JPH032121A - Anti-gastritis/anti-peptic ulcer agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 5,6-dimethyl-2-C4-<3-(1
-piperidinomethyl)phenoxy>cis-2-butenylamino:] -An anti-gastritis/anti-peptic ulcer agent containing hydrochloride of -4-(IH)-pyrimidone as an active ingredient.

Prior art and problems to be solved by the invention In recent years, excellent anti-peptic ulcer agents have been developed.

In particular, various histamine H2 receptor antagonists are known that have a strong effect of suppressing gastric acid secretion (suppressing aggressive factors). However, while these drugs are powerful, they also have problems in the duration of their action, and when they are discontinued, peptic ulcers may recur or relapse due to a rebound phenomenon, which is a major clinical problem. Therefore, in reality, these drugs are used in combination with other protective factor-enhancing drugs.

An object of the present invention is to solve the problems of the prior art described above.

Means for Solving the Problems The present inventors have carried out intensive research and have discovered a compound that has both the effect of suppressing gastric acid secretion and the effect of protecting the gastrointestinal mucosa.As a result of further investigation, the present inventors have developed the present invention. It was completed.

The present invention provides 5,6-dimethyl-2-[4-<3-(1
-piperidinomethyl)phenoxy>cis-2-butenylamine)-4-(IH)-pyrimidone [hereinafter compound (I
)] containing hydrochloride as an active ingredient.
Regarding anti-peptic ulcer agents.

Compound (I) is a compound having the following structure.

It is hydrochloride. This hydrochloride is superior to Compound 1N(I) and other salts in terms of stability and pharmacological action.

The method for producing compound (I) will be explained below according to Scheme 1.

Scheme 1 Compound (II) (X: nitroamino, methylthio, methoxy or halogen) Compound (II[> (I) Specific examples of the hydrochloride of the above compound (1) include monohydrochloride and dihydrochloride. Compound (IV) Compound (1) One of the raw material compounds, 4-(3-hydroxymethylphenoxy)-cis-2-butenylamine (hereinafter referred to as compound (II)), is disclosed in Japanese Patent Application Laid-Open No. N-[4-(3-hydroxymethylphenoxy)-
It can be prepared by decomposing cis-2-butenyl]phthalimide with methylamine. In addition, crude 4-
(3-hydroxylmethylphenoxy)”-cis-2
-Futynylamine (compound (■)) is preferably crystallized and purified as a hydrobromide salt.

This hydrobromide salt can be easily neutralized with an alkali and is subjected to the reaction after neutralization.

On the other hand, compound (III) is a known compound or can be prepared according to a known method.

For example, when X is a nitroamino group, JP-A-60-228
It can be synthesized according to the method described in No. 465. In addition, when X is a methylthio group, Pharmaceutical Journal 1976, Volume 96 No.
It can be synthesized according to the method described on page 3.384. When X is a methoxy group, Tetrahedron% 1
It can be synthesized according to the method described in 984, Vol. 40, No. 017, p. 3313.

The reaction between compound (n) and compound (I) produces compound (■)
0.5 to 2.0 mol of compound (III) per 1 mol
can be carried out in the absence or in a solvent by stirring at 50°C to 200°C, preferably at the reflux temperature of the solvent, for 12 to 72 hours. Examples of solvents include xylene,
Toluene, DMF.

D'NIS○ etc. can be used.

The compound (rV) obtained by the above reaction is halogenated by reacting with a halogenating agent (1.0 to 5.0 mol per 1 mol of compound (■)) in a solvent. Examples of the halogenating agent include thionyl chloride, thionyl bromide,
Phosphorus oxychloride, phosphorus pentachloride, etc. can be used.

Reaction conditions vary depending on the halogenating agent, but for example, when using thionyl chloride, thionyl chloride is added to the reaction system under cooling, stirred at room temperature for 30 minutes to 2 hours, and then heated, preferably Stir at reflux temperature for 1-5 hours. In addition, as a solvent, for example, dichloromethane,
Chloroform, trichloroethane, carbon tetrachloride, etc. can be used.

