NO173605B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4-AMINO-6,7-DIMETOXY-2 (6,7-DIMETOXY-1,2,3,4-TETRAHYDROISOKINOL-2-YL) -KINOLINE - Google Patents

Abstract

preparation of amino-6,7-dimethoxy-2- (6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinol-2-yl) quinoline with hypertensive effect and for the treatment of cardiac arrhythmias by cyclization of a compound of formula (II). for the preparation of a compound of formula (I)

Description

The present invention relates to an analogous process for the production of 4-amino-6,7-dimethoxy-2[6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl]-quinoline, which is a new derivative of 4 -amino-6,7-di-methoxy-quinoline. This is a therapeutically active compound that can be used as a regulator for the cardiovascular system and especially in the treatment of hypertension.

The new compound has the formula

Pharmaceutically acceptable acid addition salts of the compound are those formed from acids, which form non-toxic addition salts containing pharmaceutically acceptable anions such as hydrochlorides, hydrobromides, sulfates or bisulfates, phosphate or acid phosphate, acetate, maleate, fumarate, succinate, lactate, tartrate, citrate, gluconate and p-toluenesulfonate salts.

The new compound of formula (I) can be prepared as follows:

The cyclization can be carried out using a Lewis acid, e.g. zinc chloride, or a base, e.g. lithium diisopropylamide (LDA). Zinc chloride is preferred. Reaction with zinc chloride is usually carried out by heating the reactants, preferably by refluxing in a suitable organic solvent, e.g. dimethylacetamide for up to approx. 4 hours. The reaction with LDA is preferably carried out at a low temperature (e.g. -70°C) in a suitable organic solvent, e.g. tetrahydrofuran, after which the reaction mixture is allowed to warm to room temperature. In some cases when using LDA, heating may be necessary to complete the reaction. The product can then be isolated and cleaned in the usual way.

The compound (II) can be obtained in the usual way as illustrated under the following intermediates. Typical procedures are outlined below:

For compounds where R is as below:

R stands for:

The pharmaceutically acceptable acid addition salts of the compound of formula (I) can be prepared in a conventional manner, e.g. by reacting the free base with the corresponding acid in an inert organic solvent, and collecting the resulting precipitate of the salt by filtration or evaporation of the reaction mixture. If necessary, the product can then be cross-tallied for purification.

The antihypertensive activity of the compound of formula (I) is demonstrated by its ability to lower the blood pressure of conscious spontaneously hypertensive rats and conscious renally hypertensive dogs given oral doses of up to 5 mg/kg.

The compound of formula (I) and its salts may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected taking into account the mode of administration and standard pharmaceutical practice. E.g. they can be given orally in the form of tablets containing such fillers as starch or lactose, or in capsules either alone or mixed with fillers, or in the form of elixirs or suspensions containing flavoring or coloring agents. They are injected parenterally, e.g. intramuscularly, intravenously, or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other ingredients, e.g. sufficient salt or glucose to make the solution isotonic.

The compound of formula (I) and its salts may be administered to humans for the treatment of hypertension either orally or parenterally, and will be administered orally in dosage amounts in the range of 1-50 mg/day for an average adult patient (70 kg), given as a single dosage or up to 3 divided dosages. Intravenous dosage amounts will be 1/5 to 1/10 of the daily oral dose. Thus, for an average adult patient, individual oral doses in tablet or capsule form will be approximately in the range of 1-25 mg of the active compound. However, it should be noted that variations will necessarily occur, depending on the weight and condition of the patient being treated and the particular mode of administration chosen, which will be known to a person skilled in the art.

Example

4-amino-6,7-dimethoxy-2-[6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinol-2-yl]quinoline, m.p. 226<0->227°C was prepared in the same manner as the following preparation example using the corresponding 1-[6,7-dimethoxy-1,2,3,4-tetrahydro-iso-quinol-2-yl]ethylidene compound , except that the crude reaction residue was recrystallized from isopropanol.

