JPS637183B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to S-methyl-N-acetylcysteine derivatives and methods for producing them.
Specifically, the present invention provides S useful as a therapeutic agent for liver diseases.
-Methyl-N-acetylcysteine derivatives and their production methods. Various biochemical reactions take place in the liver. For example, detoxification, carbohydrate metabolism, protein metabolism, lipid metabolism, production and secretion of bile, regulation of hormones, production of blood coagulation agent prothrombin, regeneration of liver cells, various biological components (fat, glycogen, protein, vitamins, etc.) ), etc. The liver, which has such precise and balanced functions, has a great ability to self-repair, and if dysfunction occurs, it is an organ that can be expected to recover naturally. It can be acutely or chronically impaired due to various factors such as disorders of the hepatic circulatory system, including fatty liver, drug-induced liver disease, alcoholic hepatitis, viral hepatitis, depressive hepatitis, and cholestasis. It manifests as diseases such as liver damage, jaundice, and liver cirrhosis as the final stage of these diseases. When transition to these liver diseases occurs, recovery from the dysfunction can be accelerated by promoting the repair of hepatic parenchymal cells and reducing damage to hepatocytes by administering drugs. The present inventors have discovered that S-alkyl-N-acetyl-cysteinamides are effective for this purpose, and have arrived at the present invention. In other words, the gist of the present invention is (1) General formula () (In the formula, R ¹ represents a hydrogen atom or a methyl group; R ² represents an amino group, a monomethylamino group, a dimethylamino group, or a hydroxyl group.) An S-methyl-N-acetylcysteine derivative represented by the formula: (2) General formula () S-methyl-N-acetylcysteine alkyl ester represented by (in the formula, R ³ represents a lower alkyl group) and the general formula () (In the formula, R ¹ and R ² have the same meanings as above) General formula () characterized by reacting with an amino compound represented by (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing an S-methyl-N-acetylcysteine derivative represented by the following formula. (3) S-methyl-N-acetylcysteine or its reactive derivative and general formula () (In the formula, R ¹ and R ² have the same meanings as above.) A general formula () characterized by reacting an amino compound represented by (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing an S-methyl-N-acetylcysteine derivative represented by the following formula. (4) S-methylcysteine or its salt or its reactive derivative and general formula () (In the formula, R ¹ and R ² have the same meanings as above.) General formula () obtained by reacting an amino compound represented by (In the formula, R ¹ and R ² have the same meanings as above) A general formula () characterized by reacting an S-methylcysteine derivative or a salt thereof with acetic acid or a reactive derivative thereof (In the formula, R ¹ and R ² have the same meanings as above.) The present invention will be explained in detail below. The compound according to the present invention is an S-methyl-N-acetylcysteine derivative represented by the general formula (). In the general formula (), R ¹ is a hydrogen atom or a methyl group,
R ² represents an amino group, a monomethylamino group, a dimethylamino group, or a hydroxyl group, and examples of the S-methyl-N-acetylcysteine derivative represented by the general formula () include S-methyl-N-acetylcysteinyl hydrazine N- Methyl-N-(S-methyl-N-acetylcysteinyl)-hydrazine N-(S-methyl-N-acetylcysteinyl)
-N'-Methyl-hydrazine N-methyl-N-(S-methyl-N-acetylcysteinyl) -N'-methylhydrazine N-(S-methyl-N-acetylcysteinyl)
-N'・N'-dimethyl-hydrazine N-(S-methyl-N-acetylcysteinyl)
-Hydroxylamine N-methyl-N-(S-methyl-N-acetylcysteinyl)-hydroxylamine is mentioned. These compounds exist in D, L- and DL forms, but usually the L form or the DL form is used. The present inventors have demonstrated that the compound represented by the above general formula () activates hepatocytes, promotes carbohydrate metabolism and detoxification (e.g., alcohol detoxification) effects of the liver, and the production and secretion of bile or bile acids (choleretic effect). It has been discovered that it can be used to activate functions such as. The present inventors have also discovered that the compound represented by the above general formula () has a pharmacological action that acts on the liver that is already suffering from the disorder and reduces or eliminates the disorder. Furthermore, the present inventors have discovered that the compound represented by the above general formula () has a pharmacological action that protects liver function from certain disorders or burdens. Toxic liver disease, hepatitis, or fatty liver develops due to various causes, but the main lesions are hepatocyte necrosis,
It is a mesenchymal response or fat storage. The characteristics of necrosis vary depending on its cause, and can be divided into centrilobular, perilobular, and disseminated necrosis. In the laboratory, pathological models of these lesions can be created by administering the following drugs to test animals. Centrilobular necrosis can be induced by carbon tetrachloride, thioacetamide, chloroform, and bromobenzene. Perilobular necrosis can be caused by allyl alcohol. Lobular disseminated necrosis with mesenchymal reactions can be induced by D-galactoseamine. Furthermore, a pathological model of fatty liver can be created using carbon tetrachloride and ethionine. It is known that these acute, subacute, or chronic liver disorders can lead to liver cirrhosis as a final outcome.For example, in the laboratory, a pathological model of liver cirrhosis is created by repeatedly administering carbon tetrachloride to test animals over a long period of time. can be made. The compound of the present invention has an effective effect on liver damage by stabilizing cell membranes, radical scavenging effect, protection of in-vivo thiol compounds by antioxidant effect, and enrichment of various liver enzymes as a thiol compound when creating hepatitis in experimental animals. It was found that the For example, therapeutic effects (including prevention and mitigation) for liver disorders accompanied by centrilobular necrosis, therapeutic effects for liver disorders accompanied by perilobular necrosis, therapeutic effects for hepatitis accompanied by mesenchymal reactions in disseminated lobular necrosis, and fatty liver treatment. Effects Therapeutic effect on liver cirrhosis Therapeutic effect on toxic liver disorder Therapeutic effect on depressed liver The effect of promoting the secretion of bile and bile acids (cholelic effect) The effect of reducing toxic symptoms caused by metal salts (selenium salts, cadmium salts) Is recognized. As described above, the compound of the present invention promotes the regeneration or new generation of liver parenchymal cells when the number or function of hepatic parenchymal cells decreases due to liver diseases such as acute hepatitis, chronic hepatitis, or drug addiction, thereby restoring the original liver function. It serves as a liver function restoring agent or liver function stimulant, and is useful as a therapeutic agent for liver diseases in humans and animals. That is, according to the present invention, the compound represented by the general formula () can be used to treat fatty liver, alcoholic hepatitis, hepatitis, toxic liver disorder, congestive liver, cholestatic liver disorder, or liver cirrhosis, which is the terminal condition thereof. Can be used as a therapeutic agent. According to histopathological findings, the compounds of the present invention have a therapeutic effect on liver disorders caused by centrilobular necrosis, perilobular necrosis, and scattered lobular necrosis accompanied by mesenchymal reactions. Therefore, it is useful as a therapeutic agent for liver diseases in humans and animals that are accompanied by such necrosis. The compound of the present invention has the effect of activating hepatocytes and enhancing functions such as secretion of bile and bile acids, carbohydrate metabolism, and detoxification of hepatotoxic substances such as alcohol in the liver, so it has the effect of activating hepatocytes and enhancing functions such as secretion of bile and bile acids in the liver, carbohydrate metabolism, and detoxification of hepatotoxic substances such as alcohol. It is useful as a drug or a treatment for jaundice. When using the compound of the present invention as a therapeutic agent for liver diseases, it is used in a form convenient for obtaining the desired medicinal effect. The compounds of the present invention can be used as they are as agents for treating liver diseases, or they can be formulated with pharmaceutically acceptable diluents or with other pharmacologically active substances in accordance with pharmaceutical practice. It is also possible. A drug containing the compound of the present invention (hereinafter referred to as "the drug of the present invention")
That's what it means. ) may also be provided in dosage unit form. The medicament of the present invention can be applied orally or parenterally. Oral administration includes sublingual administration. The pharmaceuticals of the present invention may be provided in a form for oral administration, such as powders, granules, tablets, sugar-coated tablets, pills, capsules, and liquid preparations, and for parenteral administration, such as suppositories, suspensions, solutions, emulsions, etc. Examples include ampoules and injection solutions. Of course, a combination of these can also be provided. In the pharmaceutical of the present invention, the compound of the present invention is generally
Contains 0.01-100% by weight. Diluents that can be combined with the compounds of the invention may be solid, semi-solid or liquid, such as excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, etc. agent, buffering agent, flavoring agent, flavoring agent, dye, fragrance, preservative, solubilizing agent, solvent coating agent, sugar coating agent, capsule, etc. Of course, two or more of these diluents can also be used in combination. Examples of diluents include water: gelatin: sugars such as lactose and glucose: corn, wheat,
Starches such as rice, arrowroot, and starch: Fatty acids such as stearic acid: Fatty acid salts such as calcium stearate and magnesium stearate: Talc: Vegetable oils: Alcohols such as stearyl alcohol, benzyl alcohol, and polyalkylene glycol:
Gums: Oils such as petroleum oil and mineral oil; physiological saline; dextrose or similar saccharide solutions, and the like. The medicament of the present invention can be manufactured by conventional methods. For example, the compound of the present invention may be mixed with a diluent to form granules, and then the composition may be mixed with a diluent to form tablets, or granulation and powder packaging may be performed in the same manner. These capsules, tablets, granules, and powders generally contain 5 to 100% by weight, preferably 25 to 100% by weight.
The compound of the present invention is included. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the compound of the present invention are preferred. Parenterally administered preparations are usually sterile and, if necessary, isotonic with blood. Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, dextrose, intravenous fluids, electrolyte solutions (for intravenous injection and infusion), and the like. These injection solutions usually contain 0.5 to 20% by weight, preferably 1 to 10% by weight of the compound of the present invention. The dosage of the pharmaceutical of the present invention depends on the target species (human or animal), age, sex, body weight, sensitivity difference, administration method, administration timing/interval, degree of disease state,
It is determined by a doctor, taking into account your physical condition, the nature, preparation, and type of pharmaceutical preparation, and the type of active ingredient. In order to obtain effective results in animals, the active ingredient should be 0.1 to 500 mg per kg of body weight per day for oral administration, preferably 1 to 100 mg, and 0.01 to 250 mg per day for parenteral administration. 0.1~25
mg range is advantageous. Regarding the dosage for obtaining an effective result in humans, the following dosage range is advantageous, taking into account the effective dosage in animals, sensitivity differences, safety, and the like. For oral administration: 0.1 per kg body weight per day
~250mg, preferably 0.5-50mg For parenteral administration, 0.01-100mg per kg body weight per day, preferably 0.1
~25mg. Of course, depending on the aforementioned conditions, it may be sufficient to use an amount less than the above-mentioned minimum amount, and it may also be necessary to administer an amount in excess of the above-mentioned maximum amount. In addition, in the case of large-dose administration, it is preferable to divide the administration into several times a day. The compound () according to the present invention can be produced, for example, by the method described above. The methods are listed below. (1) The S-methyl-N-acetylcysteine derivative () can be produced by the reaction of S-methyl-N-acetylcysteine alkyl ester () and the amino compound represented by the general formula (). Examples of the amino compound represented by the general formula () include hydrazine, N-methylhydrazine, N・N'-dimethylhydrazine, N・N-
dimethylhydrazine, hydroxylamine, N
-Methylhydroxylamine and the like. S-methyl-N-acetylcysteine alkyl ester () versus amino compound ()
is usually used in excess. The reaction is usually carried out in an organic solvent such as methanol or ethanol at a temperature of 0° to 80°C. The reaction time is usually 1 hour to several days. (2)(i) The S-methyl-N-acetylcysteine derivative () can be produced by a condensation reaction of S-methyl-N-acetylcysteine and an amino compound represented by the general formula (). In that case, it is common to use a dehydration condensation agent, usually N・N'-dicyclohexylcarbodiimide, 1-chlorohexyl-3-(4-
Diethylaminocyclohexyl)carbodiimide, 1-ethyl-3-(3-diethylaminopropyl)carbodiimide, and the like can be used. The reaction is usually carried out in an organic solvent such as dichloromethane or chloroform at room temperature or under cooling. The molar ratio of S-methyl-N-acetylcysteine, the amino compound represented by the general formula (), and the dehydration condensation agent is approximately 1:1:1. (ii) S-methyl-N-acetylcysteine derivative () can be produced by reacting a reactive derivative of S-methyl-N-acetylcysteine with an amino compound represented by the general formula (). Examples of reactive derivatives of S-methyl-N-acetylcysteine include mixed acid anhydrides such as alkyl carbonic acid mixed anhydrides, acid chlorides, and the like. These reactive derivatives do not necessarily need to be isolated and purified, and can be used as a reaction mixture in the reaction with the amino compound of general formula (). In this reaction, S-
The molar ratio of methyl-N-acetylcysteine to the amino compound () is usually approximately 1:1. The reaction is usually carried out in the presence of a base such as triethylamine or dimethylaniline using acetone, tetrahydrofuran, dioxane, dimethylformamide, chloroform, dichloromethane,
Organic solvents such as hexamethylphosphoramide,
The reaction is carried out in a mixed solvent of these or a mixed solvent of these organic solvents and water at room temperature or under cooling. (3) S-methyl-N-acetylcysteine derivative () is a general compound obtained by reacting S-methylcysteine, a salt thereof, or a reactive derivative thereof with an amino compound represented by the general formula (). It can be produced by reacting the S-methylcysteine derivative represented by the formula () or a salt thereof with acetic acid or a reactive derivative thereof. In the above reaction, free carboxylic acid (S
-Methylcysteine or its salt; acetic acid) can be reacted by the method described in (2)(i), and when a reactive derivative of carboxylic acid is used, the method described in (2)(ii) can be used. General formula () obtained by the reaction described above
The S-methyl-N-acetylcysteine derivative represented by
It can be sufficiently purified by operations such as solvent distillation, filtration, recrystallization, and column chromatography. The present invention will be described in more detail with reference to Examples below, but the present invention is not limited by the Examples unless it exceeds the gist thereof. Example 1 Add 1.70 g (8.9 mmole) of S-methyl-N-acetyl-L-cysteine methyl ester and 6 ml of 80% hydrazine hydrate solution to 20 ml of ethanol.
After heating and refluxing for 2 hours, the reaction solution was concentrated under reduced pressure. A small amount of water was added to the residue and evaporated under reduced pressure. This operation was repeated three times to obtain white crystals. This was washed with a small amount of ethanol and then dried to obtain 0.99 g (yield: 58%) of S-methyl-N-acetyl-cysteinylhydrazine. IR ^cm-1 _KBr 3270, 3050, 1620, 1530, 955, 700 NMR (100MHz, δ) 1.84 (S, 3H, CH ₃ S-) DMSO-d ₆ 2.04 (S, 3H, -COC H ₃ ) 2.4~ 2.9 (m, 2H, -S H ₂ CH -) 3.2 - 4.0 (m, 2H, -N H ₂ ) 4.2 - 4.5 (m, 1H,

