(19)
(11)EP 0 308 059 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
09.09.1992 Bulletin 1992/37

(21)Application number: 88307351.2

(22)Date of filing:  09.08.1988
(51)International Patent Classification (IPC)5C07D 401/04, C07D 217/06, A61K 31/47

(54)

1,2,3,4-Tetrahydroisoquinoline antiarrhythmic agents

1,2,3,4-Tetrahydroisochonoline als antiarrhythmische Mittel

1,2,3,4-Tétrahydroisoquinoléines en tant qu'agents antiarhythmiques


(84)Designated Contracting States:
AT BE CH DE ES FR GB GR IT LI LU NL SE

(30)Priority: 15.08.1987 GB 8719378

(43)Date of publication of application:
22.03.1989 Bulletin 1989/12

(73)Proprietor: Pfizer Limited
Sandwich Kent CT13 9NJ (GB)

(72)Inventor:
  • Cussans, Nigel John Dr.
    Eastry Sandwich Kent (GB)

(74)Representative: Bradbrook, Geoffrey William 
PFIZER LIMITED Ramsgate Road
Sandwich Kent, CT13 9NJ
Sandwich Kent, CT13 9NJ (GB)


(56)References cited: : 
EP-A- 0 100 200
  
  • CHEMICAL ABSTRACTS, vol. 102, no. 5, February 4, 1985, Columbus, Ohio, US; CAMPBELL, SIMON F. et al.: "A convenient synthesis of 2,4-diaminoquinoline derivatives." page 571, column 1, abstract no. 46 882e
  • CHEMICAL ABSTRACTS, vol. 93, no. 19, November 10, 1980, Columbus, Ohio, US; THALER, HEINRICH: "4-Substituted piperazine-1-(N-aryl-N'-cyano)-carboximideamides intermediates for pharmacologically active 6,7-dimethoxy- or 6,7,8-thoxy-4-amino-2-(4-substituted piperazin-1-yl)quinazolines." page 671, column 2, abstract no. 186 404h
  • CHEMICAL ABSTRACTS, vol. 108, no. 19, May 9, 1988, Columbus, Ohio, US; CAMPBELL, SIMON F. et al.: "2,4-Diamino-6,7-dimethoxyquinoline derivatives asalpha1-adrenoceptor antagonists and antihypertensive agents." page 629, column 2, abstract no. 167 272a
 
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
 
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] This invention relates to certain 4-amino-6,7-dimethoxy-2-(6,7-disubstituted-1,2,3,4-tetrahydroisoquinol-2-yl)quinolines which are useful in the treatment of cardiac arrhythmias in human subjects.

[0002] EP-A-0100200 describes certain 4-amino-6,7-dimethoxyquinoline derivatives as anti-hypertensive agents. Chemical Abstracts 102:45882e (Tetrahedron Letters 1984 25(42), 4813-16 describes a synthesis for such compounds.

[0003] Thus the invention provides compounds of the formula:-

and their pharmaceutically acceptable salts, wherein one of R1 and R2 is methoxy and the other is a group of the formula -OH, -O.CO(C, -C4 alkyl), -O.COPh or -O.COCH2Ph where Ph is a phenyl group optionally substituted by one or two substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy.

[0004] Preferably, either R1 is hydroxy and R2 is methoxy or R1 is methoxy and R2 is hydroxy.

[0005] The compounds of the formula (I) in which one of R1 and R2 is methoxy and the other is hydroxy can be prepared by the cyclisation of a compound of the formula:-

wherein one of R3 and R4 is methoxy and the other is either hydroxy or a protected hydroxy group, preferably benzyloxy. It is preferred to use a protected hydroxy group.

[0006] The intermediates of the formula (II) also form a part of the invention.

[0007] The cyclisation is preferably carried out with a Lewis acid, e.g. zinc chloride or bromide, or aluminium chloride. The use of zinc chloride is preferred. The reaction is typically carried out by heating the compound (II) with zinc chloride in a suitable organic solvent, e.g. dimethylacetamide, and preferably under reflux. The reaction mixture is then treated with a base such as aqueous 2.0 - 2.5 N sodium hydroxide to destroy any complexes that the zinc chloride may form with the end product. The product can then be isolated and purified by conventional techniques.

[0008] When one of R3 and R4 is a protected hydroxy group, then the protecting group will need to be removed after cyclisation to generate compounds of formula (I) where R1 or R2 is OH. Benzyl groups are typically removed by hydrogenating the benzyloxy compound in methanol at about 2.068 x 105Pa (30 psi) at room temperature in the presence of a palladium-on-carbon catalyst.

[0009] The compounds of the formula (I) in which one of R1 and R2 is -O.CO(C1-C4 alkyl), -O.COPh or -O.COCH2Ph can be prepared by the acylation of the corresponding hydroxy-compounds according to conventional techniques, e.g. using an appropriate acid chloride or anhydride. Protection of the 4-amino group is not usually necessary.

