FR2619816A1 - AMINE DERIVATIVES AND THEIR SALTS, METHODS OF MAKING SAME, AND ANTI-ULCERE AGENT CONTAINING SAME - Google Patents

Abstract

This invention relates to novel compounds represented by the formula a

Description

AMERICAN DERIVATIVES AND THEIR USES, METHODS OF MAKING SAME,

AND ANTI-ULCERE AGENT CONTAINING THEM.

  The present invention relates to novel amine derivatives and their salts, to

  manufacture of these compounds, as well as on an anti-

ulcer containing them.

  As a result of a study carried out on the basis that compounds exhibiting H2-type antihistaminic activity are useful for the treatment of peptic ulcer, the present inventors had previously discovered novel amine derivatives which are antagonistic, competition with histamine, at histamine H2 receptors, and they have filed patent applications to protect these new derivatives [Japanese KOKAI patent applications (published) No. 88,458 / 84

and 97,958/85].

  However, the compounds specifically described in the above patent applications are not

  totally satisfactory as regards their anti-

  ulcer and their stability. Therefore, it is desired to have compounds having a better effect

  anti-ulcer and good stability.

  The present inventors have continued their studies to solve the above problem, and they have, as a result, discovered that the new compounds represented

  by the formula [I] and their salts, which are described below

  below, exhibit a remarkable anti-ulcer effect, low toxicity and good stability, as compared with the compounds specifically described in the above patent applications. The present invention has been accomplished

based on this discovery.

  An object of the present invention is therefore to

  to propose new amine derivatives and their salts.

  Another object of the present invention is to propose new derivatives of amine and their salts which

  exhibit anti-ulcer activity.

  Yet another object of the present invention is to propose a process for the manufacture of new derivatives.

of amine and their salts.

  The present invention also aims to provide a pharmaceutical composition containing a new derivative

  of amine or a salt thereof as an active ingredient.

  The present invention also aims to

  to propose a method of treatment of peptic ulcer.

  Other purposes and advantages of this

  invention will become apparent from the following description.

  According to the present invention, there is provided an amine derivative represented by the formula [I]:

NSO CH

NCH 2 CH2SCH2CH2NCNCH2.CH [I]

CH3 / NH2

  in which R is a 4-hydroxyphenyl group, a 4-carbamoyl phenyl group or a 3-methanesulfonylamino phenyl group,

or a salt of. this derivative.

  The present invention also provides a process for making the above amine derivative or its salt, as well as an anti-ulcer agent containing said amine derivative.

or its salt.

  As salts of the amine derivative represented by the formula [I], there may be mentioned, for example, salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid and the like; salts with organic acids, such as acetic acid, propionic acid, oxalic acid, citric acid, lactic acid, maleic acid, succinic acid, tartaric acid, mandelic acid, p-toluenesulfonic acid, sulfamic acid and the like; and salts with alkali metals, such as sodium,

potassium and the like.

  The amine derivatives of formula [I] and their salts according to the present invention include their isomers, such as geometric isomers, tautomers, optical isomers, racemic mixtures and the like, and they also include the whole of

  their crystalline forms and their hydrates.

  The preferred compound of the amine derivatives mentioned above of formula [I] and their salts according to the present invention is, for example, the

  compound wherein R is a 4-hydroxyphenyl group.

  The method of making a compound

  the subject of the present invention is described below.

  The compounds according to the present invention can be obtained, for example, by the following manufacturing processes: Manufacturing processes A.

NSO 2CH3 NSO 2CH3

  RNH it n 2 3OH Elimination of H SCH2 OH

H NCH2 2 S 2> NCH2HO 2H2 2 N

  H3C '' HHR protecting group H3C HH H3C3 [II] of the amino rump 1 or its salt or its salt or its salt B. CH3NH2 or its salt NSO CH and formaldehyde or NSO2CH I2 3.OHparaformaldehyde CHH 1OH O kCHCH2NCH CH NNCCHCH O CHS CHCH2NCNCH CH CH2S 2H In the above formulas, R is a protecting group for the amino group, in the presence of an acid or its salt or salt. In the above formulas, R is a protecting group for the amino group; and R has the same meaning as

indicated above.

  As salts of the compounds of formulas [II] and [III], salts analogous to those mentioned with respect to the compound of formula [I] may be mentioned. As RI, which is a protecting group of the amino group, there may be mentioned, for example, those described by T. W. Green, "Protective Groups in Organic Synthesis",

  published by John Wiley & Sons, Inc. in 1981.

  The above methods for making the compound of the present invention are described in detail below. (1) Production Method A The compound of formula [II], or its salt, is subjected to removal of the protecting group from the amino group,

  which makes it possible to obtain the compound of formula [I], or its salt.

  This reaction can be carried out specifically, for example, according to the method described by T. W. Green, "Protective Groups in Organic Synthesis" published

  by John Wiley & Sons, Inc., in 1981, or this modified method.

  (2) Process of manufacture B (i) The compound of formula [III], or its salt, is reacted with methylamine, or its salt, and formaldehyde or paraformaldehyde, which makes it possible to obtain the compound

of formula [I], or its salt.

  The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. As a solvent of this type, there may be mentioned, for example, hydrocarbons, such as hexane, benzene, toluene, xylene and the like; halogenated hydrocarbons, such as methylene chloride, chloroform and the like; nitriles, such as acetonitrile and the like; esters, such as ethyl acetate and the like; alcohols, such as methanol, ethanol, propanol-2 and the like; ethers, such as diethyl ether, tetrahydrofuran, dioxane, anisole and the like; carboxylic acids, such as acetic acid and the like, etc. These solvents can be used alone or in mixtures

two of them, or more.

  As the methylamine salt, there may be mentioned, for example, salts with a mineral acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid or

Similar.

  The amount of methylamine, or salt thereof, which is used, and the amount of formaldehyde or paraformaldehyde, which is used, are each at least equimolar to the amount of the compound of formula [III], or

of its salt.

  Although the reaction temperature and the reaction time are not critical and can be suitably varied depending on the reagents and the like, the above reaction can be carried out at a temperature of from 10 to 150 ° C. , for 10 minutes to

48 hours.

  (ii) The compound of formula [I], or its salt, can also be obtained by reacting the compound of formula [III], or its salt, with trilmethyl-1,3,5

  trimethylenetriemine in the presence of an acid.

  The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. As the solvent of this type, it is possible to use, for example, hydrocarbons, such as hexane, benzene, toluene and the like; halogenated hydrocarbons, such as methylene chloride, chloroform and the like; nitriles, such as acetonitrile and the like; esters, such as ethyl acetate and the like; alcohols, such as methanol, ethanol, propanol-2 and the like; ethers, such as diethyl ether, tetrahydrofuran, dioxane and the like; etc. These solvents can be used alone or as mixtures of two or more of them. As the acid used in the above reaction, there may be mentioned a mineral acid, such as hydrogen chloride, hydrogen bromide, or the like, or an organic acid, such as a sulfonic acid, for example, methanesulfonic acid, benzenesulphonic acid or

  p-toluenesulfonic acid, or the like.

