NO136574B - - Google Patents

Description

This invention relates to an analogue process for the production of new hydroxypyrimidines, which can be used as bronchodilators and gastric antisecretory agents.

Bronchodilators are used to counteract or

reduce general clogging of the peripheral airways that occurs in bronchitic asthma and chronic non-specific clogging lung disease. There are two main types of such agents in use - sympathomimetic compounds and inhibitors containing adenosine-351-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.

The new compounds produced according to the invention,

differs from other sympathomimetic agents mainly in two ways:

(1) they are cyclic guanosine-3<1>,5<1->monophosphate (GMP), not cyclic AMP phosphodiesterase inhibitors; (2) they are significantly more powerful

and more effective in conscious guinea pigs.

The new pyrimidinones produced according to the invention,

also has the ability to prevent gastric acid secretion. They can therefore be used in the treatment of peptic ulcers and other conditions that cause

caused or aggravated by too much stomach acid.

The invention includes the preparation of new compounds with the formula:

and pharmaceutically acceptable salts thereof, wherein:

R is hydrogen or methyl

R^ is oxygen or sulfur

R 2 is hydrogen, halogen or methyl, and

R 1 is hydrogen, chlorine, methyl or trifluoromethyl. Preferred compounds in this series of compounds are 5-(p-chlorophenoxy)-2-(1H)-pyrimidinone and 5-(p-bromophenoxy)-2-(1H)-pyrimidinone.

In the production of the new pyrimidinones according to the invention, starting materials are used which are commercially available substances, such as phenol or substituted phenol (e.g. p-chlorophenol) and chloroacetaldehyde-diethyl acetal. The phenol is first condensed with potassium hydroxide to form a potassium phenolate. This phenolate is then condensed with the above-mentioned acetal, whereby a phenoxyacetaldehyde-diethyl acetal is formed, such as p-chloro-phenoxy-acetaldehyde-diethyl acetal. This acetal is purified, e.g. by extraction with ether and washing with sodium hydroxide solution, after which it is dried.

The dried product is added slowly to a reagent prepared by reacting N,N-dimethylformamide (DMF) with phosphorus oxychloride under gentle heating. The reactants are heated for several hours or overnight in a water bath. The product, a 2-phenoxy-3-dimethylamino-acrolein which is used as starting material in the method according to the invention, is purified in the usual way, e.g. by crystallization from a solvent such as ethyl alcohol or acetone.

Another variant that leads to usable starting materials for the method according to the invention is to replace the oxygen atom connecting the two ring structures with a sulfur atom. Compounds of this type are produced by condensation of a thiophenol and 2-chloro-3-dimethylamino-acrolein, which gives a 2-thiophenoxy-3-dimethylamino-acrolein. The product is purified by crystallization from a common solvent such as ethyl acetate or ethyl alcohol.

In the method according to the invention, a reagent prepared from ethanol, sodium and urea is heated with an acrolein compound which can be prepared as described above, with the formula

where R^, R2 and R3 are as indicated above and Rg and R7 are alkyl groups with up to 3 carbon atoms, and the pyrimidinone is obtained by acidification, and optionally an alkali or alkaline earth metal salt of the pyrimidinone is reacted with hot methyl iodide to obtain compounds of formula I where R is methyl,

and optionally the compounds produced are converted into the pharmaceutically acceptable salts with acids.

It will be clear to a person skilled in the art that the new compounds produced 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 compounds of formula I 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, the addition salts formed with polycarboxylic acids, e.g. citric acid, tartaric acid, maleic acid, fumar-

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 the testing of the pyrimidinones with regard to

their action as bronchodilators became theophylline, which is a

known muscle relaxant and bronchodilator, used as a basis for 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.

In these experiments with guinea pigs, the compounds produced according to the invention showed 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 produced according to the invention 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.

When evaluating the pyrimidinones produced according to the invention with regard to their effect as gastric anti-secretory agents, the well-known Shay's method with rats as experimental animals was used. The results of these experiments are presented as average values for the acid production (yEq H<+>/100 g/4 hours) in 1 standard deviation, and the differences between the averages for the control sample and the treated groups were analyzed using the unpaired t-test .

Atropine and other well-known anticholinergic agents used in the treatment of overproduction of gastric acid decrease the total production of acid when tested according to Shay's method. One can therefore reasonably assume that the compounds will have a similar effect in humans.