[0010] The intermediates of the formula (II) in which R3 is methoxy and R4 is benzyloxy can be prepared as follows:-



[0011] Similary, the intermediates of the formula (II) in which R3 is benzyloxy and R4 is methoxy can be prepared from the corresponding 6-hydroxy-7-methoxytetrahydroisoquinoline.

[0012] The intermediates of the formula (II) in which one of R3 and R4 is methoxy and the other is hydroxy can be prepared similarly to the above but with the omission of the benzylation step and provided that the level of phosphorus oxychloride is increased in the final step.

[0013] The 1,2,3,4-tetrahydroisoquinoline hydrochloride starting materials are described in J. Org. Chem., vol. 30, pages 2247-2250 (July 1965).

[0014] Also according to the invention, there is provided a method of treatment of cardiac arrhythmias which comprises administering to a human subject suffering from or liable to cardiac arrhythmias an effective cardiac arrhythmia reducing or preventing amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0016] Also, the invention further provides the use of the compound of formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or reduction of cardiac arrhythmias.

[0017] The ability of the compounds of the formula (I) to reduce or prevent cardiac arrhythmias can be assessed by their antagonism of adrenaline-induced ventricular arrhythmias when administered intravenously to anaesthetised dogs.

[0018] The ability of the compounds of the formula (I) to reduce or prevent cardiac arrhythmias can also be assessed by their ability to antagonise picrotoxin-induced ventricular arrhythmias in anaesthetised cats.

[0019] It is expected that for human use in the prevention or reduction of cardiac arrhythmias single, oral dosages of a compound of formula (I) will be in the range from 0.1 to 10.0 mg per day for an average adult patient (70 kg), taken in up to 4 doses per day. Thus individual tablets or capsules might contain from 0.025 to 10.0 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Single dosages for parenteral, e.g. intravenous, administration would be expected to be within the range from 0.1 to 10 micrograms/kg taken in up to 4 doses per day, e.g. 5 to 1000 micrograms, as required. A severe cardiac arrhythmia is preferably treated by the intravenous route in order to effect a rapid conversion to normal sinus rhythm. Variations on these dosages may occur depending on the weight and condition of the subject being treated, as will be determined by the medical practitioner.

[0020] The compounds of the formula (I) and their pharmaceutically acceptable salts can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmias and also prophylactically to those likely to develop arrhythmias. For example they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic with blood.

[0021] The pharmaceutically acceptable acid addition salts of the compound of the formula (I) are salts formed from acids which form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. Since the compounds of the formula (I) are phenolic, they may also form metal salts, e.g. alkali metal salts such as sodium salts.

[0022] The antiarrhythmic properties of the compounds of formula (I) may also be enhanced by use in combination with a non-selective beta-adrenoceptor blocking compound, such as propranolol, or with a cardio-selective beta-adrenoceptor blocking agent, such as atenolol.

[0023] The following Examples, in which all temperatures are in ° C, illustrate the invention. "MerckArt.9385" is the trade mark of a brand of silica.

EXAMPLE 1



[0024] 4-Amino-6,7-dimethoxy-2-(6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline

[0025] 


(A) 4-Amino-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxyquinoline



[0026] N-(1-[6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl]ethylidene)-2-cyano-4,5-dimethoxyaniline (10.92 g), anhydrous zinc chloride (3.16 g) and dimethylacetamide (25 ml) were mixed at 20 and then stirred at reflux for two hours. The reaction mixture was allowed to cool to about 40 and then 2N sodium hydroxide (16 ml) was added. The mixture was cooled to 25° and stirred for fifteen minutes. 2N Sodium hydroxide (10 ml) and water (50 ml) were added and the reaction mixture was then extracted with methylene chloride (3 x 100 ml). The combined organic extracts were washed (H20), dried (MgS04) and evaporated in vacuo. The residue was chromatographed on silica (Merck "Art 9385") under medium pressure eluting with methylene chloride containing gradually increasing amounts (1 - 20%) of methanol. The combined product-containing fractions were evaporated and the residue was recrystallised from ethanol and washed (Et20) to give 4-amino-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxyquinoline (7.1 g) as a pale yellow powder, m.p. 181-2°.


