JPS648630B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula () The present invention relates to an ester compound represented by the above, a pharmaceutically usable acid addition salt thereof, a pharmaceutical containing the same, and a method for producing the same. An object of the present invention is to provide compounds useful as pharmaceuticals. The compound of the present invention has the formula () (In the formula, X represents a halogen atom) The piperonyl acid halide represented by the formula () It can be produced by reacting with 4-amidinophenol shown below. The compounds of the present invention include trypsin, plasmin,
It has strong inhibitory activity against kallikrein and thrombin, and is a useful compound as an antitrypsin agent, an antiplasmin agent, an antikallikrein agent, and an antithrombin agent. Furthermore, the compound of the present invention has strong C1-esterase inhibitory activity and anti-complement action, and is a useful compound as an anti-complement agent. Although the compound of the present invention has an ester bond in its structure, it has high stability in blood. The method for producing the compound of the present invention will be described in more detail. formula() The piperonyl acid halide represented by the formula (2) is prepared by reacting the piperonyl acid represented by the formula (2) with an acid halogenating agent such as phosphorus pentachloride, thionyl chloride, thionyl bromide, etc. Next, 4-amidinophenol (), preferably its hydrochloride,
In addition to a solvent such as dimethyl sulfoxide, the compound of formula () is added thereto, and () and () are allowed to react in the presence of a dehydrohalogenating agent. As the dehydrohalogenating agent, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, etc., and organic bases such as triethylamine, pyridine, dimethylaniline, etc. can be used, with pyridine being preferred. Reaction temperature: -30℃ to +80℃
Although the reaction proceeds easily at a temperature of
This is then preferably carried out at room temperature. Further, although the reaction is completed in 2 to 5 hours, it may be allowed to react overnight. After the reaction is completed, the reaction mixture is treated by a conventional treatment method. For example, when pyridine is used as a reaction solvent, the hydrochloride of the compound of the present invention is precipitated by adding an organic solvent such as ethyl ether or ethyl acetate to the reaction solution, which can be removed. In converting this hydrochloride to other acid addition salts, the hydrochloride is converted into saturated NaHCO ₃
The compound of the present invention can be obtained as a carbonate by adding it to an aqueous solution. Suspending the carbonate in methanol, adding an acid such as methanesulfonic acid to dissolve the carbonate, and adding diethyl ether to the resulting solution provides the corresponding acid addition salt. Acids that can be used include pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., acetic acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, fumaric acid, maleic acid, etc. There are organic acids such as Enzyme inhibitory activity Compounds of the present invention include trypsin, plasmin,
It has strong inhibitory activity against enzymes such as kallikrein and thrombin, and is effective as an antitrypsin agent for the treatment of pancreatitis, an antiplasmin agent and antikallikrein agent for the treatment of bleeding disorders, and an anti-kallikrein agent for the treatment of blood clots. It is a useful compound as an effective antithrombin agent. (1) In vitro test (enzyme inhibitory activity) Enzyme inhibitory activity was measured using the method of Muramatsu et al. [M.
Muramatsu, T. Onishi, S. Makino, Y. Hayashi
and S. Fujii, J.Biochem., 58 , 214 (1965)] using the methanesulfonate salt of the compound of the present invention. Table 1 shows the results. The data in the table is
The concentration of compound (ID ₅₀ ) that inhibits the ability of each enzyme to hydrolyze TAME (tosyl arginine methyl ester) by 50% is shown.

〔experimental method〕

This experiment was performed using the method of K. Hansson et al. (Acta Chir
Scand 121:274-283, 1961).
Rats (BW 230 g) that had been fasted overnight were anesthetized with pentoparbital sodium 40 mg/Kgi.p. and laparotomy was performed. Pancreatitis was created by injecting 0.1 ml/body of a mixture of 3 ml of 4% sodium taurocholate and 0.3 ml of 1% trypsin while preventing the inflow into the liver from the cannula inserted into the bile duct with an arterial clamp. The drug administration group received compound (1) methanesulfonate (100 mg/Kg) orally 3 hours before injecting the mixture of trypsin and taurocholate;
Those to which purified water (1 ml/100 g) was orally administered served as a control group. [Results] Table 2 shows the number of survivors 24 and 48 hours after pancreatitis.
Shown below. The drug administration group showed a survival benefit compared to the control group.

[Table] Anti-complement effect The compounds of the present invention and their pharmaceutically usable acid addition salts have strong c1 esterase inhibitory activity, complement hemolysis inhibiting activity, and activation of the complement system based on antigen-antibody reactions, which play important roles. It is said to have a therapeutic effect on falsmanshock.
This indicates that it is useful as an anti-complement agent effective for allergic diseases such as nephritis involving complement. The results of these tests are shown below. (1) In vitro test (c1 esterase inhibitory activity, inhibition of complement hemolysis) Okamura et al.'s method using the methanesulfonate of compound () [K.Okamura, M.Muramatsu and S.
Fujii: Biochem. Biophys Acta, 295 , 252―257
(1973)] and the method of Baker et al. [BRBaker and E.
H.Ericksou, J.Med.Chem., 12, 408―414
(1969)] Complement hemolysis inhibition rate (%)
are shown in Table 3.