The compounds produced according to the invention can, when used as gastric anti-secretory agents, be given alone, but will generally be used in admixture with a pharmaceutical carrier, which is chosen taking into account the method of administration and usual

o

pharmaceutical practice. They can e.g. administered orally in the form of tablets containing starch and lactose, or in pills

either alone or in a mixture with carrier or consistency materials, or in the form of elixirs or suspensions containing flavor

or dyes. They can be injected parenterally, e.g. intramuscularly or under the skin. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain

other solutes, e.g. sufficient salts or

glucose until the solution becomes isotonic.

As for the dosage level, a wide dosage range of 10-1000 mg/day would be appropriate for adults,

and a preferred range is 25-250 mg/day. The doctor wants in everything

case determine the dose that will be appropriate for the individual patient, and the dose will vary with the patient

age, weight and other conditions. The above dosage is an indication of what the average may be. Of course it can

there may be individual cases where higher or lower dosage ranges come into question.

The following examples will further illustrate

the invention.

Example 1

Step A

To a 3 liter wooden-necked flask fitted with a dropping funnel,

0 head stirs and cools with liquid outlet, 112.2 g was added

(2.0 mol) KOH granules. The dry flask was heated and, with stirring, 257.0 g (2.0 mol) were added to the KOH granules

melted p-chlorophenol (m.p. 43-45°C). The flask is kept at such a temperature that the contents had a temperature of 90-100 C, so that the phenolate anion does not precipitate and a clear solution of molten potassium p-chlorophenolate + water is obtained.

To the molten solution was added with stirring

600 g of chloroacetaldehyde-diethyl acetal (b.p. 152-6°C) with such

speed that the temperature of the mixture is kept at 90-100°C. The mixture (two phases) is stirred rapidly and heated, and an azeotrope of the acetal and water is removed via the liquid outlet on the cooler. The distillation is continued until the temperature of the vapors is 140-150°C. When cooling

the azeotrope separates into an aqueous and an acetal layer, and the acetal can be returned to the reaction mixture. The mixture is stirred vigorously and heated for 6 hours (or overnight) during which solid potassium chloride separates.

After cooling, the contaminated mixture is treated with

600 ml of water. The two-phase system is extracted with 4 x 200 ml of ether and re-extracted with 100 ml of 2N sodium hydroxide to remove unreacted phenol. After drying over anhydrous sodium sulfate, the ether is removed on a rotary evaporator. A yellow or orange oil distilled over, as follows:

The purity of the distillate can be checked by vpc 10% SE-30, 160 : Fraction no. 4; purity >99%

Fraction No. 3: purity >95%

Fraction no. 3 and no. 4 can be used in the next step.

The yield was 268.2 g. Theoretical 530 g - 53% p-chlorophenoxy-acetaldehyde-diethyl-acetal.

Step B

To 255 ml (3.3 mol) of dry distilled DMF at 0°C in a flame-dried 3 liter three-necked flask fitted with an 0-head stirrer, dropping funnel, condenser and drying tube was added 246.9 ml (2.7 mol) of POCl^ within 30-45 minutes. After the addition was complete, the ice bath was removed, and after heating to 25°C, stirring was continued for 1 hour. If the entire apparatus is very dry, a white crystalline complex will form - otherwise the solution will be orange-coloured and viscous. Then 220.2 g of p-chloro-phenoxacetaldehyde-diethyl acetal (0.9 mol) were quickly added over the course of 3-5 minutes,

and the solution was stirred for 10 minutes at room temperature. The solution was then heated very gently on a water bath. The color changed to light gray and it started bubbling. The heating was stopped, and within a few minutes a vigorous evolution of HCl gas began, and the solution turned black. After a few minutes, the HCl evolution decreased strongly, and the drying tube on the cooler was replaced. The mixture was then heated on a water bath for 5-6 hours.

The cooled, viscous, black oil was slowly poured over crushed ice with significant heat generation. Then the mixture of ice and oil was well stirred and neutralized with saturated I^CO-j solution to pH 10. The mixture was heated on a water bath for 2 hours after adding

deposition of a solution of 95% benzene and 5% ethanol.

The upper black organic layer was separated and evaporated

on a rotary evaporator, but not with a view to drying the solution. As the evaporation progressed, a brown crystalline solid was formed. The bath temperature was raised to 90°C, and by longer pumping, water and residues of DMF were completely removed. The impure brown solid was dissolved in chloroform and residual inorganic salts removed by filtration. Chloroform was evaporated, and after continuous high vacuum pumping at water bath temperature for 48 hours, a material was obtained whose nuclear magnetic resonance spectra (nmr spectra) did not show peaks due to impurities. The yield was 191.4 g of a brown granular solid, 2-(p-chloro-phenoxy)-3-dimethylaminoacrolein. Theoretical 203 g - 95% yield.

Step C

500 ml of absolute ethanol was added to a 2 liter three-necked flask equipped with a 0-head stirrer, condenser and drying tube. Sodium granules (23.0 g, 1 mol) were added at a steady rate,

and after the end of the reaction, 60.0 g (1 mol) were quickly added

urea via a powder funnel. After stirring for 10 minutes, 112.75 g of 2-(p-chlorophenoxy)-3-dimethylamino-acrolein were added and the solution was heated with stirring and reflux for 24-48 hours. The reaction solution was cooled to room temperature and poured into

600 ml ice water. A clear brown solution was obtained. After addition of glacial acetic acid to pH 5, a loose brown precipitate formed which was filtered off using a Buchner funnel, yielding 114 g of a moist solid. The nmr spectrum of this material is identical to the spectrum of the analytical sample. The best crystallization solvent was 50% acetic acid and 50% benzene. Recrystallization from this solvent gave 53.9 g of a light brown powdery solid, 5-(p-chlorophenoxy)-2-(1H)pyrimidinone (m.p. 220-221°C).

This compound showed a "% protection" of 92% at

testing according to the procedure in example III.

Example 2

The bronchodilator 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

placed in a fog chamber and nebulized for 1 minute under an air pressure of 0.42 kg/cm in a closed 8"x8"x2" plastic container. A guinea pig was immediately placed in the container and its respiratory status noted by the following system: 0- normal breathing; 1 - slightly deeper breathing; 2 - labored breathing; 3 - very labored breathing; 4 - unconscious. The sum of the scores for the treated group was compared with the control sum and a "% protection" was calculated. 8 animals were used in each group, and all experiments were performed three times.

The following compounds were prepared using the method in example I and were tested with regard to bronchodilator action:

Example 3

The compounds below were prepared according to the method in example 1 and then tested as described below with regard to the compounds' ability to inhibit gastric acid secretion.

After 48 hours of fasting (during which the animals only got 2 pieces of sugar and free access to water), female rats (100-400 g), each in their cage, were anesthetized with ether. The abdominal skin was shaved, and with the help of a midline incision, the stomach and duodenal area was laid open. The gastric port was ligated, the incision closed, the experimental compounds administered and the animal returned to its cage. • 4 hours later, the animals were killed by neck twisting, the stomach was opened again, the contents removed and flushed into a beaker. The volume of gastric juice was measured after centrifugation. Particularly dirty (more than 0.5 ml of solids) or bloody samples were discarded. The acid content of the gastric juice was determined by titration with 0.1N NaOH with phenolphthalein as an indicator. Total acid production was calculated and expressed as microequivalents of hydrogen ions/100 g body weight/4 hours.

Rats were randomly divided into groups from

6 to 10, and the compounds to be tested were administered immediately after ligation of the gastric port either intravenously (in a vein in the tail), subcutaneously or intraduodenally. An appropriate control or comparison group was used in each experiment; these experimental animals did not receive the active compounds, but otherwise the same amounts were administered in the same way as in the treated animals.

The results are expressed as mean values for acid production (yEq H<+>/100 g/4 hours) 1 1 standard deviation, and the differences between the mean for the control groups and the treated groups are analyzed using the unpaired t-test.

Claims (1)

Analogy method for producing a therapeutic act ive compounds with the formula and pharmaceutically acceptable salts thereof, where: R is hydrogen or methyl R^ is oxygen or sulfur R2 is hydrogen, halogen or methyl, and R^ is hydrogen, chlorine, methyl or trifluoromethyl, characterized by heating a reagent prepared from ethanol, sodium and urea with a compound of the formula: where R^, R2 and R^ are as indicated above and R^ and R^ are alkyl groups with up to 3 carbon atoms, and the pyrimidinone is obtained by acidification, and optionally an alkali or alkaline earth metal salt of the pyrimidinone is reacted with hot methyl iodide to obtain compounds of formula I where R is methyl, and optionally the compounds produced are converted into the pharmaceutically acceptable salts with acids.