(B) 4-Amino-6,7-dimethoxy-2-(6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline



[0027] A suspension of the product of part (A) (3.0 g) in methanol (400 ml) was warmed at about 50 ° until the majority of the product dissolved. The reaction mixture was then transferred to a hydrogenator and hydrogenated under a hydrogen pressure of 2.068 x 105 Pa (30 psi) in the presence of 5% Pd/C (400 mg) at room temperature with stirring for 1.5 hours. The reaction mixture was filtered through "Arbacel" (a microcrystalline cellulose filtration aid), and evaporated to yield impure 4-amino-6,7-dimethoxy-2-(6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline (600 mg). The catalyst was then stirred in methylene chloride/methanol (4:1, 200 ml) for 30 minutes, and the mixture was filtered and the filtrate evaporated to yield a further 1.05 g of the impure product. The total of the impure product (1.65 g) was dissolved in methylene chloride/methanol (4:1, 300 ml) and shaken with 10% sodium carbonate solution (50 ml). The organic phase was washed (H20), dried and evaporated. Medium pressure chromatography of the residue on silica (Merck "Art.9385") eluting with methylene chloride containing gradually increasing amounts of ethanol (1 - 25%) followed by collection and evaporation of appropriate fractions gave the title compound. The compound was slurried in boiling methylene chloride (20 ml), cooled, precipitated with hexane, filtered, and the solid washed with hexane and dried to give the pure title compound as a quarter-hydrate (900 mg), m.p. 250-251 ° .


EXAMPLE 2



[0028] 4-Amino-6,7-dimethoxy-2-(7-hydroxy-6-methoxy-1,2,3,4-tetra-hydroisoquinol-2-yl)quinoline

(A) 4-Amino-2-(7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxyquinoline, m.p. 198-9°, was prepared similarly to Example 1 (A), using the product of Preparation 6, zinc chloride, dimethylacetamide, and 2.5 N NaOH.

(B) 4-Amino-6,7-dimethoxy-2-(7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline hydrochloride, m.p. 204-5°, was prepared similarly to Example 1 (B) by the reduction of the corresponding 7-benzyloxy compound with H2/Pd/C in methanol. In this instance the product was isolated as a hydrochloride. This is believed to be due to the presence of chloride ions in the catalyst.



[0029] The following Preparations, in which all temperatures are in ° C, illustrate the preparation of certain starting materials:-

Preparation 1



[0030] N-Acetyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline



[0031] 6-Hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (15.47 g) was converted to the free base by dissolving it in water (about 100 ml) and adding concentrated (0.88) aqueous ammonia to pH 9-10, giving a precipitate of the free base. The precipitate refused to extract completely into chloroform (100 ml.). The aqeuous phase was therefore filtered and the solid washed (EtOH) and dried. The chloroform extract was dried (MgS04) and evaporated. The two solids were combined to give the free base as a pale powder (11.94 g).

[0032] A suspension of the free base (11.94 g) in methylene chloride (400 ml) was stirred at 10° , pyridine (5.66 ml) was added followed by the slow dropwise addition of acetic anhydride (6.6 ml) in methylene chloride (10 ml). Solution soon resulted and the reaction mixture was then stirred for two hours whilst allowing the temperature to rise slowly to room temperature. The reaction mixture was washed with water (100 ml), 2N HCI (100 ml) and then water again (100 ml), dried (MgS04) and evaporated to give the title compound as a quarter-hydrate, (14.03 g), m.p. 139-140° .



[0033] The tetrahydroisoquinoline hydrochloride starting material is described in J. Org. Chem., vol. 30, July 1965, pages 2247-2250. An alternative preparation of the title compound is described in J. Org. Chem., Vol. 36, no. 20, 1971, pages 3006-3010.

Preparation 2



[0034] N-Acetyl-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline



[0035] 7-Hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.60 g) was dissolved in water and the solution was basified to pH9 with concentrated (0.88) aqueous ammonia. The free base was extracted with methylene chloride/ethanol (9:1) (3 x 200 ml). The organic extracts were combined, washed (H20), dried (MgS04) and evaporated to dryness. The residue was azeotroped with methylene chloride, evaporated, and the residue was suspended in methylene chloride (100 ml). Pyridine (1.05 ml) was added dropwise at 10" followed by acetic anhydride (1.25 ml) and the resulting mixture was allowed to stand over a weekend (about 68 hours). The solution was washed with 2N HCI, then with water, dried (MgS04) and evaporated. Medium pressure chromatography on silica (Merck "Art.9385") eluting with methylene chloride containing gradually increasing amounts of methanol (0 -3%) followed by collection and evaporation of appropriate fractions gave the title compound as a quarter-hydrate (1.05 g), m.p. 142-144° .



[0036] The tetrahydroisoquinoline hydrochloride starting material is described in J. Org. Chem., vol. 30, July 1965, pages 2247-2250. An alternative preparation of the title compound is described in J. Org. Chem., vol. 36, no. 20, 1971, pages 3006-3010.

Preparation 3



[0037] N-Acetyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline

[0038] 



[0039] N-Acetyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline quarter-hydrate (14.0 g) was dissolved in methylene chloride (200 ml). Benzyl bromide (22.6 ml) was then added, followed by the addition of a solution of potassium hydroxide (4.62 g) in water (200 ml) and then tetra-n-butylammonium bromide (2.04 g). The resulting mixture was stirred vigorously overnight (16 hours). The organic layer was then separated, washed (H20), dried (MgS04) and evaporated. Medium pressure chromatography of the residue on silica (Merck "Art9385") eluting with methylene chloride containing gradually increasing amounts of methanol (0 -10%) gave, after collection and evaporation of appropriate fractions, the title compound as a semi-solid which was recrystallised from ethyl acetate to give the pure title compound, 16.84 g, m.p. 125-6° .


