JPH0586928B2 - - Google Patents

Description

[Detailed description of the invention]

(1) Industrial application field The present invention is directed to 2-anilino-1,6-dihydro-
The present invention relates to an antiulcer agent containing a 6-oxo-5-pyrimidinecarboxylic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient. (2) Prior Art It is said that it is preferable to treat peptic ulcer from both the suppression of aggressive factors and the enhancement of defensive factors. In terms of suppressing aggressive factors, histamine _H2 receptor antagonists, which have a strong effect of suppressing gastric acid secretion,
The invention of cimetidine was a major breakthrough and made treatment easier. Since this success, efforts have been made to search for more potent and less toxic compounds. However, while histamine _H2 receptor antagonists have a high therapeutic effect, they have a high recurrence rate after discontinuation of the drug (Derrick, FM,
Lancet, 3 :7-10 (1981)). It has also been pointed out that the cause of this recurrence depends on its mechanism of action. In other words, this is to reduce the content of prostaglandins, which play an important role in the regeneration of mucosal tissues as a result of strongly suppressing gastric acid secretion (Tetsuo Arakawa, et al., Journal of the Japanese Society of Gastroenterology, 80 : 799). 803 (1983)). Therefore, there has been a strong demand for drugs that have protective factor-enhancing effects. Prostaglandin derivatives are attracting particular attention as drugs with strong effects in this respect, and their cytoprotective action has an extremely large effect of enhancing defense factors (Kenzo Kobayashi et al., Clinical Science 20 : 1362 ~1368 (1984)). However, prostaglandin compounds have many problems because they frequently cause unique strong side effects such as diarrhea and sterility (Kenzo Kobayashi et al., Clinical Science, 20 : 1362-1368 (1984)). Therefore, there has been a strong desire for compounds other than prostaglandin derivatives that have anti-ulcer effects by enhancing protective factors such as cell protection. (3) Problems to be Solved by the Invention Therefore, under such circumstances, the purpose of the present invention is to discover a compound that has both the action of suppressing gastric acid secretion and the action of enhancing gastrointestinal mucosal protective factors, and to develop a more useful anti-ulcer therapeutic agent. This is what we are trying to develop. (4) Means for solving the problems As a result of intensive research aimed at solving the above problems, the present inventors found that some of the compounds described in JP-A No. 60-100559 were found to be suitable for the purpose of the present invention. The present inventors have discovered that the anti-ulcer effect corresponds to the anti-ulcer effect, and have completed the present invention. That is, the present invention is based on the general formula

