JPS63428B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 2-carbamoylamino-3-substituted propionamides useful as therapeutic agents for liver diseases and methods for producing them. Various biochemical reactions take place in the liver. For example, detoxification, carbohydrate metabolism, protein metabolism, lipid metabolism, production of bile and regulation of secreted hormones, production of blood coagulation agent prothrombin, regeneration of liver cells, various biological components (fat, glycogen, protein, vitamins, etc.) This includes the storage of organs. The liver, which has such precise and well-balanced functions, has a large self-repair ability, and is an organ that can be expected to recover naturally if dysfunction occurs. It can be damaged acutely or chronically by various factors such as obstruction and disorders of the hepatic circulatory system.
It manifests as diseases such as fatty liver, drug-induced liver disease, alcoholic hepatitis, viral hepatitis, congestive hepatitis, liver damage due to cholestasis, jaundice, and liver cirrhosis as the final manifestation 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 2-carbamoylamino-3-
It has been discovered that substituted propionamides are effective for that purpose, and the present invention has been achieved. That is, the gist of the present invention is (1) General formula () (In the formula, R represents a hydrogen atom, a methyl group or an ethyl group.) 2-Carbamoylamino-3-substituted-propionamides (2) General formula () (In the formula, R ¹ and R ² represent a methyl group or an ethyl group.) Reacting a 2-amino-3-alkylthio-propionic acid ester represented by the following with ammonia,
Then, by neutralizing if necessary, the general formula () [In the formula, R ¹ has the same meaning as in the general formula (). ] 2-amino-3-alkylthio-propionamides or salts thereof, and an alkali isocyanate represented by the general formula () MCNO () (wherein, M represents an alkali metal atom). General formula () characterized by reacting [In the formula, R ¹ has the same meaning as in the general formula (). ] Method for producing 2-carbamoylamino-3-alkylthio-propionamides represented by (3) General formula () [In the formula, R ¹ has the same meaning as in the general formula (). ] A 2-amino-3-alkylthio-propionic acid represented by is reacted with an alkali isocyanate represented by the general formula () to form the general formula (). [In the formula, R ¹ has the same meaning as in the general formula (). ] 2-carbamoylamino-3-alkylthio-propionic acids represented by the formula are prepared, and if necessary, this is converted into a reactive derivative, and then the 2-carbamoylamino-3-alkylthio-propionic acids or its reactive derivative are combined with ammonia. (4) A method for producing 2-carbamoylamino-3-alkylthio-propionamides represented by the general formula (), characterized by reacting cystine diamide or a salt thereof with isocyanide represented by the general formula (). The present invention relates to a method for producing 2-carbamoylamino-3-mercapto-propionamide, which comprises reacting with an acid alkali to form N.N'-dicarbamoyl-cystine diamide, and reducing this. The present invention will be explained in detail below. The compounds according to the present invention are 2-carbamylamino-3-substituted-propionamides represented by the general formula (). In the general formula (), R represents a hydrogen atom, a methyl group or an ethyl group. The 2-carbamylamino-3-substituted-propionamides represented by the general formula () include 2-carbamylamino-3-substituted-propionamides;
Mention may be made of carbamoylamino-3-mercaptopropionamide, 2-carbamoylamino-3-methylthio-propionamide and 2-carbamoylamino-3-ethylthio-propionamide. These compounds exist in D, L and DL forms, but the L form is usually used. The present inventors have discovered that the compound represented by the above general formula () binds hepatocytes, improves the liver's carbohydrate metabolism, detoxification (e.g. alcohol detoxification) action, bile
It has also been found that it has the effect of enhancing functions such as the production and secretion of bile acids (choleretic effect) and the regeneration of hepatocytes. 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 compounds of the present invention are effective against liver damage through stabilization of cell membranes, radical scavenging effect, protection of in-vivo thiol compounds through antioxidant effects, and mobilization of various liver enzymes as thiol compounds during the production of hepatitis in experimental animals. It was found to be effective. For example, treatment of liver damage with centrilobular necrosis (prevention,
(same hereinafter, including alleviation) Therapeutic action for liver damage accompanied by perilobular necrosis Therapeutic action for hepatitis accompanied by mesenchymal reactions in disseminated lobular necrosis Therapeutic action for fatty liver Therapeutic action for liver cirrhosis Therapeutic action for toxic liver damage Depression Therapeutic effects on hemorrhagic liver disease Stimulating bile and bile acid secretion (choleretic effect) Reducing blood alcohol concentration Reducing abnormally high blood sugar levels Reducing toxic symptoms caused by metal salts (selenium salts, cadmium salts) Effects such as alleviation effects are observed. 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 or 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, depressed liver, cholestatic liver disorder, or liver cirrhosis, which is the terminal stage thereof. It 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 compounds of the present invention have the effect of stimulating hepatocytes and stimulating functions in the liver, such as secretion of bile and bile acids, carbohydrate metabolism, and detoxification of hepatotoxic substances such as alcohol, and are therefore useful for humans and animals. It is useful as a bile agent or as a treatment for jaundice. The compounds of the present invention are also useful as agents for lowering blood sugar levels and can be used as therapeutic agents for diabetes in humans and animals, and are within the scope of the present invention. Furthermore, the compounds of the present invention are useful as blood alcohol concentration lowering agents or antidotes for humans, and can be used as therapeutic agents for alcohol drunkenness and hangovers, and thus fall within the scope of the present invention. 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 and arrowroot 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 and mineral oils: Physiological saline: Dextrose or similar sugar 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 carried out 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 the compound of the present invention in an amount of 0.5 to 20% by weight, preferably 1 to 10% by weight. 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 will be decided by your 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 effective results in humans, the following dosage range is advantageous, for example, taking into account the effective dosage in animals, susceptibility agents, safety, etc. For oral administration, 1 kg body weight per day
