JP2596829B2 - Method for producing pyrimidone derivative - Google Patents

Description

The present invention relates to a novel method for producing a pyrimidone derivative and a hydrochloride thereof, and a novel pyrimidone derivative hydrochloride having a gastric acid secretion inhibitory effect.

(Prior art)

Heretofore, there have been known some useful pharmaceutical compounds having an excellent H ₂ receptor antagonism and an inhibitory effect on gastric acid secretion. For example, Cimetidine, Ranitidine (Ra
nitidine), famotidine, and roxatidine are commercially available, and many compounds have been reported (Japanese Patent Application Laid-Open Nos. 60-255756, 61-85365, 61-85365).
Nos. 207375 and 60-228465]. The main effect of these compounds is the acid secretion inhibitory effect of most histamine H ₂ receptor antagonistic action, show a marked curative effect for the treatment of peptic ulcer. However, if the drug is stopped after healing, the peptic ulcer recurs due to the rebound phenomenon clinically,
It is a big problem. Conventionally, in order to prevent the peptic ulcer recurrence, or combination of pharmaceuticals bearing a gastrointestinal mucosa protective effect with an agent having acid secretion inhibitory effect such as histamine H ₂ receptor antagonists, to a medicament for the protective action Switching to maintenance therapy.

In view of the fact that an aggressive factor inhibitor such as an acid secretion inhibitor alone is not clinically sufficient, the present applicant firstly has both a gastric acid secretion inhibitory effect and a gastric mucosa protective effect, and has less gastric acid secretion. A patent application has been filed for a novel pyrimidone derivative and a salt thereof useful as an inhibitor, a therapeutic agent for gastric diseases such as peptic ulcer treatment, and the like.
No. 149774)].

[Problems to be solved by the invention]

Further, the present inventors have studied various methods for producing the pyrimidone derivative and established a new production method. In addition, many of the above-mentioned pyrimidone derivatives are viscous oils, so that there is a problem that industrial purification is difficult despite having useful medicinal effects. Therefore, one of the objects of the present invention
One is to provide a pyrimidone derivative that can be easily purified industrially.

[Means for solving the problem]

The present invention relates to 4- (3-hydroxymethylphenoxy)
-Cis-2-butenylamine and the following general formula (I) (Wherein X represents a nitroamino group, a methylthio group, a methoxy group or a halogen atom, and R ¹ and R ² each independently represent an alkyl group having 1 to 6 carbon atoms). The following general formula (II) (Wherein, R ¹ and R ² of the general formula (I) have the same meanings as R ¹ and R ²⁾ to give the compound represented by the following general formula a compound of general formula (II) is halogenated (III) (In the formula, Y is a halogen atom, R ¹ and R ² of the general formula (synonymous with R ¹ and R ² is the I)) to give the compound represented by a compound of general formula (III) and piperidine With the following general formula (IV) (Wherein, R ¹ and R ² of the general formula (synonymous with R ¹ and R ² is the I)) to obtain a compound represented by a process for the preparation of pyrimidone derivatives.

 Hereinafter, the present invention will be described.

One of the starting compounds, 4- (3-hydroxymethylphenoxy) -cis-2-butenylamine (hereinafter sometimes referred to as compound (1)), is prepared by reacting N- [4- (3-hydroxymethylphenoxy)-
[cis-2-butenyl] phthalimide can be prepared by methylamine decomposition. In addition, crude 4-
(3-Hydroxymethylphenoxy) -cis-2-butenylamine (compound (1)) is preferably used after being crystallized and purified as hydrobromide. This hydrobromide can be easily neutralized with an alkali, and is subjected to a reaction after neutralization.

On the other hand, the compound of the general formula (I) can be prepared according to a known compound or a known method. For example, when X is a nitroamino group, it can be synthesized according to the method described in JP-A-60-228465. When X is a methylthio group, it can be synthesized according to the method described in Pharmaceutical Journal 1976, 96, No. 3, page 384. Tetrahedron when X is a methoxy group, 1
It can be synthesized according to the method described in 984, Vol. 40, No. 17, page 3313.

Examples of the alkyl group having 1 to 6 carbon atoms represented by R ¹ and R ² in the general formula (I) include methyl, ethyl, n-propyl, is
Examples are o-propyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl and hexyl.