  The amount of trimethyl-1,3,5 trimethylene

  triamine, which is used, and the amount of the acid that is used, are respectively at least equimolar and at least three times molar, relative to the amount of the

  compound of formula [III], or its salt.

  Although the reaction temperature and the reaction time are not critical and can be suitably varied depending on the reagents and the like, the above reaction can be carried out at a temperature of from 10 to 150 ° C. , for 10 minutes

49 hours.

  The amine derivative of formula [I], or its salt, which is obtained in this way, can be easily isolated and collected according to a conventional procedure, such as recrystallization, concentration, extraction, optical resolution. , column chromatography or the like. The salt of the amine derivative of formula [I] can be easily obtained from the amine derivative, in the state

  free, in accordance with a standard procedure.

  The process for producing a compound of formula [II], or its salt, and a compound of formula [III], or its salt, as starting materials for the manufacture

  of the compound of the present invention, is described below.

  The compound of formula [II], or its salt, and a compound of formula [III], or its salt, can be obtained, for example, according to the following manufacturing processes. Processes of manufacture H \ NCH2 eOCHO20H [IV] or its salt Acylation CH3 Protection of the amino group R1 VI Acylation cHNCH2OCH2OH IV] or its salt R1 CH3 NCH OR lla \ - - - a

H3 | CH3 CH 2, H2

[Halogenation I

[VIbl] -

  R1 / or its salt O NHE-O '2CH2X [VIal or its salt

3 hours

  {HSCH 2CH 2 NH 2 H2 22 = -HSCH 2 CH 2 NH 2

22 2 or so, - sel- _-

or its salt / base or its salt

NCH - "FOCH CH CH NH

CH 2 2 2 2 2 2

  CH O3kCH-SCH2C2H CH SH2HNH 3 [VII] or its salt | lI 2n YIR3a - [XII or its salt y1R3a '

/] CH3SO2N = C 2 3. N

3 2 2 3, b I Co

* 1 1 VIII] ---

* 2

- after -

  O o [as UOs tO [III] Ias uos no [III H H H H H E H

  HD HDNDNOHD HDS HD HD HODNDN HDHDSOHNO HDH: HN

  H. Jjl HO - ', He HO DzOSN' HD zOSN T-S uos no [X]

C ..... HD HONZH

  this HO / izs uos no [IIX] las uos no [XI]

H H D I

z -O zHH; D IL Hz z z H;

  -DN HD HDS HD0 U-DN HD HDS HD O HDN \

úHDOOSN

F I

  In the formulas above: - R is an acyl group - R is an eliminable group; 3e 3b - R3 and R3b, which may be the same or different, are substituted or unsubstituted alkyl or aryl groups; and R3a and R3b may be combined with each other to form an opheneylene or o-naphthylene group; X is a halogen atom; y and y 2 which may be the same or different, 0 are -O-, -S- or? and -S- - R and R1 have the same definitions as those indicated above. As salt of the compound of formula [IV], [V], [VIe], [VIb], [VII], [IX], EX [, [[XI] or [XII], mention may be made of analogous salts b those mentioned with regard to the

compound of formula [I].

  As R, which is an acyl group, there may be mentioned, for example, C 1-4 alkenoyl groups, which may be substituted by halogen atoms, such as formyl, acetyl, chlorecetyl, dichloroacetyl, trichloroacetyl and the like. , as well as groups

  aroyl, such as benzoyl and the like.

  As R2 which is a removable group, there may be mentioned C1-4 alkoxy groups, such as methoxy, ethoxy and the like; C1-4 alkylthio groups such as methylthio, ethylthio and the like; of the

  aryloxy groups, such as phenoxy, naphthoxy, o-hydroxy-

  phenoxy, o-hydroxynaphthoxy and the like; groups

  arylthio, such as phenylthio, naphthylthio, o-mercapto

  phenylthio, o-mercaptonaphthylthio and the like; C1-4 alkylsulfinyl groups such as methanesulfonyl, ethanesulphinyl and the like; arylsulfinyl groups, such as benzenesulfinyl, naphthalenesulphinyl and the like; etc. R2 may have at least one substituent selected from halogen atoms, such as fluorine, chlorine, bromine and iodine; a nitro group; a cyano group; C1-4alkyl groups, such as methyl, ethyl and the like; C1-4 alkoxy groups such as methoxy, ethoxy and the like; etc. As alkyl groups for R or R, there may be mentioned, for example, C 1-4 alkyl groups such as methyl, ethyl and the like; and as aryl groups, there may be mentioned, for example, phenyl and naphthyl. In addition, R3a and R3b and the o-phenylene or o-naphthylene groups formed by R3a and R3b when taken together may have at least one substituent identical to that

mentioned with regard to R2.

  According to the above manufacturing processes, the process for producing a compound of formula [II], or its salt, and a compound of formula [III], or its salt, to constitute starting materials for the preparation of the compound of the present invention, is

described in detail below.

  (1) The compound of formula [IV], or its salt, is protected from the amino group by an amino protecting group according to a commonly employed method, thereby obtaining the

formula [V], or its salt.

  (2) The compound of formula [V], or its salt, is halogenated, which makes it possible to obtain the compound of formula

[Via], or its salt.

  This halogenation can be carried out by

  example, according to the methods described in Acta.

  Chimi. Acad. Sci. Hung., 29 (1). 91-98 (1961), Tetrahedron Lett., L 339 (1979), J. Org Chem L, 3044 (1971), or

  in accordance with these modified methods.

  (3) The compound of formula [V], or its salt, is subjected to a conventional acylation reaction, using an approximately equimolar amount of an acylating agent, which allows

  to obtain the compound of formula [VIb], or its salt.

  (4) The compound of formula [IV], or its salt, is subjected to a conventional acylation reaction, using at least two equivalents of an acylating agent, which allows

  to obtain the compound of formula [VIc].

  The compounds thus obtained of the formulas [VIa) and [VIb], and their salts, and the compounds of formula [VIc] (these compounds are hereinafter generically designated as the compound of formula [VI]), may be used in

  subsequent reactions without being isolated.

  (5) The compound of formula [VI] is reacted with 2-aminoethanethiol, or its salt, in the presence or absence of a base, which makes it possible to obtain the compound of

formula [VII], or its salt.

  The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. As a solvent of this type, there may be mentioned, for example, halogenated hydrocarbons, such as methylene chloride, chloroform and the like; nitriles, such as acetonitrile and the like; ethers, such as tetrahydrofuran, dioxane and the like; alcohols, such as methanol, ethanol and the like; amides, such as N, N-dimethylformamide and the like; carboxylic acids, such as acetic acid and the like; the water; etc. These solvents can be used alone or as mixtures of two or more of them. As a base, in the presence of which the reaction is conducted, there may be mentioned, for example, sodium methoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, triethylamine and

  1,8-diaza-bicyclo [5., 4.0] -undecene-7 (DBU).