[Table] (2) Pharmacological test (Forsmanschik) This experiment was performed using the method of IGOfferness et al. (Biochem.
Pharmacol. 27 (14) 1873-1878, 1978). Male Hartley guinea pigs weighing approximately 300 g were used. Minimum amount of hemolysin that can cause shock
0.5ml/guinea pig (commercially available hemolysin,
5000U) was injected intravenously, the time until death was measured, and this was used as a control group. In the drug treatment group, compound () methanesulfonate was administered intraperitoneally 30 minutes before hemolysin administration, and the time to death (seconds) was determined.
was measured. The results are shown in Table 4, and there was a tendency for death to be prolonged in the 60 mg/Kg administration group compared to the control group.

[Table] Despite having an ester bond, the compound of the present invention has high stability in blood. From this, it can be expected that the effect will continue. 5x for various serums
Table 5 shows the results of adding methanesulfonate of the compound of the present invention at a concentration of 10 ^-4 mmole/ml and measuring its residual rate (%) using thrombin inhibitory activity as an index.

[Table] Method of administration The compounds of the present invention are preferably administered orally, but they can also be administered by injection. A compound of the invention can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. Although they may be administered alone, they are generally administered in the form of pharmaceutical compositions. Examples of such compositions include tablets, powders, capsules, syrups, and aqueous solutions. Oral compositions may contain conventional additives such as binders, excipients, lubricants, disintegrants, and wetting agents. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be provided as a dry syrup for reconstitution with water or other suitable solvent before use. may be done. Said solutions may contain customary adjuvants such as suspending agents, flavoring agents, diluents or emulsifying agents. For injection, it can be used as an aqueous solution or an oily suspension. Dose The compound of the present invention can be administered to mammals (including human patients) from 50 to
It can be administered at an oral dosage of 200 mg/day.
In addition, for intravenous administration, it can be administered at a dosage of 5 to 20 mg/day. However, these numbers are just examples, and the most appropriate dose should be administered to the patient depending on the patient's age, weight, and severity of symptoms. Next, examples of formulations of the compounds of the present invention will be given. Formulation example 1 Capsule compound () methanesulfonate 100.0mg Lactose 59.0mg Crystalline cellulose 33.4mg Calcium carboxymethyl cellulose 3.6mg Magnesium stearate 4.0mg Total 200.0mg 2 Fine granule compound () Methanesulfonate 50.0mg Lactose 249.0 mg Mannitol 75.0mg Corn starch 110.0mg Hydroxypropyl cellulose 16.0mg Total 500.0mg Toxicity Table 6 shows the LD ₅₀ of the methanesulfonate salt of the compound of the present invention.

[Table] Next, production examples of the compounds of the present invention are shown. example 16.6g of piperonic acid to 150g of ethyl acetate
Add 20.8 g of phosphorous pentachloride to 1 ml and stir for 1 hour. The solvent was distilled off under reduced pressure, and the residue was
Piperonylic acid chloride is obtained by adding and removing hexane. 4-amidinophenol hydrochloride
Dissolve 17.3 g in 200 ml of pyridine, and add the above piperonyl acid chloride under ice cooling. Stir on ice for 1 hour and then at room temperature overnight. After the reaction is complete, ethyl acetate is added to the reaction solution to obtain 4-amidinophenyl piperonyl acid ester as a hydrochloride. When this is added to a saturated NaHCO ₃ aqueous solution, white crystals are precipitated. When this is washed with water and acetone, piperonyl acid 4-amidinophenyl ester carbonate is obtained. Yield: 29.4g (yield: 85.0%). mp92°C ~ (decomposition) IRν ^KBr _nax cm ^-1 : 3500-2800, 1740, 1280 This is suspended in 100 ml of methanol, and when 9.8 g of methanesulfonic acid is added, it foams to become a clear solution. When about 200 ml of ether is added to this, white crystals are precipitated. By taking this, piperonyl acid 4-amidinophenyl methanesulfonate is obtained. Yield: 22.8g (60% yield). mp213-216℃ IRν ^KBr _nax cm ^-1 : 3400-2900, 1730, 1280 NMRδ _ppn (DMSO-d ₆ ) 2.55 (s.3H) 6.3 (s.2H)
7.15 (d.1H.J=8) 7.6 (d.2H.J=8) 7.6
(d.1H.J=2) 7.85 (dd1H.J=8.2, 2.0)
8.05 (d.2H.J=8) Elemental analysis C ₁₆ H ₁₆ N ₂ O ₇ S=380.382 Theoretical value C50.52H4.24N7.37 Actual value C50.32H4.55N7.44

Claims (1)

[Claims] 1 Formula () Ester compounds represented by and their pharmaceutically usable acid addition salts. 2 formula () (In the formula, X represents a halogen atom) A piperonyl acid halide represented by the formula () The formula () is characterized by reacting with 4-amidinophenol represented by the formula () and optionally converting it into an acid addition salt thereof. A method for producing an ester compound represented by and a pharmaceutically usable acid addition salt thereof. 3. The method of claim 2, wherein the piperonylic acid halide is piperonylic acid chloride. 4 Formula () as active ingredient An anti-complement agent containing an ester compound represented by or a pharmaceutically usable acid addition salt thereof. 5 Formula () as active ingredient An antitrypsin agent containing an ester compound represented by the formula or a pharmaceutically usable acid addition salt thereof.