GB1585026A - Tetra alkoxy substituted 1-benzyl di- and tetra-hydroisoquinolines - Google Patents

Description

(54) TETRA ALKOXY SUBSTITUTED l-BENZYL DI- AND TETRA-HYDROISOQUINOLINES (71) We, LABORATOIRES SOBIO S.A., a French company of Immeuble Perisud, 4 rue Francois Ory, (92128)-Montrouge, France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a class of hydrogenated benzylisoquinoline derivatives which possess spasmolytic and hypotensive activity.

British Patent No. 1,417,542 discloses the use of certain hydrogenated isoquinoline derivatives of formula (I):

(wherein each R independently represents hydrogen or an alkoxy group containing 1--10 carbon atoms; and Z and X each represent hydrogen or together form a valency bond) in the form of their theophylline 7-acetate salts, for geriatric use.

The compounds disclosed in Patent No. 1,417,542 have each group R being identical to each other, a preference being stated for the tetra-ethoxy compound.

We have now found that hydrogenated benzylisoquinoline derivatives having higher alkoxy substituents on the aromatic rings, and having such substituents on one ring different to those on the other ring, have superior properties to known compounds.

Accordingly the present invention provides a compound of formula (II), or a pharmaceutically acceptable acid addition salt thereof:

wherein R' and R2 are different and one represents a C1-C6 alkyl group and the other represents a C3-C6 alkyl group; and A and B either both represent hydrogen or together represent a covalent bond.

The groups R' and R2 may be, for example ethyl, n- or iso-propyl, or n-, iso-, sec- or tert-butyl. Preferably, one of R' and R2 represents isopropyl.

Pharmaceutically acceptable acid addition salts of compounds of formula (II) are also included within this invention. Suitable acid addition salts of the compounds of formula (II) include, for example inorganic salts such as the sulphate, nitrate, phosphate, and borate; hydrohalides e.g. hydrochloride, hydrobromide and hydroiodide; and organic acid addition salts such as acetate, .oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate methanesulfphonate and p-toluenesulphonate.

Specific compounds within the scope of the present invention include the following: 6,7 - diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 3,4 - dihydroisoquinoline, or its hydrochloride; I - (3',4' - diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 - dihydroisoquinoline, or its hydrochloride or ascorbate; 6,7 - diethoxy - 1 - (3',4' - di - n - propoxybenzyl) - 3,4 dihydroisoquinoline, or its hydrochloride; 1 - (3',4' - diethoxybenzyl) - 6,7 - di - n - propoxy - 3,4 - dihydroisoquinoline, or its hydrochloride; 1 - (3',4' - diethoxybenzyl) - 6,7 - diisopropoxy - 1,2,3,4 - tetrahydroisoquinoline or its hydrochloride; 6,7 - diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 1,2,3,4 tetrahydroisoquinoline or its hydrochloride.

A preferred compound of this invention is the hydrochloride of 1 - (3',4' diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 - dihydroisoquinoline of formula (III):

The compounds of the present invention may be prepared by a process which comprises (a) cyclisation of a compound of formula (IV):

with a condensing agent (to produce a compound of formula (II) in which A and B together represent a bond); and (b) optionally reducing the resultant product (to produce a compound of formula (II) in which A and B are both hydrogen). Some of the compounds of the formula IV are novel compounds and are described and claimed in our Patent Application No. 38321/79 (Serial No. 1,585,027).

For step (a) of the above process, suitable condensing agents include phosphorus oxychloride and phosphorus pentoxide, preferably the former. The reaction is suitably carried out in a non-polar organic solvent such as benzene or chloroform, preferably under an inert atmosphere, e.g. nitrogen, at an elevated temperature e.g. 500--1000C.

The reduction step, step (b) of the above process may be carried out using catalytic hydrogenation in the presence of palladium, Raney-nickel or a precious metal as catalyst. Suitably, palladium on charcoal is employed and the reduction carried out at a pressure of 1--10 atmospheres in the presence of a polar solvent.

