GB2209163A

GB2209163A - Amine derivatives useful as anti-ulcer agents

Info

Publication number: GB2209163A
Application number: GB8819886A
Authority: GB
Inventors: Shiro Hirai; Hiroshi Hirano; Hirotoshi Arai; Hisanari Shibata; Yoshikazu Kusayanagi; Kazuhiko Hashiba
Original assignee: Toyama Chemical Co Ltd
Current assignee: Toyama Chemical Co Ltd
Priority date: 1987-08-28
Filing date: 1988-08-22
Publication date: 1989-05-04
Anticipated expiration: 2008-08-22
Also published as: IT8848303A0; SE8802997D0; FI89480B; DK476788A; SE8802997L; DE3828869C2; SE466347B; FR2619816A1; FI883967A; NL192820C; GB8819886D0; ES2014041A6; CH675244A5; AU2156688A; BE1003231A4; CA1305714C; FI89480C; NL8802089A; DE3828869A1; AU595134B2

Description

1 2209163 l This invention relates to a novel amine derivative, a salt

thereof, a process for producing the same and an anti-ulcer agent containing the same.

As a result of a study made on the basis of the fact that compounds having a histamine H 2-blocking activity are useful for the treatment of peptic ulcer, the present inventors had previously found novel amine derivatives which are competitively antagonistic to histamine at histamine H 2 receptor, and had filed applications for patent lJapanese Patent Application Kokai (Laid-Open) Nos 88,458/84 and 97,958/85 l.

However, the compounds specifically illustrated in the above patent applications are not fully satisfac- tory in anti-ulcer effect and stability Therefore, there has been desired a compound having a better anti- ulcer effect and good stability.

The present inventors have made a further study to solve the above problem and have, as a result, found that the novel compound represented by the formula lIl and its salt described below have an outstanding anti-ulcer effect, low toxicity and good stability as compared with the compounds specifically illustrated in the above patent applications This invention has been completed based on this finding.

An object of this invention is to provide 2 - 1 a novel amine derivative and its salt.

Another object of this invention is to provide a novel amine derivative and its salt which have an anti-ulcer activity.

A further object of this invention is to provide a process for producing a novel amine derivative or its salt.

A still further object of this invention is to provide a pharmaceutical composition containing a novel amine derivative or its salt as an active ingredient.

A still further object of this invention is to provide a method for treating peptic ulcer.

Other objects and advantages of this invention will become apparent from-the following description.

According to this invention, there is provided an amine derivative represented by the formula lIl:

NSO 2 CH H 11 NCH /2 CH SCH CH NCNCH CH lIl C NCH 2 J 2 2 2 E 2 ' I wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or its salt.

This invention further provides a process for producing the above amine derivative or its salt, as well as an anti-ulcer agent containing said amine derivative or its salt.

As the salts of the amine derivative 1 represented by the formula lIl, there can 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 the formula lIl and their salts according to this invention include their isomers such as geometrical isomers, tautomers, optical isomers, racemic isomers and the like and also include all of their crystal forms and hydrates.

The preferable compound among the above- mentioned amine derivatives of the formula lIl and their salts of this invention is, for example, the compound in which R is a 4-hydroxyphenyl group.

The process for producing a compound of this invention is described below.

The compound of this invention can be produced according to, for example, the following production processes:

Production processes A.

R 1 SII 2 C 3 OHRemoval of NCH 2 CH 2 SCH 2 CH NCNCH 2 CH.

C H H 2 R amino-prot( group lIIl or its salt ectinq NSO 2 CH 3 H f 1112 OH > '1 NCH Z OjCH SCH CH NCN CHC H C/ 2 2 2 2 H H 2 \ R H 3 ClIl lI or its salt B. NSO 2 CH 3 CH 2 SCH 2 CH 2 NCNCH 2 CH H H 'R lIIIl CH 3 NH 2 or its salt and formaldehyde or paraformaldehyde or 1,3,5-trimethyltrimethylenetriamine in the presence of acid NSO 2 CH 3 H 1 11,'l OH NCH -FO CH SCH CH NCNCH CH HGC' 2 2 2 2 NH H 2 -R 3 CH lil H 3 i or its salt or its salt 1 In the above formulas, R is an amino-protecting group; and R has the same meaning as defined above.

As the salts of the compounds of the formulas lIIl and lIIIl, there can be mentioned salts similar to those mentioned with respect to the compound of the formula lIl As R which is an amino-protecting group, there can be mentioned, for example, those described in T W Green, "Protective Groups in Organic Synthesis" published by John Wiley & Sons, Inc in 1981.

The above processes for producing the compound of this invention are described in detail below.

( 1) Production process A The compound of the formula lIII or its salt is subjected to removal of amino-protecting group, whereby the compound of the formula lIl or its salt can be produced.

This reaction can be specifically effected according to, for example, the method described in T W Green, "Protective Groups in Organic Synthesis" published by John Wiley & Sons, Inc in 1981 or its modified method.

( 2) Production process B (i) The compound of the formula lIIIl or its salt is reacted with methylamine or its salt and formaldehyde or paraformaldehyde, whereby the compound of the formula lIl or its salt can be produced.

The solvent used in this reaction can be any solvent as long as it does not adversely affect the 6 - 1 reaction As such a solvent, there can be mentioned, for example, hydrocarbons such as n-hexane, benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; nitrites such as acetonitrile and the like; esters such as ethyl acetate and the like; alcohols such as methanol, ethanol, 2-propanol 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 admixture of two or more.

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

The amount of methylamine or its salt used and the amount of formaldehyde or paraformaldehyde used are each at least equimolar to the amount of the compound of the formula lIIIl or its salt.

Although the reaction temperature and the reaction time are not critical and may properly be varied depending on the reactants and the like, the above reaction can be effected at 10 to 1501 C for 10 minutes to 48 hours.

(ii) The compound of the formula lIl or its salt can also be produced by reacting the compound of the formula lIIIl or its salt with 1,3,5-trimethyl- trimethylenetriamine in the presence of an acid.

1 The solvent used in this reaction can be any solvent as long as it does not adversely affect the reaction As such a solvent, there can be used, for example, hydrocarbons such as n-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, 2- propanol and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; etc These solvents can be used alone or in admixture of two or more.

As the acid used in the above reaction, there can be mentioned a mineral acid such as hydrogen chloride, hydrogen bromide or the like or an organic acid such as a sulfonic acid e g methanesulfonic acid, benzene- sulfonic acid or p-toluenesulfonic acid; or the like.

The amount of 1,3,5-trimethyl-trimethylene- triamine used and the amount of the acid used are at least equimolar and at least three-fold moles, respec- tively, relative to the amount of the compound of the formula lIIIl or its salt.

Although the reaction temperature and the reaction time are not critical and may properly be varied depending on the reactants and the like, the above reaction can be effected at 10 to 1500 C for 10 minutes to 48 hours.

The amine derivative of the formula lIl or its 8 - 1 salt thus obtained can be easily isolated and collected according to an ordinary procedure such as recrystal- lization, concentration, extraction, optical resolution, column chromatography or the like.

The salt of the amine derivative of the formula lIl can be easily obtained from the amine derivative in the free state according to an ordinary method.

The process for producing a compound of the formula lIIl or its salt and a compound of the formula lIIIl or its salt as a starting material of the compound of this invention is described below.

The compound of the formula lIIl or its salt and a compound of the formula lIIIl or its salt can be produced according to, for example, the following production processes.

Production processes NCH 2 'O CH 20 H lIVl or its salt NCH 2 OH 2 CH 3 Protection of amino group Acylation I R 1 C 7 Acylation R 1 NCH O CH 2 OH lVl or its salt > R CH 3 2 2 N CH 3 1 Halogenation R 1 NNCH O 2 CH 2 X lV Ial or its salt CH-1 2 2 CH 3 HSCH 2 CH 2 NH 2 or its salt/base -NCH 2 O CH 2 SCH 2 CH 2 NH 2 / CH 3 lVIIl or its salt CH 3 NCH 2/0 I CH 2 o Rla 2 2 lV Ibl lV Ibl HSCH 2 CH 2 NH 2 or its salt y 1 R 3 a CH 3 SO 2 N=C 2 R 3 b RlVIIIl lVIIIl la NCH O CHO Rla CH 3 2 O 2 R CH 3 lV Icl HSCH 2 CH 2 NH 2 or its salt FUZIKCH 2 SCH 2 CH 2 NH 2 lXIl or its salt lXIl or its salt Cont'd - I R 1 NSO 2 CH 3 NCH 2 O O CH 2 SCH 2 CH NC-R H 3 C H lIXl or its salt NSO 2 CH 3 I 5 fli I 2 0 CH SCH CH NC-R 2 2 2 H lXIIl or its salt / OH H 2 NCH 2 CHR lXl or its salt R 1 lDNSO 2 CH 3 f F 11 2 /OH NCH 2 CH SCH 2 CH NCNCH 2 CH 2 H 2 2 H 22 a R H 3 C lIIl or its salt NSO 2 CH 3 O CH 2 SCH 2 CH 2 NCNCH 2 CH lIIIl or its salt lIIIl or its salt h 1 -J I) 11 - 1 In the above formulas, Rla is an acyl group; R is a 3 a 3 b removable group; R 3 a and R b, which may be the same or different, are substituted or unsubstituted alkyl or aryl groups, and R 3 a and R 3 b may be combined with each other to form o-phenylene or o-naphthylene group; X 1 2 is a halogen atom; Y and Y, which may be the same or 0 1 different, are -0-, -S or +; and R and R have the -S- same meanings as defined above.

As the salt of the compound of the formula lIVl, lVl, lV Ial, lV Ibl, lVIIl, lIXl, lXl, lXIl or lXIIl, there can be mentioned salts similar to those mentioned with respect to the compound of the formula lIl.

As Rla which is an acyl group, there can be mentioned, for example, C 4 alkanoyl groups which may be substituted with halogen atoms, such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl and the like, as well as aroyl groups such as benzoyl and the like.

As R 2 which is a removable group, there can be mentioned C 4 alkoxy groups such as methoxy, ethoxy and the like; C 4 alkylthio groups such as methylthio, ethylthio and the like; aryloxy groups such as phenoxy, naphthoxy, o-hydroxyphenoxy, o-hydroxynaphthoxy and the like; arylthio groups such as phenylthio, naphthylthio, o-mercaptophenylthio, o-mercaptonaphthylthio and the like; C 1 14 alkylsulfinyl groups such as methanesulfinyl, ethanesulfinyl and the like; arylsulfinyl groups such as benzenesulfinyl, naphthalenesulfinyl and 12 - 1 the like; etc R may have at least one substituent selected from halogen atoms such as fluorine, chlorine, bromine and iodine; a nitro group; a cyano group; C 1-4 alkyl groups such as methyl, ethyl and the like; C 1-4 alkoxy groups such as methoxy, ethoxy and the like; etc.

As the alkyl groups for R 3 a or R, there can be mentioned, for example, C 1-4 alkyl groups such as methyl, ethyl and the like; and as aryl groups, there can be mentioned, for example, phenyl and naphthyl.

Further, R a and R b and the o-phenylene or o-naphthylene which R a and R form when taken together may have at least one substituent same as that mentioned with 2 respect to R According to the above production processes, the process for producing a compound of the formula lIIl or its salt and a compound of the formula lIIIl or its salt for a starting material of the compound of this invention is described in detail below.

( 1) The compound of the formula lIVl or its salt is subjected to amino group protection by an amino- protecting group according to an ordinarily known method, whereby the compound of the formula lVl or its salt can be produced.

( 2) The compound of the formula lVI or its salt is halogenated, whereby the compound of the formula lV Ial or its salt can be produced.

This halogenation can be effected according 13 - 1 to, for example, the methods described in Acta Chimi.

Acad Sci Hung { 29 ( 1), 91-98 ( 1961), Tetrahedron Lett, 4, 339 ( 1979), J Org Chem 36, 3044 ( 1971), or their modified methods.

( 3) The compound of the formula lVl or its salt is subjected to an ordinary acylation reaction using about an equimolar amount of an acylating agent, whereby the compound of the formula lV Ibl or its salt can be produced.

( 4) The compound of the formula lIVl or its salt is subjected to an ordinary acylation reaction using at least two-fold equivalents of an acylating agent, whereby the compound of the formula lV Icl can be produced.

The thus obtained compounds of the formulas lV Ial and lV Ibl and their salts and compounds of the formula lV Icl (these compounds are hereinafter referred to generically as the compound of the formula lVIl) can be used in the subsequent reactions without being isolated.

( 5) The compound of the formula lVIl is reacted with 2-aminoethanethiol or its salt in the presence or absence of a base, whereby the compound of the formula lVIIl or its salt can be produced.

The solvent used in this reaction can be any solvent as long as it does not adversely affect the reaction As such a solvent, there can be mentioned, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; nitrites such as 14 - l 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-dimethylform- amide and the like; carboxylic acid such as acetic acid and the like; water; etc These solvents can be used alone or in admixture of two or more.

As the base, in the presence of which the reaction is effected, there can be mentioned, for example, sodium methoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, triethylamine, and 1,8-diazabicyclol 5 4 01-undec-7-ene (DBU).

The amount of 2-aminoethanethiol or its salt used and the amount of the base used can be each at least equimolar to the amount of the compound of the formula lVIl.

Although the reaction temperature and the reaction time are not critical and may properly be varied depending on the reactants and the like, the above reaction can be effected at -20 to 1000 C for 1 minute to 12 hours.

( 6) The compound of the formula lVIII or its salt, or the compound of the formula lXIl or its salt is reacted with the compound of the formula lVIIIl, whereby the compound of the formula lIXl or its salt or the compound of the formula lXIIl or its salt can be produced, respectively.

The solvent used in this reaction can be any solvent as long as it does not adversely affect the - 1 reaction As such a solvent, there can 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; amides such as N,N-dimethylformamide and the like; alcohols such as methanol, ethanol, 2-propanol and the like; etc These solvents can be used alone or in admixture of two or more.

The amount of the compound of the formula lVIIIl used is at least equimolar to the amount of the compound of the formula lVIIl or its salt or the compound of the formula lXIl or its salt.

As the preferable compound of the formula lVIIIl, there can be mentioned, for example, dimethyl methanesulfonylimidodithiocarbonate, diphenyl methanesulfonylimidocarbonate, 2-methanesulfonylimino- 1,3-benzodioxole and the like.

Although the reaction temperature and the reaction time are not critical and may properly be varied depending on the reactants and the like, the above reaction can be effected at -10 to 150 C for 1 minute to 24 hours.

The compound of the formula lIXl or its salt or the compound of the formula lXIIl or its salt can be used in the subsequent reaction without being isolated.

( 7), The compound of the formula lIXl or its salt 16 - 1 or the compound of the formula lXIIl or its salt is reacted with the compound of the formula lXl or its salt in the presence or absence of a base, whereby the com- pound of the formula lIIl or its salt or the compound of the formula lIIIl or its salt can be produced, respectively.

The solvent used in this reaction can be any solvent as long as it does not adversely affect the reaction As such a solvent, there can 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, 2-propanol and the like; etc.

These solvents can be used alone or in admixture of two or more.

As the base used in the above reaction, there can be mentioned, for example, 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 formula lXI or its salt used and the amount of the base used are each at least equimolar to the amount of the compound of the formula 17 - l lIXl or its salt or to the amount of the compound of the formula lXIIl or its salt.

Although the reaction temperature and the reaction time are not critical and may properly be varied depending on the reactants and the like, the above reaction can be effected at 20 to 1501 C for 30 minutes to 24 hours.

The compound of the formula lIIl or its salt or the compound of the formula lIIIl or its salt thus obtained can be easily isolated and collected according to an ordinary procedure such as recrystallization, concentration, extraction, optical resolution, column chromatography or the like.

The salt of the compound of the formula lIII or the salt of the compound of the formula lIIIl can be easily obtained from the compound in the free state according to an ordinary method.

The pharmacological activities of the amine derivative of the formula lIl and its salt are described below.

Test compounds NSO 2 CH 3 Ra CH 12 OH NCH CHS C CH nun CH CHI C N 3 H 2 2 2 2 H 2 - 18 - No Ra R 1 H Q OH Present NHSO 2 CH compounds 2 H 2 3 3 H CONH 2 F 4 CH 3 Control compounds CH 3 9 OH 1 lIl Inhibitory activity on gastric acid secretion (pylorus ligation method) This activity was measured in accordance with the method by H Shay et al described in Gastroenterology, 5, 43 ( 1945) Groups of six or seven Wistar rats (male, 190-230 g) were fasted for 24 hours, following which the pylorus of each rat was ligated under ether anesthesia The test compounds were administered intraduodenally after ligation Thereafter, the rats were subjected to celiorrhaphy and immediately 25 mg/kg of histamine was administered to them subcutaneously at the dorsal After 3 hours, the cardia of stomach was ligated, and then the stomach was removed The gastric 19 - 1 juice was collected by centrifugation and the total amount was quantitated 1 ml of the gastric juice was taken and titrated with a 0 1 N aqueous sodium hydorxide solution to an end point of p H 7 0 In administering the test compound, the compound was dissolved in dimethyl sulfoxide (DMSO) and then diluted with distilled water to obtain a 0 25 % aqueous DMSO solution containing the test compound A 0 25 % aqueous DMSO solution containing no test compound was administered to control group.

The inhibition rate of gastric acid secretion was calculated from the following equation:

1 Acid output Acid output of Inhibition rate (of control) (drug-treated) of gastric acid = group group x 100 secretion (%) Acid output of control group Test results obtained are shown in Table 1.

Table 1

No of test compound Dose Inhibition rate (mg/kg) (%) 1 0 625 67 6 1.25 82 2 2 1 25 51 3 3 1 25 54 2 4 1 25 30 6 5 0 32 7 Note: p < 0 01 p < 0 05 - 1 lIIl Acute toxicity A test compound was administered to ICR mice (male, 27-30 g) intravenously, and the LD 50 value was calculated by the up and down method.

The results obtained are shown in Table 2.

Table 2

No of test compound LD 50 (mg/kg) 1 100 0 2 129 8 3 151 0 4 85 4 90 7 As is clear from Table 1 and Table 2, the amine derivatives of the formula lIl and their salts have an excellent inhibitory activity on gastric acid secretion and accordingly an excellent anti-ulcer activity, have a low toxicity, and therefore have a wider safety margin Further, they have excellent stability.

The anti-ulcer agent containing the amine derivative of the formula lIl or its salt can be prepared in various forms such as tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, troches, ointments, suppositories, injections, suspensions, emulsions, drops, syrups and the like 21 - l according to ordinary methods They can be administered either orally or parenterally and in particular oral administration is preferred.

In order to prepare them in various forms suitable for oral or parenteral administration, the preparation may be carried out by using pharmaceutically acceptable nontoxic additives which are ordinarily used, such as excipients, binders, lubricants, disintegrators, base for suppositories, and the like As necessary, other additives may also be used such as isotonicity, stabilizer, dispersant, antioxidant, colorant, flavor, buffer and the like.

The above forms can comprise other drugs useful viewed from treatment purposes.

With respect to the dose and administration times of the amine derivative of the formula lIl or its salt, they can be administered orally or parenterally, generally in a dose of 1 jig/kg to 10 mg/kg a day per adult in 1 to 4 portions Naturally, the dose and administration times may properly be varied depending on the administration route and the symptoms of patients.

This invention is explained below referring to Reference Examples, Examples and Preparation Examples, which are not by way of limitation but by way of illustration.

The mixing ratio of solvents in the Examples is by volume unless otherwise specified.

22 - 1 As the carrier in column chromatography, there was used a silica gel (Kieselgel 60, Art 7734; manufactured 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 with distilling off the phosphorus oxychloride generated by the reaction After the completion of the reaction, phosphorus oxychloride and residual phosphorus pentachloride were removed by distillation under reduced pressure to obtain dichloro-diphenoxymethane Thereto were added 600 ml of anhydrous ethyl acetate and 148 g of methanesulfonamide, and the mixture was refluxed for 8 hours After cooling, 1 liter of n-hexane was added to the mixture and the crystals deposited were collected by filtration The crystals were washed with water and dried to obtain 179 g (yield: 49 %) of diphenyl methanesulfonylimidocarbonate having a melting point of 124-125 5 C.

Reference Example 2 53.4 g of methanesulfonamide and 89 4 g of 2,2-dichloro-l,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 was added 200 ml of benzene, and the mixture was refluxed 23 - 1 for 10 minutes and then cooled slowly to room temperature with stirring The crystals deposited were collected by filtration and washed with benzene, water and 2- propanol in this order to obtain 83 g (yield: 83 %) of 2-methanesulfonylimino-l,3-benzodioxole.

Melting point: 161-163 C (recrystallized from ethyl acetate) Reference Example 3 ( 1) 23 5 g of 2,2,2-trichloroethyl chloroformate was dropwise added to 140 ml of methylene chloride solution containing 14 1 g of 5-N-methylaminomethyl- 2-furanmethanol and 8 9 ml of pyridine, at 4 to 5 C over a period of 60 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 removed by distillation under reduced pressure and the residue thus obtained was purified by a column chromatography (eluant:

benzene: ethyl acetate = 2: 1) to obtain 16 4 g (yield: 50 %) of oily 5-lN-methyl-N-( 2,2,2-trichloroethoxycarbonyl)aminomethyll-2-furanmethanol.

NMR (CDC 13) 6 value:

2.15 ( 1 H, bs), 3 00 ( 3 H, s), 4 47 ( 2 H, s), 4 55 ( 2 H, s), 4 76 ( 2 H, s), 6 21 ( 2 H, s) ( 2) 7 26 g of N-chlorosuccinimide was dissolved in 100 ml of methylene chloride Thereto was dropwise 24 - 1 added 4 18 ml of dimethyl sulfide at 5 to 100 C The mixture was stirred at the same temperature for 30 minutes Thereto was dropwise added 30 ml of methylene chloride solution containing 16 4 g of 5-lN-methyl-N- ( 2,2,2-trichloroethoxycarbonyl)aminomethyll-2- furanmethanol, at 5 to 10 C in 20 minutes, and stirring was effected at the same temperature for 1 hour The reaction mixture was introduced into 100 ml of ice water The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Separately, 20 0 g of a 28 % by weight sodium methoxide solution in methanol was dropwise added to ml of a methanol solution containing 5 88 g of 2-aminoethanethiol hydrochloride with ice-cooling in a nitrogen atmosphere Then, the dried organic layer obtained above was dropwise added thereto at 5 to 100 C over a period of 20 minutes The temperature of the mixture was slowly elevated to room temperature with stirring for 30 minutes The reaction mixture was introduced into 100 ml of ice water and the organic layer was separated Then, 70 ml of water was added to the organic layer and the mixture was adjusted to p H 1 5 with 6 N hydrochloric acid The organic layer was separated and the solvent was removed by distillation under reduced pressure The residue thus obtained was dissolved in 100 ml of water The resulting aqueous solution was washed with ethyl acetate, and the aqueous - 1 layer was adjusted to p H 11 with a 5 N aqueous sodium hydroxide solution and then extracted with 150 ml of ethyl acetate The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 15 6 g (yield: 80 %) of oily 2-ll 5-lN-methyl-N-( 2,2,2-trichloroethoxycarbonyl)aminomethyll-2-furyllmethylthiol- ethylamine.

NMR (CDC 13) 6 value:

1.45 ( 2 H, s), 2 45 2 95 ( 4 H, m), 3 01 ( 3 H, s), 3.68 ( 2 H, s), 4 47 ( 2 H, s), 4 77 ( 2 H, s), 6.16 ( 2 H, m) ( 3) 13 8 g of diphenyl methanesulfonylimido- carbonate was dissolved in 50 ml of acetonitrile With ice-cooling, thereto was added 17 7 g of 2-ll 5-N-methyl- N-( 2,2,2-trichloroethoxycarbonyl)aminomethyll-2-furyllmethylthiolethylamine, and the mixture was stirred for minutes Then, thereto were added 10 9 g of DL- octopamine, 2 3 g of potassium acetate, 10 ml of 2-propanol and 16 5 ml of triethylamine, and the mixture was refluxed for 2 hours After cooling, 180 ml of water and 180 ml of ethyl acetate were added thereto and the organic layer was separated The organic layer was washed with 1 N hydrochloric acid, and a saturated aqueous sodium chloride solution in this order Then, the solvent was removed bydistillation under reduced pressure The residue thus obtained was purified by 26 - 1 a column chromatography (eluant: benzene: ethyl acetate = 1: 3) to obtain 26 9 g (yield: 90 %) of oily N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N'-methane- sulfonyl-N"-l 2-ll 5-lN-methyl-N-( 2,2,2-trichloroethoxy- carbonyl)aminomethyll-2-furyllmethylthiolethyllguanidine.

NMR (CDC 13) 6 value:

2.45 2 85 ( 2 H, m), 2 84 ( 3 H, s), 2.98 ( 3 H, s), 3 10 3 60 ( 4 H, m), 3 67 ( 2 H, s), 4 43 ( 2 H, s), 4 554 95 ( 1 H, m), 4.72 ( 2 H, s), 6 17 ( 2 H, s), 6 77, 7 13 ( 4 H, A Bq, J= 8 2 Hz).

The following compounds were obtained in a similar manner.

o N-l 2-( 4-carbamoylphenyl)-2-hydroxyethyll-N'- methanesulfonyl-N"-l 2-ll 5-lN-methyl-N-( 2,2,2- trichloroethoxycarbonyl)aminomethyll-2-furyllmethylthiolethyllguanidine o N-l 2-hydroxy-2-l 3-(methanesulfonylamino)phenyllethyll- NI-methanesulfonyl-N"-l 2-ll 5-lN-methyl-N-( 2,2,2trichloroethoxycarbonyl)aminomethyll-2-furyllmethyl- thiolethyllguanidine 27 - 1 Reference Example 4 ( 1) 42 6 g of 2-methanesulfonylimino-l,3benzodioxole was suspended in 126 ml of methylene chloride Thereto was dropwise added 31 4 g of 2-l( 2- furyl)methylthiolethylamine at 10 to 15 C Stirring was effected 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 crystals deposited were collected by filtration to obtain 65 5 g (yield:

88 %) of N-l 2-l( 2-furyl)methylthiolethyll-O-( 2hydroxyphenyl)-N'-methanesulfonylisourea.

Melting point: 110-111 5 C (recrystallized from ethyl acetate) NMR (CDC 13) 6 value:

2.76 ( 2 H, s), 2 88 ( 3 H, s), 3 35-3 85 ( 2 H, m), 3.75 ( 2 H, s), 6 24 ( 2 H, m), 6 75-7 25 ( 4 H, m), 7.31 ( 1 H, m) ( 2) To 50 ml of acetonitrile were added 5 0 g of N-l 2-l( 2-furyl)methylthiolethyll-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 thereafter the solvent was removed by distillation under reduced pressure To the residue thus obtained were added 50 ml of ethyl acetate and 30 ml of water The mixture was adjusted to p H 2 0 with 2 N hydrochloric acid The organic layer was separated, washed with 28 - 1 a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: benzene: ethyl acetate = 2: 3) to obtain 2 8 g (yield: 51 %) of N-l 2-l( 2-furyl)methyl- thiol ethyll -N' l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll -N"- methanesulfonylguanidine having a melting point of 109 to 112 5 C.

NMR (d 6-DMSO) 6 value:

2.57 ( 2 H, m), 2 75 ( 3 H, s), 3 10-3 50 ( 4 H, m), 3.80 ( 2 H, s), 4 50-4 90 (l H, m), 6 34 ( 2 H, s), 6.74, 7 20 ( 4 H, A Bq, J= 8 3 Hz), 7 55 ( 1 H, s) The following compounds were obtained in a similar manner.

o N-l 2 l ( 2-furyl)methylthiollethyll-N'-l 2-hydroxy-2- l 3-(methanesulfonylamino)phenyll ethyll-N"-methane- sulfonylguanidine NMR (CDC 13) 6 value:

2 45-2 80 ( 2 H, m), 2 83 ( 3 H, s), 2 93 ( 3 H, s), 3.05-3 65 ( 4 H, m), 3 68 ( 2 H, s), 4.65-5 05 (l H, m), 6 21 ( 2 H, m), 7.00-7 50 ( 5 H, m) o N-l 2-( 4-carbamoylphenyl)-2-hydroxyethyll-N'-l 2- l( 2-furyl)methylthiolethyll-N"-methanesulfonyl- guanidine 29 - 1 NMR (d 6 DMSO) 6 value:

2.44-2 56 ( 2 H, m), 2 74 ( 3 H, s), 3.10-3 50 ( 4 H, m), 3 79 ( 2 H, s), 4.70-4 94 ( 1 H, m), 6 26-6 41 ( 2 H, m), 7 55 (l H, m), 7 44, 7 87 ( 4 H, A Bq, J= 8 3 Hz) Reference Example 5 ( 1) 45 2 g of trichloroacetyl chloride was dropwise added to 150 ml of a methylene chloride solution containing 15 3 g of 5-N-methylaminomethyl-2- furanmethanol and 36 1 ml of triethylamine at -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 ice water.

The organic layer was separated and dried over anhydrous magnesium sulfate.

The thus obtained solution was added to 28 ml of an acetic acid solution containing 18 4 g of 2- aminoethanethiol hydrochloride at room temperature.

The mixture was refluxed for 5 hours The reaction mixture was introduced into 150 ml of ice water The resulting mixture was adjusted to p H 9 5 with a 5 N aqueous sodium hydroxide solution at 5 to 10 C The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate To the resulting solution was dropwise added 200 ml of an ethanol solution containing 9 72 g of anhydrous oxalic acid Methylene chloride was - 1 removed by distillation under atmospheric pressure.

The crystals deposited were collected by filtration to obtain 30 1 g (yield: 64 %) of 2-ll 5-lN-methyl-N(trichloroacetyl)aminomethyll-2-furyllmethylthiol- ethylamine oxalate ( 1:1).

Melting point: 138-139 5 C (recrystallized from ethanol) NMR (d 6-DMSO) 6 value:

2.40-3 30 ( 4 H, m), 3 23 ( 3 H, s), 3 81 ( 2 H, s), 4 68 ( 2 H, s), 6 32 ( 2 H, s) ( 2) 43 6 g of 2-ll 5-lN-methyl-N-(trichloroacetyl)aminomethyll-2-furyllmethylthiolethylamine oxalate ( 1:1) was added to 180 ml of methylene chloride and 250 ml of water 38 ml of a 5 N aqueous potassium hydroxide solution was dropwise added thereto at 10 to 15 C and dissolved The organic layer was separated, washed with a 10 % aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

To the solution thus prepared was added 29 1 g of diphenyl methanesulfonylimidocarbonate with ice- cooling, and the mixture was stirred for 30 minutes.

Methylene chloride was removed by distillation under reduced pressure To the residue thus obtained was added 200 ml of 2-propanol The crystals deposited were collected by filtration to obtain 48 9 g (yield:

%) of N-methanesulfonyl-N'-l 2-ll 5-lN-methyl-N(trichloroacetyl)aminomethyll-2-furyllmethylthiolethyll- O-phenylisourea.

31 - 1 Melting point: 85-87 C (recrystallized from 2-propanol) NMR (CDC 13) 6 value:

2.76 ( 2 H, t, J= 6 3 Hz), 2 85 ( 3 H, s), 3 27 ( 3 H, s), 3 40-3 75 ( 2 H, m), 3 73 ( 2 H, s), 4.64 ( 2 H, s), 6 12-6 25 ( 2 H, m), 7.00-7 41 ( 5 H, m) ( 3) To 160 ml of acetonitrile were added 32 6 g of N-methanesulfonyl-N'-l 2-ll 5-lN-methyl-N-(trichloroacetyl)aminomethyll-2-furyllmethylthiolethyll-O-phenylisourea, 13.8 g of DL-octopamine, 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 removed by distillation under reduced pressure To the residue thus obtained were added 250 ml of ethyl acetate and 150 ml of water The mixture was adjusted to p H 2 0 with 2 N hydrochloric acid The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate The solvent was removed by distilla- tion under reduced pressure The residue thus obtained was purified by a column chromatography (eluant:

benzene: ethyl acetate = 1: 2) to obtain 29 9 g (yield: 83 %) of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll- N'-methanesulfonyl-N"-l 2-ll 5-lN-methyl-N-(trichloroacetyl)aminomethyll-2-furyllmethylthiolethyllguanidine.

32 - NMR (CDC 13) 6 value:

2.40-2 95 ( 2 H, m), 2 81 ( 3 H, s), 3.05-3 80 ( 4 H, m), 3 26 ( 3 H, s), 3 66 ( 2 H, s), 4.40-4 95 ( 1 H, m), 4 60 ( 2 H, s), 6 10-6 30 ( 2 H, m), 6 75, 7 11 ( 4 H, A Bq, J= 8 5 Hz) Reference Example 6 ( 1) 11 6 g of diphenyl methanesulfonylimido- carbonate was dissolved in 40 ml of methylene chloride.

With ice-cooling, thereto was added 15 g of 2-ll 5-lN- methyl-N-( 2,2,2-trichloroethoxycarbonyl)aminomethyll -2- furyllmethylthiolethylamine The mixture was stirred for 10 minutes The solvent was removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant:

benzene: ethyl acetate = 2: 1) to obtain 17 8 g (yield: 78 %) of oily N-methanesulfonyl-N'-l 2-ll 5-lN- methyl-N-( 2,2,2-trichloroethoxycarbonyl)aminomethylll-2- furyll methylthiol ethyll -O-phenylisourea.

NMR (CDC 13) 6 value:

2.77 ( 2 H, t, J= 6 4 Hz), 2 86 ( 3 H, s), 3.00 ( 3 H, s), 3 40-3 75 ( 2 H, m), 3 73 ( 2 H, s), 4.45 ( 2 H, s), 4 77 ( 2 H, s), 6 16 ( 2 H, s), 7.00-7 45 ( 5 H, m) ( 2) In 11 ml of dimethyl sulfoxide was dissolved 5.4 g of N-methanesulfonyl-N'-l 2-ll 5-lN-methyl-N-( 2,2,2trichloroethoxycarbonyl)aminomethyll -2-furyllmethylthiol - 33 - 1 ethyll-O-phenylisourea Thereto was added 2 9 g of S(+)-octopamine (lalD 25 = + 57 4 (C = 1, 0 1 N HC 1)).

D The mixture was stirred in 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 saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: benzene: ethyl acetate = 1: 3) to obtain 5.2 g (yield: 86 %) of oily S(+)-N-l 2-hydroxy-2-( 4- hydroxyphenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5-lNmethyl-N-( 2,2,2-trichloroethoxycarbonyl)aminomethyll2-furyllmethylthiolethyllguanidine.

lal = + 6 5 (C= 1, methanol) D In a similar manner and using R(-)-octopamine 1 (llD = -55 1 (C= 1, 0 1 N HC 1)) in place of S(+)octopamine, there was obtained R(-)-N-l 2-hydroxy-2- ( 4-hydroxyphenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5- lN-methyl-N-( 2,2,2-trichloroethoxycarbonyl)aminomethyll2-furyllmethylthiolethyllguanidine.

Example 1 ( 1) In 370 ml of tetrahydrofuran was dissolved 26 9 g of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N'- methanesulfonyl-N"-l 2-ll 5-lN-methyl-N-( 2,2,2trichloroethoxycarbonyl)aminomethyll-2-furyllmethylthiol- 34 - 1 ethyllguanidine Thereto were added 320 ml of a 0 5 M aqueous potassium dihydrogen phosphate solution and 42 g of an active zinc powder, and the mixture was stirred at room temperature for 3 hours The reaction mixture was adjusted to p H 9 8 with a 5 N aqueous sodium hydroxide solution and extracted with 370 ml of ethyl acetate The solvent of the extract was removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: chloroform: methanol: aqueous ammonia solution = 85: 15: 1) and then recrystallized from 95 % aqueous ethanol solution to obtain 12 6 g (yield: 65 %) of N-l 2-hydroxy-2-( 4-hydroxyphenyl)- ethyll-N'-methanesulfonyl-N"-l 2-ll 5-(methylamino)- methyl-2-furyllmethylthiolethyllguanidine having a melting point of 146 5 to 147 C.

-1 IR (K Br) cm: 1580, 1255, 1105 NMR (d 6-DMSO) 6 value:

2.24 ( 3 H, s), 2 35-2 65 ( 2 H, m), 2 74 ( 3 H, s), 3 00-3 50 ( 4 H, m), 3 56 ( 2 H, s), 3 74 ( 2 H, s), 4.50-4 80 (l H, m), 6 15 ( 2 H, m), 6 71, 7.18 ( 4 H, A Bq, J= 8 5 Hz) The following compounds were obtained in a similar manner.

o N-l 2-( 4-carbamoylphenyl)-2-hydroxyethyll-N'- methanesulfonyl-N"-l 2-ll 5-(methylamino)methyl-2- furyllmethylthiolethyllguanidine - 1 NMR (d 6-DMSO) 6 value:

2.25 ( 3 H, s), 2 35-2 65 ( 2 H, m), 2 74 ( 3 H, s), 2.90-3 60 ( 4 H, m), 3 57 ( 2 H, s), 3 75 ( 2 H, s), 4.65-5 00 ( 1 H, m), 6 18 ( 2 H, m), 7 45, 7 86 ( 4 H, A Bq, J= 8 2 Hz) o N-l 2-hydroxy-2-l 3-(methanesulfonylamino)phenyll - ethyll-N'-methanesulfonyl-N"-l 2-ll 5-(methylamino)- methyl-2-furyllmethylthiollethyll guanidine NMR (CDC 13) 6 value:

2 25 ( 3 H, s), 2 55-2 85 ( 2 H, m), 2 86 ( 3 H, s), 2.97 ( 3 H, s), 3 10-3 70 ( 4 H, m), 3 61 ( 2 H, s), 3.69 ( 2 H, s), 4 70-5 00 ( 1 H, m), 6 10 ( 2 H, s), 7.00-7 40 ( 4 H, m) ( 2) In 1430 ml of 95 % aqueous ethanol solution was dissolved 239 g of N-l 2-( 4-carbamoylphenyl)-2hydroxyethyll-N'-methanesulfonyl-N"-l 2-ll 5-(methylamino 3 methyl-2-furyllmethylthiollethyll guanidine Thereto was added a solution formed by dissolving 46 8 g of oxalic acid in 240 ml of 95 % aqueous ethanol solution.

Further, 2 5 g of a seed crystal was added thereto.

The mixture was stirred at 40 C for 3 hours and at room temperature for 3 hours and then allowed to stand overnight The crystals deposited were collected by filtration to obtain 257 g (yield: 91 %) of N-l 2-( 4carbamoylphenyl)-2-hydroxyethyll -N'-methanesulfonyl-N"- l 2-ll 5-(methylamino)methyl-2-furyllmethylthiolethyll- guanidine oxalate ( 1:1).

36 - 1 Melting point: 142 5-145 5 WC (recrystallized from % aqueous ethanol solution) NMR (D 20) 6 value:

2.62 ( 2 H, t, J= 6 4 Hz), 2 73 ( 3 H, s), 2 85 ( 3 H, s), 3 34 ( 2 H, t, J= 6 4 Hz), 3.61 ( 2 H, d, J= 5 8 Hz), 3 77 ( 2 H, s), 4.26 ( 2 H, s), 5 05 ( 1 H, t, J= 5 8 Hz), 6.34, 6 60 ( 2 H, A Bq, J= 3 4 Hz), 7.54, 7 87 ( 4 H, A Bq, J= 8 3 Hz) In a similar manner and using, as a solvent, a mixture of methanol and ethanol ( 1:2 5) and, as an acid, 98 % orthophosphoric acid, there was obtained N l 2 ( 4-carbamoylphenyl) -2-hydroxyethyll -N' -methane- sulfonyl-N" l 2 ll 5 (methylamino)methyl-2-furyll- methylthiolethyllguanidine phosphate ( 1:1) in an yield of 95 %.

Melting point: 140-142 C lrecrystallized from ethanol and acetic acid ( 4:1)l NMR (D 20) 6 value:

2 63 ( 2 H, t), 2 71 ( 3 H, s), 2 81 ( 3 H, s), 3.11 ( 3 H, s), 3 36 ( 2 H, t), 3 58 ( 2 H, d), 3.79 ( 2 H, s), 4 25 ( 2 H, s), 4 97 ( 1 H, t), 6.35, 6 59 ( 2 H, A Bq, J= 3 l Hz), 7.16-7 68 ( 4 H, m) In a similar manner, there was obtained amorphous N l 2-hydroxy-2 l 3 (methanesulfonylamino)- phenylllethyll-N'-methanesulfonyl-N"-l 2-ll 5-(methylamino) - methyl-2-furyllmethylthiol ethyll guanidine hydrochloride.

37 - 1 NMR (D 20) 6 value:

2.63 ( 2 H, t), 2 71 ( 3 H, s), 2 81 ( 3 H, s), 3.11 ( 3 H, s), 3 36 ( 2 H, t), 3 58 ( 2 H, d), 3.79 ( 2 H, s), 4 25 ( 2 H, s), 4 97 (l H, t), 6 35, 6 59 ( 2 H, A Bq, J= 3 1 Hz), 7.16-7 68 ( 4 H, m) Example 2

240 mg of methylamine hydrochloride was dissolved in a 0 27 ml of 37 % (w/w) aqueous formalin solution Thereto was added, at room temperature, 2.5 ml of a tetrahydrofuran solution containing 500 mg of N-l 2-l( 2-furyl)methylthiolethyll-N'-l 2-hydroxy-2- ( 4-hydroxyphenyl)ethyll-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 p H 9 5 with a 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 removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: chloroform: methanol: aqueous ammonia solution = 85:15:1) to obtain 220 mg (yield:

40 %) of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N'- methanesulfonyl-N"-l 2-ll 5-(methylamino)methyl-2-furyll- methylthiolethyllguanidine.

38 - 1 This compound showed the same melting point, IR spectrum and NMR spectrum as those of the compound obtained in Example 1.

Example 3

To 10 ml of a tetrahydrofuran solution containing 310 mg of 1,3,5-trimethyl-trimethylene- triamine were added 1 3 g of p-toluenesulfonic acid monohydrate and 1 0 g of N-l 2-l( 2-furyl)methylthiol- ethyll-N'-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N"methanesulfonylguanidine The mixture was stirred at room temperature for 3 hours The reaction mixture was introduced into 30 ml of water The resulting mixture was adjusted to p H 9 5 with a 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 removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: chloroform:

methanol: aqueous ammonia solution = 85:15:1) to obtain 440 mg (yield: 40 %) of N-l 2-hydroxy-2-( 4- hydroxyphenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5- (methylamino)methyl-2-furyllmethylthiolethyllguanidine.

This compound showed the same melting point, IR spectrum and NMR spectrum as those of the compound obtained in Example 1 ( 1).

39 - 1 Example 4

9.4 g of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5-lN-methyl-N(trichloroacetyl)aminomethyll-2-furyllmethylthiolethyll- guanidine was dissolved in a mixture of 8 ml of ethanol and 47 ml of a 1 N aqueous sodium hydroxide solution in a nitrogen atmosphere The mixture was stirred at room temperature for 2 hours Then, the mixture was adjusted to p H 9 7 with 6 N hydrochloric acid with ice-cooling, a seed crystal was added thereto and the mixture was stirred for 4 hours at room temperature.

The crystals deposited were collected by filtration to obtain 6 0 g (yield: 84 %) of N-l 2-hydroxy-2-( 4hydroxyphenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5(methylamino)methyl-2-furyllmethylthiolethyllguanidine.

Example 5

S(+)-N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll- N'-methanesulfonyl-N"-l 2-ll 5-lN-methyl-N-( 2,2,2trichloroethoxycarbonyl)aminomethyll-2-furyllmethylthiol- ethyllguanidine was treated in the same manner as in Example 1 ( 1) to obtain S(-)-N-l 2-hydroxy-2-( 4-hydroxy- phenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5-(methylamino)- methyl-2-furyllmethylthiolethyllguanidine.

lal = -6 6 (C=i, 0 1 N HC 1) D - 1 l The following compound was obtained in a similar manner:

o R(+)-N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll- N'-methanesulfonyl-N"-l 2-ll 5-(metylamino)methyl-2- furyllmethylthiolethyllguanidine.

2 al = + 6 3 (C=l, 0 1 N H Cl) Example 6

250 mg of methylamino hydrochloride and 170 mg of 95 % paraformaldehyde were added to 1 5 ml of methanol.

The mixture was refluxed for 90 minutes Thereto was added 1 5 ml of a methanol solution containing 500 mg of N-l 2-l( 2-furyl)methylthiolethyll-N'-ll 2-hydroxy-2- ( 4-hydroxyphenyl)lethyll-N"-methanesulfonylguanidine at room temperature The mixture was subjected to reaction at the same temperature for 2 days The solvent was removed by distillation under reduced pressure To the residue thus obtained was added 20 ml of water The mixture was adjusted to p H 9 6 with a N aqueous sodium hydroxide solution and extracted with two 30-ml portions of a 1:1 mixture of ethyl acetate and tetrahydrofuran The extract was combined and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: chloroform: methanol: aqueous ammonia solution = 85:15:1) to obtain 220 mg (yield:

%) of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N'- 41 - 1 methanesulfonyl-N"-l 2-ll 5-(methylamino)methyl-2-furyllmethylthiolethyllguanidine.

Example 7 ( 1) 5 61 g of N-l 2-l( 2-furyl)methylthiolethyll- N'-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N"-methane- sulfonylguanidine and 1 75 g of 4-(N,N-dimethylamino)- pyridine were dissolved in a mixture of 20 ml of methylene chloride and 5 6 ml of N,N-dimethylformamide.

To this solution was dropwise added 8 ml of a methylene chloride solution containing 2 00 g of benzoyl chloride at -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 sodium chloride solution in this order and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: benzene:

ethyl acetate = 1: 1) to obtain 5 40 g (yield: 77 %) of N-l 2-( 4-benzoyloxyphenyl)-2-hydroxylethyl-N'-l 2- l( 2-furyl)methylthiolethyll-N"-methanesulfonylguanidine.

NMR (CDC 13) 6 value:

2.69 ( 2 H, t), 2 88 ( 3 H, s), 3 10-3 55 ( 4 H, m), 3.73 ( 2 H, s), 4 90 ( 1 H, m), 6 15-6 35 ( 2 H, m), 42 - 1 7 10-7 70 ( 8 H, m), 8 05-8 30 ( 2 H, m) ( 2) 2 11 g of methylamine hydrochloride and 1 48 g of 95 % paraformaldehyde were added to 10 ml of methanol.

The mixture was refluxed for 1 5 hours After cooling, thereto was added 15 ml of a methanol solution contain- ing 5 40 g of N-l 2-( 4-benzoyloxyphenyl)-2-hydroxyl- ethyl-N'-l 2-l( 2-furyl)methylthiolethyll-N"-methane- sulfonylguanidine 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 p H 9 6 with a 5 N aqueous sodium hydroxide solution with ice-cooling The organic layer was separated and 30 ml of water was added thereto and the mixture was adjusted to p H 1 5 with 2 N hydrochloric acid with ice-cooling The aqueous layer was separated and 50 ml of chloroform was added The mixture was adjusted to p H 9 6 with a 5 N aqueous sodium hydroxide solution with ice-cooling The organic layer was separated and washed with 30 ml of a saturated aqueous sodium chloride solution The solvent was removed by distillation under reduced pressure The oily residue thus obtained was dissolved in 50 ml of methanol.

Thereto was added 2 0 g of a 28 % by weight sodium methoxide solution in methanol The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour.

2.6 ml of a 4 N hydrochloric acid-ethanol solution was added with ice-cooling The mixture was stirred at the same temperature for 15 minutes The solvent was 43 - 1 removed by distillation under reduced pressure The residue thus obtained was purified by a column chromatography (eluant: chloroform: methanol: aqueous ammonia solution = 85: 15: 1) to obtain 3 57 g (yield: 75 %) of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyllN'-methanesulfonyl-N"-l 2-ll 5-(methylamino)methyl-2furyllmethylthiolethyllguanidine.

Preparation Example 1 There were uniformly mixed 75 g of N-l 2hydroxy-2-( 4-hydroxyphenyl)ethyll-N'-methanesulfonyl- N"-l 2-ll 5-(methylamino)methyl-2-furyllmethylthiol- ethyllguanidine, 15 g of Avicel PH 102 (a microcrystalline cellulose manufactured by ASAHI CHEMICAL INDUSTRY, CO., LTD), 29 g of Kollidon CL (a 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 This mixture was made into slugs according to an ordinary method The slugs were ground and sieved through a 24-mesh screen 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 (a microcrystalline cellulose manufactured 44 - x% 1 by ASAHI CHEMICAL INDUSTRY, CO, LTD) and 2 36 g of magnesium stearate The mixture was made into tablets each weighing 170 mg.

Preparation Example 2 10 g of N-l 2-hydroxy-2-( 4-hydroxyphenyl)ethyll-N'-methanesulfonyl-N"-l 2-ll 5-(methylamino)methyl-2-furyllmethylthiolethyllguanidine and 5 g of L-asparatic acid were suspended in 200 ml of distilled water for injection The suspension was adjusted to p H 5 5 0 5 with 1 N 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 pm filter The filtrate was filled into vials in an amount of 2 ml per vial.

The vials were subjected to lyophilization according to an ordinary method to obtain an injection vial.

-

Claims

CLAIMS:

1 An amine derivative represented by the formula:

NSO CH H I It 11 O NCH 2-C 2 CH SCH CH 2 NCNCH 2 CH CH 3 " NCH 2 R CR 3 2 2 2 H H z R wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or its salt.

2 An amine derivative or its salt according to Claim 1, wherein R is a 4-hydroxyphenyl group.

3 An amine derivative or its salt according to Claim 1, wherein R is a 4-carbamoylphenyl group.

4 An amine derivative or its salt according to Claim 1, wherein R is a 3-methanesulfonylaminophenyl group.

A process for producing an amine derivative represented by the formula:

NSO 2 CH 3 H P IO 1 " NCH 2 i" k CH SCH CH NCNCH CH HC 2 2 2 2 H H 2 'R wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group or its salt, which comprises removing the amino-protecting group from a compound represented by the formula:

NSO 2 CH 3 RNC 11 _-OH NCH -' CH SCH CH NCNCH CH H C 222 2 H H 2 R 46 wherein R 1 is an amino-protecting group and R has the same meaning as defined above or its salt.

6 A process for producing an amine derivative represented by the formula:

NSO 2 CH 3 H Xa 11 2 > OH H 2 N CH 2 SCH 2 CH 2 NCNCH 2 CH H 3 z H H z R wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group or its salt, which comprises reacting a compound represented by the formula:

NSO CH w B 2 3 j O O D CH 2 SCH 2 CH 2 NCNCH 2 CH H H wherein R has the same meaning as defined above or its salt with methylamine or its salt and formaldehyde or paraformaldehyde or with 1,3,5-trimethyl-trimethylenetriamine in the presence of an acid.

7 An anti-ulcer agent containing an amine derivative represented by the formula:

NSO 2 CH 3 H 11 _-_ IIOH \NCH 2 v CHSCHCHNCNCH 2 CH CH 3 2 H H R wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group or its salt.

8 An anti-ulcer agent containing an amine 47 - derivative or its salt according to Claim 7, wherein R is a 4-hydroxyphenyl group.

9 An anti-ulcer agent containing an amine derivative or its salt according to Claim 7, wherein R is a 4-carbamoylphenyl group.

An anti-ulcer agent containing an amine derivative or its salt according to Claim 7, wherein R is a 3-methanesulfonylaminophenyl group.

11 Use of an amine derivative or its salt as defined in Claim 1 in manufacture of a therapeutic agent for peptic ulcer.

12 An amine derivative as claimed in Claim 1 and substantially as described in the Examples.

13 A process as claimed in Claim 5 and substantially as described in the Examples.

14 An anti-ulcer agent as claimed in Claim 8 and substantially as described in the Examples.

Pltb'lshed 1988 a Th-e Paten Offilce State House 6;H ?: L'_ on W'CIE 4 TF F-urter ccples maybeobtai ed from The Paten Offlce Sales Branch, St Mary Cray Orpmngton Kent BFS 3RD Printed by Multiplex tecirnques ltd St Mary Cray Kent Con 1 87