NO137596B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE HYDROXY-PYRIMIDINE DERIVATIVES - Google Patents

Description

This invention relates to a method for production

of new hydroxypyrimidines, which can be used as bronchodilators.

Bronchodilators are used to counteract or

reduce general clogging of the peripheral airways that occurs in bronchitic asthma and chronic non-specific clogging

obstructive lung disease. There are two main types of such agents in use - sympathomimetic compounds and inhibitors containing adenosine-3<1>,5'-monophosphate (cyclic AMP)-phosphodiesterase (PDE). The first-

the aforementioned are characterized by a very powerful effect, but they are not specific for lung tissue, and they also have certain side effects for the heart vessels which limit their applicability. Recent reports suggest that excessive use of commercially available sympathomimetic bronchodilators, particularly isoprenaline, has led to increased mortality among patients (Speizer et al., Brit.

With. J. 1:339, 1968). Typical representatives of the second type,

the cyclic AMP-PDE inhibitors are theophylline and several of its derivatives.

According to the invention, new compounds are produced with

the formula:

and pharmaceutically acceptable salts thereof, wherein:

R4 is hydrogen, halogen, lower alkyl of 1-3 carbon atoms,

methoxy or carboxy, and

R,- is hydrogen, chlorine or methyl.

Preferred compounds in this series are 5-(p-chlorophenoxy)-4-hydroxy-pyrimidine and 5-(p-fluorophenoxy)-4-hydroxy-pyrimidine.

The new hydroxypyrimidines are produced according to the invention by reacting ethanol, thiourea and sodium methylate with the sodium salt of a compound with the formula:

where R^ and R^ are as indicated above and Rg is an alkyl group with up to 3 carbon atoms, after which the obtained thiouracil is desulfurized and the pyrimidine is obtained by subsequent acidification,

and optionally converting the compound formed into a pharmaceutically acceptable salt.

It will be clear to a person skilled in the art that the new compounds according to the invention can exist either in the keto or enol form,

and both of these forms fall within the scope of the invention.

Pharmaceutically acceptable acid addition salts of the new compounds can be prepared by means of acids which form non-toxic addition salts containing pharmaceutically acceptable anions, e.g. the hydrochloride, hydrobromide, hydroiodide, sulfate or hydrogen sulfate, phosphate or an acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulfonate.

Particularly preferred salts of the new compounds which are advantageous insofar as they are soluble in the usual solvents are the addition salts formed with polycarboxylic acids, e.g. citric acid, tartaric acid, maleic acid, fumaric acid and oxalic acid. The invention further encompasses the pharmaceutically acceptable non-toxic metal salts, e.g. sodium, calcium and potassium salts, as well as ammonium and substituted ammonium salts.

In testing the pyrimidinones and hydroxypyrimidines for their action as bronchodilators, theophylline, which is a known muscle relaxant and bronchodilator, was used as a basis of comparison. The substances were dissolved in water or suspended in a suitable medium and administered orally to conscious guinea pigs. One hour after administration, each guinea pig was exposed to an aerosol of histamine hydrochloride. The condition of the airways was examined after 1 minute.

The compounds produced according to the invention showed, in these experiments with guinea pigs, levels of activity equal to and even significantly greater than what was obtained with theophylline. One can therefore reasonably assume that the compounds will have a similar effect in humans.

The compounds will preferably be used orally in the form of tablets or pills, the compounds being mixed with suitable materials, or as aqueous suspensions containing suitable diluents and emulsifying or suspending agents. Other dosage forms for parenteral or inhalation therapy may also be used.

The dosage will of course vary with the patient's age and condition and will best be determined by the doctor. A normal dosage range of approx. 0.20-7 mg/kg body weight given three times daily would be typical, although higher or lower dosages may be preferred in individual cases.

The following example will further illustrate the invention.

Example

Step n A

The product was prepared by reacting 61.0 g of ethyl chloroacetate and 64.0 g of p-chlorophenol (Aldrich) in the presence of sodium ethylate using known methods. 69.5 g of a white, crystalline product, ethyl p-chlorophenoxyacetate, m.p. 49-51°C, (m.p. 49°C according to (1) T.M. Minton and M. Stephen, J. Chem. Soc., 121 1600 (1922)); nmr (CDCl 3 ) 1.2 (t, 3H, CH 3 ), 4.2 (q, 2H, CH 2 ), 4.6 (s, 2H, CH 2 ), 6.8 (d, 2H, CgH 2 ), 7, 2 (d, 2H, CgH2).

