperature of 30.degree. To 35.degree. C. being maintained. Heating is continued for 11/2 hours after the addition is complete. 200 ecm of water and 200 ecm of methylene chloride are added to the reaction medium. The pesticide which precipitates is separated off by filtration, washed with 60 ecm of methylene chloride and then with 60 ecm of water. It is dried under reduced pressure (0.2 mm Hg) at 20 ^° C. for 20 hours. Are thus obtained 12.2 g isoquinolyl-5-dithiocarbamic acid-methylester, m.p. = 188 ⁰ C.

The! Driäthylammonium-isoohinolyl-S-dithiocarbamat can on can be produced in the following way:

G To a suspension of 72 g of 5-aminoisoquinoline in 90 cc of acetonitrile and 50.5! Driäthylamin is added dropwise 56.7 g of carbon disulfide, which is heated to 30 ⁰ C. Uach cooling to 0 ⁰ C the crystallized solid is separated by filtration, washed the cake with 200 cc of ether and dried at 20 ⁰ C under reduced pressure (0.2 mm Hg). 132 g of triethylammonium isoquinolyl-5-dithiocarbamate with a melting point of 142 ° C. are thus obtained.

Example 21

To 4.08 g of 8- (4,5-dihydro-imidazol-2-yl) amino-5-methylisoquinoline in 25 cc of acetic acid is added dropwise at 20 ⁰ C. 2.88 g of bromine in solution in 10 cc of acetic acid. A yellow solid precipitates out; it is separated off by filtration and washed with 10 ecm acetic acid. This solid is dissolved in 100 ecm of water. An insoluble matter is removed by filtration. The filtrate to 8 neutralized by adding a 1 IMJatriumhydroxidlösung to pH 7 The bodice precipitate obtained is stirred for 1 hour 'at 0 ⁰ C, and then separated by filtration, washed with 20 cc of water and finally vermindertet under. "Pressure (20 mm Hg ) dried at 20 ^{° C.}

909844/0 9 63

The product obtained is dissolved (3.8 g) in 150 cc Isopropanöl "with 5 $ water in boiling heat. The Iiösung is filtered in the heat and then cooled to 5 ⁰ C. The crystallized product is separated by filtration, washed with 10 cc Isopropanöl and dried under reduced pressure (20 mm Hg at 20 ⁰ C, then 0.1 mm "Hg at 60 ° C). 2.4 g of 7-bromo-8- (4> 5-dihydro-imidazol-2-yl) -amino-5-methyl-isoquinoliri with a P. = 282-283 ° C. are obtained in this way.

'ÖO9ÄU / 096

The medicinal product, consisting of a, product of the general Formula I as a base or as a salt or from these? containing medicinal products Compositions together with one or more compatible and pharmaceutically acceptable diluents or Aids represent a further subject of the invention. These medicaments can be used orally or parenterally will.

As solid compositions for oral administration,! Tablets, Pills, powders or granules can be used. In these compositions is the active product of the invention mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions may also contain substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, one can use the pharmaceutically acceptable emulsions, solutions, suspensions, Name syrups and elixirs that contain inert diluents such as water or paraffin oil. These compositions can also contain other substances besides diluents, for example wetting agents, sweeteners or flavorings.

The compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or carrier one can propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, for example Ethyl oleate. These compositions can also contain auxiliaries, especially wetting agents, emulsifiers and dispersants contain. The sterilization can take place in various ways, for example by means of a bacteriological one Filters by incorporating sterilizing agents into the composition, by irradiation or by heating. she can also be prepared in the form of sterile solid compositions, which at the moment of use in sterile Water or any other injectable sterile medium.

909844/0963

In human therapy are those according to the invention. Products especially applicable in the treatment of hypertension; the dosages depend on the desired effect and the duration of the treatment away; they are generally between 4 and 200 mg / day when administered orally in adults, in one or more Gifts.

In general, the attending physician will determine the posology which he or she has with regard to age, weight and others . thinks the treating patient's own factors are most appropriate. The following examples are intended to illustrate the invention Explain compositions in more detail.

Example A.

Tablets containing 25 mg of the active compound and the following composition are made according to the usual technique: 5 - / (4j5-dihydro-imidazol-2-yl) -amino7-6-methoxy-isoquinoline 0.025 g

Starch 0.200 g

precipitated silica 0.020 g

Magnesium stearate 0.005 g

Example B.