Hydrogenation may also be carried out by employing sodium amalgam or sodium in alcohol. A preferred method of carrying out the reduction of step (b) above is to employ a metallic hydride, especially lithium aluminium hydride in an organic solvent such as ether or tetrahydrofuran or sodium borohyride, in solution in a polar solvent, e.g. an alkanol such as methanol or ethanol.

The amides of formula (IV) may be prepared by known methods for preparing amides, for example by reacting a phenylethylamine of formula (V) with a compound of formula (VI):

wherein Y represents a carboxylic acid group or an ester thereof, preferably an ethyl ester. This reaction is conveniently carried out without solvent at a temperature of from 1200-2100C.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore includes within its scope a pharmaceutical composition comprising a compound of formula (II) above together with a pharmaceutical carrier or excipient.

The compositions may be formulated for administration by any route, such as oral topical or parenteral. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams of liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl phydroxybenzoate or sorbic acid, and if desired convent on flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.

Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.10/, by weight, preferably from l(60% by weight, of the active material, depending on the method of administration.

Where the compositions comprise dosage units,.each unit will preferably contain from 50-500 mg. of the active ingredient. The dosage as employed for adult human treatment will preferably range from 20500 mg. per day, for instance 100 mg. per day, depending on the route and frequency of administration.

The following Examples illustrate the preparation of a number of compounds of this invention.

Example 1 a) N-[2-(3,4-diethoxyphenyl)ethyl]-3,4-diisopropoxyphenyl acetamide A mixture of 2 - (3,4 - diethoxyphenyl) - ethylamine (40.7 g, 0.195 mole) and ethyl 3,4 - diisopropoxyphenylacetate (55.7 g, 0.195 mole) was heated with stirring at 1600C for 20 hours, allowed to cool and the resulting oil taken up in 700 ml of chloroform. The organic solution was washed 3 times with 100 ml of N hydrochloric acid and then with water to pH 7. The chloroform solution was dried over magnesium sulphate, the solvent removed under reduced pressure and purification effected by chromatography over silica gel. 64.5 g (yield 720/) of product was obtained sufficiently pure to be used in step (b) below.

By recrystallisation of a sample in cyclohexane N - [2(3,4 - diethoxyphenyl)ethyl] - 3,4- diisopropoxyphenyl - acetamide is obtained, m.p.=87 C.

Analysis C26H3,NOs=443.6 C /n H% N% Calculated 70.40 8.41 3.16 Found 70.49 8.22 3.13 b) 6,7 - Diethoxy - 1 - (3',4' - diisopropoxybenzyl - 3,4 - dihydroisoquinoline hydrochloride 5.0 g (0.0113 mole) of N - [2 - (3,4 - diethoxyphenyl)ethyl] - 3,4 diisopropoxyphenyl acetamide, 100 ml of benzene and 2.3 g (0.015 mole) of phosphorus oxychloride were introduced successively into a 250 ml flask. The reaction mixture was placed under a nitrogen atmosphere and heated under reflux for 2 hours. 70 ml of solvent was removed under reduced pressure, 30 ml of ethanol was added, followed by 1 ml of 12 N hydrochloric acid. A further 10 ml of solvent was removed, 20 ml of sodium-dried diethyl ether was added and the flask cooled externally to below -200C over a period of several hours. The crystallised product was drained under vacuum and washed 3 times with ether. Yield=80%, m.p. 2160C.

Analysis C26H35NO4HCl=462.0 CV0 H% NV0 Cl% Calculated 67.59 7.85 3.03 7.67 Found 67.50 7.83 3.13 7.76 Example 2 a) N - [2 - (3,4 - Diisopropoxyphenyl)ethyl] - 3,4 - diethoxyphenylacetamide was prepared starting from 2 - (3,4 - diisopropoxyphenyl)ethylamine and ethyl 3,4-diethoxyphenyl acetate using the process described in Example 1 (a).

Yield=67%, m.p. 710C.