Preparation 4



[0040] N-Acetyl-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline, m.p. 105°, was prepared similarly to the previous Preparation, starting from the corresponding 7-hydroxy-1,2,3,4-tetrahydroisoquinoline, benzyl bromide, aqueous potassium hydroxide and tetrabutylammonium bromide.


Preparation 5



[0041] N-(1-[6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl]ethylidene)-2-cyano-4,5-dimethoxyaniline



[0042] The free base of 2-cyano-4,5-dimethoxyaniline (see J. Amer. Chem. Soc., 68, page 1903 [1946]) was prepared by dissolving the hydrochloride in saturated aqueous sodium bicarbonate solution to pH 8, extracting with methylene chloride, washing the organic extract with water, drying (MgS04) and evaporating. Medium pressure chromatography of the residue on silica (Merck "MK.9385") eluting with methylene chloride followed by collection and evaporation of appropriate fractions gave the pure free base.

[0043] Phosphorus oxychloride (3.24 ml) was added over 1 minute to a stirred solution of N-acetyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g) in methylene chloride (100 ml) at 10° . After stirring for twenty minutes at room temperature, a solution of 2-cyano-4,5-dimethoxyaniline (5.72 g) in methylene chloride (80 ml) was added and the resulting suspension was heated at reflux for 16 hours. The reaction mixture was then allowed to cool, water (60 ml) was added followed by 40% sodium hydroxide to pH 8-9 with stirring for five minutes. The organic layer was then separated and the aqueous phase extracted with methylene chloride (3 x 50 ml). The combined organic layers were washed (H20), dried (MgS04) and evaporated. The residue was chromatographed on silica (Merck Art.9385) under medium pressure, eluting with methylene chloride containing gradually increasing amounts of methanol (0-10%). Some impure product-containing fractions were re-chromatographed on silica but using methylene chloride containing 2-4% methanol. The pure product-containing fractions were combined, evaporated, and the residue recrystallised from ethyl acetate to give the title compound as a colourless powder (11.02 g), m.p. 164-5 (d).


Preparation 6


N-(1-[7-Benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl]ethylidene)-2-cyano-4,5-dimethoxyaniline



[0044] The title compound, m.p. 72-3 ° , was prepared similarly to the procedure of the previous Preparation, starting from N-acetyl-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline, phosphorus oxychloride, and 2-cyano-4,5-dimethoxyaniline.




Claims

Claims for the following Contracting State(s) : AT, BE, CH, DE, FR, GB, IT, LI, NL, SE

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein one of R1 and R2 is methoxy and the other is a group of the formula -OH, -O.CO(C1-C4 alkyl), -O.COPh or -O.COCH2Ph where Ph is a phenyl group optionally substituted by one or two substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy.
 
2. A compound according to claim 1, in which R1 is hydroxy and R2 is methoxy.
 
3. A compound according to claim 1, in which R1 is methoxy and R2 is hydroxy.
 
4. A pharmaceutical composition comprising a compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 
5. A compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof, for use as a medicament.
 
6. Use of a compound according to claim 1, 2 or 3, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for prevention or reduction of cardiac arrhythmias.
 
7. A compound of formula (II):

wherein one of R3 and R4 is methoxy and the other of R3 and R4 is either hydroxy or a protected hydroxy group, wherein said protected hydroxy group is benzyloxy.
 


Claims

Claims for the following Contracting State(s) : ES

1. A process for preparing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein one of R1 and R2 is methoxy and the other is a group of the formula -OH, -O.CO(C, -C4 alkyl), -O.COPh or -O.COCH2Ph where Ph is a phenyl group optionally substituted by one or two substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy, which process comprises the steps of (a) cyclising a compound of formula (II):

wherein one of R3 and R4 is methoxy and the other of R3 and R4 is either hydroxy or a protected hydroxy group, (b) if necessary, removing the protecting group from said protected hydroxy group, and (c) when R1 or R2 is -O.CO(C1 -C4 alkyl), -O.COPh or -O.COCH2Ph, acylating the compound obtained from step (a) or (b).
 
2. A process according to claim 1, in which said protected hydroxy group is a benzyloxy group and the protecting group is removed by catalytic hydrogenation.
 
3. A process according to claim 1 or 2, in which the compound of formula (II) is cyclised by treatment with a Lewis acid.
 
4. A process according to claim 3, in which the product obtained by treatment with the Lewis acid is treated with a base.
 
