CH675244A5 - Amin derivative and its salt, process for producing them and containing anti-ulcusmittel. - Google Patents

Description

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

description

The invention relates to a new amine derivative, a salt of this amine derivative, a process for its preparation and an anti-ulcer agent which contains this amine derivative or its salt.

In the course of investigations based on the fact that compounds which have Hista-min-H2-blocking activity are suitable for the treatment of gastric ulcer or gastric ulcer, the applicant has already discovered novel amine derivatives which are competitive-antagonistic Histamine act on histamine H2 receptors. These amine derivatives are described in Japanese Patent Application Laid-Open 88 458/84 and 97 958/85.

However, the compounds specifically described in the above-mentioned patent applications are still in need of improvement with regard to the anti-ulcer effect and the stability. It is therefore desirable to provide a compound that has even better anti-ulcer activity and good stability.

According to the invention, further tests were carried out to solve the above problem, it being found that the new compound of the formula (I) defined below and its salts have surprising anti-ulcer activity, low toxicity and good stability in comparison with the compounds, described in the aforementioned patent applications.

The invention is based on the object of providing a new amine derivative and its salts which have good activity against ulcers or gastric ulcers and to make a process for the preparation of these new amine derivatives and their salts accessible.

It is also an object of the invention to provide a pharmaceutical composition which contains an effective new amine derivative or its salt as an active ingredient. The object of the invention is also to make a means for treating gastric ulcers accessible.

Other objects and advantages of the invention will be apparent from the description below.

The invention relates to an amine derivative of the formula (I)

NSOnCH

II i

^ NCH "

CH0SCH, CT, NCNCH2CII (i)

CH3 / 2 2 2hh 2- ^ r in which R represents a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, and its salts.

The invention also relates to a process for the preparation of the amine derivative of the formula (I) defined above, which is characterized in that the amino protective group is obtained from a compound of the formula

"" KSO.CH-

®-, JTL 11 -

^ NCHn- ^ 0 ^ CH9SCH, CH., NCNCH ÇH tic '2 H H \ R

or is removed from their salts, where R1 is an amino protecting group and R has the above-defined meaning.

The invention also relates to an anti-ulcer agent which contains this amine derivative or its salts. As salts of the amine derivatives of the formula (I), there can be mentioned, for example, salts with inorganic acids, such as with 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, salts with alkali metals such as sodium, potassium and the like.

The amine derivatives of formula (I) and their salts according to the invention also include the corresponding isomers, such as geometric isomers, tautomers, optical isomers, racemic isomers and the like, and all possible crystal forms and hydrates which form these compounds.

A preferred compound among the above-mentioned amine derivatives of the formula (I) and its salts according to the invention is, for example, the compound in which R represents a 4-hydroxyphenyl group.

The process for producing a compound according to the invention is described below.

2nd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

The compound of the present invention can be produced, for example, using the following manufacturing processes.

3rd

ai a co co ro ro o en o en o en o

production method

A.

, .. NSO „CH, removal of n n NpO-CH-

, 1 n I h * J n «u n i ^ J

-1 n r, miUJL «JL Aiuny uci m r \

R y li H ^ -OH protective group H 11 JL

nnch0 / ^ O- ^ CH0SCH0CH.NCNCH0CH. -?> nNCHO / ^ 0 ^

-OH

CH "FAST" NCNCH ,, CH

1 y \ J ^ i ^ noöun9v-, ri0iNULNuri9wn. ^ wvn ^^ \ J WA ^ WH «HUIwijwi

HjC H H of the amino group H ^ C H H ^ R

[XX] [I]

or its salt or its salt

B CH ^ N ^ or its salt n r, un <^ formaldehyde or NS0oCH_

[I II> 0H paraformaldehyde H fl II 2>

CH0SCH0CH0NCNCH9CH p- "^ NCH- ^ O ^ CH-SCH-CH-NCNCH-CH

OH

y- lNx-rir, \ J ^ urx0öunnv-, n0iNV-.iN Ln.v

2 2 2HH Z ^ R or H C 2 2 2 2H H 2 ^ R

1,3,5-trimethyl

[XII] trimethylene triamine [i]

in the presence of or its salt acid or its salt

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

In the above formulas, R1 represents an amino protecting group and R has the meaning defined above.

Suitable salts of the compounds of the formulas (II) and (III) can be mentioned the same salts as those mentioned above with regard to the compound of the formula (I). As a suitable protecting group for the amino group, R1, for example, the groups mentioned by T.W. Green, “Protective Groups in Organic Synthesis,” published by John Wiley & Sons, Inc., 1981.

The above processes for producing the compound of the present invention are explained in more detail below.

(1) Manufacturing Process A

The compound of formula (II) or its salt is subjected to a treatment for removing the amino protecting group, whereby the compound of formula (I) or a salt of this compound can be formed.

This reaction can, for example, be carried out specifically according to the method described by T. W. Green, “Protective Groups in Organic Synthesis”, published by John Wiley and Sons, Inc., 1981, or a correspondingly modified method.

(2) Manufacturing Process B •

(i) The compound of formula (III) or its salt is reacted with methylamine or its salt and with formaldehyde or paraformaldehyde, whereby the compound of formula (I) or a salt of this compound can be formed.

The solvent used in this reaction can be any solvent provided that it does not interfere with the reaction. As such solvents, 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 individually or in the form of a mixture of two or more.

Suitable salts of methylamine are, for example, salts with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or the like.

The amount of methylamine or its salt and the amounts of formaldehyde or paraformaldehyde which are used are in each case at least equimolar to the amount of the compound of the formula (III) or its salt.

Although the reaction temperature and the reaction time are not critical and can be appropriately varied depending on the reactants and the like, the above reaction can generally be carried out at 10 to 150 ° C for 10 minutes to 48 hours.

(ii) The compound of formula (I) or its salts can also be prepared by reacting the compound of formula (III) or a salt of this compound in the presence of an acid with 1,3,5-trimethyl-trimethylene triamine.

The solvent used in this reaction can be any solvent provided that it does not interfere with the reaction. As such a solvent, 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 the form of a mixture of two or more.

As the acid for use in the above reaction, there can be mentioned mineral acids such as hydrochloric acid, hydrobromic acid or the like or organic acids such as sulfonic acids such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid and the like.

The amount of 1,3,5-trimethyl-trimethylenetriamine used and the amount of acid used are at least equimolar and correspond in each case to at least three times the molar proportion, based on the amount of the compound of the formula (III) or of its salt.

Although the reaction temperature and the reaction time are not critical and can be appropriately varied depending on the reactants and the like, the above reaction can be carried out at 10 to 150 ° C for 10 minutes to 48 hours.

The amine derivative of the formula (I) or its salt thus obtained can be easily isolated and obtained by a conventional method such as recrystallization, concentration, extraction, optical cleavage, column chromatography or the like.

The salt of the amine derivative of the formula (I) can easily be obtained from that in free form5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

the amine derivative can be obtained using a conventional method.

The process for producing a compound of formula (II) or its salt and a compound of formula (III) or its salt as a starting material for the compound of the present invention will be described below.

The compound of formula (II) or its salt and the compound of formula (III) or its salt can be obtained, for example, by the following production methods.

6

en o

4 * s

4b »

o co

Ol ro o

production method

H

ch snch '2

-Us

CH OH [IV] 0 <^ er its salt

Acylation

NCH,

Protection of the amino group

-Usch ch;

Acylation

«OH [V] or its salt ^ R. JTIL

A NCH _- / 0 '^ n-

ch.

Rla n — n ch2orla ^ nch2 <^ 0 - ^ - ch? 0rla

CH.

Halogenation

** FI

^ NCH ^ - ^ - O ^

[VIb]

or its salt

CH.

g -'- '^ O' ^ CH ^ [Via] or its salt hsch2ch2nh2

Y or its salt / base

'NCH.

O

0CH "SCH" CH "NH,

CH.

'2 2 ~ 2 "2

[VII] or its salt

<r * 1

[VIc]

HSCH2CH2NH2 or its salt

2sch2ch2nh2

[XI] or its salt ch3so2n = c

X R

[VIII]

0

X

O)

Ä

s

«K>

01

- ports.

O)

O

*1

<JTX

SNCHo / ^ 0 * ^

NS0oCH_ li 2 3

H3C

CH2SCH2CH2NOR [IX] or its salt from

XX.

NS0oCH, il 2 3

Oh

'NCH 0 ^ CH SCH CH NCNCH - CH H3C ^ 1 H H ^ »R

[II] or its salt

CO

en co o ro en ro o

* 2

M

UL

NSO_CH_ h 2 3

CH, SCH CH NC-R

OH

h2nch2ch

[XII] or its salt

[X] or its salt

NSO-CH-II 2 ^ OH

0 ^ CH «SCH_CH0NCNCH0CH

2 2 2H H 2 \ r

[III] or its salt

5

10th

15

20th

25th

30th

35

40

45

50

55

60

CH 675 244 A5

In the above formulas, R1a is an acyl group, R2 is a removable group, R3a and R3b, which may be the same or different, substituted or unsubstituted alkyl or aryl groups, and R3a and R3b may be combined to form an o-phenylene or o-naphthylene group; X represents a halogen atom, Y> and Y2, which may be the same or different, mean -O-, -S- or

O

-s-

and R and R1 have the meanings defined above in each case.

The same or similar salts can be mentioned as salts of the compounds of the formulas (IV), (V), (Via), (Vlb), (VII), (IX), (X), (XI) or (XII), as mentioned above with regard to the compound of formula (I).

As the acyl group R1a, there can be mentioned, for example, Ci-4-alkanoyl groups which may be substituted with halogen atoms, such as the formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl group and the like, and aroyl groups such as the benzoyl group and the like.

As group R2, which is a removable or removable group, there may be mentioned Ci ^} - alkoxy groups, such as methoxy, ethoxy and the like, Ci-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, Ci-4-alkylsulfinyl groups such as methanesulfinyl, ethanesulfinyl and the like, arylsulfinyl groups and the like such as benzenesulfinyl groups such as benzenesulfinyl groups such as benzenesulfinyl groups , etc. R2 may have at least one substituent which is substituted by halogen atoms such as fluorine, chlorine, bromine and iodine, a nitro group, a cyano group, Ci-4-alkyl groups such as methyl, ethyl and the like, Ci ^ -alkoxy groups such as Methoxy, ethoxy and the like, etc. is selected.

As alkyl groups which represent R3a or R3b, there can be mentioned, for example, Ci_4-alkyl groups, such as methyl, ethyl and the like, and as aryl groups, for example, phenyl and naphthyl.

In addition, R3a and R3b and the o-phenylene or o-naphthylene group which R3a and R3b can form together can carry at least one substituent, which can be chosen from the same substituents that have been mentioned for R2.

According to the above-mentioned production processes, the process for producing a compound of formula (II) or its salt and a compound of formula (III) or its salt as a starting material for the compound of the present invention will be explained in more detail below.

(1) The compound of the formula (IV) or its salt is subjected to a reaction in which the amino group is protected by an amino protecting group by a conventional method, whereby the compound of the formula (V) or its salt is formed becomes.

(2) The compound of formula (V) or its salt is halogenated, whereby the compound of formula (Via) or its salt is produced.

This halogenation can be carried out, for example, using the methods described in Acta. Chimi. Acad. Be. Hung., 29 (1i. 91-98 (1961), Tetrahedron Lett., 4, 339 (1979), J. Org. Chem 36, 3044 (1971)), or according to modified methods.

(3) The compound of formula (V) or its salt is subjected to a usual acylation reaction using an approximately equimolar amount of an acylating agent to form the compound of formula (Vlb) or its salt.

(4) The compound of the formula (IV) or its salt is subjected to a usual acylation reaction using at least twice the equivalent amount of an acylating agent, whereby the compound of the formula (VIc) is prepared.

The compounds of the formula (Via) and (VIb) thus obtained and their salts and the compounds of the formula (VIc) (these compounds are referred to below with the generic term compound of the formula (VI)) can be used in the subsequent reaction stages without prior isolation .

(5) The compound of formula (VI) is reacted with 2-amino-ethanethiol or its salt in the presence or in the absence of a base, thereby producing a compound of formula (VII) or its salt.

The solvent used in this reaction can be any solvent provided that it does not interfere with the reaction. As such solvents, there can be mentioned, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like, nitriles such as acetonitrile and the like, ethers such as tetrahydrofuran, dioxane and the like, alcohols such as methanol, ethanol and the like, amides such as N, N-dimethylformamide and the like, carboxylic acids such as acetic acid and the like, water, etc. These solvents may be used alone or in the form of a mixture of two or more.

9

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

Suitable bases, in the presence of which the reaction is carried out, are, for example, sodium methoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, triethylamine and 1,8-diazabicycio [5.4.0] -un-dec-7-ene (DBU ).

The amount of 2-aminoethanethiol or its salt which is used and the amount of the base used can in each case be at least equimolar to the amount of the compound of the formula (VI).

Although the reaction temperature and the reaction time are not critical and can be appropriately varied depending on the reactants and the like, the above reaction can be carried out at -20 to 100 ° C for 1 minute to 12 hours.

(6) 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), the compound of the formula (IX) or its salt or the compound of the formula (XII) or their salt are formed.

The solvent used for this reaction can be any solvent as long as it does not interfere with the reaction. As such a solvent, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like are suitable, 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 the form of a mixture of two or more.

The amount of the compound of the formula (VIII) used is at least equimolar to the amount of the compound of the formula (VII) or its salt or the compound of the formula (XI) or its salt.

As a preferred compound of formula (VIII), there can be mentioned, for example, dimethyl methanesulfonylimidodi-thiocarbonate, diphenyl methanesulfonylimidocarbonate, 2-methanesulfonylimino-1,3-benzodioxole and similar compounds.

Although the reaction temperature and the reaction time are not critical and can be appropriately varied depending on the reactants and the like, in general, the above reaction can be carried out at -10 to + 150 ° C for 1 minute to 24 hours. The compound of formula (IX) or its salt or the compound of formula (XII) or its salt can be used in the subsequent reaction without isolation.

(7) The compound of the formula (IX) or its salt or the compound of the formula (XII) or its salt is reacted in the presence or in the absence of a base with the compound of the formula (X) or its salt, the compound of the formula (II) or its salt or the compound of formula (III) or its salt is formed.

The solvent used in this reaction can be any solvent provided that it does not interfere with the reaction. As such solvents are, 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-dimethyIformamide, N, N-dimethylacetamide and the like, sulfoxides such as dimethyisulfoxide and the like, alcohols such as methanol, ethanol, 2-propanol and the like, etc. These solvents can be used alone or as a mixture of two or more can be used.

Suitable bases for use in the above reaction are, for example, inorganic bases such as sodium carbonate, potassium carbonate and the like, and organic bases such as potassium acetate, triethylamine, tetramethylguanidine and the like.

The amount of the compound of the formula (X) or its salt and the amount of the base which is used are at least equimolar to the amount of the compound of the formula (IX) or its salt or to the amount of the compound of the formula (XII) or the salt of this compound.

The reaction temperature and the reaction time are not critical and can be appropriately varied depending on the reactants or the like, but in general, the above reaction is carried out at 20 to 150 ° 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 obtained can be easily obtained by a conventional method such as recrystallization, concentration, extraction, optical cleavage, column chromatography or the like , isolated and obtained.

The salt of the compound of the formula (II) or the salt of the compound of the formula (III) can be prepared in a simple manner from the compound in the free form using a conventional method.

The pharmacological activity of the amine derivative of the formula (I) and the salts of this compound are explained below.

10th

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

Test connections

"" NS0oCH

R * JTTL ii i ^ -oe

^ nch0- ^ 0 ^ -ch, sch, ch9ncnch-ch ch3. h h z ^ r

No ..

ra r

Invention s according to e connections

1

H

2nd

H

/ NHS02CH3

3rd

H

- <Ö ^ conh2

Comparative connections

4th

ch3

5.

ch3

- (o) -ou

(I) Inhibitory effect on gastric acid secretion (pyloric ligation method)

This effect was measured according to the method of H. Shay et al, described in Gastroenterology, 5, 43 (1945). Groups of six or seven Wistar rats (male, 190 to 230 g) were fasted for 24 hours after which each rat's pyiorus was ligated under ether anesthesia. The test compounds were administered intraduodenally after ligation. Thereafter, the rats received an abdominal wall suture (celiorraphy) and immediately afterwards they were administered histamine in a dose of 25 mg / kg subcutaneously dorsally. After 3 hours the gastric cardia was tied off, after which the stomach was removed. The gastric juice was obtained by centrifugation and the total amount was measured quantitatively. 1 ml of gastric juice was removed and titrated with a 0.1 N aqueous sodium hydroxide solution to the end point of pH 7.0. To administer the test compound, the compound was dissolved in dimethyl sulfoxide (DMSO) and then diluted with distilled water until a 0.25% aqueous DMSO solution containing the test compound was obtained. A 0.25% DMSO aqueous solution containing no test compound was administered to a control group.

11

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

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

(Acid production \ / Acid production. \ Of the control- j - (of the drug group J \ treated group /

sejcre-ci-cion = - ^^ x 100

(%) Acid production of the control group

The test results are shown in Table 1.

Table 1

Test connection number

Dose (mg / kg)

Inhibition rate (%)

1

0.625

67.6 **

1.25

82.2 **

2nd

1.25

51.3 *

3rd

1.25

54.2 *

4th

1.25

30.6

5

5.0

32.7

Note: ** p <0.01; *

p <0.05

(II) Acute toxicity

The test compound was administered intravenously to ICR mice (male, 27 to 30 g) and the LD50 value was calculated using the “up and down method”.

The results obtained are shown in Table 2.

Table 2

Test compound number LDso (mg / kg)

1 100.0

2 129.8

3 151.0

4 85.4

5 90.7

As can be seen from Table 1 and Table 2, the amine derivatives of the formula (I) and their salts according to the invention showed excellent inhibitory activity on gastric acid secretion and consequently excellent anti-ulcer activity, have low toxicity and therefore have a broader safety range. In addition, these connections have excellent stability.

Anti-ulcer agents which contain the amine derivative of the formula (I) or a salt thereof can be prepared in various forms, such as in the form of tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, lozenges, ointments, suppositories , Injection liquids, suspensions, emulsions, drops, syrups and the like, according to conventional methods. They can be administered either orally or parenterally, and oral administration is particularly preferred.

In order to prepare these agents in various forms suitable for oral or parenteral administration, the preparation can be carried out using pharmaceutically acceptable, non-toxic additives, as are normally used, such as excipients, Binders, lubricants, disintegrants, suppository bases and the like. If necessary, other additives such as an isotonic agent, stabilizer, dispersant, antioxidant, colorant, flavoring agent, buffering agent and the like can be used.

The above forms may also contain other drugs that are considered useful for the purposes of treatment.

With regard to the dosage and administration time of the amine derivatives of the formula (I) or of their salts, these can be administered orally or parenterally, in adults in general in a

12

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

a dose of 1 | ig / kg to 10 mg / kg per day in 1 to 4 proportions. Of course, the dose and administration time can be varied appropriately depending on the route of administration and the symptoms of the patient.

The invention is explained below with reference to examples, examples and preparation examples, without being restricted to these.

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

Silica gel (silica gel 60, article 7734 from Merck Co.) was used as the support for the column chromatography.

Reference example 1

267 g of diphenyl carbonate and 298 g of phosphorus pentachloride were reacted at 160 ° C. for 15 hours, the phosphorus oxychloride formed by the reaction being distilled off. After the reaction was completed, phosphorus oxychloride and residual phosphorus pentachloride were removed by distillation under reduced pressure to obtain dichlorophenoxymethane. To this compound, 600 ml of anhydrous ethyl acetate and 148 g of methanesulfonamide were added, and the mixture was refluxed for 8 hours. After cooling, 1 1-m-hexane was added to the mixture, and the deposited crystals were collected by filtration. The crystals were washed with water and dried to obtain 179 g (yield 49%) of diphenylmethanesulfonylimidocarbonate with a melting point of 124 to 125.5 ° C.

Reference example 2

53.4 g of methanesulfonamide and 89.4 g of 2,2-dichloro-1,3-benzodioxoI were heated under reflux with 400 ml of anhydrous ethyl acetate for 7 hours. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained, 200 ml of benzene was added and the mixture was refluxed for 10 minutes and then slowly cooled to room temperature with stirring. The deposited crystals were collected by filtration and washed with benzene, water and 2-propanol in this order, whereby 83 g of 2-methanesulfonylimino-1,3-benzodioxole (yield 83%) were obtained.

Melting point: 161-163 ° C (after recrystallization from ethyl acetate)

Reference example 3

(1) 23.5 g of 2,2,2-trichloroethyl chloroformate was added dropwise over a period of 60 minutes at 4 to 5 ° C to 140 ml of a methylene chloride solution containing 14.1 g of 5-N-methylaminomethyl Contained 2-fu-ranmethanol and 8.9 ml of pyridine, and the mixture was then 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 column chromatography (eluent: benzene to ethyl acetate = 2: 1), whereby 16.4 g (yield 50%) of oily 5- [N-methyl-N - (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furanmethanol were obtained.

NMR (CDCLa) S values:

2.15 (1H, bs), 3.00 (3H, s), 4.47 (2H, s), 4.55 (2H, s), 4.76 (2H, s), 6.21 (2H , s).

(2) 7.26 g of N-chlorosuccinimide was dissolved in 100 ml of methylene chloride. 4.18 ml of dimethyl sulfide were added dropwise at 5 to 10 ° C. The mixture was stirred at the same temperature for 30 minutes. For this purpose, 30 ml of a methylene chloride solution were added dropwise over a period of 20 minutes at 5 to 10 ° C., which 16.4 g of 5- [N-methyl-N- (2,2,2-trichiorethoxycarbonyl) amino-methyl ] -2-furanmethanol, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured 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 weight percent sodium methoxide solution in methanol was added dropwise to 15 ml of a methanol solution containing 5.88 g of 2-aminoethanethiol hydrochloride while cooling with ice in a nitrogen atmosphere. Then, the dried organic layer obtained above was added dropwise over a period of 20 minutes at 5 to 10 ° C. The temperature of the mixture was slowly raised to room temperature with stirring over 30 minutes. The reaction mixture was poured 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 pH of the mixture was adjusted to pH 1.5 with 6N 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 aqueous solution formed was washed with ethyl acetate and the pH of the aqueous layer was raised with a 5N aqueous sodium hydroxide solution

13

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

The pH was adjusted to 11, after which the layer was extracted with 150 ml of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure, so that 15.6 g (yield 80%) of oily 2 - [[5- [N-methyl-N - (2,2,2, -trichlorethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethylamine were obtained.

NMR (CDCIs) 5 values:

1.45 (2H, s), 2.45 - 2.95 (4H, m), 3.01 (3H, s), 3.68 (2H, s), 4.47 (2H, s), 4 , 77 (2H, s), 6.16 (2H, m).

(3) 13.8 g of diphenyl methanesulfonyiimidocarbonate was dissolved in 50 ml of acetonitrile. While cooling with ice, 17.7 g of 2 - [[5-N-methyl-N- (2,2,2, -trichloroethoxycarbonyl) aminomethyl] -2-furyl] methythio] ethylamine were added and the mixture was added Stirred for 10 minutes. Then 10.9 g of DL-octopamine, 2.3 g of potassium acetate, 10 ml of 2-propanol and 16.5 ml of triethylamine were added and the mixture was refluxed for 2 hours. After cooling, 180 ml of water and 180 ml of ethyl acetate were added and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid and a saturated aqueous sodium chloride solution in the order shown. Then the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 3), 26.9 g (yield 90%) of oily N- [2-hydroxy-2 (4-hydroxyphenyi) ethyl] -N ' -methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (2,2,2, -trichlorethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine.

NMR (CDCIs) 5 values:

2.45 - 2.85 (2H, m), 2.84 (3H, s), 2.98 (3H, s), 3.10 - 3.60 (4H, m), 3.67 (2H, s), 4.43 (2H, s), 4.55 -4.95 (1 H, m), 4.72 (2H, s), 6.17 (2H, s), 6.77.7, 13 (4H, ABq, J = 8.2 Hz).

The following compounds were prepared in the same way: o N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (2nd , 2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine;

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

Reference example 4

(1) 42.6 g of 2-methanesulfonylimino-1,3-benzodioxole was suspended in 126 ml of methylene chloride. To this was added dropwise 31.4 g of 2 - [(2-furyl) methylthio] ethylamine at 10 to 15 ° C. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was mixed with 250 ml of benzene, and the resulting mixture was stirred at the same temperature for 30 minutes. The deposited crystals were collected by filtration, whereby 65.5 g (yield 88%) N- [2 - [(2-Furyi) -methyl-thio] -ethyl] -0- (2-hydroxyphenyl) -N'-methanesulfonylisourea were obtained.

Melting point: 110-111.5 ° C (after recrystallization from ethyl acetate)

NMR (CDCI3) S values:

2.76 (2H, s), 2.88 (3H, s), 3.35-3.85 (2H, m), 3.75 (2H, s), 6.24 (2H, m), 6 , 75 - 7.25 (4H, m), 7.31 (1H,

m)

(2) To 50 ml of acetonitrile were added 5.0 g of N- [2 - [(2-furyl) methylthio] ethyl] -0- (2-hydroxyphenyl) -N'-methanesulfonyl isourea, 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 then the solvent was removed by distillation under reduced pressure. 50 ml of ethyl acetate and 30 ml of water were added to the residue thus obtained. The pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was separated, washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 2: 3), 2.8 g (yield 51%) of N- [2 - [(2-furyl) methylthio] ethyl] -N ' - [2-hydroxy-2 (4-hydroxyphenyl) ethyl] -N "-methanesulfonylguanidine with a melting point of 109 to 112.5 ° C. were obtained. NMR (de-DMSO) 5 values:

2.57 (2H, m), 2.75 (3H, s), 3.10 - 3.50 (4H, m), 3.80 (2H, s), 4.50 - 4.90 (1H, m), 6.34 (2H, s), 6.74,

7.20 (4H, ABq, J = 8, 3Hz), 7.55 (1H, s)

The following compounds were prepared in the same way: 0 N- [2- [2-furyl) methylthio] ethyl] -N '- [2-hydroxy-2- [3- (methanesulfonylamino) phenyl] ethyl] - N "-methanesulfonylguanidine NMR (CDCI3) 5 values:

2.45 - 2.80 (2H, m), 2.83 (3H, s), 2.93 (3H, s), 3.05 - 3.65 (4H, m), 3.68 (2H, s), 4.65 - 5.05 (1H, m),

6.21 (2H, m), 7.00-7.50 (5H, m)

0 N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N '- [2 - [(2-furyl) (methylthio] ethyl] -N "-methanesulfonylguanidine NMR (dsDMSO) 5 values:

14

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

2.44 - 2.56 (2H, m), 2.74 (3H, s), 3.10 - 3.50 (4H, m), 3.79 (2H, s), 4.70 - 4, 94 (1H, m) 6.26-6.41 (2H, m), 7.55 (1H, m), 7.44, 7.87 (4H, ABq, J = 8.3 Hz).

Reference example 5

(1) 45.2 g of trichloroacetyichloride was added dropwise at -30 to -20 ° C. over a period of 1 hour to 150 ml of a methylene chloride solution, the 15.3 g of 5-N-methylaminomethyl-2-furan-methanol and 36, Contained 1 ml of triethylamine. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into 100 ml of ice water. Then the organic layer was separated and dried over anhydrous magnesium sulfate.

The solution thus obtained 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 then poured into 150 ml of ice water. The resulting mixture was adjusted to a pH of 9.5 with a 5N 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 added dropwise 200 ml of an ethanol solution containing 9.72 g of anhydrous oxalic acid. The methylene chloride was removed by distillation under atmospheric pressure. The deposited crystals were collected by filtration, whereby 30.1 g (yield 64%) of 2 - [[5- [N-methyl-N- (trichloroacetyl) aminomethyl] -2-furyl] methylthio] ethylamine oxalate ( 1: 1) were obtained.

Melting point: 138 to 139.5 ° C (after recrystallization from ethanol)

NMR (de-DMSO) 5 values:

2.40-3.30 (4H, m), 3.23 (3H, s), 3.81 (2H, s), 4.68 (2H, s), 6.32 (2H, s)

(2) 43.6 g of 2 - [[5-] N-methyl-N- (trichloroacetyl) aminomethyl] -2-furyl] methylthio] ethylamine oxalate (1: 1) became 180 ml of methylene chloride and 250 given ml of water. 38 ml of a 5 N aqueous potassium hydroxide solution was added dropwise 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 obtained, 29.1 g of diphenyl methanesulfonyl imidocarbonate was added while cooling with ice, and the mixture was stirred for 30 minutes. Methylene chloride was removed by distillation under reduced pressure. 200 ml of 2-propanol were added to the residue thus obtained. The deposited crystals were collected by filtration, whereby 48.9 g (yield 90%) of N-methanesulfonyl-N '- [2 - [[5- [N-methyl-N- (trichloroacetyl) aminomethyl] -2- furyl] -methyIthio] -ethyl] -0-phenyl-isourea were obtained.

Melting point: 85 to 87 ° C (after recrystallization from 2-propanol)

NMR (CDCIs) 5 values:

2.76 (2H, t, J = 6.3 Hz), 2.85 (3H, s), 3.27 (3H, s), 3.40 - 3.75 (2H, m), 3.73 ( 2H, s), 4.64 (2H, s), 6.12 -6.25 (2H, m), 7.00-7.41 (5H, m)

(3) 32.6 g of N-methanesulfonyl-N '- [2 - [[5- [N-methyl-N- (trichloroacetyl) aminomethyl] -2-furyl] methylthio] ethyl were added to 160 ml of acetonitrile] -0-phenylisourea, 13.8 g of DL-octopamine, 21 ml of triethylamine and 2.94 g of potassium acetate. The mixture was refluxed in a nitrogen atmosphere for 1 hour. After cooling, the solvent was removed by distillation under reduced pressure. 250 ml of ethyl acetate and 150 ml of water were added to the residue thus obtained. The pH of the mixture was adjusted to pH 2.0 with 2N 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 distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 2), 29.9 g (yield 83%) of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] - N'-methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (trichloroacetyI) aminomethyl] -2-furyl] methylthio] ethyl] guanidine.

NMR (CDCIs) 5 values:

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 (1H, m), 4.60 (2H, s), 6.10 - 6.30 (2H, m), 6.75, 7.11 (4H, Abq, J = 8.5 Hz).

Reference example 6

(1) 11.6 g of diphenyi methanesulfonyl imidocarbonate was dissolved in 40 ml of methylene chloride. 15 g of 2 - [[5-N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methyl-thio] -ethylamine were added while cooling with ice. The mixture was stirred for 10 minutes. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 2: 1), 17.8 g (yield 78%) of oily N-methanesulfonyl-N '- [2 - [[5- [N-methyl- N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methyl thio] ethyl] -0-phenylisourea were obtained.

15

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

NMR (CDCIs) 5 values:

2.77 (2H, t, J = 6.4 Hz), 2.86 (3H, s), 3.00 (3H, s), 3.40 - 3.75 (2H, m), 3.73 (2H, s), 4.45 (2H, s), 4.77 (2H, s), 6.16 (2H, s), 7.00 - 7.45 (5H, m)

(2) In 11 ml of dimethyl sulfoxide, 5.4 g of N-methanesulfonyl-N '- [2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2- furyl] -methylthio] -ethyl] -0-phenylisourea dissolved. 2.9 g of S (+) octopamine ([a] 25 = + 57.4 ° (C = 1; 0.1 N HCl)) were added. The mixture was stirred at room temperature in a nitrogen atmosphere for 10 hours. 50 ml of ethyl acetate was added, and the resulting mixture was washed with 0.5N hydrochloric acid and a saturated aqueous solution of sodium chloride in the order shown and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 3), 5.2 g (yield 86%) of oily S (+) - N- [2-hydroxy-2- (4-hydroxyphenyi) -ethyl] -N'-methanesulfonyl-N "- [2 - [[5-N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guani -din were received.

([<x] 25 = + 6.5 ° (C = 1; methanol). In the same way and using R (-) - octopamine

(Wp5 = -55.1 ° (C = 1; 0.1N HCl)) instead of S (+) - octopamine, R (-) - N- [2-hydroxy-2- (4-hydroxy-

phenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl-2-furyl] methylthio] ethyl] -guanidine received.

example 1

(1) In 370 ml of tetrahydrofuran, 26.9 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesui-fonyl-N "- [2 - [[5- [N- methyl-N- (2,2,2-trich! orethoxycarbonyl) aminomethyl] -2-furyl] methyl! thio] ethyl] guanidine was dissolved in 320 ml of a 0.5 M aqueous potassium dihydrogen phosphate solution and 42 g of active zinc powder and the mixture was stirred at room temperature for 3 hours, the pH of the reaction mixture was adjusted to pH 9.8 with 5N aqueous sodium hydroxide solution, and the mixture was then extracted with 370 ml of ethyl acetate, and the solvent of the extract was removed by distillation The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1) and then recrystallized from a 95% aqueous ethanol solution, 12.6 g (yield 65%) N- [2-Hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesuifonyl-N "- [2 - [[5- (methylamino) meth yl-2-furyl] methylthio] ethyl] guanidine with a melting point of 146.5 to 147 ° C were obtained.

IR (KBr) cm-1: 1580, 1255, 1105

NMR (de-DMSO) 5 values:

2.24 (3H, s), 2.35 - 2.65 (2H, m), 2.74 (3H, s), 3.00 - 3.50 (4H, m), 3.56 (2H, s) , 3.74 (2H, s), 4.50 -4.80 (1H, m), 6.15 (2H, m), 6.71, 7.18 (4H, ABq, J = 8.5 Hz) .

The following connections were made in the same way:

o N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-

furyl] methylthio] ethyl] guanidine;

NMR (de-DMSO) S values:

2.25 (3H, s), 2.35 - 2.65 (2H, m), 2.74 (3H, s), 2.90 - 3.60 (4H, m), 3.57 (2H, s) , 3.75 (2H, s), 4.65 -5.00 (1H, m), 6.18 (2H, m), 7.45, 7.86 (4H, ABq, J = 8.2 Hz)

o N- [2-hydroxy-2- [3- (methanesulfonylamino) phenyl] ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio ] ethyl] guanidine

NMR (GDCI3) S values:

2.25 (3H, s), 2.55 - 2.85 (2H, m), 2.86 (3H, s), 2.97 (3H, s), 3.10 - 3.70 (4H, m), 3.61 (2H, s), 3.69 (2H, s), 4.70-5.00 (1H, m), 6.10 (2H, s), 7.00-7.40 (4H, m)

(2) In 1430 ml of a 95% aqueous ethanol solution, 239 g of N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) - methyl-2-furyl] methylthio] ethyl] guani-

din solved. To this was added a solution obtained by dissolving 46.8 g of oxalic acid in 240 ml of a 95 percent aqueous ethanol solution. In addition, 2.5 g of seed crystals were added. The mixture was stirred at 40 ° C for 3 hours and at room temperature for 3 hours and then left to stand overnight. The deposited crystals were collected by filtration, whereby 257 g (yield 91%) N- [2- (4-carbamoylphenyl) -2-hydroxyethy!] - N'-methanesulfonyl-N "- [2 - [[5- (methylamino ) -methyl-2-furyl] -methylthio] -ethyl] -guanidine oxalate (1: 1) were obtained.

Melting point: 142.5 to 145.5 ° C (after recrystallization from 95 percent aqueous ethanol solution)

NMR (DzO) 5 values:

2.62 (2H, t, J = 6.4Hz), 2.73 (3H, s), 2.85 (3H, s), 3.34 (2H, t, J = 6, 4Hz), 3, 61 (2H, d, J = 5, 8 Hz), 3.77 (2H, s), 4.26 (2H, s), 5.05 (1H, t, J = 5, 8 Hz), 6.34 , 6.60 (2H, ABg, J = 3, 4Hz), 7.54, 7.87 (4H, ABq, J = 8, 3Hz).

16

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

In the same manner and using a mixture of methanol and ethanol (1: 2.5) as a solvent and 98 percent orthophosphoric acid as an acid, N- [2- (4-carbamoylphenyl-2-hydroxyethyl] -N'-methanesulfonyl -N "- [2 - [[5- (methylamino) -methyl-2-furyl] -methylthio] -ethyl] -guani-din-phosphate (1: 1) was obtained in a yield of 95%.

Melting point: 140 to 142 ° C (after recrystallization from ethanol and acetic acid (4: 1))

NMR (D20) S values:

2.63 (2H, t), 2.71 (3H, s), 2.81 (3H, s), 3.11 (3H: s), 3.36 (2H, t), 3.58 (2H , d), 3.79 (2H, s), 4.25 (2H, s), 4.97 (1H, t), 6.35, 6.59 (2H, ABq, J = 3.1Hz), 7.16-7.68 (4H, m).

in the same way, amorphous N- [2-hydroxy-2- [3- (methanesulfonylamino) phenyl] ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2 -furyl] -methylthio] -ethyl] -guanidine hydrochloride obtained.

NMR (D20) 8 values:

2.63 (2H, t), 2.71 (3H, s), 2.81 (3H, s), 3.11 (3H, s), 3.36 (2H, t), 3.58 (2H , d), 3.79 (2H, s), 4.25 (2H, s), 4.97 (1H, t), 6.35, 6.59 (2H, ABq, J = 3.1Hz), 7.16-7.68 (4H, m).

Example 2

240 mg of methylamine hydrochloride was dissolved in 0.27 ml of a 37 percent (w / w) aqueous formalin solution. 2.5 ml of a tetrahydrofuran solution were added at room temperature, the 500 mg of N- [2 - [(2-furyl) methylthio] ethyl] -N '- [2-hydroxy-2- (4-hydroxyphenyl) -ethyl] -N "-methanesulfonylguanidine. The mixture was stirred at the same temperature for 5 hours. The reaction mixture was then poured into 30 ml of water. The resulting mixture was adjusted to pH 9 with 1N aqueous sodium hydroxide solution , 5 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, after which the solvent was removed by distillation under reduced pressure Column chromatography purified (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), 220 mg (yield 40%) N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl- N "- [2 - [[5- (methylamino-no) methyl-2-furyI] - methylthio-ethyl] guanidine were obtained.

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

Example 3

1.3 g of p-toluenesulfonic acid monohydrate and 1.0 g of N- [2 - [(2-furyl) methyIthio] - were added to 10 ml of a tetrahydrofuran solution containing 310 mg of 1,3,5-trimethyl-trimethylene-triamine. ethyl] -N '- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N "-methanesulfonylguanidine. The mixture was stirred at room temperature for 3 hours. Then the reaction mixture was poured into 30 ml of water. The formed The mixture was adjusted to pH 9.5 with 1N 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, after which the solvent was distilled off under reduced pressure The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), 440 mg (yield '40%) N- [2-hydroxy-2- (4- hydroxyphenyl) ethyl] -N'-methanesulfonyl-N " - [2 - [[5- (methylamino) methyl-2-furyi] methyithio] ethyl] guanidine were obtained.

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

Example 4

9.4 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 [[5-N-methyl-N- (trichloroacetyl) aminomethyl]] -2-furyl] -methylthio] -ethyl] -guanidine was dissolved in a mixture of 8 ml of ethanol and 47 ml of a 1N aqueous solution of sodium hydroxide under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours Hydrochloric acid was adjusted to pH 9.7 with ice-cooling, seed crystals were added, and the mixture was stirred at room temperature for 4 hours, and the deposited crystals were collected by filtration, whereby 6.0 g (yield 84%) of N- [2- Hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] ethyl] guanidine were obtained.

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

Example 5

S (+) - N- [2-Hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (2,2, 2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine was reacted in the same manner as in Example 1 (1), with S (-) - N- [2-hydroxy-2- (4th -hydroxyphenyl) -ethyl] -N'-methanesuifonyl-N "- [2 - [[5- (methylamino) -methyl-2-furyl] -methylthio] -ethyl] -guanidine was obtained.

17th

5

10th

15

20th

25th

30th

35

40

45

50

55

CH 675 244 A5

([oc] 25 = -6.6 ° (C = 1, 0.1 n HCl)

The following compound was prepared in the same way: R (+) - N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- ( methylamino) methyl-2-furyl] methylthio] ethyl] guanidine.

(Md5 = -6.3 ° (C = 1, 0.1N HCl).

Example 6

250 mg of methylamino hydrochloride and 170 mg of 95 percent paraformaldehyde were added to 1.5 ml of methanol. The mixture was refluxed for 90 minutes. For this purpose, 1.5 ml of a methanol solution were added at room temperature, the 500 mg of N- [2 - [(2-furyl) methylthio] methyl] -N '- [[2-hydroxy-2- (4-hydroxyphenyl)] -ethyl] -N "-methanesulfonylguanidin. The mixture was reacted at the same temperature for two days. Then the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 20 ml of water. The pH of the The mixture was adjusted to 9.6 with a 5N aqueous solution of sodium hydroxide, and the mixture was extracted with two 30 ml portions of a 1: 1 mixture of ethyl acetate and tetrahydrofuran, the extracts were combined and dried over anhydrous magnesium sulfate, followed by the solvent The residue so obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), whereby 220 mg (yield 40%) N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] - ethyl] guanidine were obtained.

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

Example 7

(1) 5.61 g of N- [2 - [(2-furyl) methylthio] ethyl] -N '- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N "-methanesulfonylguanidine 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, and this solution was added at -35 to -25 ° C. 8 ml of a methylene chloride solution, which contained 2.00 g of benzoyl chloride, were added dropwise.

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 that order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 1), 5.40 g (yield 77%) of N- [2- (4-benzoyioxyphenyl) -2-hydroxy] ethyl-N ' - [2 - [(2-furyl) -methylthio] -ethyl] -N "-methanesulfonylguanidine he was kept.

NMR (CDCIs) 5 values:

2.69 (2H, t), 2.88 (3H, s), 3.10-3.55 (4H, m), 3.73 (2H, s), 4.90 (1H, m), 6 , 15-6.35 (2H, m), 7.10-7.70 (8H, m), 8.05 - 8.30 (2H, m)

(2) 2.11 g of methylamine hydrochloride and 1.48 g of 95 percent paraformaldehyde were added to 10 ml of methanol. The mixture was refluxed for 1.5 hours. After cooling, 15 ml of a methanol solution were added, containing 5.40 g of N-2- (4-benzoyloxyphenyl) -2-hydroxy] ethyl-N '- [2 - [(2-furyl) methy! Thio] - ethyl] -N "-methanesulfonylguanidine. The mixture formed was stirred at room temperature for 24 hours. Then 50 ml of ethyl acetate and 50 ml of water were added. The pH of the mixture thus obtained was adjusted to pH 9 with 5N aqueous sodium hydroxide solution while cooling with ice , 6. The organic layer was separated and 30 ml of water was added, after which the mixture was adjusted to pH 1.5 with ice-cooling with 2N hydrochloric acid, the aqueous layer was separated and 50 ml of chloroform was added, then the pH of the mixture was adjusted to pH 9.6 with 5N aqueous sodium hydroxide solution while cooling with ice, the organic layer was separated and washed with 30 ml of a saturated aqueous sodium chloride solution, and the solvent was removed by distillate ion removed under reduced pressure. The oily residue thus obtained was dissolved in 50 ml of methanol. To this was added 2.0 g of a 28 weight percent solution of sodium methoxide in methanol. The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. 2.6 ml of a 4N-hydrochloric acid-re-ethanol solution was added while cooling with ice. The mixture was stirred at the same temperature for 15 minutes. Then the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia solution = 85: 15: 1), 3.57 g (yield 75%) of N- [2-hydroxy-2- (4-hydroxyphenyl) - ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) -methyl-2-furyl] -methylthio] -ethylj-guanidine. This compound showed the same melting point, the same IR spectrum and NMR spectrum as the compound obtained in Example 1 (1).

18th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 244 A5

Preparation example 1

75 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] ethyl ] -guanidine, 15 g of Avicei PH 102 (microcrystalline cellulose, manufactured by ASA-HI CHEMICAL INDUSTRY CO., LTD.), 29 g of Kollidon CL (cross-linked polyvinylpyrrolidone, manufactured by BASF), 29 g Adsolider 101 (anhydrous silica, manufactured by Freund IND. CO., LTD.) And 3 stearic acid and 1.5 g of magnesium stearate were uniformly mixed, and this mixture was processed into green compacts by a conventional method, which was ground and sieved through a 24-mesh sieve Powder was mixed with 4.48 g of Kollidon CL, 5.76 Adsolider 102 (anhydrous silica, manufactured by Freund IND. CO., LTD.) 4.9 g Avical PH 302 (microcrystalline cellulose, manufactured by ASAHI CHEMICAL INDUSTRY, CO., LTD. And 2.36 g of magnesium stearate. The mixture thus obtained was then converted into tablets each weighing 170 mg vera works.

Preparation example 2

10 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] ethyl ] -guanidine and 5 g of L-aspartic acid were suspended in 200 ml of distilled water for injections and the suspension was adjusted to pH 5.5 ± 0.5 with 1N hydrochloric acid to form a solution g of D-mannitol was dissolved therein, and the resulting solution was subjected to sterile filtration using a 0.22 nm filter, and the filtrate was filled into ampoules in an amount of 2 ml per ampoule, and the ampoules were made by a conventional method of freeze-drying subjected to injection vials were obtained.

Claims (11)

Claims 1. Amine derivative of the formula NS0oCH. H \ III " ^ NCH- ^ O ^ CH_SCH CH NCNCH CH ± CH / H H in which R represents a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or its salts. 2. Amine derivative or its salts according to claim 1, characterized in that R is a 4-hydroxy-phenyl group. 3. Amine derivative or its salts according to claim 1, characterized in that R is a 4-carbamoylphenyl group. 4. Amine derivative or its salts according to claim 1, characterized in that R is a 3-methane-sulfonylaminophenyl group. 5. Process for the preparation of an amine derivative of the formula _ r NSO "CH hn XTL " ^ NCHy ^ O ^ CH, SCH, CH-NCNCH, CIi H3C * H H in which R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonyl-aminophenyl group, or its salts, characterized in that the amino protective group consists of a compound of the formula 'NSO-CH- * XJk "2 3 -NCH - ^ (y ~ "CH, SCH CH-NCNCH CH H3C ^ * H H or is removed from its salts, where R1 is an amino protecting group and R has the meaning defined above. 19th 5 10th 15 20th 25th 30th 35 40 45 50 55 CH 675 244 A5 6. Process for the preparation of an amine derivative of the formula H NSO-CH. II 2 5 OH XNCH 2nd CH_SCH_CH_NCNCH_CH z H H I " in which R represents a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or its salts, characterized in that a compound of the formula in which R has the meaning defined above, or its salts, with methylamine or its Salt and formaldehyde or paraformaldehyde or with 1,3,5-trimethyl-trimethylene triamine in the presence of an acid. 7. Anti-ulcer agent containing an amine derivative of the formula in which R denotes a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or a salt of this amine derivative. 8. Anti-ulcer agent according to claim 7, characterized in that R is a 4-hydroxyphenyl group. 9. Anti-ulcer agent according to claim 7, characterized in that R is a 4-carbamoylphenyl group. 10. Anti-ulcer agent according to claim 7, characterized in that R is a 3-methanesulfonylamino-phenyl group. 11. Use of an amine derivative or a salt thereof according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of gastric ulcers. NS0oCH 20th