[Formula] (In the formula, R represents an alkyl group having 1 to 5 carbon atoms.)
2-anilino-1,6-dihydro-
The present invention relates to an anti-ulcer agent containing a 6-oxo-5-pyrimidinecarboxylic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient. In the above general formula [], specific examples of the alkyl group of R include methyl, ethyl, propyl, 1
-methylethyl, butyl, 1-methylpropyl,
Examples include 2-methylpropyl or pentyl group. These compounds according to the present invention and their production methods are all disclosed in the above-mentioned publications, but the physical properties of particularly useful compounds are as follows. Compound of R= _CH2CH ( _CH3 ) ₂ (compound 1), mp: 213-215<0>C. IR ν ^nujoL _nax cm ^-1 : 1630 (C=0), 1720 (C=0
). NMR (DMSO-d ₆ ) δ: 8.59 (IH, s, C ₄ −
H). Mass m/e: 303 (M ⁺ ). Compound of R= _CH2CH3 (compound ₂ ), mp: 226-228<0>C. IR ν ^nujoL _nax cm ^-1 : 1630 (C=0), 1720 (C=0
). NMR (DMSO-d ₆ ) δ: 8.56 (IH, s, C ₄ −
H). Mass m/e: 275 (M ⁺ ). Compound _of R= _CH2CH2CH3 (compound ₃ ), mp: 202-204°C. IR ν ^nujoL _nax cm ^-1 : 1640 (C=0), 1720 (C=0
). NMR (DMSO-d ₆ ) δ: 8.59 (IH, s, C ₄ −
H). Mass m/e: 289 (M ⁺ ). Compound of R=CH( _CH3 ) ₂ (compound 4), mp: 202-204°C. IRν ^nujoL _nax cm ^-1 : 1650 (C=0), 1725 (C=0)
. NMR (DMSO-d ₆ ) δ: 8.60 (IH, s, C ₄ −
H). Mass m/e: 289 (M ⁺ ). Compound of R=( _CH2 ) ₃ (compound 5), mp: 212-214<0>C. IR ν ^nujoL _nax cm ^-1 : 1630 (C=0), 1720 (C=0
). NMR (DMSO-d ₆ ) δ: 8.59 (IH, s, C ₄ −
H). Mass m/e: 303 (M ⁺ ). In addition, pharmacologically acceptable salts of the compound represented by the general formula [] include alkali metal salts with sodium, potassium, lithium, etc., or organic salts with triethanolamine, trishydroxymethylaminemethane, lysine, etc. An example is an amine salt. These salts can be easily obtained by reacting a compound represented by the general formula [] with a corresponding base according to a conventional method. (5) Action The compound represented by the general formula [] has been disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 60-100559 as a new compound having an antiallergic effect. It should have suppressive effects on gastric acid secretion and cell protective effects,
It has been revealed that it has a significant anti-ulcer effect. That is, in animal experiments, the compound represented by the general formula [] not only suppresses gastric juice secretion or gastric acid secretion, but also reduces the effect of non-steroidal anti-inflammatory drugs on the gastrointestinal mucosa. It has been found that it also has the effect of preventing gastrointestinal damage induced by strong irritants such as stimulants and stress. Experimental example 1 (Effect on gastric juice secretion) Male Crj: CD rats weighed 180-200g after purchase.
A healthy specimen was selected and used for the experiment. All test compounds (the above-mentioned compounds 1 to 5 and the comparative drug cimetidine) were suspended in a 0.5% carboxymethyl cellulose aqueous solution and adjusted to a concentration of 2 w/v%. Five rats per group were fasted for 24 hours, and the abdomen was opened under light ether anesthesia using Shay's method (Shay, H.,
Gastroenterology (ed by Bockus HL), 1 ,
420 (1963) Saunders Co., Philadelphia,
The pyloric region was ligated according to (London). After suturing the abdomen and leaving it for 4 hours, the animal was sacrificed with ether, the stomach was removed, and the retained gastric juice was collected. After the collected gastric juice was centrifuged at 3000 rpm for 15 minutes, the amount and acidity of the gastric juice were measured. The test compound was administered into the duodenum at a dose of 100 mg/Kg immediately after pylorus ligation. The control group received only the above solvent. The inhibition rate for gastric juice secretion and gastric acid secretion was calculated using the following formula. Inhibition rate = AB/A x 100 (%) A: Amount of gastric juice secretion or acidity in the control group B: Amount of gastric juice secretion or acidity in the compound administration group The results are shown in Table 1, and compounds 1 and 3 ，
4 and 5 strongly suppress gastric juice secretion and gastric acid secretion.

[Table] Experimental example 2 (Effect on hydrochloric acid-ethanol ulcer) Experimental animals and test compound preparation conditions were as in Experimental example 1.
It was made the same as. One group of 5 rats was used, and the method of Okabe et al. (Japan J.
Pharmacol., 40 , 329-337 (1986)).
After fasting for 24 hours, 1 ml of hydrochloric acid-ethanol (containing 50 mM HCl in 60% ethanol) was orally administered to each animal. After 1 hour, the animals were sacrificed with ether, the stomach was removed, 10 ml of 1% formalin was injected into the stomach, and the animals were immersed in the same solution for 30 minutes to fix them. Then, the animals were incised along the greater curvature and examined under a dissecting microscope (10x magnification). The length of damage occurring in the glandular stomach was measured, and the total sum per animal was taken as the damage factor. The test compound was orally administered at 30 mg/Kg 30 minutes before hydrochloric acid-ethanol administration. The control group was administered only the solvent (0.5% carboxymethylcellulose aqueous solution). The inhibition rate against ulcer formation was calculated using the following formula. Inhibition rate = AB/A x 100 (%) A: Damage coefficient of control group B: Damage coefficient of test compound administration group The results are shown in Table 2, and compounds 1 to 5 all caused gastric damage. is strongly suppressed.

[Table] Experimental Example 3 (Effect on stress ulcers) Experimental animals and test compound preparation conditions were as in Experimental Example 1.
It was made the same as. Brodie et al.'s method (Brodie, DAet al.,
The following experiment was conducted according to Proc.Soc.Exp.Biol.Med., 113 , 998 (1963). A group of 10 rats were fasted for 24 hours, placed in a stress cage, and left in a cold room at 10°C. Three hours later, the rats were killed with ether, the stomach was removed, and the rats were killed with ether.
After injecting 10ml of 1% formalin into the stomach and fixing it by immersing it in the same solution for 30 minutes, an incision was made along the greater curvature, and the length of the damage occurring in the glandular stomach was examined under a dissecting microscope (10x magnification). The damage was measured and the total sum per animal was taken as the damage coefficient. The test compound was orally administered 30 minutes before stress loading. The control group was administered only the solvent (0.5% carboxymethyl cellulose aqueous solution). The inhibition rate against ulcer formation was calculated using the following formula. Inhibition rate = AB/A x 100 (%) A: Damage coefficient of control group B: Damage coefficient of test compound administration group The results are shown in Table 3. Compound 1 has a dose-dependent inhibition rate. increased, showing a higher inhibition rate than the comparative drug (cimetidine).

