JPS6154798B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel thiamine derivative or a salt thereof represented by the formula [wherein R represents a hydrogen atom, a lower alkyl group, or an aralkyl group] and a method for producing the same. In the above general formula (), examples of the lower alkyl group represented by R include alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, and tert-butyl group. Examples of the aralkyl group include phenyl-C _1-4 alkyl groups such as benzyl group and phenethyl group. The above-mentioned thiamine derivative () is a combination of thiol-type thiamine and 3-mercapto-2-methylpropionylproline or its esters.
It can be produced by forming either one of them into a disulfide bond as a reactive derivative. For example, as a method for forming a disulfide bond, the general formula The general formula for the compound represented by Examples include a method of producing a thiamine derivative () by reacting a compound represented by the following formula [in the above formulas () and (), either X or Y is an MSO ₃ - group (M represents an alkali metal)]
, the other represents a hydrogen atom or an alkali metal,
R has the same meaning as above]. Examples of the alkali metals represented by X, Y and M include sodium and potassium, with sodium being particularly preferred. A compound in which X is a hydrogen atom or an alkali metal in the general formula () can be neutralized by adding 2 to 3 equivalents of a base (e.g., sodium hydroxide, potassium hydroxide, triethylamine) to thiamine dihydrochloride in an aqueous solution. It can be obtained as an aqueous solution by forming a salt, but is preferably prepared using 3 equivalent molar amounts of sodium hydroxide or potassium hydroxide. A compound in which X is an MSO ₃ - group in the general formula () can be easily obtained by a known method, such as the method described in Japanese Patent Publication No. 42-11588 (1967). In the other raw material compound general formula (), Y
Compounds in which is an MSO ₃ − group, so-called Bunte salts, have the general formula [In the formula, R has the same meaning as above, A represents a halogen atom or the general formula OSO ₂ R ¹ (where R ¹ is a methyl group, phenyl group, or tolyl group)] and sodium thiosulfate are mixed with water. Alternatively, it can be obtained by reacting with water in a mixed solution of ethanol, methanol, etc. Note that the compound () is, for example, the general formula A compound represented by [wherein A has the same meaning as above, and B represents a halogen atom or an active ester residue of carboxylic acid] and the general formula It can be produced by reacting proline represented by the formula [wherein R has the same meaning as above] or its esters. A compound in which Y is a hydrogen atom or an alkali metal in the general formula () is, for example, a compound with the general formula ()
By reacting the compound represented by potassium thioacetate, the general formula A compound represented by the formula [wherein R has the same meaning as above] is produced, and this is hydrolyzed under weak basic conditions (e.g., in the presence of potassium carbonate, sodium hydrogen carbonate, anion, pyridine, triethylamine, etc.) or alternatively, for example, by oxidizing a compound of the general formula () in which Y is MSO ₃ (M represents an alkali metal) with, for example, iodo-iodopotassium or hydrogen peroxide. It can be easily produced by producing a compound represented by [wherein R has the same meaning as above] and reducing this using a reducing agent such as zinc-acetic acid or sodium boron hydride. can. The method of the present invention is carried out by reacting the above compounds () and (), usually in an aqueous solution. The reaction generally proceeds easily at room temperature, but it is also possible to appropriately heat or cool the reaction rate for the purpose of controlling the reaction rate. Water is generally used for reaction dissolution, but the reaction can also be carried out in the presence of an organic solvent such as chloroform, dichloromethane, ethyl acetate, benzene, toluene, or ethyl ether for the purpose of dissolving or extracting the product. The object compound () of the present invention thus obtained can be separated and purified from the reaction mixture using conventional separation and purification methods such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography. It can therefore be isolated in free base or salt form. The free base can be prepared in a manner known per se, for example, inorganic salts (e.g. hydrochloride, hydrobromide, sulfate, nitrate, etc.), organic acid salts (e.g. maleate, fumarate, tartrate, etc.).
It can be a physiologically acceptable salt addition salt such as toluenesulfonate, methanesulfonate, naphthalenesulfonate, etc.). Since the compound represented by the general formula () of the present invention contains two asymmetric carbon atoms in the molecule, it is theoretically possible for four isomers to exist. Although both of these individual isomers and racemic mixtures thereof are naturally included within the scope of the present invention,
It is also possible to prepare these isomers individually if desired. That is, for example, a desired stereoisomer of () can be obtained by performing synthesis according to the above-mentioned route using each of the optical isomers of the starting compounds () and (). If either () or () is an optically active form and the other is a racemic form, () is obtained as a mixture of two isomers, and (),
When both () are racemic, () is obtained as a mixture of four isomers. In addition, () obtained as a racemate may be converted into each isomer by a conventional method, for example, by forming a salt with an optically active acid (e.g., d-tartaric acid, d-benzoyltartaric acid, camphor sulfonic acid, etc.). It can also be separated. In addition, as a method for obtaining a thiamine derivative () in which a thiol-type thiamine and 3-mercapto-2-methylpropionylproline or its esters are bonded by a disulfide bond, various reactions known per se can be applied in addition to the above-mentioned method, such as One example is the method shown by the following equation. (a) (b) [In the above formula, R ² is a lower alkyl group, Q is , X′ is a halogen atom, B ₁ is Indicates a group represented by ] The compound of the present invention, that is, the thiamine derivative represented by the general formula () and its salt, contains vitamin B ₁
In addition to having activity, it also has angiotensin-converting enzyme inhibitory effect and bradykinin-degrading enzyme (kininase) activity in animals, especially mammals (e.g., humans, dogs, cats, rabbits, guinea pigs, rats).