Tablets containing 25 mg of the active compound and the following composition are prepared using the usual technique: 8 - / (4,5-Dihydro-imidazol-2-yl) -aminq / -1-methylisoquinoline 0.025 g

Starch 0.200 g

precipitated silica 0.020 g

Magnesium stearate 0.005 g

Example C

Tablets containing 25 mg of the active compound and the following composition are prepared using the usual technique: 4- (4 »5-dihydro-imidazol-2-yl) -amino-

isoquinoline 0.025 g

Starch 0.200 g

precipitated silica ^ 0.020 g

Magnesium stearate y '0.005 g

9098U / O963

Claims (4)

Dr F. Zumstein Sr. - Dr. b. Ac; mr <n.n - Dr. R. Koenigsberger Diploma Phys. R. Holzbauer - Dipl.-Ing. F. Kiingsefsen - Dr. F. Zumstein jun. PATENT LAWYERS 80OO Munich 2 · Bräuhausstrasse 4 · Telephone sample no. 22 5341 ■ Telegrams Zumpat · Telex 529979 SC 4645/4666 2916577 10 / bs Claims New derivative of isoquinoline of the general formula -ίΏ V ^R 3 wherein R ₁ denotes a hydrogen atom or a hydroxyalkyl radical with 1 to 4 carbon atoms in the alkyl part, the imidazolin-2-yl-amino group bearing _{the radical R 1 being in the 4-> 5-, 6-, 7- or 8-position of the isoquinoline} can and where the symbols Rp and R ^, which are identical or different from each other, can be in the remaining positions of the isoquinoline ring and each have a hydrogen or halogen atom or an alkyl radical with 1 to 4 carbon atoms, alkoxy radical with 1 to 4 carbon atoms in the alkyl part, Alkoxyalkyl radical with 1 to 4 carbon atoms in each alkyl part, alkylthio radical with 1 to 4 carbon atoms in the alkyl part or a dialkylamino radical with 1 to 4 carbon atoms in each alkyl part, in the state of the free base or as an addition salt with an acid. 2. A method for producing a compound according to claim 1, characterized in that there is an ethylenediamine of the general formula H ₂ N - CH ₂ CH ₂ ITH - R ₁ wherein R _{1 is} as defined in claim 1 with a derivative of isoquinoline of the general formula 8098 44/0963 ORIGINAL INSPECTED brings to reaction, where R ₂ ^{and R} 3 ^{are defined as given in} claim 1 and Z, which is in the 4-, 5-, 6-, 7- or 8-position · is a 2-alkylisothioureido, alkylthiothiocarbonylainino y isothiocyanate radical means and that the product obtained is optionally isolated in the form of an addition salt with an acid. 3. Process for the preparation of a derivative of isoquinoline of the general formula wherein R- is a hydrogen atom or a hydroxyalkyl radical 1 to 4 carbon atoms, the imidazolin-2-yl-amino group bearing the substituent R ^ in 4- »5-, 6-, 7- or 8-position of the isoquinoline and one of the symbols Rp or R ~ is a halogen atom and the other is a hydrogen or halogen atom or an alkyl group with 1 to 4 carbon atoms, alkoxy group with 1 to 4 carbon atoms in the alkyl part, alkoxyalkyl group with 1 to 4 carbon atoms in each alkyl part, alkylthio radical with 1 to 4 carbon atoms in the alkyl part or dialkylamino radical with 1 to 4 carbon atoms in each alkyl part means, characterized in that a halogenating agent is used with a product of the general formula brings to reaction, wherein R ^ is defined as above, one of the symbols R ' ₂ or R'_ a hydrogen atom and the other a hydrogen or halogen atom or an alkyl radical with 1 to 4 carbon atoms, alkoxy radical with 1 to 4 carbon atoms in the alkyl part , Alkoxyalkyl radical with 1 to 4 carbon atoms in each alkyl part, alkylthio radical with 1 to 4 carbon atoms in the alkyl part or dialkylamino radical with 1 to 4 carbon atoms I098AA / O963 Means substance atoms in each alkyl part, where - if the symbols R ^! ₂ and R ¹ , each signify a Via sser st off atom - two halogen atoms can fix on the isoquinoline nucleus and that the product obtained is isolated with an acid, if appropriate in the form of the addition salt. 4. Medicament, consisting of a product according to claim 1 or a pharmaceutical composition, the at least one A compound according to claim 1 together with one or more compatible and pharmaceutically acceptable diluents or Contains tools.