JPS6345677B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions containing pyrimidone compounds and methods of treatment using the compounds.

Many physiologically active substances exert their biological activity through interaction with specific sites known as receptors. Histamine is such a substance and has various biological activities. Histamine's biological activity, which is commonly inhibited by drugs called "antihistamines" (histamine H ₁ -antagonists), typically mepyramine, diphenhydramine, and chlorpheniramine, inhibits histamine H ₁ -receptors. transmitted through. However, other biological activities of histamine include “antihistamine” (histamine H ₁
- antagonist), this type of activity was inhibited by brimamide, and histamine _H2
-Transmitted through receptors called receptors.
As used herein, histamine H ₂ -receptor is
From Black [Black et al., Nature, 236,
385 (1972)] as histamine receptors that are not blocked by mepyramine but are blocked by brimamide. Compounds that block histamine _H2 -receptors are called histamine _H2 -antagonists.

Blockade of histamine _H2 -receptors is of value in suppressing the biological activity of histamine that is not suppressed by "antihistamines" (histamine _H1 -antagonists). Histamine _H2 -antagonists are, for example,
It is effective as a gastric acid secretion inhibitor, an anti-inflammatory agent, and a drug that acts on the cardiovascular system, such as a suppressor of the effect of histamine on blood pressure.

Under certain physiological conditions, the biological effects of histamine are transmitted through both histamine _H1- and _H2 -receptors, and blockade of both receptors is useful. These conditions include, for example, inflammation mediated by histamine, such as skin inflammation, and hypersensitization reactions due to the action of histamine at _H2- and _H2 -receptors, such as allergies.

The pyrimidone compound used in the present invention is histamine.
It is an H ₂ -antagonist and also has a weak histamine H ₁ -antagonistic effect.

The present invention is based on the formula: [Wherein, D is R ¹ R ² NCH ₂ −; R ¹ and R ² are
respectively, methyl; B means 6-methyl-3-pyridyl or 2-hydroxy-4-pyridyl] A histamine H ₂ -antagonist containing a pyrimidone compound or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition is provided.

Compounds of formula [1] are shown as 4-pyrimidone derivatives, but these derivatives have the corresponding 6-pyrimidone derivatives.
Exists in equilibrium with the on tautomer. Also,
These compounds also exist to some extent as hydroxy tautomers, and the pyrimidone ring can also exist as a tautomeric form as shown in the following formula.

The compound of formula [1] has the formula: [wherein D is the same as above] and an amine represented by the formula: [In the formula, B ¹ is the above B or a protected derivative of B; Q
means nitroamino (NO ₂ NH-), lower alkylthio, benzylthio, chlorine, bromine or any other group that can be substituted with a primary amine] and then any protecting groups are removed. It can be manufactured by

The term protected derivative of B refers to a precursor of B from which B can be generated directly, for example, a compound of formula [1] of 2-hydroxy-4-pyridyl is
It can be produced by dealkylating a compound of formula [1] corresponding to a heterocyclic ring in which is substituted with lower alkoxy or benzyloxy, and the alkyl and benzyl groups can be used as protecting groups. Preferably, this dealkylation is carried out using ethanolic hydrochloric or hydrobromic acid at an elevated temperature, for example at the boiling point of the reaction mixture. The vic-hydroxy group is introduced as a ketal derivative.

Preferably, Q is methylthio, more preferably nitroamino.

This method is carried out in the absence of a solvent at high temperatures, e.g.
If is methylthio, it can be carried out at 150°C or in the presence of a solvent such as in refluxing pyridine. When Q is nitroamino, the reaction is preferably carried out in a substantially inert solvent, such as refluxing ethanol.