  The amount of 2-aminoethanethiol, or salt thereof, which is used, and the amount of the base, which is used, may each be at least equimolar to the

  amount of the compound of formula [VI].

  Although the reaction temperature and the reaction time are not critical and can be suitably varied depending on the reagents and the like, the above reaction can be carried out at a desired temperature.

  temperature of -20 & 100 ° C, for 1 minute & 12 hours.

  (6) The compound of formula [VII], or its salt, or the compound of formula [XI], or its salt, is reacted with the compound of formula [VIII], which makes it possible respectively to obtain the compound of formula [IX], or its salt, or

  compound of formula [XII], or its salt.

  The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. Examples of such solvents are aromatic hydrocarbons, such as benzene, toluene, xylene and the like; halogenated hydrocarbons, such as methylene chloride, chloroform and the like; nitriles, such as acetonitrile and the like; ethers, such as anisole and the like; esters, such as ethyl acetate; amides, such as N, N-dimethylformamide and the like; alcohols, such as methanol, ethanol, propanol-2 and the like; etc. These solvents can be used alone or as mixtures of two or more of them. The amount of the compound of formula [VIII], which is used, is at least equimolar to the amount of the compound of formula [VII], or its salt, or the

formula [XI], or its salt.

  As a compound of formula [VIII] which is preferred,

  for example, methanesulfonylimido-

  dimethyl dithiocarbonate, methanesulfonylimido

  diphenyl carbonate, methanesulfonylimino-2

benzodioxole-1,3 and the like.

  Although the reaction temperature and the reaction time are not critical and can be suitably varied depending on the reagents and the like, the above reaction can be carried out at a temperature of -10 to 150 ° C. , for 1 minute & 24 hours. The compound of formula [IX], or its salt, or the compound of formula [XII], or its salt, may be used

  in the subsequent reaction without being isolated.

  (7) The compound of formula [IX], or its salt, or the compound of formula [XII], or its salt, is reacted with the compound of formula [X], or its salt, in the presence or in the presence thereof absence of a base, which makes it possible to obtain respectively the compound of formula [III, or its salt, or the compound of formula [III], or

his salt.

  The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. As a solvent of this type, there may be mentioned, for example, aromatic hydrocarbons, such as benzene, toluene, xylene and the like; halogenated hydrocarbons, such as methylene chloride, chloroform and the like; nitriles, such as acetonitrile and the like; ethers, such as anisole and the like; esters, such as ethyl acetate and the like; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides, such as dimethyl sulfoxide and the like; alcohols, such as methanol, ethanol, propanol-2 and the like; etc. These solvents can be used alone or in mixtures of two of

them, or more.

  As the base used in the above reaction, mention may be made, for example, of inorganic bases, such as sodium carbonate, potassium carbonate and the like, as well as organic bases, such as potassium acetate, triethylamine,

  tetramethylguanidine and the like.

  The amount of the compound of formula [X], or its salt, which is used, and the amount of the base, which is used, are each at least equimolar to the amount of the compound of formula [IX], or its salt , or the quantity of

  compound of formula [XII], or its salt.

  Although the reaction temperature and the reaction time are not critical and can be suitably varied depending on the reagents and the like, the above reaction can be carried out at a desired temperature.

  temperature of 20 to 150 ° C, for 30 minutes to 24 hours.

  The compound of formula [II], or its salt, or the compound of formula [III], or its salt, which is obtained thereby, can be easily isolated and collected according to a conventional procedure, such as recrystallization. , concentration, extraction, optical resolution, column chromatography or the like. The salt of the compound of formula [II], or the salt of the compound of formula [III], can be obtained easily from the compound in the free state according to a conventional method. Pharmacological activities of the amine derivative

  of formula [I] and its salt are described below.

0 2619816

  Test compounds Ra _C NSO2CH NC H 2Ok 'CH2SCH2CH2NCNCH2CH

CH3 HH R

  No. Ra R. i H Compound Compounds 2 H NHSO2CH3 _ 3 H e -CONH2

4 CH3

compounds

t emoins.

CH3 OH

  [I] Inhibitory activity on gastric acid secretion (pylorus ligation method) This activity was measured according to the method of H. Shay et al., Described in Gastroenterology, 43 (1945). Groups of six or seven Wistar rats (male, -230 g) fasted for 24 hours, after which the pylorus of each rat was ligated under anesthesia to the ether. The test compounds were administered intraduodenally after ligation. The rats were then subjected to coeliography and, immediately thereafter, 25 mg / kg of histamine.

  were administered subcutaneously dorsally.

  After 3 hours, the cardia of the stomach was ligated, then the stomach was removed. Gastric juice was collected by centrifugation, and the total amount was measured. I ml of the gastric juice was removed and titrated with an aqueous solution of sodium hydroxide O, 1N to an end point of pH 7.0. To administer the test compound, the compound was dissolved in dimethylsulfoxide (DMSO) and then diluted with distilled water to obtain a 0.25% aqueous solution of DMSO containing the test compound. An aqueous solution of 0.25% DMSO containing no compound

  test was administered to the control group.

  The rate of inhibition of gastric acid secretion was calculated from the following equation: Production Acid Production of Group Acid Group - Treated Rate of Control Inhibition Acid Secretion Medication = ------------ x 100 gastric (%) Acid production of the control group The results of tests obtained are presented in

Table 1.

Table 1

  N 'of Test Compound Dose Inhibition Rate (mg / kg) (%)

1 0.625 6716 **

1.25 82; 2 **

2 1.25 51.3 *

3 1.25 54; 2 *

4 1.25 30.6

5 0 32.7

  Note: ** <0 p <001 * p <05 [II] Acute Toxicity A test compound was administered to ICR mice (males, 27-30 g) intravenously, and the LD50 value was calculated by the approximation method

5

  successive. The results obtained are presented in the

Table 2.

Table 2

  N of the test compound LD50 L50 ___ __ _ __ (_ <mg / kg

1,100.0

2 12918

3,151.0

4 85.4

90.7

  As is apparent from Table 1 and Table 2, the amine derivatives of formula [I], and their salts, exhibit excellent inhibitory activity on gastric acid secretion, and, therefore, excellent anti-ulcer activity. , they have low toxicity, and

  therefore, they offer a greater margin of safety.

  In addition, they have excellent stability.

  The anti-ulcer agent containing the amine derivative of formula [I], or its salt, can be prepared in various forms, such as tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, lozenges, ointments, suppositories, injections, suspensions, emulsions, drops, syrups and the like in accordance with the usual methods. They may be administered either by oral or parenteral route, and in particular oral administration is preferred. To bring them in various forms suitable for oral or parenteral administration, the preparation can be carried out using non-toxic, pharmaceutically acceptable additives, which are used in the usual way, such as excipients, binders, lubricants,

  disintegration, suppository bases and the like.

  If necessary, other additives may also be used, such as isotonicity agents, stabilizers, dispersants, antioxidants, dyes, flavors,

tampons and the like.

  The above forms may include other drugs useful from the point of view of treatment objectives. As regards the dosage for administration of the amine derivative of formula [I], or its salt, these may be administered orally or parenterally, generally at a dose of 1 μg / ml. kg at 10 mg / kg per day and per adult, in 1 to 4 doses Naturally, the dose of administration can be suitably varied depending on the route of administration and the symptoms presented by the patients. This invention is explained below with reference to the Reference Examples, Examples and Preparation Examples, which are in no way intended to limit the scope of the present invention, but

simply illustrate it.

  The mixing ratio of the solvents in the

  Examples are in volumes unless otherwise indicated.

  As a column chromatography support, silica gel (Kieselgel 60, Art 7734, manufactured by

by Merck Co.).

  REFERENCE EXAMPLE 1 267 g of diphenyl carbonate and 298 g of phosphorus pentachloride were reacted at 160 ° C for 15 hours by distilling off the phosphorus oxychloride produced by the reaction. After completion of the reaction, the residual phosphorus oxychloride and phosphorus pentachloride were removed by distillation under

  reduced pressure, to obtain dichloro-diphenoxymethane.

  600 ml of anhydrous ethyl acetate and 148 g of methanesulfonamide were added thereto and the mixture was refluxed for 8 hours. After cooling, 1 liter of n-hexane was added to the mixture, and the deposited crystals were collected by filtration. The crystals were washed with water and dried to obtain 179 g (yield: 49%) of methanesulfonylimidocarbonate.

  diphenyl, having a melting point of 124-125.5 ° C.

  Reference Example 2 53.4 g of methanesulfonamide and 89.4 g of 1,2-dichloro-1,3-benzodioxole were heated under reflux.

  with 400 ml of anhydrous ethyl acetate, for 7 hours.

  After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained, 200 ml of benzene was added, and the mixture was refluxed for 10 minutes, then cooled slowly to room temperature with stirring. The deposited crystals were collected by filtration and washed with benzene, water and 2-propanol, in that order, to obtain 83 g.

  (yield: 83%) of methanesulfonylimino-2 benzo

  dioxole-1,3. Melting point: 161-163 ° C (recrystallized from

ethyl acetate).

2 6 1 9 8 1 6

  Reference Example 3 (1) 23.5 g of 2,2,2-trichloroethylchloroformate was added, dropwise, to 140 ml of a solution of

  methylene chloride containing 14.1 g of N-methylamino-

  5-methyl-2-furan methanol and 8.9 ml of pyridine, at a temperature of 4 to 5 ° C, over a period of minutes, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was introduced into 100 ml of water. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 2: 1), to give

  obtain 16.4 g (yield: 50%) of [N-methyl-N- (tri-

  chloro-2,2,2-ethoxycarbonyl) aminomethyl] -5-furan

oily methanol.

  NMR (CDCl3) value of 8: 2.15 (1H, brs), 3.00 (3H, s), 4.47 (2H, s) 4, 55 (2H, s), 4.76 <2H, 7.26 g of N-chlorosuccinimide were dissolved in 1 ml of methylene chloride. 4.18 ml of dimethylsulfide were added dropwise at a temperature of 10 ° C. The mixture was stirred at the same temperature for 30 minutes. 30 ml of a solution of methylene chloride containing 16.4 g of [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -5-furan-methanol were added dropwise thereto. at a temperature of 5 to 10 ° C over 20 minutes, and stirring was performed at the same temperature for 1 hour. The reaction mixture was introduced into 100 ml of ice-water mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over sulfate.

anhydrous magnesium.

  Separately, 20.0 grams of a 28% by weight solution of sodium methylate in methanol was added dropwise to 15 ml of a methanol solution containing 5.8% amino acid hydrochloride. -2 ethanethiol, with cooling by ice, in a nitrogen atmosphere. Then, the dried organic layer obtained above was added dropwise at a temperature of 5 to 10 ° C over a period of minutes. The temperature of the mixture was slowly raised to room temperature with stirring for 30 minutes. The reaction mixture was introduced into 100 ml ice-water mixture, and the organic layer was separated. Then, 70 ml of water was added to the organic layer, and the mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in half of water. The resulting aqueous solution was lifted with ethyl acetate, and the aqueous layer was adjusted to pH 11 with an aqueous solution of sodium hydroxide.

  sodium 5N, then extracted with 150 ml of ethyl acetate.

  The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 15.6 g (80% yield) of [ [[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -5

  2-furyl] methylthio] -2 ethylamine oily.

  NMR (CDCl3) value of 6: 1.45 (2H, s), 2.45 - 2.95 <4H, m>, 3.01 (3H, s), 3.68 (2H, s), 4, 47 (2H, s), 4.77 (2H, s), 6.16 (2H, m) (3) 13.8g of dithphenyl methanesulfonylimidocarbonate were dissolved in 50ml of acetonitrile. Under cooling with ice, 17.7 g of [[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -5-furyl] methylthio] -2-ethylamine were added, and the mixture was stirred for 10 minutes. Then, 10.9 g of DL-octopamine, 2.3 g of potassium acetate, 10 ml of 2-propanol and 16.5 ml of triethylamine were added, and the mixture was refluxed for 2 hours. After cooling, ml of water and 180 ml of ethyl acetate were added thereto, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, and a solution

  saturated aqueous sodium chloride, in that order.

  Then, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 3), to obtain 26.9 g (yield: 90%) of

  N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl

  N - [[[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) amino]

  methyl] -5-furyl-2-methylthio] -2-ethyl] guanidine oily.

  NMR (CDCl3) value of 6: 2.45 - 2.85 (2H, m), 2.84 (3H, s), 2.98 (3H, s), 3.10 - 3.60 (4H, m). ), 3.67 (2H, s), 4.43 <2H, s), 4.55 - 4.95 (1H, m), 4.72 (2H, s), 6.17 (2H, s) ,

6.77, 7.13 (4H, ABq, J = 8.2 Hz).

  The following compounds were obtained from a

* analogous way.

  N - [(4-carbamoyl-phenyl) -2-hydroxy-ethyl] - -

  N '-methanesulfonyl-N "- [[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -5-furyl] methylthio] -2-ethyl] guanidine o N- [2-hydroxy-] - [- methanesulfonylamino) -3 phenylt-2

  ethyl] -N'-methanesulfonyl-N "- [[[[N-methyl-N- (tri-

  2,2,2-chloroethoxycarbonyl) aminomethyl] -5-furyl] methylthio] -2-ethyl] guanidine

2'619816

  Reference Example 4 (1) 42.6 g of 2-methanesulfonylimino benzodioxole1.3 were suspended in 126 ml of methylene chloride. 31.4 g of [(2-furyl) methylthio] -2-ethylamine were added dropwise at a temperature of 10 to 15 ° C. Stirring was performed at the same temperature for 30 minutes. The reaction mixture was mixed with 250 ml of benzene, and the resulting mixture was stirred at the same temperature for 30 minutes. The deposited crystals were collected by filtration, to obtain, 5 g (yield: 88%) of N - [[(2-furyl) methylthio] -2

  ethyl] -O- (2-hydroxyphenyl) -N'-methanesulfonylisourea.

  Melting point: 110-111.5 ° C (recrystallized from ethyl acetate) NMR (CDCl3) value of 5: 2.76 (2H, s), 2.88 (3H, s), 3.35 -3.85 (2H, m), 3.75 (2H, s), 6.24 (2H, m), 6.75-7.25 (4H, m), 7.31 (1H, m) ( 2) To 50 ml of acetonitrile was added 5.0 g of

  N - [[(2-furyl) methylthio] -2-ethyl] -O- (2-hydroxyphenyl) -

  N'-methanesulfonylisourea, 2.9 g of DL-octopamine and 660 mg of potassium acetate. The mixture was refluxed for 50 minutes. Then, the mixture was cooled, and the solvent was distilled off under reduced pressure. To the residue thus obtained, 50 ml of ethyl acetate and 30 ml of water were added. The mixture was adjusted to pH 2.0 with 2N hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent benzene: ethyl acetate = 2: 3) to obtain 2.8 g.

  (yield: 51%) of N - [[(2-furyl) methylthio] -2 ethyl] -

  N '- [2-hydroxy-4-hydroxy-phenyl] ethyl] -N "-methane

  sulfonylguanidine, having a melting point of 109 to

11lú, 5-C.

  NMR (d-DMSO) S value: 2.57 (2H, m), 2.75 (3H, s), 3, 10-3.50 (4H, m), 3.80 (2H, s), 4.50-4.90 (1H, m), 6.34 (2H, s),

  6.74, 7.20 (4H, ABq, J = 8.3Hz), 7.55 (1H, s).

  The following compounds were obtained from a

analogous way.

  N - [[(2-furyl) methylthio] -2-ethyl] -N '- [2-hydroxy-2-hydroxy]

  [(methanesulfonylamino> -3 phenyl] -2 ethyl] -N "-methane-

  sulfonylguanidine NMR (CDCl3) value of 8: 2.45-2.80 (2H, m), 2.83 (3H, s), 2.93 (3H, s), 3.05-3, 65 (4H, m), 3.68 (2H, s), 4.65-5.05 (1H, m), 6, 21 (2H, m),

7.00-7.50 (5H, m).

  N - [(2-Carbamoyl-phenyl) -2-hydroxyethyl] -N '- [[(2-furyl) methylthio] -2 ethyl] -N "-methanesulfonylguanidine NMR (d6-DMSO) value of 8: 2 , 44-2.56 (2H, m), 2.74 (3H, s), 3.10-3.50 (4H, m), 3.79 (2H, s), 4.70-4.94 (1H, m), 6.26-6.41 (2H, m),

  7.55 (1H, m), 7.44, 7.87 (4H, ABq, J = 8.3 Hz).

  Reference Example 5 C1) 45.2 g of trichloroacetyl chloride were added dropwise to 150 ml of a solution of methylene chloride containing 15.3 g of N-methylaminomethyl-5-furan-methanol and 36.1 g. ml of triethylamine at a temperature of -30 to -20 ° C over a period of 1 hour. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was introduced into 100 ml of a water-ice mixture. The organic layer has

  was separated and dried over anhydrous magnesium sulfate.

  The solution thus obtained was added to 28 ml of a solution of acetic acid containing 18.4 g of 2-aminoethanethiol hydrochloride at room temperature. The mixture was refluxed for hours. The reaction mixture was introduced into ml of ice-water mixture. The resulting mixture was adjusted to pH 9.5 with 5N aqueous sodium hydroxide solution at a temperature of 5-10 ° C. The organic layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. To the resulting solution was added dropwise 200 ml of ethanol solution containing 9.72 g. anhydrous oxalic acid. Methylene chloride has

  was removed by distillation under atmospheric pressure.

  The deposited crystals were collected by filtration, to obtain 30.1 g (64% yield) of oxalate (1: 1) of [[[N-methyl-N- (trichloroacetyl) aminomethyl] -5-furyl]

methylthio] -2-ethylamine.

  Melting point: 138-139.5 ° C (recrystallized from ethanol) NMR (d-DMSO) value 2.40-3.30 (4H, m), 3.23 (3H, s), 3 , 81 (2H, s>,

4.68 (2H, s), 6.32 (2H, s).

  (2) 43.6 oxalate (1: 1) of [[[N-methyl-N- (trichlo-

  Reacetyl) aminomethyl] -5-furyl-2-methylthio] ethylamine was added to 180 ml of methylene chloride and 250 ml of water. 38 ml of 5N aqueous potassium hydroxide solution was added dropwise at a temperature of 10 ° C. and dissolved. The organic layer was separated, washed with an aqueous solution of

  sodium & 10%, and dried over anhydrous sodium sulfate.

  To the thus prepared solution was added 29.1 g of diphenyl methanesulfonylimidocarbonate under ice-cooling, and the mixture was stirred for 30 minutes. The methylene chloride was distilled off under reduced pressure. To the residue thus obtained, 200 ml of 2-propanol was added. The deposited crystals were collected by filtration to obtain

  48.9 g (yield: 90%) of N-methanesulfonyl-

  N '- [[[[N-methyl-N- (trichloroacetyl) aminomethyl] -5-furyl]

  methylthio] -2-ethyl] -O-phenylisourea.

  Melting point: 85-87 ° C (recrystallized from 2-propanol) NMR (CDCl3) value of 6: 2.76 (2H, t, J = 6.3 Hz), 2.85 (3H, s), 3.27 (3H, s), 3.403.75 (2H, m), 3.73 (2H, s), 4.64 (2H, s), 6, 12-6.25 (2H, m),

7.00-7.41 (5H, m).

  (3) To 160 ml of acetonitrile was added 32.6 g of

  N-methanesulfonyl-N '- [[[N-methyl-N- (trichloroacetyl) amino]

  methyl] -5-furyl] methylthio] -2-ethyl] -O-phenylisourea, 13.8 g of DLoctopamine, 21 ml of triethylamine and 2.94 g of potassium acetate. The mixture was refluxed for 1 hour in a nitrogen atmosphere. After cooling, the solvent was distilled off under reduced pressure. To the residue thus obtained, 250 ml of ethyl acetate and 150 ml of water were added. The mixture was adjusted to pH 2.0 with 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 2), to obtain 29.9 g (yield: 83%) of N- [hydroxy-2 (4-hydroxy) phenyl) -2

  ethyl] -N'-methanesulfonyl-N "- [[[[N-methyl-N- (trichloro-

  acetyl) aminomethyl] -5-furyl] methylthio] -2-ethyl] guanidine.

  NMR (CDCl3> value of: 2.40-2.95 (2H, m), 2.81 (3H, s), 3.05-3.80 (4H, m), 3.26 (3H, m.p. s), 3.66 (2H, s), 4.40-4.95 (1H, m), 4.60 (2H, s), 6.10-6, (2H, m),

6.75, 7.11 (4H, ABq, J = 8.5 Hz).

  Reference Example 6 (1) 11.6 g of diphenyl methanesulfonylimidocarbonate were dissolved in 40 ml of methylene chloride. Under cooling with ice, we have

  Added 15 g of [[[N-methyl-N- (2,2,2-trichloroethoxy)

  carbonyl) aminomethyl] -5-furyl] methylthio] -2-ethylamine.

  The mixture was stirred for 10 minutes. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 2: 1), for

  obtain 17.8 g (yield: 78%) of N-methanesulfonyl-

  N '- [[[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) amino)

  methyl] -5-furyl-2-methylthio] -2-ethyl] -O-phenylisourea oil. NMR (CDCl3) value of 8: 2.77 (2H, t, J = 6.4 Hz), 2.86 (3H, s), 3.00 (3H, s), 3.40-3.75 ( 2H, m), 3.73 (2H, s), 4.45 (2H, s), 4.77 (2H, s), 6.16 (2H, s),

7.00-7.45 (5H, m).

  (2) In 11 ml of dimethylsulfoxide, 4 g of N-methanesulfonyl-N '- [[[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -5-furyl] methylthio were dissolved in ] -2 ethyl] -O-phenylisourea. 2.9 g of S (+) - octopamine ([+], +4.4 (c = 1, 0.1N HCl)) were added to the mixture. The mixture was stirred under a nitrogen atmosphere at room temperature for 10 hours, 50 ml of ethyl acetate was added, and the resulting mixture was washed with 0.5 N hydrochloric acid and a solution. saturated aqueous sodium chloride, in that order, and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The residue thus obtained was purified by column chromatography (eluent: benzene: acetate of ethyl = 1: 3), to obtain 5.2 g (yield: 86%) of S (+) - N- [hydroxy2 (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [ [[[N-methyl-N (2,2,2-trichloroethoxycarbonyl

  ethoxycarbonyl) aminomethyl] -5-furyl] methylthio] -2 ethyl] -

  guanidine. [? 25 = +6.5 (c = 1, methanol) Analogously and using -5 '(, H1O N) 1 R (-) - octopamine ([a] D = -55, c = 1 , HCl 0, MN) instead of S (+) - octopamine, the

  R (-) - N- [2-hydroxy-4-hydroxy-phenyl] ethyl] -N'-methane

  sulfonyl-N "- [[[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) -

  aminomethyl] -5-furyl] methylthio] -2-ethyl] guanidine.

Example 1

  (1) 370 ml of tetrahydrofuran was dissolved

  26.9 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -

  N '-methanesulfonyl-N "- [[[[N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -5-furyl] methylthio] -2-ethyl] guanidine, 320 ml was added thereto of an aqueous solution of 0.5M potassium dihydrogen phosphate and 42g of an active zinc powder, and the mixture was stirred at room temperature for 3 hours The reaction mixture was adjusted to pH 9.8 with 5N aqueous sodium hydroxide solution and extracted with 370 ml of ethyl acetate The solvent of the extract was distilled off under reduced pressure The residue thus obtained was purified by column chromatography (eluent chloroform: methanol: aqueous ammonia solution =: 15: 1>, then rescristalled in an aqueous solution of ethanol at 95%, to obtain 12.6 g (yield: 65%) of

  N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl

  N "- [[[(methylamino) methyl-5-furyl-2] methylthio] -2 ethyl] -

  guanidine, having a melting point of 146.5 to 147 ° C.

  IR (KBr) cm: 1580, 1255, 1105 NMR (d6-DMSO) value of 6: 2.24 (3H, s), 2.35-2.65 (2H, m), 2.74 (3H, s); ), 3.00-3.50 (4H, m), 3.56 (2H, s), 3.74 (2H, s), 4.50-4.80 (1H, m), 6.15 ( 2H, m), 6.71, 7.18 (4H, ABq, J = 8.5 Hz) The following compounds were obtained from

analogous way.

  N - [(4-carbamoyl-phenyl) -2-hydroxy-ethyl] -N'-methane

  sulfonyl-N "- [[[(<methylamino) methyl-5-furyl-2] methyl-

  thio] -2 ethyl] guanidine NMR (d6-DMSO) value of: 2.25 (3H, s), 2.35-2.65 (2H, m), 2.74 <3H, s), 2.90 -3.60 (414, m), 3.57 (2H, s>, 3.75 (2H, s) 4, 65-5.00 (1H, m), 6.18 (2H, m), 7. , 45, 7.86 (4H, ABq, J = 8.2 Hz) e N [2-hydroxy- [(methanesulfonylamino) -3-phenyl] -2 ethyl] -N 'methanesulfonyl-N "- [[[(methylamino 5-methyl-2-furyl] methylthio] -2-ethyl] guanidine NMR (CDCl3) value of 5: 2.25 (3H, s), 2.55-2.85 (2H, m), 2.86 (3H) , s), 2.97 C3H, s), 3.10-3.70 (4H, m), 3.61 (2H, s), 3.69 (2H, s), 4.70-5.00. O (1H, m), 6.10 (2H, s), 7.00-7.40 (4H, m) (2) In 1430 ml of an aqueous ethanol solution, 239 g were dissolved. N - [(4-carbamoyl-phenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [[[(methylamino) methyl] furyl-2] methylthio] -2-ethyl] guanidine. A solution formed by dissolving 46.8 g of acid was added.

  oxalic acid in 240 ml of an aqueous solution of ethanol 95%.

  In addition, 2.5 g of seed crystals were added.

  The mixture was stirred at 40 ° C. for 3 hours and at room temperature for 3 hours, then allowed to stand overnight. The deposited crystals were collected by filtration to obtain 257 g (yield: 91%) of oxalate (1: 1) of N- (4-carbamoyl).

  2-phenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [[[(<methyl-

  aminom) 5-methyl-2-furyl] methylthio] -2-ethyl] guanidine.

  Melting point: 142.5-145.5 ° C (recrystallized from 95% aqueous ethanol) NMR (D20) value: 2.62 (2H, t, J = 6.4 Hz), 2 , 73 (3H, s), 2.85 (3H, s), 3.34 (2H, t, J = 6.4Hz), 3.61 (2H, d, J = 5.8Hz), 3 , 77 (2H, s), 4.26 (2H, s), 5.05 (1H, t, J = 5.8 Hz), 6.34, 6.60 (2H, ABq, J = 3.4 Hz>

7.54, 7.87 (4H, ABq, J = 8.3 Hz).

  In a similar manner and using as solvent a mixture of methanol and ethanol (1: 2.5), and as acid, orthophosphoric acid & 98%, was obtained phosphate (1: 1) N - [(2-Carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [[[(methylamino) -5-methyl-2-furyl] methylthio] -2-ethyl] guanidine, with % yield Melting point: 140-142 ° C [recrystallized from a mixture of ethanol and acetic acid (4: 1)] NMR (D 2 O) value of 6: 2.63 (2H, t), 2 , 71 (3H, s), 2.81 <3H, s), 3, 11 (3H, s), 3.36 (2H, t), 3.58 (2H, d), 3.79 (2H, s), 4.25 (2H, s), 4.97 (1H, t), 6.35, 6.59 (2H, ABq, J = 3.1 Hz),

7.16-7.68 (4H, m).

  In an analogous manner, N- [2-hydroxy-2 - [(methanesulfonylamino) -3-phenyl] ethyl] -N'-methanesulfonyl-N "[[[(methylamino)) hydrochloride was obtained.

  5-methyl-2-furyl] methylthio] -2-ethyl] guanidine.

  NMR (D 0) value of: 2.63 (2H, t), 2.71 (3H, s), 2.81 (3H, s), δ 3.11 (3H, s>, 3.36 ( 2H, t), 3.58 (2H, d), 3.79 (2H, s), 4.25 (2H, s), 4.97 (1H, t), 6.35, 6.59 (2H; , ABq, J = 3.1 Hz),

7.16-7.68 (4H, m).

Example 2

  240 mg of methylamine hydrochloride were dissolved in 0.27 ml of 37% (w / w) aqueous formaldehyde solution. 2.5 ml of a solution of tetrahydrofuran containing 500 mg of N - [[(2-furyl) methylthlo] -2-ethyl] -N '- [2-hydroxy-hydroxy] was added at room temperature. 4-phenyl) -2-ethyl] -N "-methanesulfonylguanidine.

  The mixture was stirred at the same temperature for 5 hours.

  The reaction mixture was introduced into 30 ml of water. The resulting mixture was adjusted to pH 9.5 with 1 N aqueous sodium hydroxide solution and extracted with two 50 ml portions of a 1: 1 mixture of ethyl acetate and tetrahydrofuran. The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), to obtain 220 mg (yield: 40%) of N- [2-hydroxy-2 ( 4-hydroxy-phenyl) -2-ethyl] -N'-methanesulfonyl-N "- [[[(methylamino) methyl -5

  2-furyl] methylthio] -2-ethyl] guanidine.

  This compound showed the same melting point, the same IR spectrum and the same NMR spectrum as that of the compound

obtained in Example 1.

Example 3

  To 10 ml of a tetrahydrofuran solution containing 310 mg of trimethyl-1,3,5-trimethylenetriamine, 1.3 g of p-toluenesulfonic acid monohydrate and 1.0 g of N - [[(2-furyl) methylthio) were added. 2-ethyl-N '- [2-hydroxy-4-hydroxy-phenyl] ethyl] -N "-methanesulfonylguanidine The mixture was stirred at room temperature for 3 hours. The resulting mixture was adjusted to pH 9.5 with 1 N aqueous sodium hydroxide solution and extracted with two 50 ml portions of a 1: 1 mixture of ethyl acetate and tetrahydrofuran. The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), to give 440 mg <yield:

  %) of N- [2-hydroxy-4-hydroxy-phenyl] ethyl] -N'-methane

  sulfonyl-N "- [[[(methylamino) methyl-5-furyl] methylthio] -2

ethyl] guanidine.

  This compound showed the same melting point, the same IR spectrum and the same NMR spectrum as that of the compound

obtained in Example 1 (1>.

Example 4

  9.4 g of N- [2-hydroxy-4-hydroxy-phenyl-2-ethyl] -

  N'-methanesulfonyl-N "- [[[[N-methyl-N- (trichloroacetyl) amino]

  5-methyl-2-furyl] methylthio] -2-ethyl] guanidine were dissolved in a mixture of 8 ml of ethanol and 47 ml of a 1N aqueous sodium hydroxide solution in a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. Then, the mixture was adjusted to pH 9.7 with 6N hydrochloric acid under ice cooling, a seed crystal was added, and the mixture was stirred for 4 hours at room temperature. The deposited crystals were reutilized by filtration to obtain 6.0 g (yield: 84%) of

  N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl

  N "- [[[(methylamino) methyl-5-furyl-2] methylthio] -2 ethyl] -

  guanidine. This compound showed the same melting point, the same IR spectrum and the same NMR spectrum as those of the compound

obtained in Example 1 (1).

Example 5

  S (+) - N- [2-hydroxy-4-hydroxy-phenyl] ethyl] -

  N '-methanesulfonyl-N "- [[[[N-methyl-N- (2,2,2-trichloroethyl)

  ethoxycarbonyl) aminomethyl] -5-furyl] methylthio] -2 ethyl] -

  guanidine was treated in the same manner as in Example 1 (1) to give S (-) - N- [2-hydroxy-4-hydroxy-phenyl] ethyl] -N'-methanesulfonyl-N "- [[[(methylamino)

  5-methyl-2-furyl] methylthio] -2-ethyl] guanidine.

  [a] D5 = -6.6 '(c = 1, HC1 0, 1N> The following compound was obtained in the same manner:

  e R (+) - N- [2-hydroxy-4-hydroxy-2-phenyl] -ethyl] -

  N '-methanesulfonyl-N "- [[[(methylem [no] methyl-5-furyl-2] -methylthio] ethyl] guanidine [a] 5 = + 6.3 - (C = 1, 0.1 N HCl) )

Example 6

  250 mg of methylamino hydrochloride and 170 ng of

  95% paraformaldehyde was added to 1.5 ml of methanol.

  The mixture was refluxed for 90 minutes. 1.5 ml of a methanol solution containing 500 mg of N - [[(2-furyl) methylthio] 2 ethyl] -N '- [[2-hydroxy-4-hydroxy-phenyl] -2] were added thereto. ethyl] -N-methanesulfonylguanidine at room temperature The mixture was subjected to the reaction at the same temperature for 2 days The solvent was distilled off under reduced pressure To the residue thus obtained 20 ml was added The mixture was adjusted to pH 9.6 with 5N aqueous sodium hydroxide solution and extracted with two 30 ml portions of a 1: 1 mixture of ethyl acetate and tetrahydrofuran. The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), to obtain 220 mg (yield: 40%) of N- [2-hydroxy-4-hydroxy-phenyl-2-ethyl] -N'-methanesulfonyl-N "- [[[(methylamino)

  5-methyl-2-furyl] methylthio] -2-ethyl] guanidine.

  This compound showed the same melting point, the same IR spectrum and the same NMR spectrum as that of the compound

obtained in Example 1 (1).

Example 7

  (1) 5.61 g of N - [[(2-furyl) methylthio] -2 ethyl] -

  N '- [2-hydroxy-4-hydroxy-phenyl] ethyl] -N "-methane

  sulfonylguanidine and 1.75 g of (N, N-dimethylamino) -4-pyridine were dissolved in a mixture of 20 ml of

  methylene chloride and 5.6 ml of N, N-dimethylformamide.

  To this solution was added dropwise 8 ml of a solution of methylene chloride containing 2.00 g of benzoyl chloride at a temperature of -35 to -25 ° C over a period of 30 minutes. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed with 30 ml of water and 30 ml of a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 1), to obtain 5.40 g (yield: 77%) of N - [(benzoyloxy-4-phenyl) - 2-hydroxy-2-ethylhexyl N '- [[(furyl-2)

  methylthio] -2-ethyl] -N "-methanesulfonylguanidine.

  NMR (CDCl3) δ 2.69 (2H, t), 2.88 (3H, s), 3.10-3.55 (4H, m), 3.73 (2H, s), 4.90. (1H, m), 6.15-6.35 (2H, m), 7.10-7, 70 (8H, m), 8.05-8, 30 (2H, m) (2) 2.11 g of methylamine hydrochloride and 1.48 g of

  95% paraformaldehyde was added to 10 ml of methanol.

  The mixture was refluxed for 1.5 hours. After cooling, 15 ml of a methanol solution containing 5.40 g of N [(4-benzoyloxyphenyl) -2

  2-hydroxyethyl] -N '- [[(2-furyl) methylthio] -2-ethyl] -

  N-methanesulfonylguanidine The resulting mixture was stirred at room temperature for 24 hours 50 ml of ethyl acetate and 50 ml of water were added thereto The resulting mixture was adjusted to pH 9.6 by a solution The organic layer was separated and 30 ml of water was added and the mixture was adjusted to pH 1.5 with 2N hydrochloric acid under cooling. The aqueous layer was separated and 50 ml of chloroform was added The mixture was adjusted to pH 9.6 with 5N aqueous sodium hydroxide solution under ice-cooling. The solvent was removed by distillation under reduced pressure, the oily residue thus obtained was dissolved in 50 ml of methanol, and the residue was added to 30 ml of saturated aqueous sodium chloride solution. 0 g of a solution of m 28% by weight sodium thylate in methanol The mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. 2.6 ml of a hydrochloric acid ethanol solution

  4N was added under ice cooling.

  The mixture was stirred at the same temperature for minutes. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), to obtain 3.57 g (yield: 75%) of N- [hydroxyl] 2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [[[(methylamino)

  5-methyl-2-furyl] methylthio] -2-ethyl] guanidine.

  This compound showed the same melting point, the same IR spectrum and the same NMR spectrum as that of the compound

obtained in Example 1 (1>.

  Preparation Example 1 75 g of homogenous

  N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl

  N "- [[[(methylamino) methyl-5-furyl-2-methylthio] -2-ethyl] guanidine, 15 g of Avicel PH 102 (microcrystalline cellulose manufactured by ASAHI CHEMICAL INDUSTRY, CO., LTD.), 29 g of Kollidon CL (crosslinked polyvinyl pyrrolidone manufactured by BASF), 29 g of Adsolider 101 (anhydrous silicic acid manufactured by Freund IND CO., LTD.) And 3 g of stearic acid and 1.5 g of magnesium stearate. The billets were milled and passed through a 707 μm (24 mesh) mesh sieve and the resulting powder was mixed with 4.48 g of Kollidon CL. 5.76 g of Adsolider 102 (anhydrous silicic acid manufactured by Freund

  IND. CO., LTD.), 4.9 g of Avicel PH 302 (micro cellulose).

  crystalline manufactured by ASAHI CHEMICAL INDUSTRY, CO., LTD.) and 2.36 g of magnesium stearate. The mixture has been

  converted into tablets each weighing 170 mg.

  Preparation Example 2 10 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N-methanesulfonyl-N "- [[[(methylamino) methyl-5-furyl] methylthio] -2 ethyl] guanidine and 5 g of L-aspartic acid were suspended in 200 ml of distilled water for injection The suspension was adjusted to pH 5.5 with 1N hydrochloric acid with stirring, To form a solution, 25 g of D-mannitol was dissolved therein, and the resulting solution was subjected to sterile filtration using a 0.22 μm filter. 2 ml per vial The flasks were lyophilized according to a

  conventional method for obtaining a vial for injection.

Claims (8)

  1 - Amine derivative represented by the formula NSO CH H. Nw --- I 2 3 OH NCH.2'O 'CH.2SCH CH 2NCNCH2CH CH3 HH   in which R is a 4-hydroxyphenyl group, a 4-carbamoyl phenyl group or a 3-methanesulfonylamino phenyl group, or a salt of this derivative.   2 - amine derivative, or its salt, according to claim 1, characterized in that R is a group 4-hydroxyphenyl.   3 - amine derivative, or its salt, according to claim 1, characterized in that R is a group carbamoyl-4 phenyl.   4 - Amine derivative, or its salt, according to claim 1, characterized in that R is a group 3-methanesulfonylamino phenyl.   - Process for producing an amine derivative represented by the formula: NC.H NSO2CH3 k he ----- OH N C CH2SCH2CH2NCNCH2CH HNC 2 2 2 2H H 2R   in which R is a 4-hydroxyphenyl group, a 4-carbamoyl phenyl group or a 3-methanesulfonylamino phenyl group, or a salt thereof, characterized in that it consists in eliminating the protective group of the amino group of a compound represented by the formula: R1 - '$ NSO2CH   Wherein R 2 is a protecting group for the amino group, and R has the same meaning as defined above, wherein R 2 is a group protecting the amino group; or a salt of this compound.   6 - Process for the manufacture of an amine derivative represented by the formula: NSO CH H, he; _- OH X 'NCH I CH SCH CH2NCNCH CH H 2 2 2 HH 2   in which R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylamino phenyl group, or a salt thereof, characterized in that it consists in reacting a compound represented by the formula: N9O.CH. 2N02H 0 CH SCH CH NCNCH CH 2 2 2 H H 2 '- R   wherein R has the same meaning as above, or a salt thereof, with methylamine, or a salt thereof, and formaldehyde or paraformaldehyde, or with 1,3-trimethyl, Trimethylenetriamine, in the presence of a acid.   7 - Anti-ulcer agent containing an amine derivative represented by the formula NSO2CH3 HI / OH NCH CH SCH CH NCNCH CH CH31 2 2 2H H 2 R   in which R is a 4-hydroxyphenyl group, a 4-carbamoyl phenyl group or a 3-methanesulfonylamino phenyl group, or a salt of this derivative.   8 - An anti-ulcer agent containing an amine derivative, or its salt, according to claim 7, characterized by the   R is a 4-hydroxyphenyl group.   9 - An anti-ulcer agent containing an amine derivative, or its salt, according to claim 7, characterized by the   R is a 4-carbamoyl phenyl group.   An anti-ulcer agent containing an amine derivative, or its salt, according to claim 7, characterized in that R is a 3-methanesulfonylamino phenyl group. 11 - Use of an amine derivative, or a salt thereof, as defined in claim 1, in the   manufacture of a therapeutic agent for peptic ulcer.