FI89480B - Foerfarande Foer framstaellning av ett terapeutiskt aktivt aminderivat - Google Patents

Description

1 39480

This invention relates to a process for the preparation of novel amine derivatives and their salts. These compounds can be used as antiulcer agents.

As a result of research based on the utility of compounds having a histamine H2-blocking effect in the treatment of gastric ulcer, the present invention has previously discovered novel amine derivatives which are antagonistic of the histamine at the histamine H2 receptor and have filed patent applications. [JP Patent Application Kokai (Laid-Open) Nos. 88 458/84 and 97 958/85].

However, the compounds specifically described in the above-mentioned patent applications are not entirely satisfactory in terms of their antiulcer activity and stability. Therefore, it has been desired to provide a compound having better antiulcer activity and stability.

The inventors of the present invention have carried out further studies to solve the above-mentioned problem and have found, as a result of the studies, that the novel amine derivative of the formula (I)

25 „Π-Π NSO.CH

H \ Jl L H 2 ^ OH

/ NCH 2 O 2 CH 2 SCH 7 CH 9 NCNCHOCH (I) CH 3 2 H H 2 R 30 wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group and its salts have excellent antiulcer activity, low toxicity and good stability compared to to the 35 compounds described.

The present invention relates to a process for the preparation of a novel amine derivative of the formula (I) as defined above and its salts. This method is characterized in that 5 a) the amino protecting group is removed from the compound of formula (II)

, _ NSO CH

r1 5 n 11 i-oH

^ "NCH ^ O ^ CH0SCH_CH NCNCH CH (II)

H 2 2 H H 2 \ R

10 J

wherein R 1 is an amino protecting group and R is as defined above, or a salt thereof, or b) a compound of formula (III) NS00CH.

O 11 ^ 0H

^ O ^ CH-SCH-CH NCNCH-CH ιΠΙ)

1 H H ^ R

Wherein R is as defined above, or a salt thereof, is reacted with methylamine or a salt thereof and formaldehyde or paraformaldehyde or 1,3,5-trimethyltrimethylenetriamine in the presence of an acid.

As the salts of the amine derivative of the formula (I), for example, salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid and the like can be mentioned; 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; as well as salts with alkali metals such as sodium, potassium and the like.

Amine derivatives of formula (I) and their salts also include their isomers such as geometric isomers, tautomers, optical isomers, racemic isomers and the like, and all crystalline forms and hydrates thereof.

A preferred amine derivative of formula (I) according to the invention is, for example, a compound wherein R is a 4-hydroxyphenyl group.

Alternative methods of this invention for the preparation of amine derivatives of formula (I) and their salts can be represented by the following reaction scheme: 4 39480 2 O 2 ro \ x / * 2 θ 'O 05 O cn \ / (N E ro \ x / O O K' O '

Ui 2 33 O CN

2 = O cn X

2 2 O O

cm cn 2 2

2 2 = O

U (rt 2 ®

CN CN

2 O 2 «O 2 O ^ M 5 CN 2 CN - w 2 5 2 H O w V“ § _ a

= (g Cl S

9 A _ / -h

\ o "P

CN _ / 2 ^ O \

2 CN

/ N 2

2 0 O

m 2 2 / \

2 O

ro ^ 2

O Cd -H t1 I

1 -P i — I * H cd * H CO

ui m o 3 -P P -h co • n -H 3 -P p) C tn o O CO -H -H -H Q)

-P 3 Ή O '—I * H i — I

O CO C Ό> 1> i E Ή

• H CC 11) Νί> i «f O

> o: <fl 10 £ 11 -P -H

3 G E CU Ό CU P: 3

(0 -H 2 -H Ό rH E +> C

A4 β> ι 3 H 3 -H -H CO

O <P -PcoEPCad • P E P -P 0) Ή -P 33 cn M O Id)

02ί 02 33 o Μ-c Iflrl C

3 v / ^ * P 3 * ΪΡ O

CU ro \ x / ro P ro 4- · Λ 2 33 'o 33 3 3 - CU 3 O cn u -n ft h g il cn 2

O O

W 2 2 2 = 0 33 2 2 0 2 2 ~ A * / O X 'o CN 3 O cn 3 2 -H CN 2 ή O O o o o cn - 3 cn 2 2 3 cn m co 2 = 0 cn 2 m 2 2

O “C cn * -« C

/ 3 2 H CU

- (CO O H CO

\ CN M

O -H 2 - -H

I / 3 0 3

\ -P cn -P

\ CN

CN 2

2 O

o /

Ή / \ I-V

2 O O

3 2 Λ 5 39480

In the above schemes, R and R, are as defined above, 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 in connection with the compound of the formula (I). As the amino protecting group R, mention may be made, for example, of those described in T.W. Green, "Protective Groups in Organic Synthesis," published by John Wiley & Sons, Inc. in 1981.

Methods a and b of the present invention are described in more detail below.

1) Method a)

The amino protecting group is removed from the compound of formula (II) or a salt thereof to form a compound of formula (I) or a salt thereof.

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

2) Method b) (i) A compound of formula (III) or a salt thereof is reacted with methylamine or a salt thereof and formaldehyde or paraformaldehyde to give a compound of formula (I) or a salt thereof.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. Examples of such solvents include 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 35 such as acetic acid and the like; etc. These solvents may be used alone or as a mixture of two or more.

As the methylamine salt, for example, salts of mineral acids such as hydrochloric acid, bromic acid, sulfuric acid and the like can be mentioned.

The amounts of methylamine or a salt thereof and the formaldehyde or paraformaldehyde used are at least equimolar to the amount of the compound of formula (III) or a salt thereof.

