DE2034587A1 - New, especially sympatholytic, pharmaceutical compositions based on isoquinolines and new substituted isoquinolines - Google Patents

Description

AGENCE NATIONALE DE VALORIZATION DE LA RECHERCHE (ANVAR),

Puteaux / France

New, especially sympatholytic pharmaceutical additives = = «= =: = = = ::::?: =: ^ =: = = = = = = = = Sss

compositions based on isoquinolines and new ones

substituted isoquinolines

The present invention relates to new pharmaceutical compositions based on isoquinoline derivatives and new substituted isoquinolines, and more particularly relates to new sympatholytic pharmaceutical compositions genes or drugs of great value as they are used in this field have the most interest.

The pharmaceutical compositions according to the invention or Medicines contain at least one substituted substance as an active substance Isoquinoline or its direct derivatives, such as those formed by quaternizing the nitrogen atom, pdör its salts, these substituted isoquinolines being characterized in that they have the following general

00988772228

Have structural formula:

Ν —- A-

where A denotes a group - (CHp) and η denotes an integer from 1 to 4, R ₁ denotes a hydrogen atom or represents one or more halogen, alkyl, alkoxy, aralkoxy or hydroxyl groups, which can be identical or different and which are bonded in one or more positions 5, 6, 7 or 8 of the isoquinoline group, or R ^ denotes a dioxymethylene group which is bonded to two adjacent positions of the substituted isoquinoline; R represents a hydrogen atom or represents one or more halogen, nitro, amino, hydroxy, alkyl, alkoxy or aralkoxy groups, which can be identical or different and which are bonded to any positions on the phenyl nucleus of the substituted isoquinolines , or the group R ₃ denotes a dioxymethylene group which is bonded to two adjacent positions of the substituted isoquinoline.

In the case of the preferred substituted isoquinolines which are used in the pharmaceutical compositions or medicaments according to the invention are used, the radical A denotes a monomethylene group, and the groups R., denote alkoxy groups, in particular Methoxy groups, where two adjacent groups R ^ can also carry a common alkyl radical, so that a dioxymethylene group is formed as a result.

In particular, the active ingredient of the pharmaceutical compositions according to the invention is advantageously an isoquinoline the following formula:

009887/2228

- CH,

wherein R ₃ denotes a hydrogen atom or hydrogen, halogen or methoxy radicals, which can be identical or different and which are bonded at any positions on the phenyl nucleus of the substituted isoquinoline, or R. denotes a dioxymethylene radical which is attached to the phenyl nucleus in two adjacent positions is bound.

The above-mentioned substituted isoquinolines, many of which are novel compounds, can be obtained by a process manufactured under the name "Bischler-Napieralskü" - Verxfahren is known, its use for the production of the above Isoquinolines mentioned consists in the fact that a substituted or unsubstituted N-acyl-ß-phenylHthylamine, in particular a N-formyl-ß-phenylethylamine of the general formula

H - CHO

wherein R ^ has the meaning given above, in the presence a cyclizing agent, in particular phosphorus oxychloride, in the presence of a solvent such as boiling toluene or Xylene, cyclized and the 3,4-dihydroisoquinoline obtained with a phenylalkyl halide of the formula

(CH-) - X
d η

where R ₃ and η have the meanings given above and X is a halogen atom, in particular a chlorine atom, is condensed, the latter condensation preferably being carried out in a solvent such as acetonitrile under reflux,

009887/2 228

and the N-phenylalkyl-3,4-dihydroisoquinoline obtained reduced with an alkali borohydride or by catalytic hydrogenation.

The present invention also relates to certain substituted 3,4-dihydroisoquinolines which are novel compounds and which are valuable intermediates, in particular in the preparation of the substituted tetrahydroisoquinolines which are the active ingredients of the pharmaceuticals of the present invention Represent compositions.

The following examples are intended to further the present invention explain without restricting them.

The melting points were determined in a capillary tube, in a Büchi-Tottoli device (F _T ) or with the aid of a Kaquenne block (FJ or on a previously calibrated Kofier bench (P ").

The infrared spectra were used for liquids in their pure state and for solids in solution, added in chloroform or carbon tetrachloride.

The purity of the products obtained was determined by thin layer chromatography (C.C.M.) on a silica support, known under the designation "Silicon Dioxide Carrier G Merck".

example 1 Production of e.V-Dimethoxv-S ^ -dihydroisoquinoline

38.2 g (0.18 mol) of N-formylhomoveratrylamine are cyclized (obtained starting from 35.8 g homoveratrylarain and 10.1 g 85% formic acid, which were in contact for 3 hours at 180 ° C) in the presence of phosphorus oxychloride in toluene at reflux. The mixture is refluxed for 2 hours. After cooling, the contents of the flask are carefully poured out 1 kg of crushed ice. The toluene phase is separated off "Man

009887/222 8

- 5.234587

makes alkaline by adding solid sodium carbonate up to a p "value of 8. It is extracted with benzene, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After distillation, 24.8 g (yield 71%) Boiling point _Q j _{4mm H} _ «132 ° C obtained a pale yellow viscous oil. This oil slowly crystallizes, F _M "39 to 40 ^° C.".