0.1-250 mg, preferably 0.5-50 mg; in case of parenteral administration, 0.01-100 mg, preferably 0.1-25 mg per kg body weight per day. 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 compounds according to the present invention can be produced, for example, by the methods described above. First of all, 2-carbamoylamino-3-
Alkylthio-propionamides can be produced by amidating 2-amino-3-alkylthio-propionate esters and then reacting with alkali isocyanates. When reacting the 2-amino-3-alkylthio-propionic acid ester represented by the general formula () with ammonia, ammonia is usually used in excess. The reaction is usually carried out in an organic solvent such as methanol or ethanol or without a solvent at room temperature or under cooling. The 2-amino-3-alkylthio-propionamides produced by the reaction may be used as is in the next reaction, or may be used as an inorganic salt such as hydrochloric acid or sulfuric acid,
It may be used in the next reaction after being neutralized with an acid such as an organic acid such as maleic acid or succinic acid to form a salt. M in the general formula () represents an alkali metal atom such as sodium or potassium. When the 2-amino-3-alkylthio-propionamides represented by the general formula () or their salts are reacted with an alkali isocyanate, water is usually used as the solvent. The alkali isocyanate is usually used in equimolar or excess amounts relative to the 2-amino-3-alkylthio-propionamides or salts thereof. A reaction temperature around room temperature is usually sufficient. After the reaction, 2-carbamoylamino-3-alkylthio-propionamides represented by the general formula () usually precipitate, so if this is separated and dried, the purity is sufficiently high, but if necessary, It can also be purified by means such as recrystallization and column chromatography. In addition, 2-carbamoylamino-3-alkylthio-propionamides are 2-amino-3-
It can also be produced by reacting alkylthiopropionic acids with an alkali isocyanate and then reacting with ammonia. The reaction of the 2-amino-3-alkylthio-propionic acids represented by the general formula () with an alkali isocyanate can be carried out in the same manner as the usual carbamylation of amino acids. That is, a mixture of the compound of general formula (), an alkali isocyanate, and water is heated to about 80° C. for 10 to 20 minutes to form a homogeneous solution, and then stirred at room temperature for about 2 to 3 days while adjusting the pH. The pH of the system shifts to the alkaline side, so change this from time to time.
Adjust the pH by repeatedly returning it to around 5. Finally, the mixture is made acidic to a pH of about 3 and the precipitate is separated to obtain a compound of general formula (). 2-carbamoylamino produced by the reaction
The 3-alkylthio-propionic acid may be used in the next reaction as it is, or it may be converted into a reactive derivative and then used in the next reaction. 2-carbamoylamino-3-alkylthio-
Examples of reactive derivatives of propionic acid include mixed acid anhydrides such as alkyl carbonic acid mixed anhydrides, acid chlorides, and esters. These reactive derivatives do not necessarily need to be isolated or purified. 2-carbamoylamino-3-alkylthio-
The reaction between propionic acid or its reactive derivative and ammonia can be carried out in the same manner as the reaction between the 2-amino-3-alkylthio-propionic acid ester and ammonia described above. 2-Carbamoylamino-3-mercapto-propionamide in which R is a hydrogen atom in the general formula () is obtained by reacting cystine diamide or its salt with an alkali isocyanate to obtain N.N'-dicarbamoylcystine diamide. Give back S-S
It can be manufactured by cutting the bond. There are various reduction methods, but simple methods include, for example, a method of reacting with zinc in acetic acid-sulfuric acid, or a method of reacting with a phosphine in an appropriate solvent. In the latter reaction, the solvent used is water, methanol, acetone, etc., or a mixed solvent thereof, and the phosphine includes trialkylphosphines such as tri-n-butylphosphine and triarylphosphines such as triphenylphosphine. is used. As for post-reaction treatment, in the case of reduction with zinc, the target product can be obtained by removing the excess zinc and separating the precipitated crystals, and in the case of reduction with phosphine, the target product can be obtained by separating the precipitated crystals after the reaction. can be obtained. The compound obtained in this way is usually sufficiently pure, but if necessary, it can be sufficiently purified by recrystallization, column chromatography, etc. The present invention will be explained in more detail with reference to production examples and examples below, but the present invention is not limited by the following examples unless the gist of the invention is exceeded. Example 1 Synthesis of 2-carbamoylamino-3-mercapto-propionamide (i) Synthesis of N·N'-dicarbamoyl-L-cystinediamide L-cystinediamide dihydrochloride (Journal of Medicinal Chemistry Vol. 10,
6.23 g (20
(mmol) was dissolved in 15 ml of water, and 6.48 g (80 mmol) of potassium isocyanate was added while stirring at room temperature. Potassium isocyanate was dissolved to become a homogeneous solution, and after about 1 hour of further stirring, white crystals were precipitated. After this, wash with water, dry and N.
N'-dicarbamoyl-L-cystine diamide
5.70 g (17.6 mmol) was obtained. Yield 88% IR (cm ^-1 ), KBr 3420, 3380, 1680, 1655, 1615, 1545,
1525, 1400, 1340, 1295, 1165, 1135 NMR (100MHz, DMSO- _d6 ) δ (ppm) 2.9-3.1 (4H, m,

【formula】) 4.42 (2H, dt,

[Formula]) 5.74 (4H, s, -NHCONH ₂ ) 6.34 (2H, d, -NHCONH ₂ ) (ii) 2-carbamoylamino-3-mercapto-
Synthesis of propionamide 1.0 g of N・N'-dicarbamoyl-L-cystine diamide was suspended in a mixed solvent of 30 ml of 90% methanol and 1 ml of acetone.
1.37 g (2.2 times equivalent) of butylphosphine was added dropwise. After dropping, the mixture was stirred at room temperature for 5 hours, and the precipitated solid was separated. After washing with methanol and drying, 0.48 g (yield: 48%) of a white solid was obtained. C ₄ H ₉ O ₂ N ₃ S C% H N Calculated value 29.40 5.56 25.77 Analyzed value 29.61 5.56 25.86 IR ^KBr _cn-1 ; 3450, 3370, 3270, 2510, 1680,
1665, 1545 mp173.0-175.3℃ (decomposition) NMRδ ^ppm _DMSO-d6 ; 1.99 (1H, t, J=8, HS - _CH2- ) 2.66 (2H, dd, J=8.6, HS _- CH2 −CH) 4.23 (1H, dt, J=8.6

[Formula]) 5.67 (2H, br.S, -NHCON H ₂ ) 6.24 (1H, d, J=8, CH-
_NHCONH2 ) Example 2 Synthesis of 2-carbamoylamino-3-mercapto-propionamide 3.24 g (10 mmol) of N.N'-dicarbamoyl-L-cystine diamide was dissolved in 6.6 ml of 2N acetic acid.
Then, 790 mg (12 mg atoms) of powdered metallic zinc was added. After dropping 0.53ml of concentrated sulfuric acid into this,
After stirring for 1 hour at ~50°C, a nearly homogeneous solution was obtained. When the reaction solution was filtered and left to stand, white crystals precipitated, which were removed, washed with a small amount of water, and dried.
2.08 g of -carbamoylamino-3-mercapto-propionamide was obtained. The oral fluid and washings were concentrated to obtain an additional 0.42 g of crystals. Yield: 2.50 g (15.3 mmol) Yield: 77% mp171 -2°C (decomposition) Example 3 13.26 g (88.9 mmol) of 2-amino-3-methylthio-propionic acid methyl ester was dissolved in 150 ml of a saturated ammonia gas methyl alcohol solution. It was left at room temperature for three days. Methyl alcohol was distilled off under reduced pressure to obtain an oily substance. The oil was dissolved in 12 ml of methyl alcohol and 20 ml of ethyl acetate and cooled on ice. When 30 ml of 16% hydrogen chloride gas-ethyl acetate was added dropwise, white crystals were precipitated. The crystals were filtered and washed with ethyl acetate. 11.4 g of 2-amino-3-methylthio-propionamide hydrochloride (yield 75.4
%) obtained. 5.1 g (30 mmol) of 2-amino-3-methylthio-propionamide hydrochloride are dissolved in a minimum amount of water and cooled on ice. Powdered potassium cyanate 2.68g
(33 mmol) to make a homogeneous solution, and cooled on ice for 3 minutes.
Stir for an hour. The precipitated white crystals are filtered, washed with ice water, and then dried in vacuum. 2-carbamoylamino-3-methylthio-propionamide 1.8g
(Yield 34%) was obtained. mp.152~158℃ IR (cm ^-1 ), KBr 3400, 3230, 1650, 1600, 1540, 1420, 1310,
1200, 1140, 660, 580 NMR (100MHzδ) DMSO−d ₆ 2.03 (s, 3H, CH ₃ S−) 2.7 (d, 2H, −S CH ₂ −) 4.2 (q, H,