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

ii) A compound of formula (I) or a salt thereof may also be prepared by reacting a compound of formula (III) or a salt thereof with 1,3,5-trimethyltrimethylenetriamine in the presence of an acid.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. Such solvents include, 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 and the like; etc. These solvents may be used alone or as a mixture of two or more.

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

1,3, b-Trimethyltrimethylenetriamine is used in an amount of at least equimolar and the acid in an amount of at least three to 35 times the molar amount of the compound of formula (III) or a salt thereof.

Although the reaction temperature and reaction time are not critical and can be varied e.g. depending on the reagents, the above reaction can be carried out at 10 to 150 at 5 ° C for a reaction time of 10 minutes to 48 hours.

The amine derivative of the formula (I) thus obtained or a salt thereof can be easily isolated and recovered by a conventional method such as recrystallization, concentration, extraction, optical resolution, pyl-10 copper chromatography or the like.

The salt of the amine derivative of the formula (I) can be easily obtained from the free amine derivative according to any conventional method.

A process for the preparation of a compound of formula (II) or a salt thereof and a compound of formula (III) or a salt thereof for use as starting materials in the process of the invention is described below.

The compound of the formula (II) or a salt thereof and the compound of the formula (III) or a salt thereof can be prepared, for example, according to the following reaction schemes.

β 89480 (0 ^

'' U O

o <D 3

04 ΓΜ ^ 04 W

xx 2 x _ S z & zc / <- ^ 04 03 M 4 [.— <υ ac - K 01: DH cj 33 cj - D> (N £ <N '2 2 - ac 05 x 2 5 \ wd en -— t: 'θ4 - ·. 33 * 0 04 H / 5 _ ac \ + * xx -5- CJ \ CJ' - (0 / \ oo \ .- / rH X \ 04 CJ \ O --- 04 \ U / y * fO \ 1 »H _, \ 04 * 2 \ ° o \ <N 2 \ 33 s \ _ /„ e \ C \ and <o \ OM m /> a: 2 \ «Λ _ -H 5 3 \ ro ro • H \ 5 Z04W \ «« 4-> oj k 'i ™ e ac ö 5 xxog \ x ~ "\ \ / -

tJ Z \ 5 -h \ V S

S «.ha u \ \ o ~ £ s £ v \ \ en 5 t \ \ e w \ \ <o ^ (0 \ \ 4-» d -H \ \ O Ή (0 O \ \ (0

d O H p \ \ rH

H a) o u: \ \ O

ui ui d \ \ pd ui G ui \ \ ui e (0 <u ho \ v 0) -ne UI g \ e ui o ω <υ λ · <υ p ui -h \ ^ ui •• -i W ( 0 (0 is (¾ Ή + * r-4 32 Ή -MC (0 -J2 04 O 2 <0, _, ud 4- · 5, -. Χ d 04 4-i> g _ · Η (02 « x μΛ> 2 M04 CJ -

-> H - 2> X G 04 H

m ea - cj ai x m χΟ X21 n ui u> O C 0 ° XX en - 04 -H 04 ^ 04 CJ -H 04

X Ej X 2 XM (OX

CJ ^ CJ 33 CJ x 4-1 CJ

F = ^ -> {= / - * (= ^ -> F = (- ^? D ° L ° L ° C ° \ \ \ \ 04 04 <N 04 x x x ac cj cj cj cj

2 Z Z Z

X'ro χ \ ro pj 'ro 05 ro X X X 33 cj cj o u 9 89480

DC

O (S

n m J'Ag / -h u § O cn § (N <n m cn te en o os o o co i e co S tn e

Z = U § Z = xCJ S

Z te en Z X tn

CN <N

te -h ^ * h CJ rö CJ ιϋ (N 4J CN 4j S 5 -

CO M CO H

CM H CN M

CN -> K X -TT -> M H

* CJ 1-1 '\ CJ'

H K

, O o - / b = / cd

r-I

o e en

C

O <«m \ dc / -h NU td

CN + J

CC

o z -

CN X

te “te

O OJ

ro m «A® / $ 5 § 5 U (N § CN CN rn ^ 3- τη O o o ω 2 = 0 S 2 = 0 g« s * = s u 'd 5' d u u CO '- CO -

CN X CN M

KM KM

CJ '- CJ' - 'F = (w f = (

^ K

S CN CN

$ K x. Λ cj u rt z z - ^ ce cj ce u ro ro k te ίο 39 480

In the above formulas, R 1 * is an acyl group; R? is a removable group; R 3 * and R 3b, which may be the same or different, are a substituted or unsubstituted alkyl or aryl group, and R 3 * and R 3b may be joined together to form an o-phenylene or o-naphthylene group; X is a halogen atom; Y1 and Y2, which may be the same or different, are -O-, -S- or O; and R and R1 are above

S

specified.

As the salts of the compound of formula (IV), (V), (Via), (VIb), (VII), (IX), (X), (XI) or (XII), salts similar to those mentioned in formula (I) can be mentioned. in connection with a compound according to

As the acyl group Ru, there can be mentioned, for example, C 1-10 cannoyl groups which may be substituted by halogen atoms such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl and the like, and aroyl groups such as benzoyl and the like.

As the removable group R 2, there may be mentioned C 1-4 alkoxy groups such as methoxy, ethoxy and the like, C 1-4 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-mercapto-25 naphthylthio and the like; C 1-4 alkylsulfinyl groups such as methanesulfinyl, ethanesulfinyl and the like; arylsulfinyl groups such as benzenesulfinyl, naphthalenesulfinyl and the like, etc. R 2 may have at least one substituent which is a halogen atom such as fluorine, chlorine, bromine or iodine; a nitro group; cyano group; A C 1-4 alkyl group such as methyl, ethyl and the like; A C 1-4 alkoxy group such as methoxy, ethoxy and the like, etc.