Compound (V) obtained by the above reaction is then reacted with piperidine. The reaction is to convert piperidine into a compound (■)
Using 1 to 10 mole per mole, in the solvent, 10 to 10
This can be carried out by stirring at 0°C for 1 to 48 hours. As the solvent, for example, dichloromethane, chloroform, trichloroethane, etc. can be used.

The obtained compound (I) can be converted into a hydrochloride by further reacting with hydrochloric acid. This reaction can be carried out in a solvent at about room temperature, and the amount of hydrochloric acid used varies depending on the number of hydrochloric acids in the hydrochloride salt.

For example, to obtain monohydrochloride, 0.8 to 1.1 mol of hydrochloric acid is used per 1 mol of compound (■), and to obtain dihydrochloride, 2.1 to 3.0 mol of hydrochloric acid is used. The obtained reaction solution containing the hydrochloride salt can be cooled to precipitate hydrochloride crystals. The obtained hydrochloride crystals can be easily purified by recrystallization.

The hydrochloride of compound (1) thus obtained is extremely easily crystallized and can be easily purified in large quantities by recrystallization. Particularly preferred is dihydrochloride because of ease of recrystallization.

Although the hydrochloride of compound (I) may be used as it is as the drug of the present invention, it is usually preferable to use it with pharmacologically and pharmaceutically acceptable additives added thereto. When using such additives,
The amount of compound (I) in the drug of the present invention is usually 0.1 to
20% by weight, preferably 1-10% by weight.

The above additives may be used depending on the route of administration, such as internal preparations (oral preparations), injection preparations (injection preparations), mucosal preparations (buccanove troches, suppositories, etc.), and external preparations (ointments, patches, etc.). selected from among suitable formulation ingredients.

For example, for oral preparations and mucosal administration preparations, excipients (
Formulation components such as starch, lactose), disintegrants (e.g. carboxymethyl cellulose), N-thickening agents (e.g. magnesium nistearate), coating agents (e.g. hydroxyethyl cellulose), and flavoring agents are used. In addition, for injections, solubilizing agents or solubilizing agents (e.g., distilled water for injection, physiological saline, propylene glycol), suspending agents (e.g., surfactants such as polysorbate 80) that can constitute aqueous injections are used. Formulation components such as pH adjusters (e.g. organic acids or metal salts thereof), stabilizers, etc. are used. Furthermore, for external preparations, water-based or oil-based solubilizers or solubilizers (e.g., alcono-fatty acid esters), adhesives (e.g., carboxyvinyl polymers, polysaccharides), emulsifiers (e.g., surfactants), etc. formulation ingredients are used.

The above formulation ingredients are known ones [for example, A
,0. Chair+nan et al., r.Remlngt.
On'5Phar+naceutical 5cien
ce j l 933 edition), MackPublis
The formulation ingredients described by Hing Co., Ltd. (USA) can be conveniently employed.

Various manufacturing methods can be employed to manufacture the drug of the present invention having the above structure. For example, the method described in the Japanese Pharmacopoeia 11th edition (circadian cycle χ1) general rules for preparations or a method obtained by adding appropriate modifications thereto can be adopted.

Formulation example 1 (Formulation example in 1 tablet) Compound (I) dihydrochloride 50mg Magnesium aluminate metasilicate 115mg Corn starch 73mg Dextrin, 10mg total 50mg Formulation example 2 (Formulation example in 1 ampoule of injection) Compound ( I
) Propylene glycol polysorbate dihydrochloride-80 total volume 2ml! Formulation Example 3 (Formulation Example in Granules) Compound (1) Dihydrochloride Lactate Sugar Crystalline Cellulose Corn Starch Dextrin 100+ng 70mg 0ff1g 170+ng 20+ng Production Example 1-1 4-(3-hydroxymethylphenoxy) -cis
-2-Butenylamine hydrobromide Known compound N-[:4-(3-hydroxymethylphenoxy)-cis-2-butenyl]phthalimide (produced using the method described in JP-A-57-165348).

) 164g of 40% methylamine in methanol solution 15
00ml and refluxed for 1 hour while stirring. After the reaction, the solvent was distilled off under reduced pressure and the residue was dissolved in dichloromethane (80%).
Dissolved in 0-.

Dichloromethane solution to 2% NaC)H aqueous solution 100ml
After washing three times with water, it was washed once with saturated saline.

After drying with magnesium sulfate, the solvent was distilled off, and the residual pale yellow oil was dissolved in 250 ml of n-butanol, and 88 g of 47% hydrobromic acid was added to crystallize it as a hydrobromide salt. Colorless prismatic crystals with a melting point of 117-119°C were obtained by recrystallization including activated carbon treatment from Improper Tool (6
9 g; yield 48.6%).

IR (KBr, cm-'): 3350. 290
0. 1620. 1590. 1455°1285,
1240. 1145. 1035. 880°77
5, 695.

NhlR(pprn, DMSO-ds/CDCβ3
)+3.4~3.8 (m, 2H)4.55~4.
8 (d, 2H), 4.5 (s, 2
) l) , 5.7-6.0 (d, 2H)
, 6.65~7.4 (+r+, 4
H), 8.0-8.7 (b, 2) 1
).

Production Example 1-2 5.6-dimethyl-2-C4-(3-hydroxymethyl)phenoxy)-cis-2-butenylamino)-4
-(IH)-Pyrimidone Production Example 1-1 4-(3-hydroxymethylphenoxy)-cis-2-butenylamine, hydrobromide at 5%
83 g of a pale yellow oil made into a free base with an aqueous NaOH solution was added to 500 ai of xylene. Dissolved in 5゜6-dimethyl-2
-Methylthio-4-(LH)-pyrimidone (Pharmaceutical Journal 1
976, Vol. 96, No. 3, p. 384. ) was added thereto, and the mixture was refluxed for 48 hours with stirring.

After the reaction was completed, the solvent was distilled off under reduced pressure, and the residual crystals were recrystallized from Impropateur, including treatment with activated carbon, to obtain the title compound (101 g; yield: 89.4%).

Melting point 144-146℃ IR (KBr, cm-2: 3250.2890
．． 1640.1610. 14601320, 125
0.1135.1060.1020°920, 775.
715°N4. IR<ppm, DMSO-da)'1.82
(s, 3) 1), 2.1 (s, 3H), 3.8~
4.2 (m, 2) 1), 4.52 (s, 2H)
, 4.6-4.9 (d, 2H), 5.6-5.
9 (m, 2H), 6.7-7.4 (m, 4H
).

Production Example 1-3 5.6-dimethyl-2-(4-C3-(1-piperidinomethyl)phenoxy)-cis-2-butenylamino)-4-(LH)-pyrimidone H 5 produced in Production Example 1-2 , 6-dimethyl-2-C4
-(3-hydroxymethyl)-phenoxy]cis-2
-butenylamino)-4-(LH)-pyrimidone 101
g was suspended in 520 mf of dry dichloromethane, and 49 ml of thionyl chloride was added dropwise while cooling.

The mixture was stirred at room temperature for 1 hour and then under reflux for 3 hours.

After the reaction is complete, add 300 ml of 20% potassium carbonate aqueous solution under cooling.
m1 to make alkaline, and the branched organic layer was saturated with N.
After washing with aCl, it was dried with magnesium sulfate. Next, 60 g of piperidine was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was washed with 200 ml of water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The title compound was obtained as a pale yellow oil (100 g; yield 81.
7%).

IR (j2iQ, cm-'): 3400.295
0.1660.1620°1400, 1345.125
8.1160°1040, 990.860.780.7
60°NMR (CDD R3+ ppm): 1.2~
1.7 (6H, m), 1.85 (3H, s), 2, 1
(3H, s), 2.2-2.5 (4H, m), 3.
4 (2)1. s), 3, 9-4.2 (2H, m)
, 4.5-4.8 (2H, d) 5.5-6.0 (2)
1. m), 4.6 to 7.3 (4H, m) Production Example 1-
4 5.6-dimethyl-2-[4-C3-(1-piperidinomethyl)phenoxy)-cis-2-butenyl 7mi/
) -4-(LH)-pyrimidone dihydrochloride 5,6-dimethyl-2-C4-(3
-(1-piperidinomethyl)-phenoxy)-cis-
2-Butenylamine)-4-(IH)-pyrimidone 14
．． 6 g of n-butanol 100mf! 6.7 rnl of concentrated hydrochloric acid was added dropwise with stirring.

The crystals precipitated during cooling were recrystallized from n-butanol to obtain the title compound as colorless crystals (14.27 g;
yield 82.1%).

Melting point 204~6℃ IR (KBr, cm''-'): 3200.2950
．． 2710.1670.1600゜1460, 1250
．． 11?0.1030.945°855, 790.69
0.530°NMR (ppm, DMSO-d6): 1.1-1
．． 8 (6H, m), 1.8 (3)1. s), 2.
25 (3H, s), 2.4-3.5 (4) 1. m)
, 4.0-4, 45 (4H, m), 4.6-4.8
5 (2H, d), 5.7-5, 95 (2H, d),
6.8-7.5 (4H, m), 8.7-9.1 (1
8, b).

Production Example 1-5 5.6-dimethyl-2-C4-[:3-(1-piperidi/methyl)-phenoxy)-cis-2-butenylamine:]-4-(IH)-pyrimidone monohydrochloride melting point :101-102℃(d)ゝIR(KBr, cm-'): 3350. 295
0. 2670. 1600. 1530°1450,
1260. 1170. 1030. 950870
, 780. 700. 540.

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

The above dosage of the drug of the present invention for adult human beings is as follows:
In terms of the amount of Compound (I) hydrochloride, one oral preparation is preferably administered in divided doses of 10 to 300 mg/day once or 2 to 4 times a day, and injection preparations and mucosal administration preparations. For external preparations, an amount of about 1/2 to 1/10 of the above dose is often sufficient, and for external preparations, an amount of about 1 to 5 times the above dose is often sufficient.

Of course, it is desirable to increase or decrease the dose as appropriate depending on the type and symptoms of the target disease, the age and sex of the patient, etc.

Actions and effects of the invention The actions and effects of the drug of the present invention are clear from the above,
In particular, as detailed below, it has both long-lasting histamine H2 receptor antagonism and gastrointestinal mucosal protective effects, and is also low in toxicity, so it can be used to treat gastric and duodenal ulcers, etc. with little recurrence/relapse or side effects. It is useful as a preventive/therapeutic agent for peptic ulcers and gastritis.

Next, pharmacological test examples regarding the drug of the present invention will be shown.

Test Example 1 Effect of suppressing gastric acid secretion in pylorus-ligated rats SD male rats weighing 200 to 230 g (6 to 1 group per group)
4 mice) were used after fasting for 18 to 24 hours.

The method of Shay et al. [Gastroenterology, Vol. 5, No. 43]
The pyloric region of the stomach was ligated under ether anesthesia, and immediately after the ligation, a drug dissolved or suspended in a gum arabic solution was administered into the duodenum (id) according to the following procedure.

After 4 hours, the stomach was removed under ether anesthesia and the amount of gastric fluid was measured.
Gastric acid acidity was measured. From the dose-response curve of each drug or acid secretion inhibition rate relative to the control group, 50% gastric acid secretion inhibition M
(EDso value) was determined (Table 1).

Test Example 2 Histamine-stimulated gastric acid secretion suppressive effect on Heidenhain pouch dogs Method of Takagi et al. (Arch, Int, Pharmaco
dyn, Ther1 Volume 49, Page 256, 1982
year).

Heidenhain pouches were prepared for male peagle dogs (4 dogs per group) weighing 10 to 15 kg, and healthy dogs, which had been at least 1 month after surgery, were fasted for 16 hours before the experiment and used in the experiment. Histamine dissolved in physiological saline (40
(μg/kg/hour) was continuously infused. Gastric juice dripped from the gastrostomy tube was collected every 15 minutes, and the amount of gastric juice and the acidity of the gastric juice were measured.

The drug was packed into a gelatin capsule and administered orally (po) 1 hour after the start of histamine infusion. The inhibition rate against the pre-administration value at the time point showing the minimum acid excretion after drug administration was calculated, and from the dose-response curve of each drug obtained from this, 50%
To find the amount of gastric acid secretion suppression (ε [lso value)] Table 2, Part 1
Figures to Figure 3).

Test Example 3 Effect of aspirin on suppressing the occurrence of gastric damage in pylorus-ligated rats SD male rats weighing 200 to 230 g (5 to 1 group per group)
8 mice) were used after fasting for 18 to 24 hours.

The method of Shay et al. [Gastroenterology, Vol. 5]
vol., p. 43, 1945], the gastric pylorus was ligated under ether anesthesia, and immediately after the ligation, the drug dissolved or suspended in a gum arabic solution was administered into the duodenum (id).

After closure, aspirin suspended in gum arabic solution (10
0 mg/kg) was administered orally. After 4 hours, the mice were anesthetized with ether, the stomach was removed, and the length (+nm) of damage caused to the mucous membrane at the line drawing area was measured, and the statistics were taken as the damage coefficient.

The damage inhibition rate was calculated from the damage coefficient of each drug administration group relative to the damage coefficient of the control group, and the 50% damage inhibition amount (E05o value) was determined from the dose-response curve (Table 3).

The statistics were taken as damage coefficients.

The drug is dissolved or suspended in a gum arabic solution and immersed in water.
Oral administration (po) minutes before administration. To the control group, only the gum arabic solution was orally administered.

The damage inhibition rate was calculated from the damage coefficient of each drug administration group relative to the damage coefficient of the control group, and the 50% damage inhibition amount (EDso value) was determined from the dose-response curve (Table 4).

Test Example 4 Effect of suppressing gastric damage caused by water immersion restraint stress in rats Group 1 of male and female SD rats weighing 200 to 230 g 8 to 2
0 animals) were used after fasting for 18 to 24 hours.

According to the method of Takagi and Kaibe et al. [Siapan, Journal of Pharmacology, Vol. 9, p. 18, 1968], rats were placed in a stress cage of the Department of Pharmacological Sciences, University of Tokyo, and kept in a water tank at a water temperature of 23°C. The patient was immersed in water in an upright position to the depth of the xiphoid process. After 6 hours, they were anesthetized with ether, their stomachs were removed, and the length (ff1m) of the damage caused to the mucous membrane of the line drawing area was measured. Sex rats 1 group 5-1
0 animals) were used after fasting for 18 to 24 hours.

The method of Robert et al.
gy), Vol. 77, p. 761, 1979], rats were given 5 mI of special grade ethanol (99.5%)! /k
g was orally administered, and 1 hour later, the animals were anesthetized with ether, their stomachs were removed, and the length of damage (strike) generated in the mucous membrane of the line drawing area was measured, and the statistics were taken as the damage coefficient. The drug is dissolved or suspended in gum arabic solution and administered orally (
po) I did. A control group was orally administered only gum arabic solution. The damage inhibition rate was calculated from the damage coefficient of each drug administration group with respect to the damage coefficient of the control group, and the 5%
The 0% damage inhibition amount (EDS. value) was determined (Table 5).

Test Example 6 Acute toxicity test 25-28g C1dY male mice and 220-2
50g17) SD male and female rats The drug was orally administered.

The D5o value was calculated from the mortality rate 2 weeks after administration. The results are shown in Table 6.

Table 6 From the above test results, the drug of the present invention exhibits significantly higher activity than conventional drugs, for example, in suppressing gastric acid secretion in Tables 1 and 2, and in protecting gastric mucosa in Tables 3.4 and 5. That is understood. The duration of action was also significantly extended compared to conventional drugs.

[Brief explanation of the drawing]

Figures 1, 2, and 3 show the temporal changes in the histamine-stimulated gastric acid secretion suppressive effect (Test Example 2) in Heidenhain-Boach dogs, respectively, with compound (1) dihydrochloride, roxatidine hydrochloride acetate, and cimetidine. This shows a comparison. Figure 2 Time (hr) Figure 1 o-o Q, 03 mg/kg @-@ 0.1 mg/kg Time (h'') Figure 3 Time (hr)

Claims (1)

[Claims] 5,6-dimethyl-2-[4-<3-(1-piperidinomethyl)phenoxy>cis-2-butenylamino]-4
An anti-gastritis/anti-peptic ulcer agent containing -(1H)-pyrimidone hydrochloride as an active ingredient.