It exhibits inhibitory effects and is useful, for example, as a prophylactic or therapeutic agent for hypertension. The target compound of the present invention is well absorbed and has excellent stability even when administered orally, so when used for the above-mentioned medical treatments, it can be used alone or mixed with appropriate pharmaceutically acceptable carriers, excipients, and diluents. It can be safely administered orally or parenterally in the form of powder, granules, tablets, capsules, injections, etc. The dosage varies depending on the condition of the target disease and the route of administration, but when administered to adult patients for the purpose of treating hypertension, a single dose of oral administration is approximately 0.01 to 5 mg/Kg, especially approximately
Approximately 0.02 to 0.5 mg/Kg is the one-time dose for intravenous administration.
A dosage of about 0.01 to 0.5 mg/Kg, especially about 0.002 to 0.05 mg/Kg is preferred, and it is desirable to administer these doses 2 to 5 times a day depending on the symptoms. In addition, thiamine derivatives () and their salts are
From the viewpoint of chemical and physical stability, compounds in which R is a lower alkyl group or an aralkyl group are preferred, and from the viewpoint of pharmacological action, among the isomers, compounds in which the proline moiety is L-
Compounds in which the 2-position methyl moiety is D-form are preferred. The present invention will be explained in more detail below using Examples and Experimental Examples, but these are not intended to limit the present invention in any way. Example 1 2.4 g of L-proline benzyl ester hydrochloride was suspended in 25 ml of benzene, 1.6 g of pyridine was added, and while stirring under ice cooling, the suspension was suspended in 25 ml of benzene.
81, p. 1786 (1961)].
Bromo-2-methylpropionic acid chloride 1.9g
was dissolved in 5 ml of benzene and added dropwise, and stirring was continued for 2 hours under ice cooling. The reaction solution was washed with water, diluted hydrochloric acid, and water in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3-bromo-2.
2.9 g of -methylpropionyl-L-proline benzyl ester are obtained as a colorless oil. IR absorption spectrum ν ^neat _nax 1740cm ^-1 (O-CO
),
1640cm ^-1 (N-CO) 2.0g of 3-bromo-2-methylpropionyl-L-proline benzyl ester and 10ml of ethanol
Sodium thiosulfate (pentahydrate) dissolved in 1.45
g dissolved in 10 ml of water, boiled and refluxed for 4 hours while stirring, and then distilled off the solvent under reduced pressure to obtain 2-methyl-3-sulfothiopropionyl-
L-proline berdyl ester sodium salt is obtained as a colorless syrupy substance. IR absorption spectrum ν ^neat _nax 1740cm ^-1 (O-CO
),
1640cm ^-1 (N-CO), 1240cm ^-1 ( _SSO3 ), 1180cm
^-1 (SSO ₃ ), 1030cm ^-1 (SSO ₃ ) 5ml solution of this product in water, 2g thiamine dihydrochloride
Dissolve in 3 ml of water and add 10% sodium hydroxide aqueous solution 7
ml to the prepared aqueous solution of thiol-type thiamine. Pour the precipitated candy-like substance into 10 ml of ethyl acetate.