[Formula]) 5.63 (s, 2H, NHCO NH ₂ ) 6.24 (d, H,

[Formula]) 7.1 and 7.5 (S, 2H, 2, -CHCO NH ₂ ) Example 4 6.76 g (41.4 mmol) of 2-amino-3-ethylthio-propionic acid methyl ester was dissolved in 60 ml of saturated ammonia-methyl alcohol. After standing at room temperature for 3 days, it was concentrated under reduced pressure. The oil was dissolved in 5 ml of methyl alcohol and 10 ml of ethyl acetate, and 15 ml of 16% hydrogen chloride gas-ethyl acetate was added dropwise under ice cooling. White crystals were precipitated, washed with ethyl acetate, and dried under vacuum to obtain 5.56 g (yield: 78.1%) of 2-amino-3-ethylthio-propionamide hydrochloride. 4.39 g (23.8 mmol) of 2-amino-3-ethylthio-propionamide hydrochloride is dissolved in 23 ml of water and cooled on ice. Powdered potassium cyanate 2.12g
(26.2 mmol) was added, and after stirring for 3 hours under ice cooling,
Filter and wash with ice water. When vacuum dried, 2-
2.31 g (yield 50.8%) of carbamoylamino-3-ethylthio-propionamide was obtained. mp.165.2~167.6℃ IR (cm ^-1 ), KBr 3420, 1650, 1600, 1540 NMR (100MHzδ) DMSO−d ₆ 1.17 (t, 3H, CH ₃ CH ₂ S−) 2.5 (q, 2H, CH ₃ CH ₂ S-) 2.7 (d, 2H, -S- CH ₂ CH) 4.20 (q, H, SCH ₂ CH CO) 5.62 (s, 2H, NHCO NH ₂ ) 6.2 (d, H, NH CO) 7.1 and 7.5 (S, 2 bottles, 2H, NHCO NH ₂ ) Next, in describing the usefulness of the compound of the present invention, the test method and test results will be explained in detail. 1 Effect on acute liver injury accompanied by centrilobular necrosis (model test with one dose of carbon tetrachloride) Administration of carbon tetrachloride causes cell membrane damage due to the generation of carbon trichloride free radicals in the liver;
Central necrosis of hepatocytes is induced, along with a decrease in diphosphopyridine nucleotide (DNP) glycogen and coenzymes and an increase in triglycerides. It is known that when hepatocytes are damaged in this way, enzymes within the hepatocytes leak out, resulting in an increase in enzyme activity in the serum. Measurement of glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) activities in serum is an appropriate method as an indicator of the degree of liver damage caused by carbon tetrachloride and the preventive effect of drugs on that damage. be. Test method The test compound was dissolved in water or suspended with polyoxyethylene sorbitan monooleate (trade name: Twin 80, Kao Atlas Co., Ltd.), and orally administered to rats (body weight 100-150 g) at a rate of 125 mg/Kg. After an hour, 0.25 ml/Kg of carbon tetrachloride was administered intraperitoneally, and 24 hours later, the animals were sacrificed, blood was collected, plasma was obtained by centrifugation, GOT activity was measured, and the activity was expressed in international units. The results are shown in Table 1.