The compound of formula [1] has the following formula: (i) Formula: GS( _CH2 ) _2NH2 [wherein G is hydrogen or _a thiol protecting group, e.g. 4-methoxybenzyl, ethylcarbamoyl or -S( _CH2 )nNH] ₂ (meaning that the thiol is protected as a disulfide in this case)] with the pyrimidone of the above formula [3], and then the existing thiol protecting group is removed, (ii) this product , the formula: [Wherein, D is the same as above; L is a group that can be substituted with thiol, such as hydroxy, acyloxy (preferably acetoxy, methanesulfonyloxy or p-toluenesulfonyloxy),
means lower alkoxy (preferably methoxy), chlorine, bromine, or triarylphosphonium (preferably triphenylphosphonium)] and can be produced by removing the protecting group.

Preferably, step (i) is carried out under the same conditions as in the reaction with the amine of formula [2] above. Preferably in step (ii) L is hydroxy or methoxy and the reaction is carried out under acidic conditions, for example in aqueous hydrochloric or hydrobromic acid.

The amine of formula [2] can be produced by the method described in Belgian Patent No. 857388.

The intermediate of formula [3] in which Q is nitroamino is obtained by converting nitroguanidine into the formula: [In the formula, R means lower alkyl or aryl lower alkyl] It can be produced by reacting with a compound represented by the following formula. Preferably, the reaction is carried out using sodium lower alkoxide as a base in a lower alkanol at the boiling point of the reaction mixture.

The activity of the compound of formula [1] as a histamine H ₂ -antagonist is demonstrated by the suppression of histamine-stimulated gastric acid secretion from the rumen-perfused stomach of rats anesthetized with urethane at an intravenous dose of less than 16 micromol/Kg. I can do it. This method is based on Ash and Schild [Ash and Schild, Brit.J.
Pharmac.Chemther., 27, 427 (1966)]. In addition, the histamine H ₂ of the compound
-Activity as an antagonist is also demonstrated by the ability to suppress other effects of histamine, which are said in the above-cited Atsushi and Shields paper to be not transmitted by histamine H ₁ -receptors. For example, the compounds inhibit the effects of histamine on isolated guinea pig atria and isolated rat uteruses. The compounds also inhibit basal secretion of gastric acid and gastric acid secretion stimulated by pentagastrin or food. In conventional tests, such as in blood pressure measurements in anesthetized cats, 0.5 to
Upon intravenous administration at 256 micromol/Kg, the compound suppresses the vasodilatory effects of histamine. The potency of these compounds is determined by the effective dose that produces a 50% inhibition of gastric acid secretion in anesthetized rats and the dose that produces a 50% inhibition of histamine-induced tachycardia in isolated guinea pig atria (10 ^-4 molar or less).
It is represented by.

The efficacy of the compounds of the present invention is long-lasting.

For example, 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-
(6-Methyl-3-pyridylmethyl)-4-pyrimidone (compound of Example 1 described below) sustains the suppression of gastric acid secretion induced by histamine in Heidenhain dogs with small stomachs, as shown below.
It is much longer than the known _H2 -antagonist cimetidine.

(i) After intravenous injection of the compound at doses of 0.25 and 0.5 micromol/Kg, an inhibitory peak appeared at approximately 60 minutes, suppressing the histamine response by 68% and 96%, respectively, and even after 3.5 hours, 33 % and 55%
showed inhibition. On the other hand, cymetidine (4 micromol/Kg) reached its peak inhibition 30 minutes after intravenous injection, and suppressed gastric acid secretion induced by histamine stimulation by approximately 65%.
However, after 2 hours, it no longer showed any suppressive effect.

(ii) 65% and 65% of histamine-stimulated maximal gastric acid secretion at 2.25 hours after oral administration of the compound at doses of 0.625 and 1.25 micromol/Kg, respectively;
88% inhibition, and even after 3.75 hours, 62% and 86% inhibition, respectively. On the other hand, cymetidine (20 micromol/Kg orally) showed a peak response of 82% inhibition 1.75 hours after administration, but the inhibition rate had decreased to 35% 2.25 hours later (4 hours after administration).