As the alkyl groups R3 'or R, b, for example, C 1-4 alkyl groups such as methyl, ethyl and the like can be mentioned; and as aryl groups, for example, phenyl and naphth-b9480 style can be mentioned. In addition, R 3 * and R 3b and o-phenylene or o-naphthylene formed together by R 3 * and R 3b may have at least one substituent which is the same as mentioned in connection with R 2.

The processes according to the above reaction schemes for the preparation of the compound of the formula (II) or a salt thereof and the compound of the formula (III) or a salt thereof used as starting materials in the process of the present invention are described in detail below.

1) The compound of formula (IV) or a salt thereof is protected with an amino protecting group by a method known per se to form a compound of formula (V) or a salt thereof.

2) A compound of formula (V) or a salt thereof is halogenated to form a compound of formula (Via) or a salt thereof.

This halogenation can be achieved, for example, by the methods described in Acta. Chimi. Acad. Sci. Hung., 29 (1), 91-98 (1961), Tetrahedron Lett.

20 4, 339 (1979), J. Org. Chem. 36, 3044 (1971), or by methods modified from them.

3) The compound of formula (V) or a salt thereof is subjected to conventional acylation using an approximately equimolar amount of an acylating agent to form a compound of formula (VIb) or a salt thereof.

4) The compound of the formula (IV) or a salt thereof is conventionally acylated using at least two equivalents of an acylating agent to form a compound of the formula (VI) or a salt thereof.

The compounds of the formulas (VI) and (VIb) thus obtained, or their salts, and the compounds of the formula (VI) (hereinafter collectively referred to as the compound of the formula (VI)) can be used in the following reactions without isolation.

5) A compound of formula (VI) is reacted with 2-aminoethanethiol or a salt thereof, either in the presence or absence of a base, to form a compound of formula (VII) or a salt thereof.

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

Examples of the base in which the reaction is carried out include sodium methoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, triethylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

The amounts of 2-aminoethanethiol or a salt thereof and the base used may each be at least equimolar to the amount of the compound of formula (VI) used.

Although the reaction temperature and reaction time are not critical and can be varied e.g. according to the reagents, the above reaction can be carried out at -20 to 100 ° C for a reaction time of 1 minute to 12 hours.

6) A compound of formula (VII) or a salt thereof or a compound of formula (XI) or a salt thereof is reacted with a compound of formula (VIII) to form a compound of formula (IX) or a salt thereof or a salt of formula (XII) or a salt thereof.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. As such solvents, for example, 13,39480 aromatic hydrocarbons such as benzene, toluene, xylene and the like can be mentioned; halogenated hydrocarbons such as methylene chloride, chloroform and the like; nitriles such as acetone triil and the like; ethers such as anisole and the like; Esters such as ethyl acetate and the like, amides such as N, N-dimethylformamide and the like; alcohols such as methanol, ethanol, 2-propanol and the like; etc. These solvents may be used alone or as a mixture of two or more.

The amount of the compound of formula (VIII) or a salt thereof used is at least equimolar with the amount of the compound of formula (VII) or a salt thereof or the compound of formula (XI) or a salt thereof used.

As the preferred compound of formula (VIII), for example, dimethylmethanesulfonylimidodithiocarbonate, 2-methanesulfonylimino-1,3-benzodioxole and the like can be mentioned.

Although the reaction temperature and reaction time are not critical and can be varied e.g. according to reagents 20, the above reaction can be carried out at -10 to 150 ° C for a reaction time of 1 minute to 24 hours.

The compound of the formula (IX) or a salt thereof and the compound of the formula (XII) or a salt thereof can be used in the next reaction without isolation.

7) A compound of formula (IX) or a salt thereof or a compound of formula (XII) or a salt thereof is reacted with a compound of formula (X) or a salt thereof in the presence or absence of a base to form a compound of formula (II) or a salt thereof or a compound of formula (III) or a salt thereof.

The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. As such solvents, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like can be mentioned; halogenated hydrocarbons such as methylene chloride, chloroform and the like; nitriles such as aceto-nitrile and the like; ethers such as anisole and the like; esters such as ethyl acetate and the like; amides such as N, N-dimethylformamide Ν, Ν-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 may be used alone or as a mixture of two or more.

As the base used in the above reaction, 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 can be mentioned.

The amount of the compound of the formula (X) or a salt thereof used is at least equimolar with the amount of the compound of the formula (IX) or a salt thereof or the compound of the formula (XII) or a salt thereof used.

Although the reaction temperature and reaction time are not critical and can be varied e.g. according to the reagents, the above reaction can be carried out at 20 to 150 ° C for a reaction time of 30 minutes to 24 hours.

The compound of the formula (II) or a salt thereof or the compound of the formula (III) or a salt thereof thus obtained can be easily isolated and recovered by a conventional method such as recrystallization, concentration, extraction, optical resolution, column chromatography or the like.

A salt of a compound of formula (II) or a salt of a compound of formula (III) may be readily obtained from the free compound according to any conventional method.

The pharmacological properties of the amine derivative of the formula (I) and its salt are described below.

Compounds tested: is 39480 -,, _η NSO_CH „

R \ XX li j ^ oH

NCH _- ^ O ^ CH-SCH_CH-NCNCH_CH CH3 2 2 2 2H H 2 5 10 r3 R Xu _ no____

1 H - <O> -0H

η (5 / NHSO-CH-

2 h / - \ Δ J of the invention

according to - / Q> preparation \ - / tut compounds --- 3 H - / (0 / - C ° Nh2 20 4 CH3) - \

Comparative ~ \ ^ ~ V

compounds ---

25 5 * CH 3 ^ 5) -OH

* Known from FI patent application 834143.