Analysis C26H37NOs=443.6 C% H% N% Calculated 70.40 8.41 3.16 Found 70.73 8.09 3.07 b) 1 - (3',4' - Diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 - dihydroisoquinoline hydrochloride 5.0 g (0.0113 mole) of N - [2 - (3,4 - diisopropoxyphenyl) - ethyl] - 3,4 diethoxyphenylacetamide, 100 ml benzene, and 2.3 g (0.015 mole) of phosphorus oxychloride were introduced successively into a 250 ml 3-necked flask after being passed through an atmosphere of nitrogen. The mixture was heated under reflux with stirring over a period of 2 hours, 70 ml of solvent removed by distillation, 30 ml of ethanol, 1 ml of 12 N hydrochloric acid added and the bulk of solvent removed by distillation under reduced pressure. The residue obtained was washed several times with ether, taken up again in solution in 15 ml of ethanol, and 120 ml of ether added slowly. The slowly precipitated product was dried to give 2.93 g of I - (3',4' diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 - dihydroisoquinoline hydrochloride, Yield=57%, m.p. 187 C.

Analysis C26H35NO4HCl=462.0 CV MV NV CIV Calculated 67.59 7.85 3.03 7.67 Found 67.68 7.78 3.22 7.43 Example 3 a) N - [2 - (3,4 - diethoxyphenyl)ethyl] - 3,4 - di - n - prqpoxy - phenylacetamide was prepared from 2 - (3,4 - diethoxyphenyl) - ethylamine and ethyl 3,4 - di n - propoxyphenyl acetate using the process described in Example 1 (a).

Yield=77.5%, m.p. 99 C.

Analysis C26H3,NOs=443.6 CV MV NV Calculated 70.40 8.41 3.16 Found 70.20 8.37 3.20 b) 6,7 - Diethoxy - 1 - (3',4' - di - n - propoxybenzyl) - 3,4 - dihydroisoquinoline hydrochloride The procedure of Example 1 (b) was employed using 26.76 g (0.0602 mole) of N - [2 - (3,4 - diethoxyphenyl)ethyl] - 3,4 - di - n - propoxyphenylacetamide, 350 ml of bezene and 12.3 g (0.0-81 mole) of phosphorus oxychloride, Yield =85%, m.p.

214 C. analysis C26H35NO4HCI=462.0 C% H% N% CI% Calculated 67.59 7.85 3.03 7.67 Found 67.29 7.76 2.98 7.79 Example 4 a) N - [2 - (3,4 - di - n - propoxyphenyl)ethyl] - 3,4 - diethoxy - phenylacetamide was prepared from 2 - (3,4 - di - n - propoxyphenyl)ethylamine and ethyl 3,4 - diethoxyphenylacetate using the process described in Example 1(a). b) 1 - (3',4' - Diethoxybenzyl) - 6,7 - di - n - propoxy - 3,4 - dihydroisoquinoline hydrochloride The procedure of Example 1 (b) was employed using 34.28 g (0.0773 mole0 of N - [2 - (3,4 - di - n - propoxyphenyl)ethyl] - 3,4 - diethoxyphenylacetamide, 350 ml of benzene and 15.8 (0.103 mole) of phosphorus oxychloride, Yield=75%, m.p.

210 C.

Analysis C26H35NO4HCl=462.0 C% H% N% Cl% Calculated 67.59 7.85 3.03 7.67 Found 67.30 7.95 2.97 7.91 Examples 5-8 Preparation of free bases The following method was employed for Examples 5-8 to convert the hydrochlorides of Examples 1-4 to their corresponding bases: 0.001 mole of the hydrochloride and 30 ml of sodium-dried diethyl ether are introduced into a 100 ml flask, and a stream of nitrogen passed into the suspension.

1 ml of a solution of methanol saturated with ammonia is added at 0 C, the suspension stirred for a few moments and the precipitate drained rapidly e.g. under suction, The solvent is removed under reduced pressure at 20 C and the product dried in an oven at 40 C at 0.01 mm pressure. The pressure is then returned to atmospheric pressure under nitrogen.

N.m.r. spectra for Examples 5-8 The n.m.r. spectra were obtained on the products of Examples 5-8 in solution in CDCl3 at 35 C, using tetramethylsilane as reference.

The chemical shifts which were common to each of the compounds of Examples 5-8 were as follows:

6.8 ppm (multiplet): the three 'a' protons; 6.6 ppm (singlet): the 'b' proton; 7.0 ppm (singlet): the 'c' proton; 2.6 ppm (triplet): the two 'd' protons; 3.7 ppm (triplet): the two 'g' protons; 3.9 ppm (singlet): the two 'f, protons.

Example 5 6,7 - Diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 3,4 - dihydroisoquinoline Prepared from the compound of Example 1, this product is pale yellow. n.m.r. characteristics 3.95 ppm (quadruplet) (4H) -O.CH2.CH3 1.3 ppm (triplet) (6H) -O.CH2.CH3 4.4 ppm (multiplet) (2M) -O.CH.(CH3)2 1.2 ppm (doublet) (12H) -O.CH.(CH3)2 Example 6 1 - - (3',4' - Diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 - dihydroisoquinoline Prepared as a beige product from the compound of Example 2. n.m.r. characteristics 4.1 ppm (multiplet) (1H) -O.CH.(CH3)2 4.5 ppm (multiplet) (lM) -O.CH.(CH3)2 1.2 ppm (two overlapping doublets) (l2H) -O.CM.(CH3)2 4.0 ppm (quadruplet) (4H) -O.CH2.CMa 1.3 ppm (triplet) (6H) -O.CM2.CH3 Example 7 6,7 - Diethoxy - I - (3',4' - di - n - propoxybenzyl) - 3,4 - dihydroisoquinoline Prepared from the compound of Example 3. M.p.=79-800C. n.m.r. characteristics 4.0 ppm (multiplet) (8H) -O.CH2.CH3 and -O.CH2.CH2.CH3 1.4 ppm (multiplet) (6H) -).CH2.CH3 1.75 ppm (sextuplet) (4H) -O.CH2.CH2.CH3 1.0 ppm (triplet) (6H) -O.CH2.CH2.CH3 Example 8 1, (3',4' - Diethoxybenzyl) - 6,7 - di - n - propoxy - 3,4 - dihydroisoquinoline Prepared as yellow flakes from the compound of Example 4. M.p. 70.5- 71.5 C. n.m.r. characteristics 3.9 ppm (multiplet) (8H) -O.CH2.CH3 & -O.CH2.CH2.CH3 1.7 ppm (2 superimposed sextuplets) (4H) -O.CH2.CH2.CH3 0.95 ppm (triplet) (3H) -O.CH2.CH2.CH3 1.0 ppm (triplet) (3H) -O.CH2.CH2.CH3 1.35 ppm (triplet) (6H) -O.CH2.CH3 Example 9 1 - - (3',4' - Diethoxybenzyl) - 6,7 - diisopropoxy - 1,2,3,4 - tetrahydroisoquinoline 14 g (0.0303 mole) of 1 - (3',4' - diethoxy - benzyl) - 6,7 - diisopropoxy 3,4 - dihydroisoquinoline hydrochloride was dissolved in 280 ml methanol in a 1 litre 3-necked flask.

The solution was cooled in an ice/water bath and 1.4 g (0.037 mole) of sodium borohydride was added in 2 portions with agitation. The agitation was maintained for half an hour, the solvent removed under reduced pressure and the residue taken up in 500 ml of diethyl ether. The ethereal solution was washed with water to pH 7, dried over sodium sulphate and the solvent removed under reduced pressure. The oil obtained was left overnight under isopropyl ether to crystallise out the product.

8.6 g of the title product was obtained. Yield=66%, m.p. 76-80 C.

Analysis C26H37NO4=427.6 CV MV NV Calculated 77.03 8.72 3.28 Found 77.11 8.65 3.35 Example 10 1 - . (3',4' - Diethoxybenzyl) - 6,7 - diisopropoxy - 1,2,3,4 - tetrahydroisoquinoline hydrochloride 8.15 g (0.019 mole) of 1 - (3',4' - diethoxybenzyl)- 6,7 - diisopropoxy 1,2,3,4 - tetrahydroisoquinoline was dissolved in 50 ml ethanol. 10 ml of a solution of hydrochloric acid in diethyl ether was added with agitation and cooling in an ice/water bath, (to pH=2). The solvent was removed under reduced pressure, the residue was stirred in suspension in 100 ml of isopropyl ether for a few minutes, excess solvent removed and the product dried to give 8.75 g of the title hydrochloride. Yield=99V. m.p. 1 580C.

Analysis C26H37NO4HCI=464.1 CV MV NV ClV Calculated 67.29 8.25 3.02 7.64 Found 66.87 8.17 3.27 7.76 Example 11 6,7 - Diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 1,2,3,4 - tetrahydroisoquinoline hydrochloride 21 g (0.0455 mole) of 6,7 - diethoxy - 1 - (3',4i-- diisopropoxybenzyl) - 3,4 dihydroisoquinoline hydrochloride was dissolved in 300 ml of methanol in a 1 litre 3-necked flask. The solution was cooled in an ice/water bath and 2.1 g (0.0555 moles) of sodium borohydride was added in two portions with agitation. Stirring was continued for half an hour, the solvent removed under reduced pressure and the residue obtained taken up in 500 ml of diethyl ether. The ethereal solution was washed 3 times with 200 ml of water, dried over sodium sulphate and the solvent removed under reduced pressure. The oil obtained was dissolved in 20 ml of isopropyl ether, and allowed to crystallize. The product was filtered and redissolved in 200 ml of diethyl ether, then a solution of hydrochloric acid in diethyl ether added to pH 2. The solvent was removed under reduced pressure and the residue obtained triturated, firstly in isopropyl ether and then in diethyl ether.

After drying, 19.5 g of the title hydrochloride was obtained, Yield=92.5%, m.p.

168 C.

Analysis C26H3lNO4HCl=464.1 CV MV NV CIV Calculated 67.29 8.25 3.02 7.64 Found 67.21 8.36 3.11 7.52 Example 12 6,7 - Diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 1,2,3,4 - tetrahydroisoquinoline was prepared from the hydrochloride of Example 11 by the general procedure described above for Examples 5-8. The product is obtained as a white crystalline product, m.p. 620C.

Pharmaceutical Compositions Example 13 Tablets are prepared as follows: 1 - (3',4' - Diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 dihydroisoquinoline hydrochloride 50 mg Excipient (lactose/starch/magnesium stearate) 150 mg The active ingredient is diluted with the lactose, coated with previously prepared 10V starch paste, granulated and dried at low temperature. The granulate is calibrated, magnesium stearate added and compressed to a final weight of 200 mg.

Example 14 Tablets are prepared by the method described in Example 13 using the following ingredients: I - (3',4' - Diethoxybenzyl) - 6,7 - diisopropoxy - 1,2,3,4 - tetrahydroisoquinoline hydrochloride 100 mg Excipient (lactose/starch/magnesium stearate) 250 mg Example 15 An injectable preparation is prepared as follows: 6,7 - Diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 3,4 dihydroisoquinoline hydrochloride 20 mg Water for injectable preparation 2 ml The active principle is dissolved with slight warming in water and the pH adjusted to 4 with N hydrochloric acid. The solution is filtered under sterile conditions and divided aseptically into previously sterilised ampoules, which are then sealed.

Pharmacology In the tests below, the compound papaverine is used for comparative purposes. Papaverine is 1 - (3',4' - dimethoxybenzyl) - 6,7 - dimethoxy isoquinoline and is employed therapeutically for its spasmolytic and vasodilatory properties.

I) Acute Toxicity LD50 values in mice for several compounds of the invention were obtained by the method of Litchfield and Wilcoxon (J. Pharmacol. (1949), 96,99) after the administration of the test compound by intravenous route (i.v.) in the mouse (CD, males 18-24 g) in a volume of 0.40 ml/20 g of body weight. The mortality is noted 7 days after administration. The results obtained are expressed in milligrams/kilogram of body weight (mg/kg), and are shown in Table 1.

TABLE I Acute Toxicity LD50 (mg/kg i.v.) and Product limits (p=0.05) Example 1 19.0(17.7to20.3) Example 2 8.2 (6.4 to 10.9) Example 3 17.5(14.6 to 21.0) Example 4 13.5 (11.9 to 14.9) Example 10 19.0 (16.7 to 21.7).