Tri nn B

The product was prepared from 150 ml of ethyl ether, 8.3 g of sodium granules, 69.5 g of ethyl p-chlorophenoxyacetate and 39.0 g of methyl formate using methods known from the literature. 55.7 g of a light, white powder, the sodium salt of ethyl α-(p-chlorophenoxy)-(3-hydroxyacrylate..

Step C

The desired product was prepared by heating 55.7 g

of the sodium salt of ethyl α-(p-chlorophenoxy)-3-hydroxyacrylate,

23.6 g of thiourea and 16.6 g of sodium methylate in 200 ml of ethyl alcohol for 14 hours under reflux, following methods known per se. After evaporation of the solvent, the residue was dissolved in 200 ml of ice and water, acidified to pH 5.0 with concentrated hydrochloric acid, stirred for 20 minutes, after which the precipitate was filtered off. 77.6 g of the impure product was obtained. Recrystallization from chloroform/ethyl alcohol/acetic acid gave 42.0 g of light white microcrystals of 5-(p-chlorophenoxy)-2-thiouracil, m.p. 286-287°C;

nmr (DMS0) 7.1 (d, 2H, Cgf^), 7.45 (d, 2H, CgH2), 7.7 (s, 1H, H-6), 12.5 (broad s, 2H, 0H , SH)..

Step D

The product was prepared by adding 30.0 g of Ra/Ni

in small portions to a solution of 30 ml of water, 1.2 g of sodium hydroxide and 3.5 g of 5-(p-chlorophenoxy)-2-thiouracil at 60°C (oil bath) under nitrogen. The reaction mixture was stirred for 1.5 hours at 60°C. The filtrate obtained by filtering out Ra/Ni was poured over ice and acidified to pH 3.0 with concentrated hydrochloric acid.

After stirring for 5 minutes, the precipitate was filtered off, washed with ethyl ether and air dried, yielding 1.5 g of a white powder, 5-(p-chlorophenoxy)-4-hydroxy-pyrimidine, m.p. 163-164°C; nmr (DMSO) 7.05 (d, 2H, C6H2), 7.5 (d, 2H, CgH2), 8.0 (s, 1H, H-6), 8.2

(s, 1H, H-2), 12.6-13.1 (broad s, 1H, 0H).

Analysis: Calculated for C"10H7C1N2O2: C 54 , 37 ; H 3.17; N 12.59; Cl 15.92.

Found: C 54.21; H 3.39; N 12.57; Cl 15.46.

This compound showed a "% protection" of 92% when tested according to the procedure in the following comparative experiment.

Compare ingsfor search

The 3ronchodilator effect was determined by experiments with

conscious female guinea pigs (Reed-Willet) weighing 200-260 g and challenged with histamine. A certain time after the test compound or the agent used for control and comparison had been administered orally, a 0.2% aqueous solution of histamine dihydrochloride was placed in a fog chamber and atomized for 1 minute under an air pressure

o

at 0.42 kg/cm 2 in a closed 8"x8"x2" plastic container. A guinea pig was immediately placed in the container and its respiratory status indicated by the following system: 0 - normal breathing, 1 - slightly deeper breathing, 2 - strained breathing, 3 - very labored breathing, 4 - unconscious The sum of the scores for the treated group was compared

with the checksum and a "% protection" calculated. Eight animals were used in each group, and all experiments were performed three times.

The following compounds were prepared by the method

in the example and was tested with regard to bronchodilating effect.

Claims (1)

Analogous process for the preparation of therapeutically active compounds of the formula: and pharmaceutically acceptable salts thereof, where: R^ is hydrogen, halogen, lower alkyl with 1-3 carbon atoms, methoxy or carboxy and R,, is hydrogen, chlorine or methyl, characterized by reacting ethanol, thiourea and sodium methylate with the sodium salt of a compound with the formula: where R. and Rj. is as stated above and R^ is an alkyl group with up to 3 carbon atoms, after which the obtained thiouracil is desulfurized and the pyrimidine is obtained by subsequent acidification, and optionally the compound formed is converted into a pharmaceutically acceptable salt.