30 I Inhibitory effect on digestive acid secretion (py-35 lorous ligation method) i ie 3 4 4 80 This effect was measured by H. Shayn et al. by the method described in Gastroenterology, 5, 43 (1945). Groups of six or seven Wistar rats (male, 190-230 g) were fasted for 24 hours, after which the pylorus of each rat was ligated under ether anesthesia. Test compounds were administered intraduodenally after ligation. The rats were then subjected to chelation and 25 mg / kg of histamine was immediately administered subcutaneously in the back. After 3 hours, the stomach was ligated and the gastric bag was removed. The digestive fluid was collected by centrifugation and its total amount was measured. A 1 ml sample of the digestive fluid was titrated with 0.1 N aqueous sodium hydroxide to pH 7.0. Upon administration of the test compound, the compound was dissolved in dimethyl sulfoxide (DMSO) and then diluted with distilled water to give a 0.25% aqueous solution of DMSO containing the test compound. The control group was given a 0.25% aqueous solution of DMSO containing no test compound.

20 The inhibitory effect on gastrointestinal acid secretion was calculated from the following equation: / Control \ _ / Drug-

Group 1 J Group 1 J

25 Digestive \ acid production / \ ^ acid production ^ / inhibition of acid secretion = - x 100 (Z) Acid production of the control group

The results obtained are shown in Table 1.

η η λ π η 17 '' ϋ

table 1

Test compound Dose xnhibit nrn __ (mg / kg) __ (% _) _ χ 0.625 67.6 ** 1.25 82.2 ** 5 2 1.25 51.3 * 3 1.25 54.2 * 4 1 .25 30.6 5 5.0 32.7 10__7__1_

Note: ** p <0.01 * p <0.05 II Acute toxicity

The test compound was administered intravenously to ICR mice (male, 27-30 g) and the LDS0 value was calculated by the up-down method.

The results obtained are shown in Table 2.

Table 2

Test compound ^ D50 No. (mg / kg) 20__ 1100.0 2 129.8 3 151.0 25 4 85.4 5 90.7

As can be seen from Table 1 and Table 2, the amine derivatives of formula (I) and their salts have an excellent inhibitory effect on digestive acid secretion and thus an excellent gastric ulcer effect, have low toxicity and therefore a higher safety margin. In addition, their stable-35 thesis is excellent.

89480 BC

The antiulcer agent containing the amine derivative of the formula (I) or a salt thereof can be prepared in various forms such as tablets, hard capsules, soft capsules, granules, powders, small granules, pills, troches, oils, suppositories, injections, suspensions, as emulsions, drops, syrups and the like according to conventional methods. They can be administered either orally or parenterally, and in particular oral administration is preferred.

They can be formulated into various forms suitable for oral or parenteral use using pharmaceutically acceptable non-toxic additives commonly used, such as fillers, binders, lubricants, disintegrants, suppository bases and the like. Other additives such as an isotonicity adjusting agent, a stabilizer, a dispersant, an antioxidant, a colorant, a flavoring agent, a buffer and the like can be used as needed.

The above forms may contain other drugs useful in therapy.

The amine derivative of formula (I) or a salt thereof may be administered orally or parenterally, generally in a dose of 1 Mg / kg to 10 mg / kg per day to an adult in 1 to 4 parts. The dosage and timing of administration may, of course, be varied depending upon the route of administration and the symptoms of the patients.

The following are reference examples, examples, and preparation precursors, which are not intended to be limiting but to illustrate.

The starting materials used in the process according to the invention can be prepared, for example, as described in the following reference examples. The method according to the invention is illustrated by the following examples.

Mixture ratios of solvents are reported as volume ratios unless otherwise indicated.

19 39480

Silica gel (Kieselgel 60, Art. 7734; manufactured by Merck Co.) was used as a support for column chromatography.

Reference Example 1,267 g of diphenyl carbonate and 298 g of phosphorus penta-5 chloride were reacted at 160 ° C for 15 hours by distilling off the phosphorus oxychloride formed in the reaction. After completion of the reaction, phosphorus oxychloride and residual phosphorus pentachloride were removed by distillation under reduced pressure to give dichlorodiphenoxymethane. 600 ml of anhydrous ethyl acetate and 148 g of methanesulfonamide were added thereto, and the mixture was refluxed for 8 hours. After cooling, 1 liter of n-hexane was added to the mixture, and the collected crystals were collected by filtration. The crystals were washed with water and dried to give 179 g (yield: 49%) of diphenyl-15-methanesulfonylimidocarbonate, m.p. 124-125.5 ° C.

Reference Example 2 53.4 g of methanesulfonamide, 89.4 g of 2,2-dichloro-1,3-benzodioxole and 400 ml of anhydrous ethyl acetate were heated under reflux 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 for 10 minutes and then slowly cooled to room temperature with stirring. The collected crystals were collected by filtration and washed with benzene, water and 2-propanol, respectively, to give 83 g (yield: 83%) of 2-methanesulfonyliminool, 3-benzodioxole.

Melting point: 161-163 ° C (recrystallized from 30 ethyl acetate)

Reference Example 3 (1) 23.5 g of 2,2,2-trichloroethyl chloroformate were added dropwise to 140 ml of a methylene chloride solution containing 14.1 g of 5-N-methylaminomethyl-2-furanimine-35-ethanol and 8.9 ml of pyridine, 4 At -5 ° C for 60 minutes while reading and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to 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: ethyl acetate = 2: 1) to give 16.4 g (yield: 50%) of oils from 5- [N-methyl-N - (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furanmethanol.

NMR (CDCl 3) δ value: 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 were dissolved in 100 ml of methylene chloride. To this was added dropwise 4.18 ml of dimethyl sulfide at 5-10 ° C. The mixture was stirred at the same temperature for 30 minutes. To this was added dropwise 30 ml of a methylene chloride solution containing 16.4 g of 5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furanmethanol at 5-10 ° C for 20 minutes. 20 na and stirred at the same temperature for 1 hour. The reaction mixture was added to 100 ml of ice water. The organic layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Separately, 20.0 g of a 28% by weight methanolic solution of sodium 25 methoxide was added dropwise to 15 ml of a methanol solution containing 5.88 g of 2-aminoethanethiol hydrochloride under ice-cooling under a nitrogen atmosphere. The dried organic layer obtained above was then added dropwise at 5-10 ° C over 20 minutes. The temperature of the mixture was slowly raised to room temperature with stirring for 30 minutes. The reaction mixture was added to 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 1.5 with 6 N hydrochloric acid. The organic phase was separated and the solvent 35 was removed by distillation under reduced pressure. The residue thus obtained, 21,39480, was dissolved in 100 ml of water. The resulting aqueous solution was washed with ethyl acetate, and the pH of the aqueous layer was adjusted to 11 with 5 N aqueous sodium hydroxide solution, and then extracted with 150 ml of ethyl acetate. The extract was washed with saturated aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to give 15.6 g (yield: 80%) of oils from 2 - [[5- [N-methyl-N- (2,2,2-trichloro). -tetoxycarbonyl) amino] -2-furyl] methylthio] -10 ethylamine.

NMR (CDCl 3) δ value: 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 diphenylmethanesulfonylimidocarbonate were dissolved in 50 ml of acetonitrile. 17.7 g of 2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethylamine were added thereto under ice-cooling, and the mixture was stirred for 10 minutes. 10.9 g of DL-octopamine, 2.3 g of potassium acetate, 10 ml of 2-propanol and 16.5 ml of triethylamine were then added thereto, and the mixture was refluxed for 2 hours. After cooling, 180 ml of water and 180 ml of ethyl acetate were added thereto, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium hydroxide solution, respectively. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 3) to give 26.9 g (yield: 90%) of oils from N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl]. -N'-Methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methyl] ethyl] guanidine.

NMR (CDCl 3) δ: 2.45-2.85 (2H, m), 2.84 (3H, s), 2.98 (3H, s), δ 3.10-3.60 (4H, m), 3.67 (2H, s), 4.43 (2H, s), 4.55-4.95 22,39480 (1H, m), 4.72 (2H, s), 6.17 (2H , s), 6.77, 7.13 (4H, ABq, J = 8.2 Hz)

The following compounds were obtained in a similar manner.

N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-5 methanesulfonyl-N "- [2 - [[5- [N-methyl-N- (2,2,2-trichloro - ethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine 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 were suspended in 126 ml of methylene chloride. To this was added dropwise 31.4 g of 2 - [(2-furyl) methylthio] ethylamine at 10-15 ° C. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was stirred with 250 ml of benzene, and the resulting mixture was stirred at the same temperature for 30 minutes. The collected crystals were collected by filtration to give 65.6 g (yield 80%) of N- [2 - [(2-furyl) methylthio] ethyl] -O- (2-hydroxyphenyl) -N'-methanesulfonyl isourea.

Melting point: 110-111.5 ° C (recrystallized from ethyl acetate) δ NMR (CDCl 3) δ value: 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) in 50 ml of acetonitrile 5.0 g of N- [2 - [- (2-furyl) methylthio] ethyl] -O- (2-hydroxyphenyl) -N '- 30-methanesulfonyl isourea, 2.9 g of DL-octopamine and 660 mg of potassium acetate were added. The mixture was refluxed for 50 minutes. The mixture was then cooled, and then 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 pH of the mixture was adjusted to 2.0 with hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure.

The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 2: 3) to give 2.8 g (yield: 51%) of N- [2 - [(2-furyl) methyl] ethyl] -N, - [2-Hydroxy-2- (4-hydroxyphenyl) ethyl] -N "-methanesulfonyl-guanidine, m.p. 109-112.5 ° C (recrystallized from ethyl acetate) 10 NMR (d 6 -DMSO) δ value: 2.57 (2H, m), 2.75 (3H, s), 3.10-3.50 (4H, m), 3.80 (2H, s), 4.50-4.90 (1H, m), 6.34 (2H, s), 6.74, 7.20 (4H, ABq, J = 8.3 Hz), 7.55 (1H, s)

The following compounds were obtained in a similar manner.

N- [2 - [(2-furyl) methylthioethyl] -N '- [2-hydroxy-2- [3- (methanesulfonylamino) phenyl] ethyl] -N "-methanesulfonyl-guanidine NMR (CDCl 3) δ- value: 2.45-2.80 (2H, m), 2.83 (3H, s), 2.93 (3H, s), 3.05-3.65 (4H, m), 3.68 (2H, s), 4.65-5.05 (1H, m), 6.21 (2H, m), 7.00-7.50 (5H, m) N- [2- (4-carbamoyl) if 1 -2) -hydroxyethyl] -N '- [2 - [(2-furyl) methylthioethyl] -N "-methanesulfonylguanidine 2 NMR (d 6 -DMSO) δ value: 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 trichloroacetyl chloride was added dropwise to 150 ml of a methylene chloride solution containing 15.3 g of 5-N-methylaminomethyl-2-furanmethanol and 36.1 ml of triethylamine at -30 to -20 ° C: within 1 hour. The mixture was stirred at the same temperature for 30 minutes.

The reaction mixture was added to 100 ml of ice water. 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 added to 150 ml of ice water. The resulting mixture was adjusted to pH 9.5 with 5 N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. To the resulting solution was added dropwise 200 ml of an ethanolic solution containing 9.72 g of anhydrous oxalic acid. Methylene chloride was removed by distillation at atmospheric pressure. The collected crystals were collected by filtration to give 30.1 g (yield: 64%) of 2 - [[5- [N-methylthio-N- (trichloroacetyl) aminomethyl] -2-furyl] methylthio] -15 ethylamine oxalate (1: 1). .

Melting point 138-139.5 ° C (recrystallized from ethyl acetate) NMR (dft-DMSO) δ value: 2.40-3.30 (4H, m), 3.23 (3H, s), 3.81 (2H, s), 4.68 2 (2H, s), 6.32 (2H, S) (2) 43.6 g 2 - [[5- (N-methylthio-N- (trichloroacetyl) aminomethyl] -2-furyl ] methylthio] ethylamine oxalate (1: 1) was added to 180 ml of methylene chloride and 250 ml of water, 38 ml of a 5 N aqueous solution of potassium hydroxide at 10-15 ° C was added dropwise and dissolved, and the organic layer was separated, washed with sodium hydroxide 10% aqueous solution and dried over anhydrous sodium sulfate.

To the solution thus obtained, 29.1 g of diphenyl 30-methanesulfonyl imidocarbonate was added under ice-cooling, and the mixture was stirred for 30 minutes. Methylene chloride was removed by distillation under reduced pressure. To the residue thus obtained was added 200 ml of 2-propanol. The collected crystals were collected by filtration to give 48.9 g (yield: 90%) of N-metho-3-sulfonyl-N '- [2 - [[5- [N-methyl-N- (trichloroacetyl). ) aminomethyl] -2-furyl] methylthio] ethyl] -ofenyl isourea.

Melting point: 85-87 ° C (recrystallized from 2-propanol) δ NMR (CDCl 3) δ value: 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) To 160 ml of acetonitrile was added 32.6 g of 10 N-methanesulfonyl-N '- [2 - [[5- [N-methyl-N- (trichloro (acetyl) aminomethyl] -2-furyl] methylthio] ethyl] -O-phenylisourea, 13.8 g of DL-octopamine, 21 ml of triethylamine and 2.94 g of potassium acetate. The mixture was refluxed for 1 hour under a nitrogen atmosphere. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 250 ml of ethyl acetate and 150 ml of water. The pH of the mixture was adjusted to 2.0 with 2 N hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium hydroxide 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) to give 29.9 g (yield: 83%) of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N ' -methanesulfonyl-N "- (2 - [[5- (N-methyl-N- (trichloroacetyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine.

NMR (CDCl 3) δ: 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, 30 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 diphenylmethanesulfonylimidocarbonate was dissolved in 40 ml of methylene chloride. 15 g of 2 - [[5- [N-methyl-N-35 (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] -2,239,480 methylthio] ethylamine were added thereto under ice-cooling. 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 = 1: 2) to give 17.8 g (yield: 78%) of oily N-methanesulfonyl-N '- [2 - [[5- (N- methyl N- (2,2,2-trichloroethoxycarbonyl) -aminomethyl] -2-furyl] methyl] ethyl] -O-phenyl-urea.

NMR (CDCl 3), δ value: 2.77 (2H, t, J = 6.4Hz), 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) 5.4 g of N-methanesulfonyl-N '- [2 - [[5- [N-methyl- (2,2,2-trichloro-15-methoxycarbonyl) aminomethyl] was dissolved in 11 ml of dimethylsulfoxide. 2-furyl] methylthio] ethyl] -O-phenylisourea. To this was added 2.9 g of S (+) - octopamine [α] D = + 57.4 ° (C = 1, 0.1 N HCl). The mixture was stirred under a nitrogen atmosphere at room temperature for 10 hours. 50 ml of ethyl acetate was added, and the resulting mixture was washed with 0.5 20 N hydrochloric acid and saturated aqueous sodium chloride solution, respectively, 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) to give 5.2 g (yield: 86%) of an oily S (+) - N- [2-hydroxy-2- (4 -hydroxyphenyl 1-ethyl] -N'-methane isophenyl-N '- [2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) -aminomethyl] -2-furyl] methyl] -ethyl] Guan-didine.

30 [α] D = + 6.5 ° (C = 1, methanol) D ... 25

Similarly, using R (-) - octopamine [α] β = -55.1 ° (C = 1, 0.1 N HCl) instead of S (+) - octopamine 3a, R (-) - N- [2-hydroxy 2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N '- [2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] - 2-furyl] methylthio) ethyl] -27 39 480 guanidine.

Example 1 (1) In 370 ml of tetrahydrofuran was dissolved 26.9 g of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methane-5-sulfonyl-N "- [2 - [[5- [N-methyl-N- (2,2,2-trichloroethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine To which were added 320 ml of 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, adjusted to pH 9.8 with 5 N aqueous sodium hydroxide solution and extracted with 370 ml of ethyl acetate, and the solvent of the extract was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography (eluent: chloroform: methanol). aqueous ammonia = 85:15 15: 1) and then recrystallized from 95% aqueous ethanol to give 12.6 g (yield: 65%) of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] - N'-Methanesulfonyl-N "- [2 - [[5-methylamino) methyl-2-furyl] methylthio] ethyl] guanidine, m.p. 146.5-2047 ° C.

IR (KBr) cm -1: 1580, 1255, 1105 NMR (da 6 -DMSO) δ value: 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 = 8.5Hz)

The following compounds were obtained in a similar manner.

N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) -2-furyl] methylthio] ethyl] guanidine 30 NMR (d6- DMSO) δ value: 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) N- [2-hydroxy-2- [3- (methanesulfonylamino) phenyl] ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) -2,239,480 methyl-2-furyl] methylthio] ethyl] guanidine NMR (CDCl 3 δ value: 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), δ 4.70-5.00 (1H, m) , 6.10 (2H, s), 7.00, 7.40 (4H, m) (2) To 1430 mL of 95% aqueous ethanol was dissolved 239 g of N- [2- (4-carbamoylphenyl) -2- hydroxyethyl] -N'-methanesulfonyl-N "- [2- [{5- (methylamino) -2-furyl] methylthio] ethyl] guanidine. To this was added a solution obtained by dissolving 46.8 g of oxalic acid in 240 ml. 95% aqueous ethanol. An additional 2.5 g of seed crystals was added. The mixture was stirred at 40 ° C for 3 hours and at room temperature for 3 hours and then allowed to stand overnight. The collected crystals were collected by filtration to give 257 g (yield: 91%) of N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl-N "- [2 - [[5- ( methylamino) methyl 2-furyl] methyl lithio] ethyl] guanidine oxalate (1: 1).

Melting point: 142-145.5 ° (recrystallized from 95-20% aqueous ethanol) NMR (D 2 O) δ value: 2.62 (2H, t, J = 4Hz), 2.73 (3H, s), 2.85 (3H, s), 3.34 (2H, t, J = 6.4Hz), 3.61 (2H, d, J = 5.8Hz), 3.77 (2H, S), 4, 26 (2H, S), 5.05 (1H, t, J = 5.8Hz), 6.34, 6.60 (2H, 25 ABq, J = 3.4Hz), 7.54, 7.87 ( 4H, ABq, J = 8.3Hz)

In a similar manner and using a mixture of methanol and ethanol (1: 2.5) as solvent and 98% orthophosphoric acid as acid, N- [2- (4-carbamoylphenyl) -2-hydroxyethyl] -N'-methanesulfonyl- N "- [2 - [[5- (methylamino-30) methyl] 2-furyl] methyl] ethyl] guanidine phosphate (1: 1) in 95% yield.

Melting point: 140-142 ° C [recrystallized from ethanol and acetic acid (4: 1)] NMR (D 2 O) δ value: 35 2.63 (2H, t), 2.71 (3H, s), 2.81 (3H , s), 3.11 (3H, s), 3.36 (2H, s), 3.58 (2H, d), 3.79 (2H, s), 4.25 (2H, s), 4 .97 (1H, t), 6.35, 6.59 (2H, ABq, J = 3.1 Hz), 7.16-7.68 (4H, m) 29 39480

In a similar manner, amorphous N- [2-hydroxy-2- [3-5-methanesulfonylamino) phenyl] ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] was obtained. ] methyl] ethyl] guanidine hydrochloride.

NMR (D 2 O) δ: 2.63 (2H, t), 2.71 (3H, s), 2.81 (3H, s), 3.11 (3H, 10 s), 3.36 (2H , t), 3.58 (2H, d), 3.79 (2H, s), 4.25 (2H, S), 4.97 (1H, t), 6.35, 6.59 (2H, ABq, J = 3.1 Hz), 7.16-7.68 (4H, m)

Example 2 240 mg of methylamine hydrochloride was dissolved in 0.27 in 15 ml of a 37% by weight aqueous formalin solution. To this was added 2.5 ml of a tetrahydrofuran solution containing 500 mg of N- [2 - [(2-furyl) methylthio] ethyl] -N '- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -NM-methane at room temperature. -sulfonyyliguanidiinia. The mixture was stirred at the same temperature for 20 hours. The reaction mixture was added to 30 ml of water.

The resulting 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, and the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia = 85: 15: 1) to give 220 mg (yield: 40%) of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl]. -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] ethyl] guanidine.

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

Example 3 To 10 ml of a tetrahydrofuran solution containing 30 39 4 80 310 mg of 1,3,5-trimethyltrimethylenetriamine were added 1.3 g of p-toluenesulfonic acid monohydrate and 1.0 g of N- [2 - [(2-furyl) li) methyl spore] ethyl] -N '- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N "-methanesulfonylguanidine. The mixture was stirred at room temperature for 3 hours. The reaction mixture was added to 30 ml. The resulting mixture was adjusted to pH 9.5 with 1 N aqueous sodium hydroxide and extracted with two 50 mL portions of a 1: 1 mixture of ethyl acetate and tetrahydrofuran, the extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. : chloroform: methanol: aqueous ammonia = 85: 15: 1) to give 440 mg (yield: 40%) of N- [2-hydroxy-2- (4-hydroxy-15-phenyl) ethyl] -N'-methanesulfonyl- n '- [2 - [[5- (methyl-amino) methyl-2-furyl] m ethylthio] ethyl] guanidine.

This compound had the same melting point. IR spectrum and NMR spectrum as in 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 Iguanidine was dissolved in a mixture of 8 ml of ethanol and 47 ml of 25 N aqueous sodium hydroxide solution under nitrogen, and the mixture was stirred at room temperature for 2 hours, then the pH of the mixture was adjusted to 9.7 6 N under hydrochloric acid and ice-cooling, seed crystals were added thereto, and the mixture was stirred for 4 hours at room temperature, and the collected crystals were collected by filtration to give 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.

This compound had the same melting point, IR spectrum 35 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-Trichloro-5-rethoxycarbonyl) aminomethyl] -2-furyl] methylthio] ethyl] guanidine was treated in the same manner as in Example 1 (1) to give S (-) - N- [2-hydroxy-2- (4-hydroxy) -phenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] ethyl] guanidine. [α] 25 = -6 ° ( c = 1 »O / 1 N Hcl)

The following compound was obtained in a similar manner.

R (+) - N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -N'-methanesulfonyl-N "- [2 - [[5- (methylamino) methyl-2-furyl] methylthio] ethyl] guanidine.

15 [α] D 25 = + 6'3 ° (c = 1 / ° '1 N HCl)

Example 6 250 ml of methyl aminohydrochloride and 170 mg of 95% paraformaldehyde were added to 1.5 g of methanol. The mixture was refluxed for 90 minutes. To this was added 1.5 ml of a methanol solution containing 500 mg of N- [2 - [(2-furyl) methylthio] ethyl] -N '- [[2-hydroxy-2- (4-hydroxyphenyl)] ethyl] -N '' - methanesulfonylguanidine at room temperature. The mixture was allowed to react at the same temperature for 2 days. The solvent was removed by distillation at 25 ° C under reduced pressure. To the residue thus obtained was added 20 ml of water. The pH of the mixture was adjusted to 9.6 with 5 N aqueous sodium hydroxide solution and extracted with two 30 ml portions of a 1: 1 mixture of ethyl acetate and tetrahydrofuran.

The extracts were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia = 85: 15: 1) to give 220 mg (yield: 40%) of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl]. ] -N'-methanesulfonyl-N '- [2 - [[5-methylamino] methyl] -2-furylmethyl] methyl] guanidine.

This compound had the same melting point, 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- (Ν, Ν-dimethylamino) pyridine were dissolved in a mixture of 20 ml of methylene chloride and 5.6 ml of Ν, Ν-dimethylformamide, to which was added dropwise 8 ml of a methylene chloride solution containing 2, 00 g of benzoyl chloride at -35 to 25 ° C. The mixture was stirred at the same temperature for 30 minutes, and the reaction mixture was washed with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution in that order, and dried over anhydrous magnesium sulfate. The residue thus obtained was purified by column chromatography (eluent: benzene: ethyl acetate = 1: 1) to give 5.40 g (yield: 77%) of N- [2- (4-benzoyloxyphenyl) -2-hydroxy] ethyl ] -N '- [2 - [(2-furyl) methylthio] ethyl] -NM-methane sulfonylguanidine.

NMR (CDCl 3) δ value: 2.69 (2H, t), 2.88 (3H, s), 3.10-3.55 (4H, m), 3.73 (2H, s), 4 , 90 (1H, m), 6.15-6.35 (2H, m), 7.10-7.70 (8H, m), 8.05-8.30 (2H, m) (2) 2 , 11 g of methylamine hydrochloride and 1.48 g of 95% paraformaldehyde were added to 10 ml of methanol. The mixture was refluxed for 1.5 hours. After cooling, 15 ml of a methanol solution containing

5.40 g of N- [2- (4-benzoyloxyphenyl) -2-hydroxy] ethyl] -N '- [2 - [(2-furyl) methyl] ethyl] -N "-methanesulfonylguanidine The resulting mixture was stirred at room temperature for 24 hours, 50 ml of ethyl acetate and 35 ml of water were added, and the pH of the resulting mixture was adjusted to 9.6 5 N

33 89480

with aqueous sodium hydroxide solution under ice-cooling. The organic layer was separated and 30 ml of water was added thereto, and the pH of the mixture was adjusted to 1.5 with 2 N hydrochloric acid under ice-cooling. The aqueous layer was separated and 50 mL of chloro-5 Form was added. The pH of the mixture was adjusted to 9.6 5 N

with aqueous sodium hydroxide solution under ice-cooling. The organic layer was separated and washed with 30 ml of saturated aqueous sodium chloride solution. The solvent was removed by distillation under reduced pressure. The oily residue thus obtained was dissolved in 50 ml of methanol. To this was added 2.0 g of a 28% by weight methanolic solution of sodium methoxide. The mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour.

2.6 ml of 4N ethanolic hydrochloric acid solution was added under ice-cooling. The mixture was stirred at the same temperature for 15 ml to 15 minutes. The solvent was removed by distillation under reduced pressure.

The residue thus obtained was purified by column chromatography (eluent: chloroform: methanol: aqueous ammonia = 85: 15: 1) to give 3.57 g (yield: 75%) of N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl]. -N'-methanesulfonyl-20'-N "-2- [2 - [[5- (methylamino) methyl-2-furyl] methyl] ethyl] guanidine.

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

Claims (4)

A process for the preparation of a therapeutically active amine derivative of formula (I) 5 - NSO-CH H Π H ^ NCH- ^ O- ^ CH SCH CH NCNCH CH (I) CH 3 ^ 2 1 1 2H H "^ R 10 wherein R is a 4-hydroxyphenyl group, a 4-carbamoylphenyl group or a 3-methanesulfonylaminophenyl group, or a salt thereof, characterized in that a) an amino-protecting group is removed from a compound of formula (II) 15. NSO CH- (CH) SCH CH NCNCH CH III) H3Cl2HH2 wherein R1 is an amino protecting group and R is as defined above, or a salt thereof, or b) a compound of formula (III) _NSO „CH, 25 Π [I II 2 jU0H ^ CT ^ CH SCH-CH-NCNCH CH (III) 2. H H 2 "^" R wherein R is as defined above, or a salt thereof, is reacted with methylamine or a salt thereof and formaldehyde or paraformaldehyde or 1,3,5-trimethyltrimethylenetriamine in the presence of an acid. 35 89480 For the preparation of therapeutically active compounds of formula (I) 5 „_ NSO_CH H \ FT 11 Τ'011 NCH ~ ^ O ^ CH_SCH„ CH_NCNCH_CH (1) CH * 1 10 color R is en 4-hydroxyphenyl The 4-carbamoylphenyl group or the 3-methanesulfonylphenyl group, or the same is obtained, to give a compound of formula (II) 15. __ NSO CH RT flL 11 i "0H ^ NCHn ^ O ^ CH, SCH, CH.NCNCH CH (II) h3c ^ 2 2 2 2h h \ r color R1 is a group of amino acids and R is defined by 20, or, in the case of a plant of which a group of amino acids is used, or (b) in the case of formula (III) NSO_CH, 11 D 11 ^ O ^ CH_SCH_CH NCNCH CH (m) 1. H ^ R color is defined by the fact that it is obtained with methylene or that it is obtained with octaldehyde or paraformaldehyde or with 1,3,5-trimethyltrimethyltriamine in the nerve.