[Table] Experimental example 4 (Indomethacin effect on ulcer) Experimental animals and test compound preparation conditions were as in Experimental example 1.
It was made the same as. Each group consisted of 10 rats, and after fasting for 24 hours, 25 mg/Kg of indomethacin was administered subcutaneously. After 7 hours, the rats were killed with ether, the stomach was removed and fixed in formalin, and an incision was made along the greater curvature, and the length of the damage occurring in the glandular stomach was measured under a dissecting microscope (10x magnification). , the total sum per animal was taken as the damage coefficient. The test compound was orally administered 10 minutes before indomethacin administration. The control group was administered only the solvent (0.5% carboxymethyl cellulose aqueous solution). The inhibition rate against ulcer formation was calculated using the following formula. Inhibition rate = AB/A x 100 (%) A: Damage coefficient of control group B: Damage coefficient of test compound administration group The results are shown in Table 4. Compound 1 has a dose-dependent inhibition rate. is on the rise.

[Table] Experimental Example 5 (Acute Toxicity) A group of 10 DDY male mice weighing 20 to 25 g were suspended in a 0.5% carboxymethylcellulose aqueous solution with the test compound (compounds 1 to 5 above).
mg/Kg was administered orally. After administration, the progress was observed for 7 days, but no deaths were observed in any case. From the above experimental results, it has been found that the compound represented by the general formula [] has a remarkable anti-ulcer effect and has extremely low toxicity, and can be used for the prevention or treatment of peptic ulcers. The compound represented by the general formula [] or a pharmacologically acceptable salt thereof is usually used as a composition containing a pharmaceutical carrier, an excipient, and other additives. Pharmaceutical carriers can be solid or liquid;
It can take various formulation forms. When a solid carrier is used, it can be in the form of a tablet, powder, granule, hard gelatin capsule, suppository, or troche. When a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, sterile injectable solution such as an ampoule, or an aqueous or non-aqueous suspension. Further, the compound represented by the general formula [] can be used by placing it in a cyclodexrin, a cyclodextrin derivative, a liposome, or a lipid microsphere. Specific examples of formulations are shown below as Examples, but these Examples do not limit the scope of the present invention in any way. Example 1 Tablet The following ingredients are mixed in a conventional manner and tableted using a conventional device. Compound represented by the general formula [] 50 mg Crystalline cellulose 21 mg Lactose 65 mg Corn starch 33 mg Magnesium stearate 1.3 mg Example 2 Soft capsules The following ingredients are mixed in a conventional manner and filled into soft capsules. Compound represented by the general formula [] 50mg Olive oil 105mg Lecithin 6.5mg Example 3 Granules The following ingredients are mixed and granulated according to a conventional method to obtain granules. Compound represented by the general formula [] 50mg Lactose 270mg Valley starch 100mg Talc 70mg Magnesium stearate 10mg Example 2 Injectable preparation The following ingredients are mixed according to a conventional method, and the ampoule filling is sterilized to make an injectable preparation. . Compound represented by the general formula [] 5 mg Solubilizing agent (used as desired) Appropriate amount of sodium (used as desired) Appropriate amount of distilled water for injection Less than 1 ml Total 1 ml When using the anti-ulcer agent of the present invention clinically, oral or rectal administration is recommended. When administered, the active ingredient is 1
~1000mg/dose 1-4 times a day; for intravenous injection, 0.1-100mg/dose of the active ingredient 1-4 times a day
Administer twice. It is preferable that the above dosage is adjusted as appropriate depending on age, symptoms, body weight, etc. (6) Effects of the Invention The compound represented by the general formula [] has anti-ulcer effects through cell protection and gastric acid secretion suppression, and is therefore effective against ethanol-induced hemorrhagic gastric erosion, gastric damage induced by trauma or stress, It can be used to prevent or treat gastric ulcers and duodenal ulcers caused by various causes such as drug-induced gastric damage and bile salt-induced gastric damage, as well as erosive gastritis, erosive esophagitis, and the like. That is, according to the present invention, it is possible to provide an anti-ulcer agent that has both an effect of suppressing an attack factor and an effect of enhancing a defense factor.

Claims (1)

[Claims] 1 General formula [Formula] (In the formula, R represents an alkyl group having 1 to 5 carbon atoms.)
2-anilino-1,6-dihydro-
An anti-ulcer agent comprising a 6-oxo-5-pyrimidinecarboxylic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient.