AU595134B2 - Amine derivative and its salt, process for producing the same, and anti-ulcer agent containing the same - Google Patents

Description

AUSTRALIA

Patents Act CCMiPLETE SPECIFICATIMI

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority 51M Marc 5 4 -7 Related Art: *000 p

OP..

V 0C A~PPLICANT'S REFEMMICE: B3453-16 Name(s) of Applicant(s): Toyama Chemical Co., Ltd Addeess(es) of Applicant(s): 3-chome,, Nishishin juku, Shin juku- ku, Tokyo,

JAPAN.

Address for Service is: PHILLIPS 0ONUQE FITPIC.K Patent and Trade MIark Attorneys 367 Cols Street Melbourne 3000 AUSTRALIA Complete Specification for the invention entitled: M~IM-, DERWVM~IVE MID ITS SALT, PrCJ-SS FOR PRODUCIMG 'PM, SMIE, MN 1AJME-ULCM AMMN CCZAIUNG ME~ SM1 Our Ref 104560 POP Code 2 1096/46850 The following statement is a full description of this invention, including the best method of perfotming it known to applicant(s): 6003q/1 .1 1 acetonitrile and the like; ethers such as '.etrahydrofuran, 1 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 0 0° derivatives which are competitively antagonistic to 00o0 °o histamine at histamine H2 receptor, and had filed a 00 0o 10 applications for patent [Japanese Patent Application Kokai (Laid-Open) Nos. 88,458/84 and 9',958/85].

o a 0 However, the compounds specifically illustrated in the above patent applications are not fully satisfac- 0 0 O 0 tory in anti-ulcer effect and stability. Therefore, 9 00 there has been desired a compound having a better anti- 0 00 0 0 ulcer effect and good stability.

The present inventors have made a further 0 o' study to solve the above problem and have, as a result, 0 0 0 0o 0o found that the novel compound represented by the formula 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 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 i provide a pharmaceutical composition containing a novel amine derivative or its salt as an active ingredient.

o A still further object of this invention is to 0 0 0 000 0° provide a method for treating peptic ulcer.

0 0 0o80 S° Other objects and advantages of this invention o 0 will become apparent from the following description.

I

15 According to this invention, there is provided an amine derivative represented by the formula 0 0 0o NSO CH 3 H II OH NCH CH SCH CH NCNCHCH [I] 0 CH HH R 00 CH wherein R is a 4-hydroxyphenyl group. a 4-carbamoylphenyl o 09 o0 o group or a 3-methanesulfonylaminophenyl group, or its 0a0 0 09 0 0 o0 salt.

V 20 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 3 1 represented by the formula 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 ace'ic 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 and 0o their salts according to this invention include their #q00 °isomers such as geometrical isomers, tautomers, optical Sisomers, racemic isomers and the like and also include all of their crystal forms and hydrates.

The preferable compound among the abovementioned amine derivatives of the formula and their 9 O0 0 a9salts of this invention is, for example, the compound 4 0 So° in which R is a 4-hydroxyphenyl group.

o 0" The process for producing a compound of this 0 0o invention is described below.

o .o The compound of this invention can be produced oo 0 according to, for example, the following production 0 00 processes: 4 000 C 00 0 00 0 0 0000 00 C 000 0 0 0 0 00 0 0 0 0 0 000 00 00 o 0 00 0 0 0 0 0 00 04 00 0 0 0 0 0 0 0 0 OS 00 00 000 000 0 0 0 Production processes, 1 _1 RI C 2 lilt"- NSO 2CR13 CHR SCR CH 2NCNCH CR.

2 22 2 Removal of amino-protecting group NSO 2CH3 H11 IVT' 2 OH NNCH UO C SCH2 CHR NCNCH2 CH H 3C HRH or its salt [IIIl or its salt NSO 2CR "0-,CH 2 2 CH2- 2 N1'NCH CR HRH CR NH 2or its, salt and formaldehyde or paraformaldehyde or 113 trimethylenetriamine in the presence of acid NSO 2CH H 11 ___-123 NCR 0' CR SCH CR NCNCH CR H 3C 2 2 2 2 H H 2

R

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 [II] and [III], there can be mentioned salts similar to those mentioned with respect to the compound of the formula 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 Son of this invention are described in detail below.

uooo S.0 Production process A 0 So, The compound of the formula [II] or its salt 000 0 o0 000.* is subjected to removal of amino-protecting group, 0, "0 15 whereby the compound of the formula or its salt can be produced.

0 04 Sa,,00 This reaction can be specifically effected 0 0 0 0 0o according to, for example, the method described in 0o 0 0 T. W. Green, "Protective Groups in Organic Synthesis" published by John Wiley Sons, Inc, in 1981 or its a 0o modified method.

S(2) Production process B The compound of the formula [III] or its salt is reacted with methylamine or its salt and formaldehyde or paraformaldehyde, whereby the compound of the formula or its salt can be produced.

The solvent used in this reaction can be any solvent as long as it does not adversely effect 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; 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, anisole and the like; carboxylic acids such as acetic acid and the like; etc. These solvents can be used alone or o oo in admixture of two or more.

l oo o 0 o°o As the salt of methylamine, there can be a000 Soo mentioned, for example, salts with a mineral acid such 000 0 a. as hydrochlori acid, hydrobromic acid, sulfuric acid o a a J 15 or the like.

The amount of methylamine or its salt used oa o 0oao and the amount of formaldehyde or paraformaldehyde used Oa so are each at least equimolar to the amount of the oOo compound of the formula [III] or its salt.

a 0 Although the reaction temperature and the a oo reaction time are not critical and may properly be 6 00 a varied depending on the reactants and the like, the a 00 above reaction can be effected at 10 to 150 0 C for minutes to 48 hours.