CC-.M. Rf «0.42 (methylene chloride + 8% methanol), blue spot that fluoresces in the UV.

IR 1615cm " ¹ (C>N); 294OCm ^-1 (CH).

The iodine methylate obtained by heating the raw materials described above Base obtained with methyl iodide in absolute alcohol has the following after recrystallization from alcohol Features on:

F _M * 218 ° C

Analysis; C ₁₂ H ₁₅ OMJ (332)

Calculated: C 43.41 H 4.55 N 4.22 J 38.23 0 9.59% Found: 43.22 5.04 4.05 37.68 9.66

Example 2

Preparation of 6 _T 7 ~ dimethoxy - 2 ~ benzyl-3,4-dihydroisoquinolinium bromide

5.73 g (0.02 mole) of pure 6,7-dimethoxy-3,4-dihydroisoquinoline are dissolved in 25 ecm acetonitrile and placed in a flask, which is provided with a descending cooler · Man gives 5.13 g (0.03 mol) of benzyl chloride in 25 .ecm acetonitrile with the aid a dropping funnel. . ... add. Leave for 1 hour stand at room temperature and then refluxed for 1/2 hour. 40 ml of the solvent are evaporated off in vacuo. The above bromide quickly crystallizes and is obtained 10 g of a yellow compound (yield 83%). This compound is crystallized from 96% ethanol to constant

009887/2228

Melting point around, F _T »191 to 192 ° C.

Analysis: C ₁₈ H ₂₀ O ₂ NBr ί362)

Calculated: C 59.72 H 5.57 N 3.87 Br 22.08 % Found: 59.92 5.64 3.69, 22.01

Example 3

Preparation of 6,7-Dlmethoxy-2-benzyl-l, 2 _t 3,4-tetrahydroisoquinoline

In a flask fitted with a reflux condenser and a dropping funnel is provided, 0.83 g (0.022 mol) of sodium borohydride are added. The mixture is stirred with the aid of a magnetic stirrer and cooled an ice bath, and then as quickly as possible 7.9 g (0.022 mol) 6,7-dimethoxy-2-benzyl-3,4-dihydroisoquinolinium bromide, dissolved in 50 ecm of pure methanol, added. After the addition, remove the ice bath and stir one night at room temperature « Half of the solvent is evaporated off under reduced pressure, 100 ecm of water are added and the mixture is extracted with Ether, wash with water, dry over anhydrous sodium sulfate and then evaporate on a water bath. 6.1 g of a yellowish liquid are obtained (yield 98.5%).

IR (film) absence of band C «N»

Preparation of the hydrobromide of 6,7-di, me |: hoxy-2 "benzyl- 1,2,3,4-tetrahydroisoquinoline

3 g of the base are used in the minimum amount of 96% ethanol dissolved (dissolve in the heat and then let it cool). 3 ecm of 40% hydrobromic acid are added. The hydrobromide quickly crystallizes out «, one crystallizes: it from ethanol to a constant melting point«. 2.6 g are obtained of the pure hydrobromide "P" = 224 to 225 ° C.

Analysis: C ₁₈ H ₂₂ O ₃ HBr (364)

Calculated? C 59.39 H 6 "09 M 3.85

Found: 59.11 6.16 3 ₉ <S5

009887/222

Example 4

Production of 6, 7-dimethoxy-2- (3'.4 ^l -dimethoxvbenzvl) -3.4-dihydroisoquinolinium chloride

First of all, 3,4-dimethoxybenzyl chloride is prepared. 40 g (0.16 mol) of 3,4-dimethoxybenzyl alcohol in 250 are placed in a flask fitted with a reflux condenser carrying a calcium chloride tube and a dropping funnel also closed with a calcium chloride tube ecm anhydrous ether and 10 ecm anhydrous pyridine, which was dried over potassium hydroxide. Gradually 40 ecm of freshly distilled thionyl chloride are added. After the addition, the mixture is refluxed for 1 1/2 hours. After cooling, it is carefully poured onto 500 g of crushed ice. It is extracted with Xther, the ether phases are washed with a dilute sodium carbonate solution and then with water and dried over. Sodium sulfate and evaporated on a water bath. 30.8 g (yield 70%) of an oily liquid are obtained, which soon crystallizes out. P _M «45.5 ° C. Because of the instability of the chloride, it is used directly.

The 6,7-dimethoxy-2- (3 *, 4 ^t -dimethoxybenzyl) -3,4-dihydroisoquinolinium chloride is obtained according to the process as described in Example 2 for the preparation of 6,7-dimethoxy-2-benzyl-3, 4-dihydroisoquinolinium bromide was described, starting from 10 g (0.052 mol) e ^ -dimethoxy-S ^ -dihydroisoquinoline in 50 ecm acetonitrile and 9.70 g (0.052 mol) 3,4-dimethoxybenzyl chloride in 50 ecm acetonitrile. After the reaction, the solvent is evaporated off in vacuo and a little acetonitrile and then Xther are then added again. The ether is decanted off, a mixture of ether and methylene chloride (1/1) is added and the result is a slight cloudiness. It is decanted off and only methylene chloride is added. The salt crystallizes out. It is recrystallized from a mixture of ether and methylene chloride (1/1) to a constant melting point and 15.9 g of the above-mentioned chloride with a temperature of 153 to 154 ° C. (yield: 81%) are obtained.

009887/2228

Example 5

Preparation of 6,7-dimethoxy-2- (3 ', 4'-dimethoxybenzyl) -1,2,3,4-tetrahydroisoquinoln

It is obtained using the procedure described in Example 3, starting from 1.7 g (0.042 mol + 10 % excess) of sodium borohydride and 15.9 g (0.042 mol) of the above salt, and 12, 5 g of the hydrogenated base in the form of a reddish oil (yield: 86%).

I, R. Absence of band C * N.

Preparation of the hydrobromide of the above-mentioned substituted isochinoline

9 g of the base are dissolved in the minimum amount of ethanol. A minimal amount of 40% hydrobromic acid is added up to an acidic p ^ value (p _H = 1). It is left to stand at room temperature overnight. If the salt does not crystallize out, it is evaporated in vacuo and the residue is taken up in acetone. The crystallization is started by scratching the wall of the Erlenmeyer flask. The hydrobromide is recrystallized from ethanol to a constant melting point. 7.1 g of the pure hydrobromide are obtained.

Yield: 97%. P. τ ^β 2O5 ~ C. N 3 , 30 Br 18, 85 Analysis: C 2O ^H 26 ° 4 NBr (424) 3 , 45 18 77 Calculated: C 56, 65 H 6.18 Found: 56, 81 6.21

Production of the iodine meth ylate of the above-mentioned substituted isoquinoline

40 g (17.6 ecm) of methyl iodide are added to 8.2 g (0.024 mol) of the base in 150 ecm of acetonitrile. The mixture is left to stand for 1 hour and then refluxed for 1/2 hour. After 2/3 of the solvent has evaporated, the iodine methylate crystallizes out, and 9.4 g (yield 82 %) of a yellow compound are obtained, which is recrystallized from 96% ethanol to a constant melting point. F _T = 219-220 ° C.

009887/2228

Analysis: C ₂ 1 ^H 2 £ ° 1 ^{NJ ί483)}

Calculated: C 52.22 H 5.43 N 2.90 O 13.25 %

Found: 52.05 5.88 2.59 13.42

Example 6

Production of 6, 7 ~ dimethoxy> -2 ~ o-chlp r ben 2 _r vl-3 _v 4-dihydroisoquinolinium chloride "

It is obtained according to the process as described in Example 4, starting from 11.46 g (0.06 mol) of 6,7-dimethoxy-3,4-dihydroisoquinoline in 50 ecm of acetonitrile and 9.7 g (O, 06 mol) o-chlorobenzyl chloride in 50 ecm acetonitrile. After standing for 1 hour and 1/2 hour under reflux, 80 ecm of the solvent is evaporated and the salt crystallizes out. Is recrystallized to constant melting point from acetonitrile and _r are obtained 17.9 g (yield 85%) of the above chloride. F _T «196 to 197 ° C. Analy ^ ej_ C ₁₈ H ₁₉ O ₂ NCl ₂ + 0.5 H ₃ O (361)

Calculated: C 59.88 H 5.58 N 3.90 Cl 19.64 % Found: 59.65 5.60 3.64. 19.62

Example 7

Production of 6, 7-difflethoxy ~ 2-o-chlorobenzyl-1,2,3,4-tetrahydroisoquinoline

It is obtained by reduction with the aid of borohydride according to the procedure described in Example 3. Starting from 19 g (0.05 mol) of the isoquinolinium salt in 100 ecm of pure methanol and 2.45 g (0.05 mol) of sodium borohydride in the minimum amount of methanol, 16.8 g (98 %) of the base is obtained in the form of a reddish oil.

IR (film) absence of the C = N band. . .

Preparation of the hydrobromide of the substituted isoquinoline mentioned above

To 16.8 g of the base dissolved in the minimum amount of ethanol . 009887/2228

L 10 «·

an F-, * 211 to 212 ° C. 98 Analysis: C ₁
JL ₈ H ₂₁ O ₂ NClBr C3 31 Calculated: C 54.24 H 5, 51 Found: 53.94 5, Example 8 , ho Manufacturing of 6, 7-dim et isoquinolinium chloride

are, you give 20 ecm of 40% hydrobromic acid “You give add a little ether to cause crystallization * Man crystallized from 96% ethanol to ssum constant Melting point around, and S g of the hydrobromide is obtained with

M 3.51 Sr 2O _$ 05 % 3 _$ 45 20.26

It is obtained in the manner described for the corresponding o-chlorobenzyl salt in Example 6, starting from 11.5 g (0.06 MoD 6.7 * dimethoxy <-3 _s 4 -dihydroisoquinoline 'in 50 ecm acetonitrile and 9.7 g (0.06 mol) of p-chlorobenzyl chloride in 50 ecm of acetonitrile are obtained. 16.5 g (yield 78 %) of the above-mentioned chloride, which is recrystallized from acetonitrile to a constant melting point up to 184 ° C.

Analysis; ^c ₁ 8 ^H i9 ° 2 ^NC1 2 ^i3S2)

Calculated: C 61.41 H 5.44 N 3.98 CX 20.15%

Found: 61.24 5 _S 59 4.21 19.96

Example 9

Manufacture of .6. «7 ^ Dlmeth oxy * 2 ^ p ^ chlorbengyl-» l _T 2,3. _y 4 ° -tetrahydroi spchino.lin

It is obtained according to the procedure as described in Example 7. Starting from 16.5 g (0 ^ 047 mol) of the salt from Example 8 in 110 ecm of pure methanol and 2.13 g (0.047 mol) of sodium borohydride in the minimum amount of methanol, 13.1 g are obtained after the treatment (yield 75 % ) of an orange-yellow oil.

I, R. (Movie) No C »N bands.

009887/2228

Preparation of the hydrobromide of the above-mentioned substitute ~ ten isoquinolines

13.1 g of the base are dissolved in 10 ecm of 96% ethanol and 19 ecm of 40% hydrobromic acid are added. Crystallization occurs immediately. It is recrystallized from 96% ethanol to a constant melting point, and 6 g of the hydrobromide »F _T > 248 to 249 ° C. are obtained.

AnalY_se ^. C ₁₈ H ₂₁ O ₂ NClBr (398.5).

Calculated: C 54.24 H 5.31 N 3.51 Br 20.05% Found: 54.32 5.41 3.46 20.33

Example 10 '

The following isoquinolinium salts are prepared in a similar manner and the 2-substituted tetrahydroisoquinolines:

6,7-dimethoxy-2- (o-fluorobenzyl) -3 _? 4-dlhydrolsoquinolinium chloride

Recrystallization from acetonitrile _{/ F T} «2O4 ° C; 50% Analysis ^ C ₁₈ H ₁₉ O ₂ NFCl + 0, SH ₃ O (345) Calculated: C 62.66 H 5.84 N 4.06 F 5.51 Cl 10.28% Found: 62.47 5, 82 3.75 5.21 10.55

6,7-Dimethoxy-2- (o-fluorobenzyl) -l, 2,3,4-tetrahydro-iso «quinoline hydrobromide *

Recrystallization from isopropanol; F_ = 212 ° C; 57%

(382)

Calculated: C 56.59 H 5.54 N 3.67 F 4.97 Br 20.92% Found: 56.30 5.50 3.92 4.64 20.94

6, 7-Dimethoxy-2 "- (m-fluorobenzyl) -3,4-dihydroisochinolinium chloride

Recrystallization from acetonitrilej F _T ■ 225 ° Cj 62%

009887/2228

Analysis;

Calculated: C 62.66 H 5.84 N 4.06 F 5.51 Cl 10.28% Found: 62.55 5.81 3.82 5.30 10.50

Hydrobromide of 6,7- Dimethoxy-2- (m ~ fluorobenzyl) -l, 2,3,4- tetrahydroisoquinoline

Recrystallization from isopropanolj F ^ = 218 ⁰ Cj 80% Analysis: C ₁₈ H ₂₁ O ₂ NFBr (382)

Calculated: C 56.59 H 5.54 N 3.67 F 4.97 Br 20 * 92% Found: 56.44 5.45 3.71 4.89 20.90

6 _it 7 - di-methoxy - 2 ~ (p-fluc> rbenzyl) -3 _t 4 - dihydroisoquinolnlunnchlorld

ttncrystallized from acetonitrile? F _T «165 ° Cj 54.4 % analysis: C ₁₈ H ₁₉ O ₂ NFCl + H ₃ O (354)

Calculated: C 61.07 H 5.98 N 3.96 F 5.37 Cl 10.02 % Found: 61.01 x 5.73 3.98 5.16 10.00

Hydrobromide des 6 ₁ 7 ~ p ± methoxv-2- (p.-fluorobenzyl) .- !. 2,3,4-tetrahydroisoquinoline

ttncrystallized from ethanol + 10 % water? F _T * 262 ⁰ Cj 80 % analysis: C ₁₈ H ₂₁ O ₂ NFBr (382) '

Calculated: C 56.59 H 5.54 N 3.67 F 4.97 Br 20.92 % Found: 56.56 5.44 3.73 4.68 21.16

e.7 ~ Dimethoxy-'2 ~ (2 ^t ^ ♦ py ^^ Y chloride

uracrystallized from acetonitrile? F ₁ «138 ° C; 57 % Anal ^ sej, C ₁₈ H ₁₈ O ₂ NCl ₃ + 0.5 H ₃ O (395.5) Calculated: C 54.73 H 4.84 N 3.55 Cl 26.90% Found: 54.77 4.88 3.49 26.74

0 0 9887/2228

Hydrobromide of 6,7-dimethoxy-2- (2 '^' - dichlorobenzyl ) - 1,2,3,4 ~ tetrahydro- isoquinoline

Recrystallized from isopropanolj F _T ~ 245 ⁰ Cj 80%

Br (433)

Calculated: C 49.93 H 4.57 N 3.24 Cl 16.38 Bf 18.46 % Found: 49.72 4.63 3.36 16.33 18.74

6, 7 ~ Dimethoxy-2- (2 ', 6'-dichlorobenzyl) -3,4-dihydroisoquinoli- » nium chloride

Recrystallized from acetonitrile; _Mp = 190 ° C; 67 % Analy_3e ^ C ₁₈ H ₁₈ O ₂ NCl ₃ (386.5)

Calculated: C 55.93 H 4.70 N 3.62 Cl 27.50 % Found: 55.78 4.79 3.49 27.64

Hydrobromide of 6, 7-dimethoxy-2- (2 *, 6 'Dichloro benzyD- _1.2? 3.4 ~ tetrahydroisoquinoline

Recrystallized from isopropanol + 10 % water; F _T = 125 ⁰ C, 88% analy ^ ej. C ₁₈ H ₂₀ O ₂ NCl ₂ + 0.5 HgO (442) Calculated: C 48.91 H 4.79 N 3.17 Cl 16.04 Br 18.08% Found: 48.45 4.74 2.95 15.83 18.76

6, 7-Dimethoxy-2- (3 ', 4' - dichlorobenzene-3,4-dihvdroisoquinoline chloride

Recrystallized from acetonitrile; F _T «190 ⁰ C; 70.5% analy ^ e ^. C ₁₈ H ₁₈ O ₂ NCl ₃ (386.5) Calculated: C 55.93 H 4.70 N 3.62 Cl 27.50% Found: 55.98 4.93 3.51 27.73

Hydrobromide des 6, 7-Dimethoxy-2 ~ (3 '^' - dichlorobenzyD-l _T 2 _t 3,4 - tetrahydroisoquinoline "

Recrystallized from isopropanol + 10% water; F ^, »26O ° Cj 98%

009887/2228

(433)

Calculated; C 49.93 H 4 ₉ 58 M 3.24 Cl 16 ₉ 38 Br 18.46 % Found: 49.93 4.63 3.41 16-02. 18.44

έ _Λ 7 _r pimethosey- _r 2 ° »C 3 '. 4 ⁸ ~ dip% ymethylenbensyl) -3 _? 4-dihydro- »i so ch i no 1 iniumbromi O _n

Recrystallized as acetonitrile ι P _T »215; 55 % analysis: C ₁₉ H ₂₀ O ₄ KBr C406)

Calculated! C 56.20 H 4.97 M 3.45 Br 19.68 % Found: 56.08 4.97 3.49 19.84

Hyd rpbromiCl _-1 des S ₁ 7 ^ BiTOethoxy - »2 °" - _i (3 " _t 4 ^ 1,2 _? 3,4-tetrahydroisochi noljns .. ünicrystallized ays isopropanol | F ^ - 256 ° C; 72 Analysis: C ₁₉ H ₃₂ O ₄ NBr (408)

Calculated: C 55.93 H 5 ₈ 44 N 3.43 Br '19.59 %, Found: 55.74 5 _? 42 3 _S 51 19.65

It was found that the above-mentioned substituted isoquinolines have a sympatholytic effect of the kind like the of yohimbine show without any toxicity nor side effects or negative effects show »®

In order to explain the present invention further, some results of the pharmacological investigations carried out with these substances are given below.

For the sake of simplicity, the substances examined are designated by the following abbreviations!

PV ₅ for the hydrobromide of 6,7-dimethoxy-2 "benzyl - 1,2,3,4-tetrahydroisoquinoline?

PV ₆ for the hydrobromide of 6,7 ~ dimethoxy-2-p- »chlorobensyl ~ 1,2,3,4-tetrahydroisoquinoline;

009887/2228

PV _? for the hydrobromide of 6,7-dimethoxy-2-o-chlorobenzyl-1,2,3,4-tetrahydroisoquinoline

PV ₀ for the iodine methylate of 6 ₁ 7-dimethoxy-2- (3 *, 4 "-dimethoxyben2yl) -l, 2,3,4" tetrahydroisoquinoline *

Determination of toxicity

The acute toxicity was determined on the fasting mouse. The products were administered orally. The lethal dose (DLg ₀ ) was determined using the method of Litchfield and Wilcoxon (J. PharnuExp.Therap *, 1949, 95, 99-113). The results obtained are shown in Table I below.

. '■;-.' ■ ':' Table I ■■ '. ■': " :. ■ '.. Product DL ₅₀ (mg / kg)

PV ₅ <1000

PV ₆ > 25OO

PV ₇ 1400

> 25OO yohimbine 80

The comparison of the toxicity of the gene according to the invention with that of the yohimbine, which under the same conditions As can be seen from the table, shows a clear advantage of the compounds according to the invention.

The sympatholytic effect of the compounds according to the invention was shown particularly well by their effect on the cardiovascular system and the vegetative nervous system, and particularly:

a) on the arterial pressure of the dog and the cat towards adrenaline and noradrenaline}

b) on the cat's nictitating membrane.

009887/2228

These effects were measured by the method described by Burn in "Practical Pharmacology, Blackwell, Oxford, 1952 "was determined on dogs and cats that were given a dose of 40 mg / kg pentobarbital, the intraperitoneally. was anesthetized and those doses of 0.004 tng / kg are administered intravenously. Adrenaline or noradrenaline. The following tables II and III show the results obtained on these animals 15 Minutes after the intravenous injection of the indicated doses of the substances tested were observed.

The arterial pressure was determined in the dog in the range of Head artery with the help of a mercury manometer, and this pressure was recorded on a kymographic trace.

The inhibiting effect on the effects of adrenaline and Norepinephrine produced by the compounds administered (each horizontal row relates to a different one Dog or another cat), according to the result obtained, either by the sign =, which is the complete Blocking of the effects means, or expressed by the sign, that shows a marked reduction in the same effects, or the percentage inhibition of these effects, which was determined is indicated. It should be noted that in certain cases even under the influence of the investigated Compounds an inversion of the effect of adrenaline was observed.

009887/2228

Tabel II Norepinephrine Products Dose mq / kg adrenaline 50% PV 5 10 se - PV 5 10 S. - 14% PV 5 10 - 54% PV 5 10 B. - 52% , PV 5 15th B. - 38% PV 6 10 3 - 21% PV 6 10 - 33% - 27% PV 7. 10 - 34% - 47% PV 7 10 - 62% - 63% PV 9 10 - 79%

The movements of the cat's nictitating membrane were made with the help of a Compulsory standard of measure registered. The inhibitory effect caused by the tested compounds on cats (each horizontal row relates to a different cat) is given in Table III below as the percentage reduction in the effect of adrenaline

Products

Table III

Dose mg / kg

Effect on the nictitating membrane

PV 5 10 - 56% PV 5 10 - 42% PV 5 15th - 48% PV 6 10 - 47% PV 6 10 - 19% PV 7 10 - 33% PV 7 10 - 18%

These studies thus show that the compounds according to the invention have a considerable adrenolytic effect, which has been confirmed by positive tests in both dogs and cats.

⁺⁾ (jauge de contrainte)

009887/2228

It was also found that the compounds in question, at least to some extent, are free from secondary effects that sometimes disrupt the possibilities the use of certain common sympatholytic drugs.

In particular, in the test carried out by Winter (J * Pharmacol., 1948, 94-97), in which one uses the deepening of sleep with the help of hexobarbital in the mouse, the practical absence of any effect on the central nervous system of the compounds in question, even at considerable ones Cans shown.

The substances to be examined (in suspension in 10% Gum arabic) were administered intraperitoneally in the amounts given in Table IV below, 15 minutes before the intraperitoneal injection of hexobarbital at a dose of 100 mg / kg in female mice of the Swiss strain, which weighed between 20 and 25 g. The comparison mice (which previously administered only the 10% gum arabic solution had been), were treated in the same way with hexobarbital (first horizontal row of numbers in Table IV).

The results given in Table IV below show that the compounds in question are effective even at very high doses have practically no effect on the mean sleep times of the treated animals.

Products

15 min. Before the administration of 100 mg / kg Hexo barbital ,, ip

comparison 5 PV 6th PV 7th PV 9 PV

Table IV At
number
the
animals Medium
Sleep duration
Minutes dose
mg / kg
iD 35 33 _ 10 36 50 8th 30th 50 8th 29 50 8th 31. 50

009887/2228

All of these examinations clearly show the high sympatholytic effect of the compounds examined.

Furthermore, this effect, which can be found in the various substituted isoquinolines examined, confirms, that they can be used by analogy with what is generally used in relation to the retention of the pharmacological effect in the case of known alkaloids observed when looking at these structurally changed, the following basic structure on which all isoquinolines are based:

N / A

can be attributed to such that the substituents on shifted to the isoquinoline and phenyl nuclei of this structure and can be changed without the isoquinolines of the kind in question being impaired in terms of their pharmacological or therapeutic properties Lose effect.

The pharmaceutical compositions or medicaments according to the invention can be administered in all customary forms, for oral, rectal or parenteral use, especially in the form of tablets, lozenges, granules, syrups, suppositories, injectable solutions, etc., where the active ingredient in all of these forms is associated with conventional carriers, diluents or extenders, particularly those used in conjunction with papaverine. You can on oral route in maximum daily doses ranging from IO mg to 2 g and preferably ranging from 100 mg to 500 mg.

009887/2228

The compositions or medicaments according to the present invention Invention are indicated for all diseases that are vasodilator Adrenolytic-type medication required do. They are particularly indicated for treating arteritis and coronary artery infections and alike to treat hypertension.

According to the present invention, sympatholytic ones are obtained pharmaceutical compositions or medicaments which are particularly interesting for use because of their action and the absence of toxicity and undesirable side effects in human and veterinary medicine.

The studies on the mouse, especially with the substances PV 6 and PV 7, using the test of Wolfe and MacDonald, J. Pharm.Exp.Therap., 1944, 80, 301 showed no signs of analgesia, even at doses of 100 mg / kg administered by the intraperitoneal route.

It goes without saying that the present invention does not rely on the procedures given in the description and areas of application is limited, but that it also includes all variants in contrast.

009887/2228

Claims (1)