Similarly, 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-
(2-Hydroxy-4-pyridylmethyl)-4-pyrimidone (compound of Example 2(iv) below) also showed a more sustained effect than cymetidine in Heidenhain small stomach dogs.

Moreover, all the compounds of the present invention are low toxicity compounds.

For example, the LD ₅₀ of intravenous administration of the trihydrochloride of the compound of Example 2 (iv) below in mice is, respectively:
32.2, 85.5 and 42.4mg/Kg. Furthermore, the LD ₅₀ of the trihydrochloride of the compound of Example 3 below was 69 → 106 mg/Kg when administered intravenously to mice, and 3810 mg/Kg when administered orally.
mg/Kg, 75→121mg/Kg when administered intravenously to rats, and >4000mg/Kg when administered orally.

Furthermore, the trihydrochloride of the compound of Example 1 described later,
Beagle dogs were orally administered via capsule at a dose of 4→144 mg/Kg daily for 30 days.
It was administered daily to rats at doses of 50→1250 mg/Kg via gastric lavage for 30 days without causing any toxic effects. This is highly desirable from a therapeutic point of view. In addition, no teratogenic effects were observed in oral teratogenicity tests in rats.

The pharmaceutical composition of the present invention comprises a medicinally active compound of formula [1] in the form of a free base or an addition salt with a pharmaceutically acceptable acid, and a pharmaceutical carrier. Such addition salts include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and maleic acid, and can be conveniently produced from the corresponding compound of formula [1] according to conventional methods. For example, in lower alkanols,
The compound can be treated with an acid or an ion exchange resin can be used to form the desired salt directly from the free base form of the compound or from another acid addition salt.

The pharmaceutical carrier used can be solid or liquid. Examples of solid carriers include lactose, corn starch, potato starch, modified starch, dicalcium phosphate, white china clay, sugar, cellulose, talc, gelatin,
Examples include agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycol, and water.

If a solid carrier is used, it may be in the form of a tablet, powder or granulated pellet, troche or lozenge. The amount of solid carrier in a dosage unit form is generally from about 25 mg to about 300 mg. If a liquid carrier is used, it can be a syrup, emulsion, multiple emulsion, sterile injectable solution, or an aqueous or non-aqueous solution or suspension. For example, preservatives such as antioxidants or antibacterial agents and/or other additives such as flavors and colors may also be included. Sterile solutions can be prepared in ampoules, multi-dose vials, and unit-dose single-use systems. They can also be in semi-solid or liquid or aerosol forms such as creams, pastes, ointments, gels, etc. for topical administration. Pharmaceutical compositions are prepared by grinding, mixing, granulating and tabletting the ingredients suitable for the desired dosage form;
Manufactured by conventional techniques including operations such as spray drying, freeze drying or dissolving, dispersing. The active ingredient is present in the composition in an amount effective to block histamine _H2 -receptors. Preferably, each dosage unit will contain from about 50 mg to about 250 mg of the active ingredient.

The active ingredient is preferably administered from 1 to 6 times per day. The daily dosage is preferably about 150
mg to about 1500 mg. The route of administration may be oral or parenteral.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

The pharmacological data in each example was measured according to the following method.

(i) Rat gastric acid secretion test (measurement of histamine H ₂ -antagonistic activity) Ghosh and Schild [Ghosh and Schild, Brit.J.Pharmac.
Chemother., 13, 54 (1958)] was used to measure the suppression of gastric acid secretion induced by histamine stimulation using the rumen-perfused stomach of rats anesthetized with urethane.

Female Sprague Dawley Rat (Weight
(160 to 200 g) were fasted overnight and anesthetized by intraperitoneally administering 200 mg of urethane once. The trachea and jugular vein are cannulated and a midline abdominal incision is made to expose the stomach and separate it from the connective tissue. A small incision is made in the forestomach region of the stomach and the stomach is irrigated with 5% w/v glucose solution. The esophagus is partially freed from the connective tissue, cannulated with a polyethylene tube, and the esophagus and vagus nerve are severed at the top of the cannula. The antrum is incised and a cannula is passed into the stomach through the forestomach incision, passing through the antrum and positioning the head of the cannula within the body of the stomach.
Insert the funnel-shaped cannula into the forestomach incision and tie it where the line between the forestomach and the stomach body coincides with the tip of the funnel. The antral cannula is tied to reduce the effect of gastrin released from the antrum on gastric acid secretion. Two holes are made in the abdominal wall and a cannula leading to the stomach is passed through. The stomach is perfused with a 5.4% w/v glucose solution at 1-2 ml/min at 37°C through the esophageal and gastric cannula. Pass the effluent through a micro-flow PH electrode;
Recorded with a PH meter connected to an inverse logarithm unit and flatbed recorder. Measure the pH of the perfusion effluent to monitor basal secretion of gastric acid. Submaximal doses of histamine are continuously injected into the jugular vein to produce a stable plateau of gastric acid secretion, and once this condition is achieved, the PH of the effluent is measured. Infusion of histamine at a rate of 0.25 micromol/Kg/min results in 70% of the maximum histamine-stimulated gastric acid secretion. The test compound was then administered into a second jugular vein at 5.4% w/
Wash with vglucose solution. From the difference in effluent PH, the difference between basal gastric acid secretion, histamine-stimulated plateau, and the decrease in acid secretion caused by the test compound is calculated. One dose of the test compound is administered to one rat and this is repeated in at least four rats at three or more dose levels to determine the ED ₅₀ value (50% inhibition of submaximal gastric acid secretion).
Measure. The results obtained are then used to calculate the ED ₅₀ of the test compound using standard least squares methods.

(ii) Morimoto's atrial test (measurement of histamine H ₂ -antagonistic activity) In the Morimoto's atrial test, the isolated naturally beating right atrium of a Morimoto is placed under tension (300 mg) in a 15 ml bath with a stator. Fixed between transducers and immersed in McEwens solution at 37°C with constant aeration. Amplify the output from the converter. The output is further sent to a flatbed recorder. A known amount of histamine is added to the bath and the histamine concentration is increased in steps until the heart rate reaches a maximum. The bath is flushed out and filled with fresh Macuence solution containing the test compound. This solution is left in contact with the tissue for 60 minutes and again a known amount of histamine is added until the maximum heart rate is recorded. Repeat the analysis with increasing concentrations of the test compound and record the amount of histamine that gives 50% of the maximum heart rate.
Calculate the dose ratio (DR) by comparing the concentration of histamine required to produce 50% of the maximal response in the presence and absence of the test compound. logDR
-1 is plotted against logD (test compound concentration) and the intersection with the logDR-1 coordinate axis is taken as a measure of activity (pA ₂ value).

(iii) Heidenhain small stomach dog gastric acid secretion test (measurement of histamine H ₂ -antagonistic activity) A Heidenhain small stomach dog is prepared as follows. Open the abdomen of a male beagle (weighing 14-16 kg) and remove the stomach from the abdomen. The blood vessels are ligated, two cuts are made above the greater curvature, and a portion of the stomach fundus is cut away from the stomach body to form a small stomach. A stainless steel cannula is inserted into the small stomach and one end exits through a hole in the abdominal wall, allowing gastric juices to drain under gravity. Finally, close the abdomen with running sutures.
The dog can be used for experiments in about three weeks after surgery.

Prior to the experiment, the dogs were fasted for approximately 20 hours and then placed on a Pavlov stand. A polyethylene cannula is connected to the leg vein and saline is infused for approximately 1 hour. Check for basal gastric acid secretion. Instead of saline, histamine (20 micromoles/hour) or pentagastrin (8 micromoles/Kg/hour) are infused continuously. After 1.5-2 hours, a plateau of gastric acid secretion is reached and the test compound is administered intravenously or orally (in hard gelatin capsules). Gastric fluid is collected by draining under gravity into a perspex tube attached to a gastric cannula. Usually the sample is
Collect for 15 minutes. Measure the volume of the sample and titrate a portion of it with 0.1N sodium hydroxide to pH 7.4. Gastric acid secretion is expressed as the product of volume and acid concentration, and the peak inhibition rate (%) at each dose of the test compound is calculated.

Example 1 (i) 51.57 g of 6-methylpyridyl-3-carboxaldehyde, 44.30 g of malonic acid, 6 piperidine
ml and 300 ml of pyridine was stirred at 100°C for 3 hours and allowed to cool. The mixture was evaporated to dryness, water was added to the residue, and the solid was removed. Recrystallized from ethanol acetic acid to give 3-(6-methyl-
41.25 g of 3-pyridyl)acrylic acid are obtained. Melting point 213.5-215.5℃.

(ii) 50.70 g of 3-(6-methyl-3-pyridyl)acrylic acid, 350 ml of dry ethanol and concentrated sulfuric acid.
Heat 25 ml of the stirred mixture to reflux for 18 hours, then 250 ml
Evaporate and remove the ethanol. Pour the residue into ice-aqueous ammonia and extract the mixture with ether. The ether extract was washed with water and evaporated to obtain an oil, which was left to crystallize into 3-(6-
Ethyl methyl-3-pyridyl)acrylate is obtained. Melting point 36-37℃.

(iii) 60.36 g of ethyl 3-(6-methyl-3-pyridyl)acrylate is hydrogenated in ethanol using 1.0 g of 10% palladium-carbon catalyst at 35° C. and 355 kPa. The mixture is filtered and the liquid is evaporated to give an oily ethyl 3-(6-methyl-3-pyridyl)propionate.

(iv) 57.79 g of ethyl 3-(6-methyl-3-pyridyl)propionate and 23.71 g of ethyl formate.
Sodium wire cooled in an ice-salt bath
2.5 to a stirred mixture of 6.88 g and 200 ml of ether.
Add it over time. The mixture is stirred for 20 hours and the ether is removed by evaporation. 22.76 g of thiourea and 175 ml of ethanol are added to the residue and the mixture is heated under reflux for 7 hours and evaporated to dryness. Add 200 ml of water to the residue and adjust the pH to 6 with acetic acid. The solid is collected and recrystallized from methanol-acetic acid to obtain 17.24 g of 5-(6-methyl-3-pyridylmethyl)-2-thiouracil.
Melting point 240-241℃.

(v) 13.79 g of methyl iodide was converted into 5-(6-methyl-3
-pyridylmethyl)-2-thiouracil 22.66g
and 8.0 g of sodium hydroxide in 250 ml of water, heated at 70° C. for 1 hour, and stirred at room temperature overnight. Acetic acid is added until the pH is 5 and the mixture is evaporated to a volume of 50 ml. Take the solid,
Recrystallized from ethanol-acetic acid to give 5-(6-
10.16 g of methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone are obtained. Melting point 197~
197.5℃.

(vi) 1.30 g of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine, 5-(6
-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone 1.41 g and pyridine 10
ml of the mixture is heated under reflux for 46 hours and evaporated to dryness. The residue is washed with hot water and the oil is treated with excess hydrogen chloride in ethanol and evaporated to dryness.
The residue was recrystallized from aqueous ethanol containing hydrogen chloride to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl).
-4-pyrimidone trihydrochloride is obtained. Melting point 210~
213 °C, melting point of the sample recrystallized from aqueous ethanol further containing hydrogen chloride 224-227
℃.

Rat gastric acid secretion test: ED ₅₀ = 0.1 micromol/Kg intravenous, Guinea rat atrial test: pA ₂
= 7.8, Heidenhain Small Stomach Dog Test: Peak Suppression = 68% (0.25 micromol/Kg iv).