The reaction of the compound (1) with the compound of the general formula (I) is carried out in an amount of 0.5 to 2.0 mol per mol of the compound (1).
Compound in the absence or in a solvent of 50 ° C to 200 ° C.
C., preferably at the reflux temperature of the solvent, for 12 to 72 hours with stirring. As the solvent, for example, xylene, toluene, DMF, DMSO, or the like can be used.

The compound of the general formula (II) obtained by the above reaction is reacted with a halogenating agent (per mole of the compound of the general formula (II)) in a solvent.
(1.0-5.0 moles). As the halogenating agent, for example, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride and the like can be used. The reaction conditions vary depending on the type of halogenating agent.For example, when thionyl chloride is used, thionyl chloride is added to the reaction system under cooling, and the reaction is carried out at room temperature for 30 minutes.
After stirring for 2 minutes to 2 hours, the mixture is stirred under heating, preferably at reflux temperature for 1 to 5 hours. Further, as the solvent, for example, dichloromethane, chloroform, trichloroethane, carbon tetrachloride and the like can be used.

The compound of the general formula (III) obtained by the above reaction is
Then react with piperidine. The reaction can be carried out by using 1 to 10 mol of piperidine per 1 mol of the compound of the formula (III) and stirring the mixture in a solvent at 10 to 100 ° C for 1 to 48 hours. As the solvent, for example, dichloromethane, chloroform, trichloroethane and the like can be used.

The obtained compound of the general formula (IV) can be further reacted with hydrochloric acid to form a hydrochloride of the compound of the general formula (IV). This reaction can be performed at about room temperature in a solvent, and the amount of hydrochloric acid used varies depending on the number of hydrochloric acid in the hydrochloride.

For example, to obtain the monohydrochloride, 0.8 to 1.1 mol of hydrochloric acid per mol of the compound of the formula (IV) is used, and to obtain the dihydrochloride, 2.1 to 3.0 mol of hydrochloric acid is used. By cooling the obtained reaction solution containing the hydrochloride, crystals of the hydrochloride can be precipitated. The crystals of the obtained hydrochloride can be easily purified by recrystallization.

The hydrochloride of the compound of the general formula (IV) thus obtained crystallizes very easily and can be purified in a large amount and easily by recrystallization. Because of the ease of recrystallization,
Particularly, dihydrochloride is preferable.

The compound of general formula (IV) and its hydrochloride obtained by the above method have a gastric acid secretion inhibitory effect.

 Hereinafter, this point will be specifically described.

The compound of the present invention represented by the general formula (IV) was subjected to various tests and compared with cimetidine, which is widely used clinically as a peptic ulcer having histamine H ₂ receptor antagonism.

(A) Inhibitory effect of histamine on gastric acid secretion enhancement in pyloric ligation raft This study was conducted by Watanabe et al., Applied Pharmacology, 3 (1), 1969, 7-
The method on page 14 was modified and implemented.

Wistar weighing around 160g (Wister) fasted for 24 hours
A male raft was intraperitoneally injected with 1.2 g / kg of urethane and anesthetized. The esophagus and pyloric stomach were then ligated and an incision was made in the forestomach and a double polyethylene-cannula was installed. The stomach wall was washed with 5 ml of physiological saline every 30 minutes, and the stomach of stomach acid contained in the washing solution was measured by titration.

First, the basal acid secretion was measured three times, and then the compound of the present invention was administered into the duodenum at 1 to 9 mg / kg, and 30 minutes later, histamine was injected subcutaneously at 3 mg / kg. Thereafter, gastric acid secretion was measured up to 3 hours. The three time points showing the highest acid secretion increase in each time zone were selected, and the average value was taken as the acid secretion increase amount of each sample group, and the inhibition rate for the control group was calculated by comparing with the control group acid secretion increase amount. , ED ₅₀ values were determined.

(Experimental values represent the average of 5 cases).

 The results are shown in Table 1.

(B) Inhibitory effect on ethanol ulcer This study was performed by Robert et al.
1045-1047, 1975 (Robert, A, Gastroenterology, 6
9 , 1045-1047, 1975). A 30 mg / kg test subject was orally administered to a male Wister raft weighing around 160 g, which was fasted for 24 hours, and 30 minutes later, 1 ml of 100% ethanol was orally administered per animal. One hour later, the stomach was removed, fixed in formalin, and the length of the hemorrhagic ulcer generated in the glandular stomach was measured under a stereoscopic microscope to determine the ulcer index.

(Experimental values are average values of eight cases.) The results are shown in Table 2.

(C) Acute toxicity test 500 mg / kg of a test sample was orally administered to a ddy male mouse weighing about 22 g fasted for 8 hours, and the general symptoms and survival were observed immediately after the administration for 14 days. Table 3 shows the results.

As shown in Table 1, the compound of the present invention showed an inhibitory effect on histamine-stimulated gastric acid secretion enhancement by about 3% of cysotidine.
It is twice as potent and, as shown in Table 2, is characterized by a strong inhibitory effect on ethanol damage not found in cimetidine.

The preparation containing the compound represented by the general formula (IV) and a pharmaceutically acceptable salt thereof as a main component can be prepared by an arbitrary preparation carrier or another known method.

Administration may be oral or parenteral.
The dose is determined depending on symptoms, age of the administration subject, sex and the like. In general, for an adult, the dose is 10 to 500 mg per day, and it is preferable to administer the dose in 1 to 2 to 4 times.

 Hereinafter, the present invention will be further described with reference to Examples.

Reference Example 4- (3-hydroxymethylphenoxy) -cis-2-
Butenylamine hydrobromide Known compound N- [4- (3-hydroxymethylphenoxy) -cis-2-butenyl] phthalimide (JP-A-57
Manufactured using the method described in -165348. ) 164g to 40
The resulting solution was dissolved in 1500 ml of a methanol solution of methylamine (%) and refluxed for 1 hour with stirring. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 800 ml of dichloromethane.

The dichloromethane solution was washed three times with 100 ml of a 2% aqueous NaOH solution and then once with a saturated saline solution.

After drying over magnesium sulfate, the solvent was distilled off, and the pale yellow oil residue was dissolved in 250 ml of n-butanol, and 88 ml of 47% hydrobromic acid was added to crystallize as hydrobromide. Recrystallization from isopropanol including activated carbon treatment and melting point
Colorless prisms of 117-119 ° C. were obtained (69 g; yield 48.6).
%).

IR (KBr, cm ^-1 ): 3350, 2900, 1620, 1590, 1455, 128
5, 1240, 1145, 1035, 880, 775, 695.

_{NMR (ppm, DMSO-d 6} / CDCl 3): 3.4~3.8 (m, 2H), 4.55
~ 4.8 (d, 2H), 4.5 (s, 2H), 5.7 ~ 6.0 (d, 2H), 6.65
-7.4 (m, 4H), 8.0-8.7 (b, 2H).

Example 1 5,6-dimethyl-2- [4- (3-hydroxymethyl)
Phenoxy] -cis-2-butenylamino] -4- (1
H) -Pyrimidone Reference example 4- (3-hydroxymethylphenoxy)-
83 g of a pale yellow oil obtained by using cis-butenylamine and hydrobromide as a free base with a 5% aqueous NaOH solution was dissolved in 500 ml of xylene, and 2-methylthio-4- (1H) -pyrimidone (Pharmaceutical Magazine, 1976, vol. 96) , No. 3, page 384.) 61 g was added, and the mixture was refluxed for 48 hours with stirring.

After completion of the reaction, the solvent was distilled off under reduced pressure, and the crystals of the residue were recrystallized from isopropanol including activated carbon treatment,
The title compound was obtained (101 g; 89.4% yield).

Melting point 144-146 ° C IR (KBr, cm ^-1 ): 3250, 2890, 1640, 1610, 1460, 132
0, 1250, 1135, 1060, 1020, 920, 775, 715.

_{NMR (ppm, DMSO-d 6} ): 1.82 (s, 3H), 2.1 (s, 3H), 3.8
~ 4.2 (m, 2H), 4.52 (s, 2H), 4.6 ~ 4.9 (d, 2H), 5.6
5.9 (m, 2H), 6.7 to 7.4 (m, 4H).

Example 2 5,6-Dimethyl-2-[[4- (1-hyperidinomethyl) phenoxy] -cis-2-butenylamino] -4-
(1H) -pyrimidone The 5,6-dimethyl-2- [4- (3
-Hydroxymethyl) -phenoxy] cis-2-butenylamino] -4- (1H) -pyrimidone (101 g) was suspended in dry dichloromethane (520 ml) and cooled with thionyl chloride 4
9 ml was added dropwise.