[Formula]) 8.06 (d, 1H, -NHCO-) 9.24 (br, S, 1H, CON H NH ₂ ) mp 150-151°C Example 2 This reaction was carried out under a nitrogen stream. Hydroxylamine hydrochloride 832mg (12mmole)
Dissolve in 20ml of methanol and cool on ice at +9° to +10°C.
Potassium hydroxide (85%) 1.32g while maintaining the temperature of
A solution of (20 mmole) dissolved in 15 ml of methanol was added dropwise. Subsequently, under ice cooling, S-methyl-N
-acetyl-L-cysteine methyl ester 1.91
A solution of g (10 mmole) dissolved in 15 ml of methanol is added dropwise. After the dropwise addition was completed, the mixture was returned to room temperature and allowed to stand for 3 days, and then ethyl acetate containing hydrogen chloride gas was added to adjust the pH to approximately 4. The precipitate was removed, methanol was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent was chloroform containing 10% methanol) to obtain 1.68 g of N-(S-methyl-N-acetylcysteine)-hydroxylamine. (yield 88%). mp 126.3～127.2℃ IR ^cm-1 _KBr 3340, 3230, 2900, 1660, 1605, 1540 NMR (100MHz, δ) 1.85 (S, 3H, CH ₃ S−) DMSO−d ₆ 2.08 (S, 3H, −COC H ₃ ) 2.4-2.9 (m, 2H, -SC H ₂ CH) 4.1-4.5 (m, 1H,