Add dilute hydrochloric acid to the extract until acidic and shake. The hydrochloric acid layer is separated and neutralized with sodium hydrogen carbonate, and the precipitated colorless candy-like substance is extracted again with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then evaporated. The residue was dissolved in 3 ml of 10% ethanolic acid salt, poured into 60 ml of ether, and left at room temperature for 2 days to give 3-[2-N-(4 -amino-2-methyl-5-pyrimidinyl)methylformamide-1-(2-hydroxyethyl)-1-propenyldithio]-2-methylpropionyl-L-
Proline benzyl ester (I:R=
1.0 g of C ₆ H ₅ CH ₂ ) hydrochloride are obtained as colorless granular crystals. Melting point 127-131°C (decomposition). Elemental analysis value C ₂₈ H ₃₇ N ₅ O ₅ S ₂・HCl Calculated value: C 53.88, H 6.14, N 11.22 Experimental value: C 53.58, H 6.17, N 11.19 Example 2 L-proline benzyl ester in Example 1 By carrying out the same operation as in Example 1 using L-proline methyl ester hydrochloride instead of the hydrochloride, 3-[2-N-(4-amino-2-methyl-5-pyrimidinyl) Methylformamide
1-(2-Hydroxyethyl)-1-propenyldithio]-2-methylpropionyl-L-proline methyl ester (I:R= _CH3 ) hydrochloride is obtained as colorless crystals. Since this product is hygroscopic, it was confirmed by converting it into picrate using a conventional method. Picrate: yellow granular crystals, melting point 119-124°C (decomposition). Elemental analysis value C ₂₂ H ₂₃ N ₅ O ₅ S ₂・C ₆ H ₃ N ₃ O ₇ Calculated value: C 45.39, H 4.90, N 15.13 Actual value: C 45.04, H 4.94, N 15.15 Example 3 Example 3-[2-N-(4-amino-2-methyl -5-pyrimidinyl)methylformamide-1-
(2-Hydroxyethyl)-1-propenyldithio]-2-methylpropionyl-L-proline ethyl ester (I:R=C ₂ H ₅ ) hydrochloride is obtained as colorless granular crystals. Melting point 135-138°C (decomposition). Elemental analysis value C ₂₃ H ₃₅ N ₅ O ₅ S ₂・HCl Calculated value: C 49.14, H 6.46, N 12.46 Actual value: C 48.98, H 6.47, N 12.40 Example 4 3-mercapto-2-methylpropionyl- L
-2.4g of proline ethyl ester to 10% of ethanol
After adding a solution of 0.7 g of sodium ethoxide in 5 ml of ethanol, the ethanol was distilled off under reduced pressure, 5 ml of water was added to the residue, and 3.8 g of S-sulfothiamine was dissolved in a 10% aqueous sodium hydroxide solution. 4
Pour into the neutralized solution with ml. The precipitated oily substance is extracted with chloroform, dilute hydrochloric acid is added to the extract, shaken, and the hydrochloric acid layer is neutralized with sodium hydrogen carbonate. The precipitated oily substance was extracted with chloroform,
The extract was dried over anhydrous sodium sulfate and then evaporated, the residue was dissolved in 2 ml of 10% ethanolic hydrochloric acid, 20 ml of ether was added, and the mixture was left at room temperature for 2 days. The precipitated crystals were collected and dried to form 3-[2
-N-(4-amino-2-methyl-5-pyrimidinyl)methylformamide-1-(2-hydroxyethyl)-1-propenyldithio]-2-methylpropionyl-L-proline ethyl ester (I:R=C ₂ H ₅ ) 0.15 g of hydrochloride is obtained. This product mixed with the specimen obtained in Example 3, showed no drop in melting point, and the IR spectra (Nujol) of both were completely identical. Experimental example Compounds for the pressor action of angiotensin and the hypotensive action of bradykinin (R=CH ₂ −
Effect of C ₆ H ₅ ) [Experimental Method] Experiments were conducted without anesthesia using a male beagle (weighing 10 kg) in which a cannula was chronically inserted and fixed in the femoral artery. First, systolic blood pressure and diastolic blood pressure in the control period were recorded using an electric sphygmomanometer (Nihon Kohden, MP-4T), and then angiotensin was administered at 300 ng/kg.
Kg and then angiotensin at 15 ong/Kg was injected into the radial osteocutaneous vein, and its pressor effect was investigated. Furthermore, 500 ng/Kg of bradykinin was injected in the same manner and its hypotensive effect was recorded. Next, add 5 mg/Kg of the compound (R=CH ₂ C ₆ H ₅ ) hydrochloride obtained in Example 1 to 5 ml/kg.
Kg dissolved in distilled water and administered orally, 20, 60 hours after administration
After 120 minutes, angiotensin, angiotensin, and bradykinin were repeatedly injected to monitor the hypertensive or hypotensive response. [Experimental Results] Table 1 summarizes the blood pressure responses to angiotensin, angiotensin, and bradykinin before and after administration of the compound (R=CH ₂ C ₆ H ₅ ).

[Table] As seen in Table 1, the compound (R=CH ₂ −
C ₆ H ₅ ) The response to angiotensin after administration is
A clear tendency to suppress was observed after 20 minutes, and after 60 minutes,
At 120 minutes, it was completely suppressed and actually showed a hypotensive effect. However, the pressor effect of angiotensin was not significantly changed by the compound. The antihypertensive effect of bradykinin was clearly enhanced by administration of the compound. These facts indicate that the compound (R=CH ₂ C ₆ H ₅ ) is an effective angiotensin converting enzyme inhibitor when administered orally.

Claims (1)

[Claims] 1. General formula A thiamine derivative or a salt thereof represented by [wherein R represents a hydrogen atom, a lower alkyl group, or an aralkyl group]. 2 General formula The general formula for the compound represented by A general formula characterized by reacting a compound represented by A method for producing a thiamine derivative or a salt thereof. [In each of the above formulas, either X or Y is
MSO ₃ - group (M represents an alkali metal), the other represents a hydrogen atom or an alkali metal, and R represents a hydrogen atom, a lower alkyl group, or an aralkyl group]