The mixture was stirred at room temperature for 1 hour and further at reflux for 3 hours. After the completion of the reaction, 300 ml of a 20% aqueous potassium carbonate solution was added to the mixture to make it alkaline under cooling, and the separated organic layer was washed with saturated NaCl and dried over magnesium sulfate. Then piperidine
60 g was added, and the mixture was stirred at room temperature for 12 hours. After the reaction is complete, add water 2
After adding 00 ml and washing with water and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The title compound was obtained as a pale yellow oil (100 g; 81.7% yield).

IR (liq, cm ^-1 ): 3400, 2950, 1660, 1620, 1400, 134
5, 1258, 1160, 1040, 990, 860, 780, 760.

_{NMR (CDDl 3, ppm):} 1.2~1.7 (6H, m), 1.85 (3H, s),
2.1 (3H, s), 2.2 to 2.5 (4H, m), 3.4 (2H, s), 3.9 to
4.2 (2H, m), 4.5-4.8 (2H, d), 5.5-6.0 (2H, m),
4.6-7.3 (4H, m).

Example 3 5,6-Dimethyl-2- [4- [3- (1-piperidinomethyl) phenoxy] -cis-2-butenylamino] -4
-(1H) -pyrimidone dihydrochloride The 5,6-dimethyl-2- [4- [3- [3-
(1-Piperidinomethyl) -phenoxy] -cis-2-
Butenylamino] -4- (1H) -pyrimidone
-Dissolved in 100 ml of butanol, and 6.7 ml of concentrated hydrochloric acid was added dropwise with stirring.

The crystals precipitated upon cooling were recrystallized from n-butanol to give the title compound as colorless crystals (14.27 g; yield 82.
1%).

Melting point 204-6 ° C IR (KBr, cm ^-1 ): 3200, 2950, 2710, 1670, 1600, 146
0, 1250, 1170, 1030, 945, 855, 790, 690, 530.

_{NMR (ppm, DMSO-d 6} ): 1.1~1.8 (6H, m), 1.8 (3H,
s), 2.25 (3H, s), 2.4-3.5 (4H, m), 4.0-4.45 (4
H, m), 4.6-4.85 (2H, d), 5.7-5.95 (2H, d), 6.8-
7.5 (4H, m), 8.7-9.1 (1H, b).

Example 4 5,6-Dimethyl-2- [4- [3- (1-piperidinomethyl) -phenoxy] -cis-2-butenylamino]-
4- (1H) -pyrimidone monohydrochloride Melting point: 101-102 ° C (d) IR (KBr, cm ^-1 ): 3350, 2950, 2670, 1600, 1530, 145
0, 1260, 1170, 1030, 950, 870, 780, 700, 540.

_{NMR (DMSO-d 6, ppm} ): 0.9~1.15 (3H, d), 1.4~2.0 (9
H, m), 2.1 (3H, s), 2.6-3.4 (4H, m), 3.85-4.2 (2
H, m), 4.25 (2H, s,), 4.1-4.9 (2H, m), 5.5-5.9
(2H, m), 6.7-7.5 (4H, m).

Claims (4)

(57) [Claims] (1) 4- (3-hydroxymethylphenoxy)
-Cis-2-butenylamine and the following general formula (I) (Wherein X represents a nitroamino group, a methylthio group, a methoxy group or a halogen atom, and R ¹ and R ² each independently represent an alkyl group having 1 to 6 carbon atoms). The following general formula (II) (Wherein, R ¹ and R ² of the general formula (I) have the same meanings as R ¹ and R ²⁾ to give the compound represented by the following general formula a compound of general formula (II) is halogenated (II
I) (In the formula, Y is a halogen atom, R ¹ and R ² of the general formula (synonymous with R ¹ and R ² is the I)) to give the compound represented by a compound of general formula (III) and piperidine With the following general formula (IV) (Wherein, R ¹ and R ² are the same meanings as R ¹ and R ² is in general formula (I)) to obtain a compound represented by the production method of the pyrimidone derivatives. 2. The method according to claim 1, wherein X is a methylthio group. 3. The method according to claim ^1, wherein R ¹ and R ² are both methyl groups. 4. A method for producing a hydrochloride of a pyrimidone derivative, comprising reacting a compound represented by the general formula (IV) according to claim 1 with hydrochloric acid to obtain a hydrochloride of the compound represented by the general formula (IV). .