Claims 1 *) Pharmaceutical Sympathikoly.tische compositions, which together with a physiologically acceptable carrier at least a substituted isoquinoline or direct derivatives like those that can be quaternized by the Nitrogen atom receives, or its salts contain, thereby - characterized in that the substituted isoquinoline has the following general formula: - A wherein A denotes a group - ^ ^CH 2 ^ n "" ^{and n} * ^b * " ^{s 4} , R ^ denotes a hydrogen atom or represents one or more halogen, alkyl, alkoxy, aralkoxy or hydroxyl groups which are identical or can be different and which are bonded to the isoquinoline group in one or more positions 5, 6, 7 or 8, or R ^. denotes a dioxymethylene group which is bonded to two adjacent positions of the substituted isoquinoline, R denotes a hydrogen atom or represents one or more halogen, nitro, amino, hydroxyl, alkyl, alkoxy or aralkoxy radicals, which can be identical or different and which can be bonded to the phenyl nucleus of the substituted isoquinolines at any position, or RJ means a dioxymethylene group, which is bound to two adjacent positions of the substituted isoquinoline. 2.) Pharmaceutical compositions according to claim 1, characterized in that characterized in that the group A is a methylene group 009887/222 8 3.) Pharmaceutical compositions according to one of claims 1 or 2, characterized in that the substituents R-alkoxy groups are _5, in particular methoxy groups, and two adjacent sub stl tu en. R- can carry a common alkyl radical, so that they form a dioxymethylene radical «. - 4 *) Pharmaceutical compositions according to claim 1, because <through characterized in that they contain at least one substituted Isoquinoline of the formula η ~ , wherein R ₃ represents a hydrogen atom or water 'serstoff-, halogen or methoxy radicals, which are identical or different and which are bonded to the phenyl nucleus of the substituted isoquinoline, or R ₃ also represents a dioxymethylene group "adjacent to two positions of the phenyl nucleus is bound " 5.) Pharmaceutical compositions according to claim 1, characterized characterized in that they are as active ingredient at least. contain one of the following substituted isoquinolines: 6,7-dimethoxy-2-benzyl-1,2,3,4-tetrahydroisoquinoline, 6,7-Dimethoxy-2- (3 · ^ '- dimethoXybenayl) -1,2,3,4-tetrahydroisoquinoline, 6,7-Dimethoxy-2-o-chlorobenzyl-lj 2,3,4 "" tetrahydroisoquinoline, 6,7-Dimethoxy-2-p-chlorobenzyl-1,2,3,4 "tetrahydroisoquinoline. New 6,7-dimethoxy-2-benzyl-l ₉ 2,3,4 ^ tetrahydroisoquinolines which are substituted or unsubstituted on the benzyl radical. 009887/2228 - 23 7.) e ^ -Dimethoxy ^ -benzyl-l ^ S ^ -tetrahydroisoquinoline. 8.) 6,7-Dimethoxy-2- (3 ·, 4V-dimethoxybenzyl) -!, ^, 3,4-tetrahydroisoquinoline. 9.) e ^ -Dimethoxy ^ -o-chlorobenzyl-l ^ jS ^ -tetrahydroisoquinoline. 10.) 6,7-Dimethoxy-2-p -chlorobenzyl-1,2,3,4-tetrahydroisoquinoline. 11.) 6,7-Dimethoxy-2- (o-fluorobenzyl) -1, 2,3,4-tetrahydroisoquinoline. 12.) 6, 7-Dimethoxy-2- (m-fluorobenzyl) -1, 2,3,4-t-ethrahydroi sochinolin. 13.) 6,7-Dimethoxy-2- (p-fluorobenzyl) -l _t 2,3,4-tetrahydroisoquinoline. 14.) 6 _{l of} 7-dimethoxy-2- (2 ^l , 4 ^l -dichlorobenzyl) -1, 2,3,4-tetrahydroisoquinoline. 15.) 6,7-Dimethoxy-2- (2x, e'-isoquinoline. 16.) 6,7-Dimethoxy-2- (3 ^l , 4 ^t -dichlorobenzyl) -1, 2,3,4-tetrahydroisoquinoline. '- 17.) 6,7-Dimethoxy-2- (3 ^l , 4 ^f -dioxymethylene benzyl) -1, 2,3,4-tetrahydroisoquinoline. 18.) Compounds according to any one of claims 6 to 17, characterized characterized in that they are in the form of the salts of the corresponding substituted isoquinoline, such as the hydrobromide, are present. 19 ·) 6,7-Dimethoxy-2-benzyl-3,4-dihydroisoquinoline, which is attached to the Benzyl radical is not substituted. 009887/7228 20.) 6,7-Dimethoxy-2- (3 ·, 4'-dimethoxybenzyl) -3,4-dihydroisoquinoline. 21.) G ^ -Dimethoxy ^ -o-chlorobenzyl-S ^ -dihydroisoquinoline. 22.) 6,7-Dimethoxy-2-p ~ chlorobenzyl-3,4-dihydroisoquinoline. 23.) 6,7-Dimethoxy-2- (o-fluorobenzyl) -3,4-dihydroisoquinoline. 24.) 6.7 ~ dimethoxy-2 ~ (m-fluorobenzyl) ~ 3.4 ~, dihydroisoquinoline. 25.) 6,7-Dimethoxy-2- (p-fluorobenzyl) -3,4-dihydroisoquinoline. 26.) 6,7-Dimethoxy-2- (2 ·, 4 · -dichlorobenzyl) -3,4-dihydroisoquinoline. 27.) 6,7-Dimethoxy-2- (2x, 6'-dichlorobenzyl) -3,4-dihydroisoquinoline. 28.) 6,7-Dimethoxy-2- (3 », 4 · -dichlorobenzyl) -3,4-dihydroisoquinoline. 29.) 6,7-Dimethoxy-2- (3x, 4'-dioxymethylene benzyl) -3,4-dihydroisoquinoline. 30.) Process for the preparation of the substituted isoquinolines according to claim 1 ,, characterized in that the Cyclization of an N-acyl-ß-phenylethylamine of the general Formula: wherein R ^ is as defined above in besitztj pres- 'ence of a cyclizing causes and the resulting 3,4-dihydroisoquinoline with a Phenylalkylhalogenid the formula: 009 887/7 22 8
^;; "^S; OBIGiNAL INSPECTED -25 - ^: ■ ■■■■ - ■: condensed, in which R- and η have the meanings given above Have and X is a halogen atom, and the N-phenylalkyl-S ^ -dihydroisoquinoline obtained with a Alkali borohydride or reduced by catalytic hydrogenation. 009887/7228 ORIGINAL INSPECTED