[Formula]) 8.08 (d, 1H, -N H CO -) 8.82, 10.68 (br, S, 2H, CON H OH ) Example 3 S-Methyl-N-acetyl-L-cysteine methyl ester 1.91 g ( 10 mmole) in 20 ml of ethyl alcohol. Methylhydrazine 5.4ml
(100 mmole) was added and stirred at boiling for 3 hours, then left at room temperature for 1 day. The precipitate was removed, and ethyl alcohol and excess methylhydrazine were distilled off under reduced pressure to precipitate crystals. 1.05 g (5.1 m
mole) obtained in a yield of 51%. mp 156.1~157.3℃ IRcm ^-1 3290, 3040, 2980, 2970, KBr disk 2930, 1640, 1535, 1500, 1445,
1418, 1385, 1370, 1318, 1280, 1260, 1200,
1110, 1090, 1040, 1020, 1000, 970, 940,
880, 780, 740, 710, 680, 610, 600, 530,
500 NMR (100MHz) 1.84 (S, 3H,

[Formula]) DMSO-d ₆ 2.05 (S, 3H, CH ₃ SCH ₂ ) 2.42 (S, 3H, -N( CH ₃ )NH ₂ ) 2.64 (m, 2H, -SC H ₂ CH-) 4.32 (q, 1H, -SCH ₂ C H -) 4.74 and 9.48 (bS, 2H, -N(-CH ₃ )NH ₂ ) 8.04 (d, 1H,