5. A process according to claim 3 or 4, in which the Lewis acid is zinc chloride.
 
6. A process according to any one of the preceding claims, in which the compound of formula (II) is prepared by treating a compound of formula (III):

with 2-cyano-4,5-dimethoxyaniline and phosphorus oxychloride.
 
7. A process according to claim 6 in which one of R3 and R4 is benzyloxy, in which the compound of formula (III) is prepared by treating N-acetyl-6-methoxy-7-hydroxytetrahydroisoquinoline or N-acetyl 6-hydroxy-7-methoxytetrahydroisoquinoline, with benzyl bromide in the presence of potassium hydroxide and tetra-n-butylammonium bromide.
 
8. A process according to claim 7, in which the N-acetyl 6-methoxy-7-hydroxytetrahydroisoquinoline or N-acetyl 6-hydroxy-7-methoxytetrahydroisoquinoline is prepared by acetylating 6-methoxy-7-hydroxy tetrahydroisoquinoline or 6-hydroxy-7-methoxytetrahydroisoquinoline, respectively.
 


Claims

Claims for the following Contracting State(s) : GR

1. A process for preparing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein one of R1 and R2 is methoxy and the other is a group of the formula -OH, -O.CO(C, -C4 alkyl), -O.COPh or -O.COCH2Ph where Ph is a phenyl group optionally substituted by one or two substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy, which process comprises the steps of (a) cyclising a compound of formula (II):

wherein one of R3 and R4 is methoxy and the other of R3 and R4 is either hydroxy or a protected hydroxy group, (b) if necessary, removing the protecting group from said protected hydroxy group, and (c) when R1 or R2 is -O.CO(C1 -C4 alkyl), -O.COPh or -O.COCH2Ph, acylating the compound obtained from step (a) or (b).
 
2. A process according to claim 1, in which said protected hydroxy group is a benzyloxy group and the protective group is removed by catalytic hydrogenation.
 
3. A process according to claim 1 or 2, in which the compound of formula (II) is cyclised by treatment with a Lewis acid.
 
4. A process according to claim 3, in which the product obtained by treatment with the Lewis acid is treated with a base.
 
5. A process according to claim 3 or 4, in which the Lewis acid is zinc chloride.
 
6. A process according to any one of the preceding claims, in which the compound of formula (II) is prepared by treating a compound of formula (III):

with 2-cyano-4,5-dimethoxyaniline and phosphorus oxychloride.
 
7. A process according to claim 6 in which one of R3 and R4 is benzyloxy, in which the compound of formula (III) is prepared by treating N-acetyl 6-methoxy-7-hydroxytetrahydroisoquinoline or N-acetyl-6-hydroxy-7-methoxytetrahydroisoquinoline, with benzyl bromide in the presence of potassium hydroxide and tetra-n-butylammonium bromide.
 
8. A process according to claim 7, in which the N-acetyl 6-methoxy-7-hydroxytetrahydroisoquinoline or N-acetyl 6-hydroxy-7-methoxytetrahydroisoquinoline is prepared by acetylating 6-methoxy-7-hydroxy tetrahydroisoquinoline or 6-hydroxy-7-methoxytetrahydroisoquinoline, respectively.
 
9. A compound of formula (II):

wherein one of R3 and R4 is methoxy and the other of R3 and R4 is either hydroxy or a protected hydroxy group, wherein said protected hydroxy group is a benzyloxy group.
 


Ansprüche

Patentansprüche für folgende(n) Vertragsstaat(en) : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE

1. Verbindung der Formel (I)

oder ein pharmazeutisch annehmbares Salz hievon, worin eines von R1 und R2 Methoxy ist und das andere eine Gruppe der Formel -OH, -0.CO(C1-C4-Alkyl), -O.COPh oder -O.COCH2 Ph darstellt, wobei Ph eine Phenylgruppe gegebenenfalls substituiert durch einen oder zwei Substituenten, jeweils unabhängig ausgewählt aus F, Cl, Br, I, CF3, C1-C4-Alkyl und C1-C4-Alkoxy, ist.
 
2. Verbindung nach Anspruch 1, in der R1 Hydroxy und R2 Methoxy bedeuten.
 
3. Verbindung nach Anspruch 1, in der R1 Methoxy und R2 Hydroxy bedeuten.
 
4. Pharmazeutische Zusammensetzung umfassend eine Verbindung nach Anspruch 1, 2 oder 3 oder ein pharmazeutisch annehmbares Salz hievon und einen pharmazeutisch annehmbaren Träger.
 
5. Verbindung nach Anspruch 1, 2 oder 3 oder ein pharmazeutisch annehmbares Salz hievon zur Verwendung als Medikament.
 
6. Verwendung einer Verbindung nach Anspruch 1, 2 oder 3 oder eines pharmazeutisch annehmbaren Salzes hievon zur Herstellung eines Medikaments für die Verhütung oder Verminderung von Herzarrhythmien.
 
7. Verbindung der Formel (II)

worin eines von R3 und R4 Methoxy und das andere von R3 und R4 entweder Hydroxy oder eine geschützte Hydroxygruppe ist, wobei die geschützte Hydroxygruppe Benzyloxy ist.
 


Ansprüche

Patentansprüche für folgende(n) Vertragsstaat(en) : ES

1. Verfahren zum Herstellen einer Verbindung der Formel (I)

oder eines pharmazeutisch annehmbaren Salzes hievon, worin eines von R1 und R2 Methoxy ist und das andere eine Gruppe der Formel -OH, -0.CO(C1-C4-Alkyl), -O.COPh oder -O.COCH2 Ph darstellt, wobei Ph eine Phenylgruppe gegebenenfalls substituiert durch einen oder zwei Substituenten, jeweils unabhängig ausgewählt aus F, Cl, Br, I, CF3, C1-C4-Alkyl und C1-C4-Alkoxy, ist, welches Verfahren die Schritte (a) des Cyclisierens einer Verbindung der Formel (II)

worin eines von R3 und R4 Methoxy und das andere von R3 und R4 entweder Hydroxy oder eine geschützte Hydroxygruppe ist, (b) wenn notwendig, des Entfernens der Schutzgruppe von der geschützten Hydroxygruppe und (c) wenn R1 oder R2 die Bedeutung -0.CO(C1-C4-Alkyl), -O.COPh oder -O.COCH2Ph hat, des Acylierens der in Schritt (a) oder (b) erhaltenen Verbindung umfaßt.
 
2. Verfahren nach Anspruch 1, in dem die geschützte Hydroxygruppe eine Benzyloxygruppe ist und die Schutzgruppe durch katalytische Hydrierung entfernt wird.
 
3. Verfahren nach Anspruch 1 oder 2, in dem die Verbindung der Formel (II) durch Behandlung mit einer Lewis-Säure cyclisiert wird.
 
4. Verfahren nach Anspruch 3, in dem das durch Behandlung mit der Lewis-Säure erhaltene Produkt mit einer Base behandelt wird.
 
5. Verfahren nach Anspruch 3 oder 4, in dem die Lewis-Säure Zinkchlorid ist.
 
6. Verfahren nach einem der vorhergehenden Ansprüche, in dem die Verbindung der Formel (II) durch Behandeln einer Verbindung der Formel (III)
 


mit 2-Cyano-4,5-dimethoxyanilin und Phosphoroxychlorid hergestellt wird.
 
7. Verfahren nach Anspruch 6, in dem eines von R3 und R4 Benzyloxy ist, wobei die Verbindung der Formel (III) durch Behandeln von N-Acetyl-6-methoxy-7-hydroxytetrahydroisochinolin oder N-Acetyl-6-hydroxy-7-methoxytetrahydroisochinolin mit Benzylbromid in Anwesenheit von Kaliumhydroxid und Tetra-n-butylammoniumbromid hergestellt wird.
 
8. Verfahren nach Anspruch 7, in dem das N-Acetyl-6-methoxy-7-hydroxytetrahydroisochinolin oder N-Acetyl-6-hydroxy-7-methoxytetrahydroisochinolin durch Acetylieren von 6-Methoxy-7-hydroxytetrah- ydroisochinolin bzw. 6-Hydroxy-7-methoxytetrahydroisochinolin hergestellt wird.
 


Ansprüche

Patentansprüche für folgende(n) Vertragsstaat(en) : GR

1. Verfahren zum Herstellen einer Verbindung der Formel (I)

oder eines pharmazeutisch annehmbaren Salzes hievon, worin eines von R1 und R2 Methoxy ist und das andere eine Gruppe der Formel -OH, -0.CO(C1-C4-Alkyl), -O.COPh oder -O.COCH2 Ph darstellt, wobei Ph eine Phenylgruppe gegebenenfalls substituiert durch einen oder zwei Substituenten, jeweils unabhängig ausgewählt aus F, Cl, Br, I, CF3, C1-C4-Alkyl und C1-C4-Alkoxy, ist, welches Verfahren die Schritte (a) des Cyclisierens einer Verbindung der Formel (11)

worin eines von R3 und R4 Methoxy und das andere von R3 und R4 entweder Hydroxy oder eine geschützte Hydroxygruppe ist, (b) wenn notwendig, des Entfernens der Schutzgruppe von der geschützten Hydroxygruppe und (c) wenn R1 oder R2 die Bedeutung -0.CO(C1-C4-Alkyl), -O.COPh oder -O.COCH2Ph hat, des Acylierens der in Schritt (a) oder (b) erhaltenen Verbindung umfaßt.
 
2. Verfahren nach Anspruch 1, in dem die geschützte Hydroxygruppe eine Benzyloxygruppe ist und die Schutzgruppe durch katalytische Hydrierung entfernt wird.
 