[Table] Carbon tetrachloride is a drug suitable as a pathological model of acute hepatitis in experimental animals, and as a result of experiments using this method, the present compound showed a remarkable effect on preventing liver damage as described above. This effect was superior to that of methionine. 2 Effect on acute liver injury accompanied by lobular disseminated necrosis (model test with one dose of D-galactosamine) D-galactosamine causes disseminated hepatocyte necrosis accompanied by a mesenchymal reaction similar to the pathology of viral hepatitis in humans. It is a compound that causes viral hepatitis and is often used as a model for viral hepatitis. This compound suppressed the onset of acute hepatitis caused by D-galactosamine and exhibited a preventive effect. Test method: The test compound was dissolved in water or suspended with polyoxyethylene sorbitan monooleate (described above), and given to rats (weighing 200 to 250 g) at 125 g.
Orally administered at a rate of ~1000mg/Kg, 3 hours later
400 mg/Kg of D-galactosamine was administered intraperitoneally. After another 2 hours, 125 mg/Kg of the test compound was administered, and after 22 hours, the animals were sacrificed and blood was collected. Plasma was obtained by centrifugation, and GOT and GPT activities were measured.
Units are expressed in international units. The results are shown in Table 2.

[Table] D-galactosamine is suitable for creating a pathological model of acute hepatitis in experimental animals. As a result of experiments using this method, as mentioned above, the present compound exhibited a remarkable effect on preventing liver damage, and showed an effect comparable to that of methionine, which is currently commercially available as a liver drug. Therefore, the compounds of the present invention are useful as therapeutic agents for human and animal liver disorders accompanied by centrilobular necrosis or hepatitis accompanied by mesenchymal reactions and diffuse necrosis.

Claims (1)

[Claims] 1 General formula () (In the formula, R represents a hydrogen atom, a methyl group or an ethyl group.) 2-carbamoylamino-3-substituted-
Propionamides. 2 General formula () (In the formula, R ¹ and R ² represent a methyl group or an ethyl group.) By reacting the 2-amino-3-alkylthio-propionic acid ester represented by the formula with ammonia, and then neutralizing as necessary, General formula () [In the formula, R ¹ has the same meaning as in the general formula (). ] 2-amino-3-alkylthio-propionamides or salts thereof, and an alkali isocyanate represented by the general formula () MCNO () (wherein, M represents an alkali metal atom). General formula () characterized by reacting [In the formula, R ¹ has the same meaning as in the general formula (). ] A method for producing 2-carbamoylamino-3-alkylthio-propionamides. 3 General formula () (In the formula, R ¹ represents a methyl group or an ethyl group.) 2-Amino-3-alkylthio-propionic acids represented by the general formula () MCNO () (wherein, M represents an alkali metal atom). ) is reacted with an alkali isocyanate represented by the general formula (). [In the formula, R ¹ has the same meaning as in the general formula (). ] 2-carbamoylamino-3-alkylthio-propionic acids represented by the formula (), which are optionally converted into reactive derivatives and then reacted with ammonia. [In the formula, R ¹ has the same meaning as in the general formula (). ] A method for producing 2-carbamoylamino-3-alkylthio-propionamides. 4 Cystine diamide or a salt thereof is reacted with an alkali isocyanate represented by the general formula () MCNO () (in the formula, M represents an alkali metal atom) to form N・N'-dicarbamoyl-cystine diamide. A method for producing 2-carbamoylamino-3-mercapto-propionamide, which comprises reducing 2-carbamoylamino-3-mercapto-propionamide.