[Formula]) Test Example 1 Effect on acute liver injury accompanied by centrilobular necrosis (hepatitis model with single administration of carbon tetrachloride) Administered carbon tetrachloride is metabolized by drug-metabolizing enzymes in liver microsomes to form trichlor radicals. occurs. These radicals damage hepatocyte membranes, mitochondrial membranes, or microsomal membranes, causing loss of the original functions of hepatocytes and causing centrilobular necrosis. When hepatocytes are damaged in this way, enzymes are extravasated and various enzyme activities appear in the serum. Therefore, it is an appropriate method to measure serum transaminase activity as an indicator of the disorder.
Serum transaminases include GOT (glutamine-
Oxaloacetate transaminase) and GPT (glutamine-pyruvate transaminase) were both enzyme activities measured as indicators of liver damage. Test method The test compound was orally administered to rats (wistar male, weighing around 100 g) at 125 mg/Kg, and 3 hours later, carbon tetrachloride was administered at 0.25 ml/Kg (with olive oil to
After 24 hours, the blood was collected from the abdominal vena cava, and the serum was obtained by centrifugation (3000 rpm for 10 minutes).
GOT and GPT were measured and the activity was expressed according to the international unit method. The results are shown in Table 1.

[Table] The efficacy of the test compound exceeds that of the control drug α-mercaptopropionylglycine, which is 125 mg/Kg.
Inhibits strong carbon tetrachloride liver damage. Therefore, these test compounds are useful as therapeutic solutions for human and animal liver disorders accompanied by centrilobular necrosis. Test Example 2 Effect on acute hepatitis accompanied by mesenchymal reaction and lobular disseminated necrosis (D-galactoseamine single dose model test) By administering a large amount of D-galactoseamine,
UDP glucose (uridine diphosphonate-glucose) that should be synthesized in the liver
is competitively inhibited by D-galactoseamine and its amount decreases. Therefore, it is thought that glycogen synthesis and glucuronide synthesis via UDP glucose are suppressed, leading to inhibition of protein synthesis and hepatocyte dysfunction accompanied by membrane protein abnormalities. The histology causes diffuse destruction with a mesenchymal reaction similar to viral hepatitis in humans. Test method Test compound (

[Formula] S-methyl-N-acetylcysteinylhydrazine) and NKK100 (diisopropyl-1,3-dithiolane-2-ylidenemalonate, Nihon Nohyaku Co., Ltd.)
rats (body weight 200
g, Wistar, male), part 3
After an hour, D-galactosamine was intraperitoneally administered at 400 mg/Kg, and 24 hours later, the animal was sacrificed. Blood was collected from the abdominal vena cava, and serum was collected by centrifugation. GOT and GPT values in the serum were measured. was expressed according to the international unit method, and the results are shown in Table 2.

[Table] The test compound (S-methyl-N-acetylcysteinylhydrazine) was used as a control drug.
It exhibits almost the same medicinal efficacy as NKK100 (diisopropyl-1,3-dithiolane-2-ylidenemalonate), and therefore this compound has been shown to cause mesenchymal reactions and disseminated necrosis in liver disorders in humans and animals. It is expected to be useful as a therapeutic agent.

Claims (1)

[Claims] 1 General formula () (In the formula, R ¹ represents a hydrogen atom or a methyl group; R ² represents an amino group, a monomethylamino group, a dimethylamino group, or a hydroxyl group.) An S-methyl-N-acetylcysteine derivative represented by the formula: 2 General formula () (In the formula, R ³ represents a lower alkyl group) S-methyl-N-acetyl cysteine alkyl ester and the general formula () (In the formula, R ¹ and R ² have the same meanings as above.) A general formula () characterized by reacting an amino compound represented by (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing an S-methyl-N-acetylcysteine derivative represented by the following formula. 3 S-methyl-N-acetylcysteine or its reactive derivative and general formula () (In the formula, R ¹ and R ² have the same meanings as above.) A general formula () characterized by reacting an amino compound represented by (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing an S-methyl-N-acetylcysteine derivative represented by the following formula. 4 S-methylcysteine or its salt or a reactive derivative thereof and general formula () (In the formula, R ¹ and R ² have the same meanings as above.) General formula () obtained by reacting an amino compound represented by (In the formula, R ¹ and R ² have the same meanings as above) A general formula () characterized by reacting an S-methylcysteine derivative or a salt thereof with acetic acid or a reactive derivative thereof (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing an S-methyl-N-acetyl-cysteine derivative.