3. Verfahren nach Anspruch 1 oder 2, in dem die Verbindung der Formel (II) durch Behandlung mit einer Lewis-Säure cyclisiert wird.
 
4. Verfahren nach Anspruch 3, in dem das durch Behandlung mit der Lewis-Säure erhaltene Produkt mit einer Base behandelt wird.
 
5. Verfahren nach Anspruch 3 oder 4, in dem die Lewis-Säure Zinkchlorid ist.
 
6. Verfahren nach einem der vorhergehenden Ansprüche, in dem die Verbindung der Formel (II) durch Behandeln einer Verbindung der Formel (III)

mit 2-Cyano-4,5-dimethoxyanilin und Phosphoroxychlorid hergestellt wird.
 
7. Verfahren nach Anspruch 6, in dem eines von R3 und R4 Benzyloxy ist, wobei die Verbindung der Formel (III) durch Behandeln von N-Acetyl-6-methoxy-7-hydroxytetrahydroisochinolin oder N-Acetyl-6-hydroxy-7-methoxytetrahydroisochinolin mit Benzylbromid in Anwesenheit von Kaliumhydroxid und Tetra-n-butylammoniumbromid hergestellt wird.
 
8. Verfahren nach Anspruch 7, in dem das N-Acetyl-6-methoxy-7-hydroxytetrahydroisochinolin oder N-Acetyl-6-hydroxy-7-methoxytetrahydroisochinolin durch Acetylieren von 6-Methoxy-hydroisochinolin hergestellt wird. hydroisochinolin hergestellt wird.
 
9. Verbindung der Formel (II)

worin eines von R3 und R4 Methoxy und das andere von R3 und R4 entweder Hydroxy oder eine geschützte Hydroxygruppe ist, wobei die geschützte Hydroxygruppe Benzyloxy ist.
 


Revendications

Revendications pour l'(les) Etat(s) contractant(s) suivant(s) : suivants : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE

1. Composé de formule (1) :

ou d'un sel pharmaceutiquement acceptable d'un tel composé, dans laquelle l'un des radicaux R1 et R2 est un groupe méthoxy et l'autre est un groupe de formule -OH, -O.CO-(alkyle en C1-C4), -O.COPh ou -O.COCH2Ph où Ph est un groupe phényle éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les radicaux F, CI, Br, I, CF3, alkyle en C1-C4 et alcoxy en Ci - C4.
 
2. Composé selon la revendication 1, dans laquelle R1 est un groupe hydroxy et R2 est un groupe méthoxy.
 
3. Composé selon la revendication 1, dans laquelle R1 est un groupe méthoxy et R2 est un groupe hydroxy.
 
4. Composition pharmaceutique comprenant un composé selon la revendication 1, 2 ou 3, ou un sel pharmaceutiquement acceptable d'un tel composé, et un support pharmaceutiquement acceptable.
 
5. Composé selon la revendication 1, 2 ou 3, ou sel pharmaceutiquement acceptable d'un tel composé, pour une utilisation comme médicament.
 
6. Utilisation d'un composé selon la revendication 1, 2 ou 3, ou d'un sel pharmaceutiquement acceptable d'un tel composé, pour la fabrication d'un médicament destiné à la prévention ou à la réduction des arythmies cardiaques.
 
7. Composé de formule (II) :

dans laquelle l'un des radicaux R3 et R4 est un groupe méthoxy et l'autre des radicaux R3 et, R4 est soit un groupe hydroxy, soit un groupe hydroxy protégé, ledit groupe hydroxy protégé étant un groupe benzyloxy.
 


Revendications

Revendications pour l'(les) Etat(s) contractant(s) suivant(s) : suivant : ES

1. Procédé de préparation d'un composé de formule (1) :

ou d'un sel pharmaceutiquement acceptable d'un tel composé, dans laquelle l'un des radicaux R1 et R2 est un groupe méthoxy et l'autre est un groupe de formule -OH, -O.CO-(alkyle en C1-C4), -O.COPh ou -O.COCH2Ph où Ph est un groupe phényle éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les radicaux F, CI, Br, I, CF3, alkyle en C1-C4 et alcoxy en C1-C4, lequel procédé comprend les étapes de (a) cyclisation d'un composé de formule (II) :

dans laquelle l'un des radicaux R3 et R4 est un groupe méthoxy et l'autre des radicaux R3 et R4 est soit un groupe hydroxy soit un groupe hydroxy protégé, (b) si nécessaire, élimination du groupe protecteur dudit groupe hydroxy protégé, et (c), lorsque R1 ou R2 représentent -O.CO(alkyle en C1-C4), -O.COPh ou -O.COCH2Ph, acylation du composé issu de l'étape (a) ou (b).
 