(ii) The compound of the formula or its salt can also be produced by reacting the compound of the formula [III] or its salt with 1,3,5-trimethyltrimethylenetriamine in the presence of an acid.

7 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, 2propanol 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 0 o more.

0000 o 0o 0a 0 As the acid used in the above reaction, there 0 1 can be mentioned a mineral acid such as hydrogen chloride, 0" "o0 15 hydrogen bromide or the like or an organic acid such as a sulfonic acid e.g. methanesulfonic acid, benzene- 0 0 0o ad sulfonic acid or p-toluenesulfonic acid; or the like.

0 00 0 0 0 The amount of 1,3,5-trimethyl-trimethylene- 0 O0o triamine used and the amount of the acid used are at f o0 o least equimolar and at least three-fold moles, respec- 00 tively, relative to the amount of the compound of the o 4 o 0 o formula [III] 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 150° C for 10 minutes to 48 hours.

The amine derivative of the formula or its 8- I II 1 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 amine derivative of the formula 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 [II] or its salt and a compound of the formula o o 0[III] or its salt as a starting material of the compound 0o 0 of this invention is described below.

000 The compound of the formula [II] or its salt Ss^o and a compound of the formula [III] or its salt can be

Q

0 o 15 produced according to, for example, the following production processes.

0 0 0o o o 00 0 0 00 0 0 0 00 00 0 S0 09 0 00 ru r 0 000 000 a 00 0 C C 0 o ~00 0 0 0 CO 00 a 0 o 0 0 00 C 0 00 00 a c 0 0 a 0 CIO 000 0 0 00 0 00 00 ~0 0 0 0 000 000 0 0 0 Production processes NCH 0CH OH [IV] CH 2 22 3 Acylation or 4-ts salt Protection of amino group CHNC 2OH [VI or 3 Acylation its salt 1 R NNH CHOla CH-, 2

C

3 [VIb] Halogenation R1 -1 NNCH -to CH X [VIaj or its salt

C

3 {HSCH C'H2 tor its salt/base XNCH [j C C CH NH CH 2 2 2 3 [VII] or its salt HSCH CH NH oris salt aTCH 2 -L O-1C [iVIC] HSCH 2CH 2NH2 or its salt CH2 SH2 CH2 NH2 [XI] or its salt CH SO N=C I1YIR3 3 2 Y 2 3b [VIII I Cont'd 0 to 0 0 0 o 0 0000 0 0 0 00 0000 00 0004~ 0 0 0 0 0 coo 0 0 0 000 0.0 0 00 00

Q

*0 00 000 1 NSO 2CHI3 R fF111 2 NCIZ u*CH SCH CHI 2

NC-R

H1 C 2 H 2 [IX] or its salt WSO 2CH 3 0 CH 2 SCH 2

CH

2

NC-R

2 [XII] or its salt

,,OH

H 2NCHC2HC- LXI Or its salt 1 NSO 2CH3 R J77 2 Nk L SH i -OH N CH C 2CI NCNCH CH U3C 2 2 2 [III or its. salt NSO 2GHB fT'7L~~CH SCI IIjj2 01 0 H2 SH2 CH 2 CCH 2

CH

[III] or its salt 1 In the above formulas, R lais an acyl group; R 2is a 3a 3b removable group; R and PR which may be the same or different, are substituted or unsubsti alkyl or aryl groups, and R 3 and R 3bmay be combined with each other to form o-phenylene or o-naphthylene group; X is a halogen atom; YIand Y 2 which may be the same or different, arc or ~'and P. and R. have the same meanings as defined above,.

As the salt of the compound of, the formula [IV]i [Vii [VIa] [V~bj [VII] [IX] or [XII] there can be mentioned salts similar to those mentioned 0 00 O""Dwith respect to the compound of the formula [I.

00 As R awhich is an acyl group, there can b e 0 00 mentioned, for ex<ample, C 14 alkanoyl groups which a' 00 a 15 be substituted with halogen atoms, such as formyl., acetyl, cdhloroacetyj, dichloroacetyl, triehioroacetyl 0 and the like, as well as aroAyl groups such as benzoy, 0 0 and the like.

As R 2which is a removable group, there can be o 20 mention~ed C 1 4 alkoxy groups such as methoxy, ethoXy Anid the like; C 1 4 allkylthio groups such as methy3,thio, 0 0ethylthio and the like; aryloxy groups such as phonoxyl 0 0naphtho,(y, o-hydroxyphenoxy, o-hydroxyniaphthoxy and the like; arylthlo groups such as phenylthio, naphthylthio, o-mercaptophenylthio, o-Mezrcaptonaphthylthio and the like; C 1 4 alkylsulfinyl groups such as methanesulfinyl, ethanesulfinyl and the like; arylsulfinyl qroups such as ben ,Onesulfinyl, naphthalenesulfinyl and 12 p0 4 4 44 44 pi& p g I 444 I 4 4 44 4 4 44i 4 44o 4 44 44 '4 '4 44 4 44 44 ,4i 4 r 4 44 4: 4 4 r44 4 u44 44 4 49 4 4 2 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; Cl_ 4 alkyl groups such as methyl, ethyl and the like;

C

1 _4alkoxy groups such as methoxy, ethoxy and the like; etc.

As the alkyl groups for R 3a or R there can be mentioned, for example, C_14alkyl groups such as methyl, ethyl and the like; and as aryl groups, there can be mentioned, for example, phenyl and naphthyl.

Further, R 3a and R 3b and the o-phenylene or o-naphthylene which R and R 3b form when taken together may have at least one substituent same as that mentioned with 2 respect to R.

15 According to the above production processes, the process for producing a compound of the formula [II] Or its salt and a compound of the formula [III] or its salt for a starting material of the compound of this invention is described in detail below.

20 The compound of the formula [IV] or its salt is subjected to amino group protection by an aminoprotecting group according to an ordinarily known method, whereby the compound of the formula or its salt can be produced.

The compound of the formula or its salt is halogenated, whereby the compound of the formula [Via] or its salt can be produced.

This haltgenation can be effected according 13

I

09 $0 0 0 0 0 So Qr 00 0 0 0 04; 0P 0a 0 01 00rll i 0.49 0 0.B 1 to, for example, the methods described in Acta. Chimi.

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

The compound of the formula 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 [VIb] or its salt can be produced.

The compound of the formula [IV] 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 [VIc] can be produced.

The thus obtained compounds of the formulas 15 [VIa] and [VIb] and their salts and compounds of the formula [VIc] (these compounds are hereinafter referred to generically as the compound of the formula can be used in the subsequent reactions without being isolated.

20 The compound of the formula [VI] is reacted with 2-aminoethanethiol or its salt ir the presence or absence of a base, whereby the compound of the formula [VII] 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; nitriles such as 14 1 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 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 .o example, sodium methoxide, potassium t-butoxide, sodium I 1 0 hydroxide, potassium hydroxide, triethylamine, and S"o l,8-diazabicyclo(5.4.0]-undec-7-ene (DBU).

0 The amount of 2-aminoethanethiol or its 0 o "o salt used and the amount of the base used can be each at least equimolar to the amount of the compound of the 15 formula [VI].

0 9* Although the reaction temperature and the a reaction time are not critical and may properly be a 0 varied depending on the reactants and the like, the a above reaction can be effected at -20 to 100 0 C for 1 20 minute to 12 hours.

The compound of the formula [VII] or its salt, or the compound of the formula [XI] or its salt is reacted with the compound of the formula [VIII], whereby the compound of the formula [IXI or its salt or the compound of the formula [XII] 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 15 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 tie 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 10 admixture of two or more.

04 Sa, The amount of the compound of the formula S00 0 o [VIII] used is at least equimolar to the amount of the So a compound of the formula [VII] or its salt or the compound of the formula [XI] or its salt.

15 As the preferable compound of the formula 0 00 [VIII], there can be mentioned, for example, dimethyl a methanesulfonylimidodithiocarbonate, diphenyl methanesulfonylimidocarbonate, 2-methanesulfonylimino- 1,3-benzodioxole and the like.

o oa 20 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 0 C for 1 minute to 24 hours.

The compound of the formula [IX] or its salt or the compound of the formula [XII] or its salt can be used in the subsequent reaction without being isolated.

The compound of the formula [IX] or its salt 16 1 or the compound of the formula [XII] or its salt is reacted with the compound of the formula or its salt in the presence or absence of a base, whereby the compound of the formula [II] or its salt or the compound of the formula [III] 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 I reaction. As such a solvent, there can be mentioned, 0 0 S 10 for example, aromatic hydrocarbons such as benzene, o toluene, xylene and the like; halogenated hydrocarbons oi such as methylene chloride, chloroform and the like; 0 0 0 nitriles such as acetonitrile and the like; ethers such as anisole and the like; esters such as ethyl acetate 15 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 20 or more.

0 0 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 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 1' [IX] or its salt or to the amount of the compound of the formula [XII] 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 150 0 C for 30 minutes to 24 hours.

The compound of the formula [II] or its salt or the compound of the formula [III] or its salt thus oV 10 obtained can be easily isolated and collected according to an ordinary procedure such as recrystallization, concentration, extraction, optical resolution, column e chromatography or the like.

The salt of the compound of the formula [II] or the salt of the compound of the formula [III] 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 and its salt are described S 20 below.

tQ Test compounds a NSO 2

CH

3 RII 11 3-.OH NCH2 -O-CH2SCH 2CH2NCNCH2CH

CH

3 H H R 18 No. Ra

R

1 H 0OH Present NHSO CH compounds 2 H 2 3 3 H CONH 2 te 4 CH P3 O Control compounds P 6 *r 5 CH 3

OH

t 1 Inhibitory activity on gastric acid secretion S*(pylorus ligation method) This activity was measured in accordance with the method by H. Shay et al. described in III a 5 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 -t 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 pH 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.

o* o* The inhibition rate of gastric acid secretion was calculated from the following equation: t Acid output Acid output of Inhibition rate of control (drug-treated of gastric acid group group x 100 secretion Acid output of control group r*t Test results obtained are shown in Table 1.

Table 1 o o No. of test compound Dose Inhibition rate (mg/kg) 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 20 1 [II] 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 0 40 00 01 I 0I 0, 00 0 00 00 0 W"0 0 oor 0 0 00O 0 .1 No. of test compound (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 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 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 fHfNMffc 1 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, a 0 SQQ O buffer and the like.

49444 The above forms can comprise other drugs useful viewed from trea-ment purposes.

15 With respect to the dose and administration *t .oc* times of the amine derivative of the formula or its salt, they can be administered orally or parenterally, generally in a dose of 1 pg/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 o o 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 hours with distilling off the phosphorus oxychloride a generated by the reaction. After the completion of the ao reaction, phosphorus oxychloride and residual phosphorus 0 o i10 pentachloride were removed by distillation under reduced .of: pressure to obtain dichloro-diphenoxymethane. Thereto o"*o were added 600 ml of anhydrous ethyl acetate and 148 g of methanesulfonamide, and the mixture was refluxed for o 1 8 hours. After cooling, 1 liter of n-hexane was added S°oe* 15 to the mixture and the crystals deposited were collected o o0 by filtration. The crystals were washed with water and 0 0 4 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-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 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 2propanol in this order to obtain 83 g (yield: 83%) of 2-methanesulfonylimino-1,3-benzodioxole.

Melting point: 161-163°C (recrystallized from ethyl acetate) Reference Example 3 23.5 g of 2,2,2-trichloroethyl chloroformate a o' 10 was dropwise added to 140 ml of methylene chloride I solution containing 14.1 g of 2-furanmethanol and 8.9 ml of pyridine, at 4 to 5°C over a period of 60 minutes, and the mixture was stirred I at the same temperature for 30 minutes. The reaction 15 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-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furanmethanol.

NMR (CDCl 3 value: 2.15 (1H, bs), 3.00 (3H, 4.47 (2H, s), 4.55 (2H, 4.76 (2H, 6.21 (2H, s) 7.26 g of N-chlorosuccinimide was dissolved in 100 ml of methylene chloride. Thereto was dropwise 24 4 -rr. i mu a 1 added 4.18 ml of dimethyl sulfide at 5 to 10 0 C. The mixture was stirred at the same temperature for minutes. Thereto was dropwise added 30 ml of methylene chloride solution containing 16.4 g of (2,2, 2 -trichloroethoxycarbonyl)aminomethyl]-2furanmethanol, 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 S water. The organic layer was separated, washed with tt@# 10 a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Separately, 20.0 g of a 20% by weight sodium ,i 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 over a period of 20 minutes. The temperature of the mixture was slowly elevated to room temperature with 20 stirring for 30 minutes. The reaction mixture was D o 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 pH 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 25 i" i e 1 layer was adjusted to pH 11 with a 5 N aqueous sodium hydroxide solution a,'d then extracted with 150 mi 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-[[5-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl)aminomthylj-2-furyl]methylthioJethylamine.

NDMR (CDCl 3 6 value: 1,45 (2H, 2.,45 2.95 (4H, 3.01 (31, s) 3.68 (2H, 4.47 (2H, 4,77 (2H, s, 6,16 (2N, m) 1 3 8 g of diphenyl methanesulfonyllmidocarbonate was dissolved in 50 ml of acetonitrile. With ice-cooling, thereto was added 17.7 g of 2-trichloroethoxycarbonyl)aminomethy1l-2-furyl]methylthio]ethylamine, and the mixture was stirred for minutes. Then, thereto were added 10.9 g of DL- 20 octopamine, 2.3 g of potassium acetate, 10 M1 of 2-propanol and 16.5 ml of triethylaMine, and the mixture was refluxed for 2 hours. After cooling, 180 mi 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 by distillation under reduced pressure. The residue thus obtained was purified by 26 1 a column chromat-c~ jhy (eluant: benzene ethyl acetate =1 3) to obtain 26.9 g (yield: 90%) of oily N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -methanesulfonyl-N"- 15-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furylljmethylthio] ethyl] guanidine.

NMR (CDC 3 6 value: 2.45 -2,85 PH1, tin), 2.84 (3H, s), 2.98 (3H, s9), 3.10 3,60 (4H, mn), 3 .6 7 (2 H, s) 4, 4 3 (2 H, 55 4. 95 (lH, m) .00 0 4.72 (2H, 6417 (2H, 6.77, 7.13 two 0 (4H, A~q, J=8.2Hz).

t I The following 7,Qmpounds were obtained in a simila.- manner.

Q, N-[2-(4-carbainoylphenyl)-2-hydroxyethyl--N'methanesulfonyl-N t [2-1 [5-[-N-inethyX-N- (2,2,2trichloroethoxycarbonyl) amiriomethy,1-2-furyl] rnelhylthiojethyl] guanidine o N- [2-hydroxy-2- (methanesulfonylanino) phenyl] ethyll- 1 20 NI-ethanestfonyl-N"-[2-[5[EN-methyl-N-(2,2,2a ~t ih 1or o ethoxyc arbo ny1) amnnone t hyI I- 2 -f ury1 ]me thyl1thiolethyl] guanidine -27 -4 nr~ra*-- 1 Reference Example 4 42.6 g of 2-methanesulfonylimino-l,3benzodioxole was suspended in 126 ml of methylene chloride. Thereto was dropwise added 31.4 g of furyl)methylthio]ethylamine 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 S ,temperature for 30 minutes. The crystals deposited S, 10 were collected by filtration to obtain 65.5 g (yield: 88%) of N-[2-[(2-furyl)methylthio]ethyl]-0-(2hydroxyphenyl)-N'-methanesulfonylisourea.

4 4 S, ,Melting point: 110-111.5°C (recrystallized from ethyl acetate) NMR (CDC1 3 6 value: 2.76 (2H, 2.88 (3H, s) 3.35-3.85 (2H, m), 3.75 (2H, s) 6.24 (2H, 6.75-7.25 (4H, m), 7.31 (1H, m) To 50 ml of acetonitrile were added 5.0 g of N- 2- (2-furyl)methylthio]ethyl]-0-(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 pH 2.0 with 2 N hydrochloric acid. The organic layer was separated, washed with 28 so.ivent as -Long as it does not adversely atiect tne 15 'If 4 44 44 0 4* i 4 0 4044 4 4 4 4 4 ~414 44 4 4 44 4 44 4 I~ 4~ ft I 4 40 4 4, 44 *0 4 4* 0 40 00 4 0 0~ 0 04 00 0 000 0 4" 0 0 00 00 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-[2-[(2-furyl)methylthiol ethyl] [2-hydroxy-2- (4-hydroxyphenyl) ethyl] methanesulfonylguanidine having a melting point of 109 to 112.51C.

10 NMR (d 6 -DD4SO) rS value: 2. 57 (2H, in), 2.75 (3H, s) 3. 10-3. 50 (4H, in), 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 (lH, s) The following compounds were obtained in a similar manner.

(2-furyl) methylthiol ethyl] -N [2-hydroxy-2- (methanesulf onylamino) phenyllI ethyl]I -methanesulfonylguanidine NMR (CDCl.

3 rS value: 20 2 .45-2. 80 (2H, in), 2. 83 (3H, s) 2. 93 (3H, s), 3. 05-3. 65 (4H, mn), 3. 68 s) 4. 65-5. 05 (111 rnm) 6. 21 in), 7.00-7.50 (51H, m) N-E2-(4-carbarnoylphenyl)-2-hydroxyethyl]-N'-[2- (2-f uryl) inethylthio] ethyl] -methane sulf onylguanidine 29 1 NMR (d 6 DMSO) 6 value: 2.44-2.56 (2H, 2.74 (3H, s), 3.10-3.50 (4H, 3.79 (2H, s), 4.70-4.94 (1H, 6.26-6.41 (2H, m), 7.55 (1H, m) 7.44, 7.87 (4H, ABq, J=8.3Hz) Reference Example 45.2 g of trichloroacetyl chloride was dropwise added to 150 ml of a methylene chloride solution S, containing 15.3 g of 5-N-methylaminomethyl-2- S«o 10 furanmsthanol and 36.1 ml of triethylamine at -30 to -20 0 C over a period of 1 hour. The mixture was stirred 0o9, aat the sane temperature for 30 minutes. The reaction mixture was introduced into 100 ml of ice water.

The organic layer was separated and dried over anhydrous 15 magnesium sulfate.

C 9* The thus obtained solution was added to 28 ml Q of an acetic acid solution containing 18.4 g of 2aminoethanethiol hydrochloride at room temperature.

The mixture was refluxed for 5 hours. The reaction 0 00 mixture was introduced into 150 ml of ice water. The resulting mixture was adjusted to pH 9.5 with a 5 N aqueous sodium hydroxide solution at 5 to J]0C. 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 30 -eam,~rnr hv rintillation under reduced pressure. The i 1 removed by distillation under atmospheric pressure.

The crystals deposited were collected by filtration to obtain 30.1 g (yield: 64%) of (trichloroacetyl) aminomethyl]-2-furyl]methylthio]ethylamine oxalate Melting point: 138-139.5 0 C (recrystallized from ethanol) NMR (d 6 -DMSO) 6 value: 2.40-3.30 (4H, m) 3.23 (3H, s) 3.81 (2H, s), 10 4.68 (2H, 6.32 (2H, s) 0 43.6 g of aminomethyl]-2-furyl]methylthio]ethylamine oxalate (1:1) o So, was added to 180 ml of methylene chloride and 250 ml of 0. f 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, o a 10% aqueous sodium chloride solution and dried over ao*, anhydrous sodium sulfate.

To the solution thus prepared was added 29.1 g of diphenyl methanesulfonylimidocarbonate with icecooling, 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 (trichloroacetyl) aminomethyl] -2-furyl]methylthio] ethyl] 0-phenylisourea.

31 anc~narrr~rr~: 1 Melting point: 85-87 0 C (recrystallized from 2-propanol) NMR (CDC1l) 6 value: 2.76 (2H, t, J=6.3Hz) 2.85 (3H, s), 3.27 (3H, 3.40-3.75 (2H, 3.73 (2H, s), 4.64 (2H, 6.12-6.25 (2H, m), 7.00-7.41 (5H, m) To 160 ml of acetonitrile were added 32.6 g of N-methanesulfonyl-N'-[2- 1; 0 aminomethyl]-2-furyl]methylthio]ethyl]-O-phenylisourea, 4 13.8 g of DL-octopamine, 21 ml of triethylamine and St* 2.94 g of potassium acetate. The mixture was refluxed ,for 1 hour in a nitrogen atmosphere. After cooling, ,t S' the solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 250 tt' ml of ethyl acetate and 150 ml of water. The mixture was adjusted to pH 2.0 with 2 N hydrochloric acid. The s organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous 20 magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained S 0o was purified by a column chromatography (eluant: benzene ethyl acetate 1 2) to obtain 29.9 g (yield: 83%) of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyllacetyl)aminomethyl]-2-furyl]methylthiolethyl]guanidine.

-32 1NMR (CDCl 3 6 value: 2.40-2.95 (2H, m) 2.81 (3H, s)' 3. 05-3. 80 (4H, m) 3. 26 (3H, s) 3. 66 (2H, s) 4.40-4.95 (lH, mn), 4.60 (2H, s), 6.10-6.30 (2H, in), 6.75, 7.11 (4H, ABq, Reference Example 6 11.6 g of diphenyl methanesulfonylimidocarbonate was dissolved in 40 ml of methylene chloride.

With ice-cooling, thereto was added 15 g of methyl-N- 2-trichloroethoxycarbonyl) aiinomethyl] -2furyllmethylthiolethylanine. The mixture was stirred 4~ s,;for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue thus obtained was 15 purified by a colunln chromatography (eluant: benzene ethyl acetate 2 1) to obtain 17.8 g (yield: 78%) of oily N-methanesulfonyl-N'-[2-[ methyl-N- 2-trichloroethoxycarbonyl) arinomethyl] -2- 0 sofuryllmethylthioljethyl] -O-phenylisourea.

.0 20 NMR (CDCl 3 6 value: 2.77 (2H, t, J=6.4 Hz), 2.86 (3H, s), 3.00 (3H, 3.40-3.75 (2H, in), 3.73 (2H, s), 4. 45 (2H, s) 4 .77 (2H, s) 6.16 (2Hl, s), 7.00-7.45 (5H, in) In 11 ml of diinethyl sulfoxide was dissolved 5.4 g of N-methanesulfonyl-N'-[2-[ N-methyl-N-(2,2,2trichioroethoxycarbonyl) amninomethyl] -2-furyllmethylthiol 33 1 ethyl]-O--phenylisourea. Thereto was added 2.9 g of k2 S(+)-octopamine ([al5 +57.40 (C 1, 0.1 N HCl)).

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 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 =11 3) to obtain 5.2 g (yield: 86%) of oily S(+)-N-[2-hydroxy-2--' (4hydroxyphenyl) ethyl] -N'-nethanesulfonyl-N'- [Na methyl-N- (2,2 ,2-trichloroethoxycarbonyl) aminomethyll 2-furyllmethylthiolethylllguanidine.

4 a 25 +6.50 methanol) a In a similar manner and using R(-)-octopamine ~55.1o 0.1 N HCl)) in place of octopamine, there was obtained R(-)-N-[2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl1-W-[2-[ [N-methyl-N- 2-trichloroethoxycarbonyl) amiromethyl 1- 2-furyllmrethylthio] ethyl] guanidine.

Example 1.

In 370 ml of tetrahydrofuran was dissolved 26.9 g of N-[2-hydroxy-2-(4-hydroxyphenyl)ethylb-N'methanesulfonyl-N"- [N-methyl-N- (2,2,2trichloroethoxycarbonyl) aminomethyl] -2-furyllmethylthio] 34 i 1 1 ethyl]guanidine. 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 pH 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 10 chromatography (eluant: chloroform methanol aqueous ammonia solution 85 15 1) and then recrystallized from 95% aqueous ethanol solution to obtain 12.6 g 1 (yield: 65%) of N-[ 2 -hydroxy-2-(4-hydroxyphenyl)- If 1 ethyl] -methanesulfonyl-N"- (methylamino) methyl-2-furyl]methylthio]ethyl]guanidine having a melting point of 146.5 to 147 0

C.

-l IR (KBr) cm 1580, 1255, 1105 NMR (d 6 -DMSO) 5 value: 2.24 (3H, 2.35-2.65 (2H, 2.74 (3H, s), 20 3.00-3.50 (4H, 3.56 (2H, s) 3.74 (2H, s), o* S 4.50-4.80 (1H, m) 6.15 (2H, 6.71, 7.18 (4H, ABq, The following compounds were obtained in a similar manner.

o N-[2-(4-carbamoylphenyl)-2-hydroxyethyl]-N'methanesulfonyl-N"-[2- [5-(methylamino)methyl-2furyl ]methylt etlthioethyl]guanidine 35 1NMR (d 6 -DMSO) S value: 2. 25 (3HK, s) 2. 35-2. 65 (2H, in), 2. 74 (3H, s) 2. 90-3 60 (4H, mn), 3. 57 (2H, s) 3. 75 (2H, s) 4. 65-5 .00 (1H, in), 6. 18 (2H, mn), 7. 7.86 (4H, ABq, J=8. 2Hz) o N- [2-hydroxy-2- 3- (rethanesulf onylainino) phenyl] ethyl]-N '-methane sulf onyl-N" (inethylainino) methyl-2-f uryl I rethylthio I ethyl] guanidine NMR (CDC 3 5 value: 2. 25 (3H, s) 2.55-2. 85 (2H, in), 2.86 (3H, s), 2. 97 (3H, s) 3.10-3. 70 (4H, mn), 3. 61 (2H, s), 3. 69 (2KH, s) 4.7 0 00 (lH, in,6. 10 (21H, s) 7.00-7.40 (4H1, In 1430 ml of 95% aqueous ethanol solution was dissolved 239 g of N-E2-(4-carbamoylphenyl)-2hydroxyethyl]1 -mnethane sulf onyl-N t 2-1 5- (methylarnino) rethyl-2-furyl] m'ethylthio] ethyl] guanidine. Thereto was 4 4, add~ed 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.

old 10The mixture was stirred at 400C for 3 hours and at room temperature for 3 hours and then allowed to stand overnight. The crystals deposited were collected by filtraton to obtain 257 g (yield- 91%) of carbaMoylphenyl) 2 -hydroxyethyl I -N'I -methane sualfonyl-N" (methylarnino) inethyl-2-.furylimethylthio] ethyl] guanidine oxalate 36- '4 Melting point: 142.5-145.5*C (recrystallized from aqueous ethanol solution) NMR (D 2 0) 6 value: 2.62 (2H, t, J=6.4Hz) 2.73 (3H, s), 2.85 (3H, 3.34 (2H, t, J=6.4Hz), 3,61 d, J=5.8 Hz), 3.77 (2H, s), 4.26 (2H, 5.05 (1H, t, J=5.8Hz), 6.34, 6.60 (2H, ABg, J=3.4Hz), 7.54, 7.87 (4H, ABq, J=8.3Hz) In a similar manner and using, as a solvent, a mixture of methanol and ethanol and, as an acid, 98% orthophosphoric acid, there was obtained s,11f o ny 1-N" [5 (me th y Iami no) me thy1- 2- f ury I Irethylthiollethyllguanidine phosphate in an, yield of a 0 o 0Melting point: 3,40-3,42 0 C [recrystallized from 0 Q 0 ethanol and acetic aciel (4;l)1 NMP. (D 2 0) 6 value: 2.63 (2H, t) 2.71 (3H, 2,81 (3Mt s) 3.11 s) 336 t) 3. 58 (2H,0 d) 3.79 4. 25 4. 97 t), 6.35, 6.59 (2H, A~q, j--3.lHz), 7.16-7.68 (4H, in) In a siilar, manner, there was obtained amorphous N- (2-hyu"roxy-2- (inthanesu2lfonylainino) phenyl ]ethy. -N '-iethanesulfony1-N"-( (iethylamino) rnethyl-2-furyllinethylthio] ethyl] guanidine hydrochloride.

37 1NMR (D 2 0) 6 value: 2.63 (2H, 2. 71 (3H, 2.81 (3H, s) 3.11 O3H, 3.36 (2H, 3.58 (2H, d) 3.79 (2H, 4.25 (2H, 4.97 (1H, t), 6.35, 6.59 (211, A~q, J=3.lHz), 7.16-7.68 (4H, m) Example 2 240 mg of methylarnine hydrochloride was "too dissolved in a 0.27 ml of 37$ aqueous formalin .:111 10 solution. Thereto was added, at room temperature, 6 a 02.5 ml of a tetrahydrofuran solution containing 500 mg of N- [E(2-f uryl) methylthiol ethyl] -N'-[2-hydroxy-2- (4-hydroxyphenyl) ethyl],-NII-methanesulf onyjlguanidine.

The mixture was stirred at the same temnoerature for hours. The reaction mixture was introduced into 3Q m! of water, The resulting mixture was adju-sted to pH with a 1 N aqueous sodium hydroxide solution and extracted with two 50-mi portions of a 1:1 mixture of ethyl acetate 2 20and tetrahydrofuran, The extracts were combined and 04114 20dried 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- (2-hydroxy-2- (4-hydroxyphenyl) ethyl] -NI methane sulf onyl-N (methylamino) methyl- 2-f urylj methylthio I ethyl) guanidine.

'18 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-trimethylenetCriamine were added 1.3 g of p-toluenesulfonic acid monohydrate and 1..0 g of N-[2-[(2-furyl)methylthio]ethyl] 12-hydroxy--2- (4-hydroxyphenyl) ethyl] V 10 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 pH 9.5 with a 1 N aqueous sodium hydrox<ide solution and extracted with two 50-mI portions ,15 of a, 1:1 mixture of ethyl acetate and tetrahydrofuran. The extracts were combined and dried over anhydrous magnasium o sulfate and the solvent was remov-,I by distillation under reduced pressure. The. residue thus obtained was purified by a columni chromatography (eluant: chlaroform t 0 mnethanol1.4 aqueous ammonia solution t 85:15:4) tQ a 0 obtain 440 mg (yield-. 40%) of N-[2-hydroxy-2-(4hydroxyphenyl) ethyl] -N'-methanesulfonyl-N 1 [2-1 (methyJlamino) methyl- 2- furyl 1 methylthio I ethyl] Iguanidine.

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-[2-hydroxy-2'-(4-hydroxyphenyl)ethyl]I-N' -methanesulfonyl-N"- [2-Il [N-rnethyl-N- (trichloroacetyl) aminornethyl]I -2-furyJ1jinethylthio]I ethyl]I guanidine was dissolved in a nt~c of 8 ml of ethanol and 47 ml of a I, N aq'ueous 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 6 N hydrochloric acid with ice-cooling, a seed cxystal was added thereto and the m ixture was stirred for 4 hours at room temperature.

The crystals deposited were collected by filtration to D44 obtain 6.0 g (yield; 84%) of N"[2-hydroxy-2-(4hydroxyphenyl) ethyl]I -N 0 -mothanesulf onyl-N (me thyl amiro) me thy I- 2 -furyl ImeQthy Ith io I-e thyl Iguani1,d ine.

This compound showed the same melting point, IP. spectrum and NMR spectrum as those, of the compound 4 obtained in Example 21 a "0 Example t2 -hydroxy-2 -hydroxyphenyl) ethyl)trichloroethoxycarbony,) atinomethyl 1 2 fuayl I methylthio IethylIguanidine wais treated in the same manner az in Examnple 1 to obtain S(-)-N-[2.-hyde:oxy-2-(4-hydtoxKyphenyl)ethy~i-N'--methanesulfonyt-N"-12- 5- (no-thylamino)methyl-2-fUryl I methylIthio I e thyl) I qUanidine.

66 (*001 il 4 0 The following compound was obtained in a similar manner: o R(+)-N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]- N'-methanesulfonyl-N"-[2-[[5-(metylamino)methyl-2furyl]methylthio]ethyl]guanidine.

25 +6.30 0.1 N HC1)

D

Example 6 250 mg of methylamino ydrochloride 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-[2-[(2-fujryl)methyletioethyl-N'-[ 2-hydroxy-2- (4-hydroxyphenyl)]ethyl]-N"-methanesulfonylquanidine 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 pH 9.6 with a se 5 N aqueous sodium hydroxide solution and extracted with 20 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-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'- 41 1 methanesulfonyl-N"-[2-[[5-(methylamino)methyl-2-furyl]methyithiol ethyl] guanidine.

This compound showed the same melting point, IR spectrum and NMR spectrum as those of the compound obtained in Example 1 Example 7 5.61 g of N-[2-[(2-furyl)methylthiolethyli [2-hydroxy-2-(4-hydroxyphenyl)ethyl]--N'-methanesulfonylguanidine and 1.75 g of 4-(N,N-dimethylamino)pyridine were dissolved in a mixtrof2mlf t i 4, 1,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 benzoy, chloride at -35 to -251C over a period of 30 minutes. The mixture was stirred at the same temperature for minutes. The reaction mixture was washed with 30 ml of water and 30 ml of~ a saturated aqueous sodium chloride solution in this orcJ-r and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatogr'aphy (eluant: benz-ene ethyl acetate =2 1) to obtain 5.40 g (yield: 7/7k) of N-[2.-(4-benzoyloxyphenyl)-2-hydroxylethyl-N-2- ((s'-fur yl) methylthio] ethyl] -N"-rethanesulfonylguat* idie.

NMP, (CDCl 6 value: 2.69 (2H, t) 2.88 O3H, s)e 3.10-3.55 m), 3.73 s) 4.90 (111, 6.15-6.35 (2H1, mn), 42 1 7.10-7.70 (8H, 8.05-8.30 (2H, m) 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 containing 5.40 g of N-[2-(4-benzoyloxyphenyl)-2-hydroxy]ethyl-N'-[2- (2-furyl)methylthiol]ethyl]-N"-methanesulfonylguanidine. The resulting mixture was stirred at room temperature for 24 hours. 50 ml of ethyl acetate 1 10 and 50 ml of water were added thereto. The resulting S0 mixture was adjusted to pH 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 pH 1.5 with 2 N hydrochloric acid with ice-cooling. The aqueous layer was separated 4 and 50 ml of chloroform was added. The mixture was S" adjusted to pH 9.6 with a 5 N aqueous sodium hydroxide o'l solution with ice-cooling. The organic layer was separated and washed with 30 ml of a saturated aqueous o oa 20 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 0- 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-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]- N'-methanesulfonyl-N"-[2-[[5-(methylamino)methyl-2furyl]methylthio]ethyl]guanidine.

This compound showed the same melting point, IR spectrum and NMR spectrum as those of the compound obtained in Example 1 Preparation Example 1 There were uniformly mixed 75 g of N-[2hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-methanesulfonyl- N"-[2-[[5-(methylamino)methyl-2-furyl]methylthio]ti 15 ethyl]guanidine, 15 g of Avicel PH 102 (a microcrystalline cellulose manufactured by ASAHI CHEMICAL INDUSTRY, os <o CO., LTD.), 29 g of Kollidon CL (a crosslinked polyvinyl pyrrolidone manufactured by BASF), 29 g of 4o C Adsolider 101 (anhydrous silicic acid manufactured by ^o 20 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 L 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-[2-hydroxy-2-(4-hydroxyphenyl)ethyl] -methanesulfonyl-N"- (methylamino) methyl-2-furyl]methylthio]ethyl]guanidine and 5 g of L-asparatic acid were suspended in 200 ml of distilled water for injection. The suspe',uion was adjusted to pH 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 uer vial.

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

B

9 u 45

Claims (7)

1. An amino derivative represented by the formula: NSO2CH HrNCH II 2 OH SNCH CH SCH CHNCNCH CH CH 2 H H 2 R 3 wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or its salt. o aa 2. An amine derivative or its salt according to n Claim 1, wherein R is a 4-hydroxyphenyl group. g 0

3. An amine derivative or its salt according to o Claim 1, wherein R is a 4-carbamoylphenyl group. o c S4. An amine derivative or its salt according to Claim 1, wherein R is a 3-methanesulfonylaminophenyl So group. o 0 A process for producing an amine derivative represented by the formula: NSO CH 3 So H NCH1 2 -OH 0 s NCH O CH2SCH CH NCNCH CH "HC H 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: 1 NSO CH3 1 11 2 O 3 NCH 2 O CH2SCH 2 CH NCNCH CH H3C/ 2 2 H H 2 HR 46 -H 46 wherein R 1is 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 2CH3 H NCH C CH 2 O CNNCH CH NCl riMNCH CH H 3C~ 2 IF 2 2 2 H H 2 R wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-utethanesulfonylaminophenyl group or its 0 o0 salt, which comprises reacting a compound represented 00 a by the formula: OP CH NSO CH H H 4: e i wherein R, has the same meaning as defined above or its 0 salt with methylamine or its salt and formaldehyde or 0 paraformaldehyde or with 1,3 triamnine in the presence of an acid.

7. An anti-ulcer agent containing an amine o derivative represented by the formula: NSO 2 CH3 H 117 ___fO 'NCH 2-1'NCH 2SCH 2CHiNCNCH C H CH 2 2 H H R wherein R is a 4-hydrox<yphenyl group, a 4-carbaruoylphenyl group or a 3-methanesulfonylaminophenyl group or its salt.

8. An anti-ul.cer 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 0 o defined in Claim 1 in manufacture of a therapeutic t *agent for peptic ulcer. t I DATED 23 August 1988 PHILLIPS ORMONDE FITZPATRICK Attorneys for: TOYAMA CHEMICAL CO. LTD 0 0 4 04 9 n 0 0 UQ 9 48