Example 2 (i) 115.53 g of 2-chloro-4-cyanopyridine in 850 ml of methanol-dioxane (1:1) are added to a solution of sodium methoxide (prepared from 20.8 g of sodium) in 285 ml of methanol and kept under reflux for 2.5 hours. Bring to a boil and leave to cool. Filter this mixture, evaporate the liquid to a volume of 200ml, and add water.
Add 400ml. Take the precipitated solid and 2-
57.2 g of methoxy-4-cyanopyridine are obtained.
Yield 50%, melting point 93-95.5℃.

(ii) 57.2 g of 2-methoxy-4-cyanopyridine,
Semicarbazide hydrochloride 71.24g, sodium acetate
A mixture of 69.86 g, 1200 ml of ethanol, and 370 ml of water was mixed with 1.0 g of Raney nickel catalyst.
Hydrogenate at 344kPa. The mixture was evaporated to a volume of 450 ml, 900 ml of water was added, and the mixture was left overnight at 0°C. Filter the mixture, wash the solid with water,
Dissolve in 950ml of 10% hydrochloric acid. Add 420 ml of formaldehyde solution (36% w/v), warm the mixture for 30 minutes, allow to cool, and add 280 ml of sodium acetate.
g in 840 ml of water. This mixture was extracted three times with 500 ml of ether each time, and the extracts were combined.
Wash with aqueous potassium carbonate, then water. Dry and evaporate to give 2-methoxypyridine-4-
20.5 g of carboxaldehyde are obtained. Yield 35
%, melting point 33-35 °C, melting point of the sample recrystallized from petroleum ether 33-36 °C.

(iii) 2-methoxypyridine-4-carboxaldehyde is condensed with malonic acid, esterified and then hydrogenated according to the method of Example 1(i)-(iii). The product was formylated with ethyl formate and sodium hydride to give an oily 2-formyl-
Ethyl 3-(2-methoxy-4-pyridyl)propionate is obtained. This is treated with nitroguanidine and sodium methoxide in methanol under reflux to give 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone. Yield 59%, mp 194-195.5°C (from aqueous acetic acid).

(iv) A mixture of 2.50 g of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine, 2.77 g of 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and 15 ml of ethanol. Boil under reflux for 19 hours,
Evaporate. Trituration of the residue with hot water gives 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone. A mixture of 3.04 g of this pyrimidone, 20 ml of 2N hydrogen chloride in ethanol and 80 ml of ethanol is boiled under reflux for 48 hours and evaporated to dryness. The residue was recrystallized from methanol-ethanol to give 2-[2-(5-dimethylaminomethyl-
2-Furylmethylthio)ethylamino]-5-
(2-hydroxy-4-pyridylmethyl)-4-
Pyrimidone trihydrochloride is obtained. Melting point 181-185℃.

Rat gastric acid secretion test: ED ₅₀ = <0.1 micromole/Kg intravenous, Mormotu atrial test:
_pA2 =7.6.

Example 3 A pharmaceutical composition is obtained according to the following recipe.

2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl-4-pyrimidone trihydrochloride
150mg Cane sugar 75mg Starch 25mg Talc 5mg Stearic acid 2mg Pass these ingredients through a sieve, mix and place in a hard gelatin capsule.

Other compounds of formula [1] can be formulated into pharmaceutical compositions as well, and these compositions are administered in the dosage ranges described above to block histamine _H2 -receptors.

Claims (1)

[Claims] 1 Formula: [Wherein, D is R ¹ R ² NCH ₂ −; R ¹ and R ² are
methyl; B means 6-methyl-3-pyridyl or 2-hydroxy-4-pyridyl] or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or carrier. Histamine H ₂ −
Antagonist composition. 2. The histamine of item 1 above, wherein the pyrimidone compound is 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone. _H2 -antagonist composition. 3. The histamine of item 1 above, wherein the pyrimidone compound is 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone. _H2 -antagonist composition.