2. Procédé selon la revendication 1, dans lequel ledit groupe hydroxy protégé est un groupe benzyloxy et ledit groupe protecteur est éliminé par hydrogénation catalytique.
 
3. Procédé selon la revendication 1 ou 2, dans lequel le composé de formule (II) est cyclisé par traitement avec un acide de Lewis.
 
4. Procédé selon la revendication 3, dans lequel le produit issu du traitement avec l'acide de Lewis est traité par une base.
 
5. Procédé selon la revendication 3 ou 4, dans lequel l'acide de Lewis est du chlorure de zinc.
 
6. Procédé selon l'une quelconque des revendications précédentes, dans lequel le composé de formule

(II) est préparé par traitement d'un composé de formule (III) :

avec de la 2-cyano 4,5-diméthoxyaniline et de l'oxychlorure de phosphore.


 
7. Procédé selon la revendication 6, dans lequel l'un des radicaux R3 et R4 est un radical benzyloxy, et dans lequel le composé de formule (III) est préparé par traitement de la N-acétyl-6-méthoxy-7-hydroxytétrahydroisoquinoline ou de la N-acétyl-6-hydroxy-7-méthoxytétrahydroisoquinoline, avec du bromure de benzyle en présence de l'hydroxyde de potassium et de bromure de tétra-n-butylammonium.
 
8. Procédé selon la revendication 7, dans lequel la N-acétyl-6-méthoxy-7-hydroxytétrahydroisoquinoline ou la N-acétyl-6-hydroxy-7-méthoxytétrahydroisoquinoline est préparée par acylation, respectivement, de la 6-méthoxy-7-hydroxytétrahydroisoquinoline ou de la 6-hydroxy-7-méthoxytétrahydroisoquinoline,
 


Revendications

Revendications pour l'(les) Etat(s) contractant(s) suivant(s) : suivant : GR

1. Procédé de préparation d'un composé de formule (1) :

ou d'un sel pharmaceutiquement acceptable d'un tel composé, dans laquelle l'un des radicaux R1 et R2 est un groupe méthoxy et l'autre est un groupe de formule -OH, -O.CO-(alkyle en C1-C4), -O.COPh ou -O.COCH2Ph où Ph est un groupe phényle éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les radicaux F, CI, Br, I, CF3, alkyle en C1-C4 et alcoxy en C1-C4, lequel procédé comprend les étapes de (a) cyclisation d'un composé de formule (II) :

dans laquelle l'un des radicaux R3 et R4 est un groupe méthoxy et l'autre des radicaux R3 et R4 est soit un groupe hydroxy soit un groupe hydroxy protégé, (b) si nécessaire, élimination du groupe protecteur dudit groupe hydroxy protégé, et (c), lorsque R1 ou R2 représentent -O.CO(alkyle en C1-C4), -O.COPh ou -O.COCH2Ph, acylation du composé issu de l'étape (a) ou (b).
 
2. Procédé selon la revendication 1, dans lequel ledit groupe hydroxy protégé est un groupe benzyloxy et ledit groupe protecteur est éliminé par hydrogénation catalytique.
 
3. Procédé selon la revendication 1 ou 2, dans lequel le composé de formule (II) est cyclisé par traitement avec un acide de Lewis.
 
4. Procédé selon la revendication 3, dans lequel le produit issu du traitement avec l'acide de Lewis est traité par une base.
 
5. Procédé selon la revendication 3 ou 4, dans lequel l'acide de Lewis est du chlorure de zinc.
 
6. Procédé selon l'une quelconque des revendications précédentes, dans lequel le composé de formule

(II) est préparé par traitement d'un composé de formule (III) :

avec de la 2-cyano-4,5-diméthoxyaniline et de l'oxychlorure de phosphore.


 
7. Procédé selon la revendication 6, dans lequel l'un des radicaux R3 et R4 est un radical benzyloxy, et dans lequel le composé de formule (III) est préparé par traitement de la N-acétyl-6-méthoxy-7-hydroxytétrahydroisoquinoline ou de la N-acétyl-6-hydroxy-7-méthoxytétrahydroisoquinoline, avec du bromure de benzyle en présence de l'hydroxyde de potassium et de bromure de tétra-n-butylammonium.
 
8. Procédé selon la revendication 7, dans lequel la N-acétyl-6-méthoxy-7-hydroxytétrahydroisoquinoline ou la N-acétyl-6-hydroxy-7-méthoxytétrahydroisoquinoline est préparée par acylation, respectivement, de la 6-méthoxy-7-hydroxytétrahydroisoquinoline ou de la 6-hydroxy-7-méthoxytétrahydroisoquinoline
 
9. Composé de formule (II) :

dans laquelle l'un des radicaux R3 et R4 est un groupe méthoxy, et l'autre des radicaux R3 et R4 est soit un radical hydroxy soit un groupe hydroxy protégé, ledit groupe hydroxy protégé étant un groupe benzyloxy.