Example 11 22.0(18.3to26.4) 2) Spasmolytic activity in vitro The tests are carried out on isolated ileum of the guinea pig surviving in Tyrode liquid, aerated and maintained at 370 C. The products are added 30 seconds before affusion of barium chloride used as contracting agent. The concentrations required to cause inhibition of contraction in 50V of the population (ECso) was given in Table II compared with papaverine.

TABLE 11 Product ECso (moles/litre) Papaverine HCI 9.8x 10-4 Example 1.1x10-5 Example 2 4.2x 10-6 Example 3 3.2x 10-6 Example 4 3.7x 10-B Example 10 1.0x10-5 Example 11 6.0x 10-5 It can be seen that the spasmolytic activity of each of the compounds tested is greater than that of papaverine.

3) Cardiovascular Activity The following parameters were recorded in dogs anaesthetized with chloralose, and under artifical respiration: mean aortic pressure; cardiac frequency; left ventricular contractile force.

The compounds tested were injected intravenously in a dose of from 1/15 to 1/30 of the LDso (i.v.) previously determined in mice.

Results: Whereas papaverine caused a transient hypotension accompanied by tachycardia and an increase of the ventricular contractile force, each of the compounds of the present invention which were tested (compounds of Examples 1, 2, 3, 4, 10 and 11) produced a transient hypotension accompanied by a reduction in the amplitude of ventricular contraction.

These results represent a distinct advantage over papaverine because the cardiovascular effect of the compounds is accompanied by a decrease in cardial work and consequently in the exertions and energy requirements of the heart.

Claims (16)

1. WHAT WE CLAIM IS: 1. A compound of formula (II) or a pharmaceutically acceptable acid addition salt thereof:

   wherein Rl and R2 are different and one represents a C1-C6 alkyl gr.oup and the other represents a C3-C6 alkyl group; and A and B either both represents hydrogen or together represent a covalent bond.
2. 2. A compound as claimed in Claim 1 wherein R' and R2 represent ethyl or propyl.
3. 3. A compound as claimed in Claim 2 wherein either R' or R2 represents isopropyl.
4. 4. A compound as claimed in any one of Claims I to 3 wherein A and B together represent a covalent bond.
5. 5. A compound as claimed in any one of Claims 1 to 4 in the form of a pharmaceutically acceptable acid addition salt.
6. 6.-A compound as claimed in Claim 5 in the form of its hydrochloride salt.
7. 7. - 6,7 - diethoxy - I - (3',4' - diisopropoxybenzyl) - 3,4 dihydroisoquinoline, or its hydrochloride.
8. 8. 1 - (3',4' - diethoxybenzyl) - 6,7 - diisopropoxy - 3,4 dihydroisoquinoline, or its hydrochloride or ascorbate.
9. 9. 6,7 - diethoxy - 1 - (3',4 - di - n- propoxybenzyl)- 3,4 dihydroisoquinoline, or its hydrochloride.
10. 10. 1 - (3',4' - diethoxybenzyl)- 6,7 - di - n - propoxy - 3,4 dihydroisoquinoline, or its hydrochloride.
11. 11. I - (3',4' - diethoxybenzyl) - 6,7 - diisopropoxy - 1,2,3,4 tetrahydroisoquinoline or its hydrochloride.
12. 12. 6,7 - diethoxy - 1 - (3',4' - diisopropoxybenzyl) - 1,2,3,4 tetrahydroisoquinoline or its hydrochloride.
13. 13. A process for the preparation of a compound as claimed in Claim 1, which process comprises (a) cyclisation of a compound of formula (IV):

    wherein R1 and R2 are as defined in Claim I with a condensing agent: and (b) optionally reducing the resultant product; and (c) after step (a) and/or (b) optionally forming an acid addition salt.
14. 14. A process as claimed in Claim 13 substantially as described with reference to any one of Examples 1 to 4, 9 and 11.
15. 15. A compound according to Claim 1 whenever prepared by a process.as claimed in either Claim 13 or 14.
16. 16. A pharmaceutical composition which comprises a compound as claimed in Claim I together with a pharmaceutically acceptable carrier or excipient.