Analysis

Found: C 66.0; H 6.3; N 10.9. Calculated for CH22<H>25<N>304: C 66.8; H 6.4; N 10.6.

Manufacturing example

13.5 g of N-[1-(4-benzylpiperazin-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline and 4.86 g of zinc chloride in 90 ml of dimethylacetamide were stirred under reflux for 2 hours, a further 0.5 , 0.2 g of zinc chloride was added after thawing hour and 1 thawing hour respectively. The mixture was cooled, treated with 700 ml, 2 x 100 ml of ether and the supernatant was discarded each time. The residual tar was then treated with sodium hydroxide solution (2N, 100 ml) and 100 ml methylene chloride and the mixture was stirred at room temperature for 5 minutes. The organic layer was separated, the aqueous phase extracted with methylene chloride and the total organic extracts washed with water. The dried (Na 2 SO 4 ) extracts were evaporated in vacuo and the brown residue (~13 g) purified by chromatography on silica gel (Merck 9385, 250 g) eluted with chloroform-methanol (100:0 -> 88:12). A sample

of the pure product (6.95 g) was taken up in ethanol, treated with hydrogen chloride in ether and evaporated in vacuo. The residue was recrystallized from methanol to give 4-amino-6,7-dimethoxy-2-(4-benzylpiperazin-1-yl)quinoline dihydrochloride sesquihydrate, m.p. 260-263°C.

Analysis %

Found: C 54.9; H 5.9; N 11.5. Calculated for C 22 H 26 N 4 O 2 . 2 HC 1 .lt 0 H 2 O: c 55.2; H 6.5; N 11.7.

Mel1or product front i11ing

The compound was prepared according to the same general method as in the following example of intermediate preparation, starting from the corresponding acetyl derivative with formula R.COCH3, where R has the previously shown formula III

Example of intermediate product manufacturing<g>

1.0 ml of phosphorus oxychloride was added to a stirred solution of 2.8 ml of dimethylacetamide in 10 ml of chloroform at room temperature. The mixture was stirred for 5 minutes, 1.78 g of 2-cyano-4,5-dimethoxyaniline was added and the reaction stirred under reflux for 4 hours. The mixture was cooled, poured onto ice and extracted with chloroform and the organic phase discarded. The aqueous layer was basified (solid NaOH), extracted with chloroform, the combined extracts washed with water, dried (Na 2 SO 4 ) and evaporated in vacuo. A sample of the brown oily residue (2 g) was crystallized from diisopropyl ether to give N,N-dimethyl-N<1-(2-cyano-4,5-dimethoxyphenyl)-acetamidine, m.p. 94-96<0>C.

Analysis %

Found: C 63.3; H 6.9; N 17.2. Calculated for C^H^^C^: C 63.1; H 6.9; N 17.0.

Investigation of antihypertensive activity

Groups of 5 spontaneously hypertensive male Okamoto rats were used with systolic blood pressure in excess of 200 mm Hg (compared to 130 mm Hg in normal rats). Blood pressure was measured using an inflatable tail cuff and a variable capacitance transducer to detect the systolic pressure pulse; animals were placed in a heated box at a constant 33°C prior to blood pressure measurement to facilitate accurate measurement of heart rate. After blood pressure and heart rate were controlled, animals received the compound orally at a dose level of 3 mg/kg and blood pressure was measured 1 ,4 and 4 hours after dosing.

The results are expressed as the maximum recorded percentage drop

in blood pressure, based on mean blood pressure in the 5 rats before dosing. Observed drop in blood pressure: 42%

Alpha-adrenoceptor affinity and antihypertensive activity of representative quinoline and isoquinoline derivatives

The new compound of formula I has also subsequently proven to be exceptionally effective in the treatment of heart rhythm disturbances, used alone or in conjunction with a known non-selective ε-adrenoceptor blocking compound, such as propranolol.

Claims (1)

Analogous process in the preparation of a therapeutically active 4-amino-6,7-dimethoxy-2-[6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl]-quinoline with the general formula: as well as acid addition salts thereof, characterized by cyclizing a compound with the general formula II: