JPS58219174A - Novel aminoalkylfuran derivatives, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to histamine receptors.
The present invention relates to novel aminoalkylfuran derivatives having selective action against ce-ptors, a method for producing the same, and pharmaceutical compositions containing these derivatives.

Histamine receptors (H-receptors) H1- and )12
- Ash and silt (A
@h and 8child, Br, J, Pha
rmacol.

Clhemother, 1966* 27e 427
) and Black et al.
Nature 1 9 7 2. 2 3 6゜3
85). Stimulation of bronchial and gastrointestinal smooth muscle is mediated by H,-receptors, and their effects can be prevented by conventional histamine antagonists such as mepyramine. Stimulation of gastric acid secretion and ventricular contractility is mediated by H,-receptors, and their effects are not attenuated by mevilamine but can be prevented or abolished by the more H,-antagonist metiamide. Histamine is H, - and H! - Stimulate receptors.

The inventors have demonstrated that certain novel aminoalkylfuran salt conductors are selective 112-antagonists, i.e., that these derivatives stimulate gastric acid secretion via the histamine 142-receptor'fc [7]. It is known that 0histamine exhibits an inhibitory effect (see the above-mentioned report by Asch and Schild) via the 1I2-receptor.
Le 1958+13+541 using the method of flushed rat stomach and Black et al. (Nature,
1972, 236, 385) using the same method as that of Hei-denhaln.
pouch) can be seen in dogs in a sentient state. The compounds according to the invention do not alleviate the histamine-induced contractions of isolated gastrointestinal smooth muscle.

Hintami 11. -Block (histamine)j-
Compounds with bloc-king action can be used in the treatment of conditions in which there is hypersecretion of gastric acid, such as -1 ulcers and peptic ulcers, and in the treatment of allergic conditions in which histamine is known to be a mediator. can.

It can be used alone or in combination with other active ingredients in the treatment of allergic and inflammatory conditions such as levazine.

According to the present invention, the compound represented by the general formula (1) [wherein RI and R2 are the same and different groups, hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl, or the group -N( R
4)-(In the formula, R4 may contain other heteroatoms selected from O and -N(R4)- together with hydrogen or a bonding nitrogen atom to form a heterocycle, and R3 is Hydrogen, lower alkyl, lower alkenyl i fc is alkyloxyalkyl, ori
In the formula, FLS is H1 nitro, cyano, lower alkyl, alkylsulfonyl or arylsulfonyl, and R6
represents nitro), Alk means a straight or branched alkylene chain having 1 to 6 carbon atoms, m is an integer of 2 to 4, and n is an integer of 1 to 2. , or when X = 8 or 1011□-, n is 0,
1-4 fc(r, J-2. However, 7, RI *
All of R2 and It3 are methyl groups, Alk
When is a methylene group, X is S, and n is 1 and m is 2, Y is not a group =OHN 02. ] and its salt which can be used for medical purposes can be obtained 3,
Alkyl groups preferably refer to groups having 1 to 8 carbon atoms. When used for alkenyl groups, “
The term "lower" preferably refers to groups having 3 to 6 carbon atoms. "Aryl" used as part of a group preferably refers to phenyl or a phenyl group substituted with e.g. It has the advantage of being easily manufactured from available starting materials.

Since all compounds of formula (1) can exhibit tautomerism, formula (1) is intended to include all tautomers. When Alk represents a branched alkylene group, optical isomers may exist, so formula (1) is intended to include all diastereoisomers and optical isomers.

However, lt+, R2 and FL are all methyl groups, Alk is a methylene group, X is a λ to sulfur, R7)+1 and m are 2, and Y is a group =O )INO2, Chiru N-[2-([(5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-methyl-2-nitro-1゜1-ethenediamine and its medical use Excluded from this invention are salts that can be subjected to.

Preferred compounds of the present invention are those in which lt and R2 independently represent real names, alkyl, phenylalkyl, dialkylaminoalkyl, or a 5-membered or 6-ki saturated compound with nitrogen atom after p. Heterocycles such as morpholino, pi'veridino, pyrrolidino or N-alkylpiperidino, Alk represents a linear alkylene chain of 1 to 4 carbon atoms, Y is 251=0, =OHN
Oz or =NR5 (in the formula R6 hydrogen, nitro, cyano, lower alkyl, alkylsulfonyl)
' is sulfonyl), and X, m, mouth and R3 are as described above, and is a compound with zero taste.

11. A compound suitable for unpronounced erections. and R2 each independently represent hydrogen, alkyl of 1 to 3 carbon atoms, or phenethyl, or form a pyrrolidine ring together with an adjacent nitrogen atom, Alk represents an alkylene chain of 1 to 3 carbon atoms, and Y = 8 -0Hh02- or =NRs, where Rs is nitro, cyano, methylsulfonyl or benzenesulfonyl, and a
s is hydrogen, argyl having 1 to 3 carbon atoms, propenyl, or alkoxyargyl having 3 carbon atoms, n-
1-m is 3 or 4, and X has the above meaning.

Another preferred compound of the invention is ltI and R2
7% - each independently represents an alkyl group of 1 to 3 carbon atoms, or phenethyl, or forms a pyrrolidine ring together with an adjacent nitrogen atom, Alk represents an alkylene group of 1 to 3 carbon atoms, and Y = 8, =011NO □′ or = N tLs (wherein 1-R5 is nitro, cyano, methylsulfonyl it is benzenesulfonyl) and X is 8- or -C1 (2- and lt3
is hydrogen, melamine fc is methoxyethyl, n is 1, and m is 2f or 3.

Another preferred compound for non-5G brightness is one in which ILl is hydrogen,
is methyl or ethyl, R2 is methyl or ethyl, Alk represents a methylene group, and Y is = NON
, = N N Ox or = 014 N Ox, a3 is hydrogen or methyl, X is 8 or 1002-, n is 1, and m is 2. Particularly preferred specific compounds include the following compounds.

N-(2-(C[s-(dimethylamino)methyl-2-
Furanyl]ethyl]thio]ethyl]-N-methylthiourea N-cyano-N'-C,2-(C[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl:]
-Nl-Methylguanidine N-cyano-N'-C2-(((5-(methylamine)
Methyl-2-furanyl]ethyl]thio]-ethyl)-N
l-Methylguanidine N-(2-(([5-(diethylamino)methyl-2-
Furanyl]ethyl]thio)-r-f]-Nl-)fk
-2-nitro1,1-ethenediamine N-(2-[:
[(5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl)-Nl-(2-methoxyethe#)
-2-2)0-1.1-ethenediamine N-[2-(:(1:5-(methylamine)methyl-2
1-ethenediamine N-(3-
((5-(dimethylamino)methyl-2-furanyl]thio]furovir) -Nl-methyl-2-nitro 1.1
-ethenediamine N-[2-[:[(s-tethylmethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-Nl-methyl-2-nitro-1,1-ethenediamine N-(2 -[(5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl) -Nl-nitroguanidine N-[2-[(5-(dimethylamino)methyl-2-furanyl]ethyl]thio] ethyl)-N'-methanesulfonyl-N'-methylguanidine N-(4-(5-(dimethylamino)nonal-2-furanyl]punal)-N/-
Methylthiourea N-benzenesulfonyl-N'-(2-
(((5-(dimethylamino)methyl-2-furanyl)
-ethyl]thio]ethyl) + N/-methylguanidine N-(5-(5-(dimethylamino)methyl-2-furanyl]henthyl)-N'~methyl-2-nitro1.
1-ethenediamine N-cyano-N'-(5-(5-(dimethylamino)methyl-2-furanyl]henthyl)-N'-methylguanidine N-[4-[5-(dimethylamino)methyl-2 -furanyl]phthyl) -NZ-methyl-2-nitro-1,1
-ethenediamine N-cyano-N'-(4-(5-(dimethylamino)methyl-2-furanylcobutyl), -N/-methylguanidine N-[2-([5-(3-(-jmethylamine) ) propylcou-2-furanyl]-'≠ru]thio]ethyl]-N'
-Methyl-2-nitro-1,1-ethenediamine N-[:2-[(5-((2-(dimethylamino)ethyl]amino]methyl-2-furanyl]-methyl]thio)
ethyl) -N'-methyl-2-nitro-1,1-ethenediamine The compounds of the present invention readily form medically acceptable salts.

These salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulfates. Particularly useful salts of organic acids are salts with aliphatic mono- or dicarboxylic acids,
Examples are acetate, maleate and fumarate. The compounds of the invention can also be hydrated. The compounds of the present invention can also be N-oxides.

The compounds of the present invention can be administered orally, topically or parenterally, or as suppositories. The preferred method of administration is oral administration. The compounds are used as bases or as physiologically acceptable salts and are generally combined with pharmaceutically acceptable carriers or diluents into pharmaceutical compositions.

The compounds of the invention may optionally be administered in combination with other active ingredients, such as conventional antihistamines. For oral administration, the pharmaceutical composition is most conveniently in the form of capsules or tablets, and may also be in the form of slow-release tablets. The composition can also be in the form of a dragee or syrup. Preferred topical formulations include ointments, lotions, creams, powders or sprays.

Convenient daily dosage for oral administration is in unit dosage form 20-2
100 to 1.2 in unit dosage form containing 00 to 1.2
f Keep it for about 1 day. The convenient frequency of administration for slow release tablets is two to three times per day.

Parenteral administration is by spaced injections or by continuous infusion. Injectable solutions can contain from 10 to 100/- of active ingredient.

Sprays, ointments, creams or lotions can be used for topical application. These compositions can contain active ingredients in an amount of, for example, 1.5 to 2% of the total charge of the composition.

The compound of the present invention is a primary amine represented by formula (8) (wherein 1.J, n, X
and m have the meanings given above) and the group -0NH)L3 (
In the formula, R8 and Y have the above-mentioned meanings. Amines can be used as free bases or in the form of salts of weak acids such as acetic acid.
) Rs NOO, isothiocyane R6. The reaction between the amine of formula (1) and Rs NHO-P can be carried out by leaving the amine and incyanate or inthiocyanate in a solvent such as a7tonitrile. The reaction can also be carried out by mixing nitric acid 1 R6.

When the ILs are hydrogen, alkali metal cyanates or thiocyanates can be used.

The leaving group is, for example, norogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, preferably thiomethyl. The derivation of the group -0NHRs can also be carried out by first reacting the amine of formula (II) with a compound of the formula 1HR6 or 1Rs, in which P is a leaving group as described above.

be able to. The product compound represented by the formula (g) R+ (wherein Q is = N Rs 't:
Treatment of the primary amine R, NH2 at temperatures from room temperature to reflux provides the desired final compound.

An alternative method for preparing compounds of formula (1) where Y is sulfur is to heat the amine of formula (II) with carbon disulfide and then react with ethyl chloroformate, e.g. ), which is then reacted with the amine Rs N H, preferably in an alkanol such as ethanol as solvent.

In another method, the compound of formula (1) in which X is sulfur, n is 1, fLm and R are both hydrogen, and Y is a group other than =OHNow can be prepared by formula (V) or (Vl). It can be prepared from a starting material of the formula 11L or (Vl) where 11L7 is hydrogen or an acyl group such as acetyl or P-nitrobenzoyl. If R1 and 111 in the target product are both hydrogen, they can be protected, for example as a phthalimide group, in the compound of formula (V).

The above-mentioned product compound has the formula (b)H8(0)h)mHNO
It is reacted with a thiol represented by NHRs 1 Y (■), and then the holding group is removed if necessary. When using compounds of formula (V), the reaction is preferably carried out in concentrated hydrochloric acid at 0°C. When using compounds of formula (IV), the reaction can be carried out in an organic solvent such as dimethylformamide at room temperature. Formula (V
The chloromethyl compound of l) can be prepared from the corresponding alcohol using, for example, thionyl chloride or concentrated hydrochloric acid.

The product of formula (1) where Y is a NON group is produced by combining the compound of formula (1) where Y is sulfur with a heavy metal cyanamide, such as
It can be prepared by heating cyanamide of lead, cadmium or mercury in an aqueous solution.

The compound of formula (1) in which Y is =NR5 and Alk is a methylene group or a branched hyperbenzened alkylene can be obtained from the compound represented by the formula (■) (VW) by the corresponding aldehyde and secondary amine or primary amine. ′-! or by the Mannich reaction using salts of secondary amines. For example (OHa)zNOH snow-groups can be introduced using dimethylamine and formaldehyde)
The production can be carried out by reacting an aqueous formaldehyde solution with a compound of formula (■) and an amine salt, or by heating an amine salt with paraformaldehyde and a compound of formula (■) under reflux.

In the foregoing description of the process for making compounds of the invention, formula (II
) mentioned primary amines. These amines are new compounds, and the present invention encompasses these compounds. These intermediate compounds can be made by various methods described below.

An amine of formula (It) in which X is 8 and n is 1 has the formula (
IK) It can be produced by reacting furfurylthiol represented by formula (X) with ω-bromoalkylphthalimide represented by formula (X). A group LI can be introduced into the resulting compound of the formula (χ)O(XI) by, for example, Mannich reaction.

Removal of the protective group, for example by reaction with hydrazine hydrate, produces the amine of formula (II).

In another method of preparing amines of formula (If) where X is 8 and n is 1, 2-furfuryl chloride can be used as a starting material. Furfuryl chloride and ω-aminoalkylthiols with protected amine groups, such as those of formula (X
Reaction with phthalimide of ll) produces an intermediate compound of formula (XI). When this is processed as described above, the formula (It
) produces amines.

Yet another method for preparing amines of formula (II) where X is 8 and n is 1 uses starting materials of formula (Xllll).

This compound t-formula (which can optionally be protected by amine radicals)
Compounds of XIII) can be reacted with ω-aminoalkylthiols under acidic conditions. Or the formula (XI[
The compound of I) may be converted into the corresponding acetate ester and then reacted with the ω-aminoalkylthiol under basic conditions.

Formula (II) other than amines in which X is 8 and % n is O
The primary amine of is reacted with furan-butyllithium to form a lithium derivative of formula (XIV), which is then converted into an α,ω-dihalo compound of formula (1) (where Hal is chlorine, (II) potassium phthalimide. Formula (X
The reaction product of V) is then subjected to, for example, a Mannich reaction and firstly the protecting group is removed, for example by reaction with hydrazine hydrate.

Intermediate compound 16, where
□It can be produced by reacting with sulfur and firstly reacting with ω-bromoalkylphthalimide of formula (X). The intermediate compound ft represented by the formula (XVII) 0(X■) is then reacted with hydrazine aqueous solution to remove the protective base.

In the preparation of intermediate compounds where is chlorine) in the presence of chlorine, especially potassium electrolyte.

Intermediate compounds of formula (n) where m is 2 and %X is 8 times 0 can also be made by using ethyleneimine. Ethylene imine is reacted with an isosyl thiol compound of formula (XIl[).

The amine of formula (II) can also be prepared from a compound of the formula (bird) where n, m and X have the meanings given above as starting materials.

This nitrile compound #11 is subjected to a JK Mannich reaction and then reduced with lithium aluminum hydride to produce a compound of formula (It).

When using the Mannich reaction, the group 1 can be introduced at any convenient stage, but preferably for compounds of the Mannich reaction formula (■) or (XX) υ (XX). It is carried out using aldehydes and amines. A Mannich reaction tube using the appropriate aldehyde and amine is used to prepare a compound in which Alk is a methylene group or a branched chain alkylene group. Formaldehyde is used when Alk is methylene.

Another method for preparing compounds in which Alk is methylene uses furan-2-carboxylic acid as a starting material.

Furan-2-carzenic acid is reacted with an amine of formula RIRINH to give an amide of formula (XXI) and the amide is then reduced with, for example, lithium aluminum hydride to give a compound of formula (XXII).

To convert a compound of formula (XXIl) into a compound of formula (Xl[I), a hydroxymethyl group can be introduced using formaldehyde and acetic acid.
When and R are both hydrogen, the amino group is protected as phthalimide during hydroxymethylation.

The protecting group is subsequently removed using hydrazine hydrate.

Alternatively, if R1 and R3 are not both hydrogen, hydroxymethylation can be carried out using butyllithium, IK formaldehyde.

When Alk is a linear alkylene group having two or more carbon atoms, the following two-way method can be used.

In the case of the methylene derivatives mentioned above, a convenient method used for the methylene derivatives of the order is to use car2-at of the formula (XXIu) in place of furan-2-car2-carinoic acid.

When the alkyl chain of Alk is longer than 2IR elementary atoms, the lithium derivative of formula (XIV) is sequentially converted into K(1) formula Hal-
Alk-Hal dihaloalkane (where Hal is chlorine,
bromine or iodine) primary (If) R11'
Treatment with an amine represented by hNHm yields a compound of formula (XVI) in which Alk is 3 to 6 carbon atoms.

When R1 and R3 are both hydrogen, potassium phthalimide is substituted for the amine in FLIR, NH, in both of the above reactions. The reaction products of both reactions are as described above (hydroxymethyl group), and then the protecting group is removed if applicable to form a compound of formula (XI).

a, and R1 are other than hydrogen, free amine compounds can be prepared, for example, by the Eschweiler-01arke method.
(ace-dure) using formaldehyde and formic acid to give a suitably substituted amino group to give a dimethylamine compound.

It is preferred to use substituted amines at appropriate steps in the reaction.

An amine of formula (II) in which n is 2 is prepared as a starting material of formula (
XXIV) wherein 1 is a leaving group such as tosyloxy, mesyloxy or bromine. This compound has the formula (Xl
l) with the ω-phthalimido alkylthiol;
The resulting compound t is subjected to a Mannich reaction and subsequent removal of the protecting group results in the formula (formerly the target amine).

When producing the compound of the present invention, the compound t' of formula (V)
It can be reacted with a thiol of formula (Vll) where bY is especially =01(NO), where Y is ;0HNO,.

The f arsenic compound of formula (■) where m is 2 can be prepared by reacting the thiazolidine intermediate of formula (XXV) with the amine RsNH°4° of formula (XXV)
The thiazolidine can be prepared from cysteine amine and a bismethylthio compound of formula (XXVI).

Y=0)1. No, and the formula (VM) where m is 2
The thiols are newly discovered compounds and therefore the present invention also encompasses these compounds and the aforementioned methods of making them.

To further understand the invention, the following examples are provided for illustrative purposes. Prior to Examples, Manufacturing Method 1~
4 describes the production of starting materials. Reference examples A-L are based on the formula (11
) and Examples 1 to 34 fully illustrate the preparation of compounds of formula (1). Example 35 exemplifies the pharmaceutical industry'I#J warehouse.

Production method 1 (a15-(methylamino)methyl-2-furanmethanol 2-furanmethanol 49t, methylamine hydrochloride 51
．． A mixture of 5f and 50d of 36% formaldehyde solution was stirred at 0-3°C for 3 hours, left for 16 hours, excess charcoal was added, the resulting slurry was extracted with ethyl acetate, and the solvent was removed from the extract. When the residue obtained after removal is distilled, the boiling point is 111-113℃ 70.2■Fi
36.2f of 5-(methylamine)methyl-2-furanmethanol of t was obtained.

The following compounds were similarly prepared from 2-furanmethanol and the corresponding amine hydrochloride.

(b) 5-[(2-phenylethyl)aminocomethyl-
Oily liquid chromatography of 2-furanmethanol (silica/acetone); Rf=0.45 nuclear magnetic resonance spectrum (001,) 7.29 (broad singlet.

4H), 6.8 (Singlet 2) (), 6.40 (Singlet, 2H), 5.62 (Singlet, 2H)
, 4.0 (broad multiplet, 2H) 2.87 (singlet, 5H) (c) 5-[(1-methylethyl)aminocomethyl-2
- Furanmethanol oil Rt=o, 55 (silica/methanol) elemental analysis 20,
63.35%, H, 8.78%, N.

Calculation from 8.09%(0,)11sNO, [: 0.
63.88%, H, 8.94%, N, 8.28%) (
dls-(ethylmethylamino')methyl-2-furanmethanol 1'Lf=0.32 (Silica/Acetone) Nuclear Magnetic Resonance Spectrum (ODOL, '): 8.93 (Triple line, 3H), 7.80 ( Singlet 53H) s7
．． 5 s (quartet, 2H).

6.50 (singlet, 2H), 6.33 (wide singlet, IH), 5.47 (singlet).

2H), 3.80 (multiplet, 2H) (e) 5- (: C2-(dimethylamino)ethyl]amino]methyl-2-furanmethanol bismaleate Melting point 119-121°C Production method. 2 N, N -dimethyl-2-furanethanamine 9.81P
, 17.5 t of 30X formaldehyde aqueous solution and 1B. ~100°C (0.5 cm Hf)t'' was obtained.

Elemental analysis: Oh64. ON, H, 8, 1%, N, 8.
0% (calculated value from 0, Hl, NO, "L63-9%,
H2S, 9%, N, 8.2%) Preparation Method 3 2 [1-(4-bromobutyl)]Furan A solution of 40.8 t of furan in 375 d of dry tetrahydrofuran to a solution of 1.6 M n-butyllithium in hexane 375 d - and stirred the mixture at 40°C for 3 hours.
．． Add 129.6F of 4-dibromobutane, stir the reaction mixture at room temperature for 4 hours, add water, extract the mixture with ethyl acetate, distill the extracted ffI, and obtain an S point of 60-62C.
A colorless transparent liquid of (0.5wHf) was obtained.

Add 56f of dimethylamine to a bath solution of 82t of 2'-[1-(4-bromobutyl)]furan in 500m of toluene, stir the resulting solution at room temperature for 2 days, acidify it with hydrochloric acid, and separate the hydrochloric acid layer. The solution was washed with ether, made basic with water and aqueous sodium chloride, extracted with ether, and the ether extract was distilled to obtain a colorless transparent liquid with a boiling point of 55-58°C (0.8 mHt).

Touch point of hydrochloride: 133-136℃ Elemental analysis: 0,59.01X, H, 9,02%, N%6
．． 87% (01@H17NO! Calculated value from a HCu 20% 58.96.H, 8,91%, N16
．． 88%) (,) Dry Tetrahydrofuran 125
-N inside.

N-dimethyl-4-(2-furanyl)butanamine 33
．． 125 mi of a solution of 1.6 M n-butyllithium in n-hexane was added to a water-cooled solution of 4F and the mixture was heated at room temperature for 4
Stir for a while and then pour formaldehyde 6. o? was added, the mixture was stirred for another hour, water was added to the reaction mixture, extracted with chloroform, and the organic extract was distilled to obtain a colorless transparent liquid with a boiling point of 100-105°C (0.1 wHf).

Melting point: 26-28.5℃ Elemental analysis: 0.67.09%-HblO-01%, N.

7.06% (011H1GN (calculated value from 1: 0.
66.97%, H, 9,71%s Ns 7-10%)
The following compounds were produced in the same manner.

(bls-[3-(·,dimethylamino)propyl]-
2-7 run methanol Boiling point: 160°C (O, OS■Ht) Melting point: about 20°C Elemental analysis 20, 64.66%, H2O, 36%%N.

7.39% (01o8.7NO2@'< )I, (>
Calculated values from: C164, 28%, H2O, 39%, N
% 7.50%) Production method 4 5-[4-(dimethylamino)butyl]-2-furan methanol 4.9t, acetic anhydride 25f and benzene 25
- A mixture of 1 () v of melted and ground sodium acetate in the whole was stirred at room temperature for 24 hours.The 2 reaction mixture was diluted with 100 - of water, extracted with ethyl acetate, and the two extracts were combined and distilled.
A colorless transparent liquid with a boiling point of 100°C (0.5 an If?) was obtained.

Elemental analysis: 0% 65.62%, H, 9.03%, N.

5.95% (calculated value from GxB H21NO3: 0,
65.24%, #1.8.85%, N15.85%) Reference example A -2-Furan methanol 15.5ft drop,
After being left at 0°C for 18 hours, excess sodium carbonate was added, and the resulting solid was extracted with diethyl ether. The solvent was completely removed from the extract, and the residue was t-distilled to give a boiling point of 10.
2-[[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio] at 4-106°C (0.1 Hf)
Ethanamine 11.6 times.

Melting point of picrate salt = 142-144°C. The following compounds were similarly prepared from the corresponding furanmethanol and cysteamine hydrochloride.

(b) 2-[[[5-(methylamine)methyl-
・Melting point of 2-furanyl]thio]-ethanamine monopicrate: 116-118°C (C) 2- [[[5-[(1-methylethyl)aminocomethyl-2-furanyl]methyl]thio]ethanamine Rf (Clica/methanol: 0.880 ammonia 79:1): 0.4 fal 2- CC[5-(diethylaminomethyl)
-2-furanyl]ethyl]thio]-ethanamine boiling point:
134-135℃ (1wx HP) (e) 2-
C[[5-(1-piperidinyl)methyl-2-furanyl]ethyl]thio]-ethanamine 1(f(silica/methanol: 0.880 ammonia 79:1) 0.37 (f) 2-C[[s -(aminomethyl)-2-
Melting point of furanyl]ethyl]thio]ethanamine dihydrochloride: 222-224°C (decomposition) (g)
N-[5-C[C(2-aminoethyl)thio]ethyl]-2-furanyl]methyl]-benzenethanamineItf(silica/methanol20.880 ammonia=
79:1) 0.33 (hl 2- ([[5-C2-(dimethylamino)
1:1 ethyl]22-furanyl]megel]thio]-ethanamine boiling point = 150-155°C (0.04wHf) (+)
2- [[[s-Ca-dimethylamino)propyl]
-2-Furanyl]methyl]thio]-ethanamine Boiling point: 150°C (0.05ms+Hf) (jl 2-
[[[5-(Ethylmethylamino)methyl-2-furanyl]ethyl]thio]-ethanamine nf (V lyca/methanol: 0.880 ammonia 79
:1):0.34 (k) 2- [[[5-[(2-dimethylamineethyl)aminocomethyl-2-furanyl]methyl]thio]
Melting point of ethanamine trismaleate: 132-135℃ (112
Melting point of -[CC5-(1-pyrrolidino)methyl-2-furanyl]ethyl]thio]-ethanamine bisuccinate: 136.5-138.5°C Reference example B Potassium in 125 tnt of dimethylformamide Add 4.5 f of cysteine amine hydrochloride to the cold bath solution of 8.98 f of -butoxide, stir the mixture for 20 minutes, and then stir [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanony)9. The reaction mixture was heated at 90°C for 4 hours, poured into a mixture of ice and water, extracted with chloroform, and distilled the organic extract to form a yellow oily liquid. Treated and stripped with methanol:0.880 ammonia (9:1).

Further distillation gave a colorless oil with a boiling point of 140° C. (0.05 HP).

Elemental analysis: 0.60.81%, H, 9.86%, N.

10.44% (calculated value 20 from own aHxiN108.

60.91%, H, 9.44%, N, 10.93%) Reference Example 0 Dione 80% hydrogenation to a solution of 1.03f of 2-phthalimido-ethanethiol in dry dimethylformamide at 0°C)
Added IJum 0.155fi each.

4-Methylbenzenesulfonate 1.33f of 2-7 run ethanol in dry dimethylformamide after 20 minutes
The resulting bath solution was stirred overnight at room temperature, and the mixture was poured into ice water to give 2-[[2-(2-furanyl)ethyl]thio]ethyl-IH-isoindole-113 (21()
1.3 t of a white solid having a melting point of -dione of 53 to 55°C was obtained.

Reference Example D Furfuryl mercaptan 6fOfj1 in dry dimethylformamide 50. 80 for liquid! Sodium hydride 1.
58f1 little by little, and after 30 minutes add 2-bromoethyl phthalimide 16 with 65 sd of dry dimethylformamide.
．． 71F solution was added, the resulting solution was heated at 110°C for 2 days, the solvent was removed, the resulting residue was washed with water, extracted with ethyl acetate, the ethyl acetate extracts were combined, and the solvent was removed. The resulting residue is recrystallized from 7 chlorohexane to give z-[z-[[(2-furanyl)
methyl]thio]ethyl]-IH-isoindole-1,
7.8 tons of 3(2H)-dione were obtained.

The following compound was obtained in the same manner from ω-bromoalkylphthalimide and fur7lyl mercaptan.

fbl 2- [3-(: [(2-furanyl)methyl]thio]propyl]-1H-isoindole-1゜3
(2H)-dione nuclear magnetic resonance spectrum (ODOI3) near, 7-8.
3 (multiplet, 2H), 7.2-7.7 (multiplet, 2H)
.

6.29 (singlet, 2H), 6.23 (triple line).

2H), 3.7 (multiplet, 2H), 2.7 (multiplet.

IH) % 2-4 (Multiplet, 4 days) (C) 2
- [4-[[(2-furanyl)methyl]thio]butyl]-1H-inindole-1,3(2H)-dione nuclear magnetic resonance spectrum (ODOIs): 8-8.5
(Multiplet, 4H), 7.49 (Triplet, 2H), 6.
33 (multiplet, '4H), 3.7 (multiplet %2H), 2
．． 7 (multiplet, IH), 2.3 (multiple i, 4H) Reference example E 2-[2-[[(2-furanyl)methyl]thio]ethyl]-1H-isoindole- in acetic acid 50- 1, 3 (2
H)-dione 10f, dimethylammonium chloride 3.1
f and 36N formamide solution 3tR1t heated over steam for 9 hours, the resulting solution was cooled, the solvent was removed in vacuo and the resulting residue was made basic with 5N sodium hydroxide, extracted with ethyl acetate, The organic layer is treated with activated carbon.

Dry, evaporate, and chromatograph the resulting oily liquid!
(Clica/ethanol:ethyl acetate=1:l) was used to prepare flv, and 5.7 tons of the target product was obtained.

l1Lf: (1,4 Nuclear Magnetic Resonance Spectrum (ODOIs/DM8(1)
: 7.71 (singlet, 5H), 7.22 (triplet, 2H).

6.52 (singlet, 2H), 6.2 (singlet, 2H), 6.1 (triplet, 2H), 3.8 (multiplet, 2H), 2.2 (multiplet, 4H) 2-[ ω− [[(2
The following compound was similarly obtained from -furanyl]ethyl]thio]alkyl]-1H-isoindole-1,3(2H)-dione, the corresponding amine and formaldehyde.

(bl 2- C2-C[[5-[(1-pyrrolidinyl)methyl]-2-furanyl]methyl]thio]ethyl]
-1H-isoindole-1,3(2H)-dione nuclear magnetic resonance spectrum (ODOIg): 8-8.
4 (multiple*1ms 4H), 7~7.6 (multiple lines, 6H)
, 6-6.5 (multiplet, 6H)% 3.7-4.0 (multiplet.

2H), 2-2.4 (multiplet, 4H) (cl2-[3-[[C5-(dimethylamino)
Methyl-2-7ranyl]methyl]thio]propyl]-I
H-indo-1.3(2H)-dione Rf (silica/methanol): 0.45(d) 2-
[4-CCC5-(dimethylamino)methyl-2-7
Ranyl]methyl]thio]butyl]-1H-isoindole-1,3(2H)-dione Rf (crican ethanol): 0.26 Nuclear magnetic resonance spectrum (0DOI, ): 8.85 (multiplet, 4
H), 7.7 (singlet, 6H), 7.42 (triple line% 2H)% 6.52 (singlet, 2H\6.
29 (multiplet, 4H), 3.9 (multiplet, 2H).

2-2.4 (multiplet, 4H) (e) 2-[2-C[[5-[(4-methyl-1
-piperazinyl)methyl]-2-furanyl]methyl]thio]ethyl]-1H-(twindol-1゜3(2H)
-Dione nuclear magnetic resonance spectrum (ODOIs): 7.75
(singlet, 3H), 7.52 (7n route h)
8 H) s7-7.5 (multiplet, 2H), 6.5 (S
/ singlet 2H), 6-6.3 (multiplet h 4 H
) h J, 85 (multiplet % 2 H) s 2~2
．． 4 (multiplet, 4H) (tl 2- C2-C[[5
-[(4-morpholinyl)methyl]-2-furanyl]methyl]thio]ethyl] -1H-inindole-1,
3(2H)-dione nuclear magnetic resonance spectrum (ODOIg): 7.54
(Multiple IM line, 4H), 7.24 (Multiple line, 2H), 6
．． 50 (singlet, 2H), 6.22 (multiplet, 8
H), 3.8 (multiplet, 2H), 2.0-2.4 (multiplet, 4H) Reference example F 2-CC2-(2-furanyl)ethyl]thio]ethyl]
-IH-isoindole-1w3(2H)-dione O, St, diethylamine hydrochloric acid 0.27? and Nozora Formaldehyde 0.102fr. Heated at reflux in ethanol for 5 hours and further dimethylamine salt o, 2rt and Nozora Formaldehyde 0.102F.
was added and heating was continued for a further 16 hours, then all the solvent was removed, the resulting residue was made basic, extracted with ethyl acetate, and the residual oil obtained from the extract was subjected to column chromatography (silica/methanol). Then, z-[2-[[2
-[s-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-1H-inindole-1゜3
0.43 t￥r of a light-colored oily liquid of (2H)-dione was obtained.

Elemental analysis: 0.61.48%t Hs 6-13%, N
.

7.63% (calculated value from 0reH*sH Snow 03.83/4H, 0 20% 61-35%, H16° 37%, N1
7.53X) Reference Example G Method (1) A solution of 6.22 f.
A solution of methanesulfone 1111.61P in the solution was added, and the oily residue obtained by evaporation was heated at 98 to 100°C for 10 minutes, and after 18 hours, 5N sodium hydroxide 6
The solution was evaporated to dryness, anhydrous sodium sulfate and ethyl acetate were added to the residue, and after 2 hours, the suspension was filtered, decolorized with activated carbon, and evaporated to give an oily state. Chromatography is carried out using Liquid CareAlica, first eluting with VC methanol: 0.88 ammonia = 79.1, the liquid is discarded, first methanol: 0.88 ammonia - 19:
It is obtained from an oily liquid obtained by evaporating the liquid eluted with l.
When crystallized from ethanol.

0.2 tk of pisciewate of 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine having a melting point of 125-128°C was obtained.

Method (11) Potassium t-putokind 8.96t and 5-(dimethylamino)methyl-2- in dry dimethylformamide
A solution of 6.25 f of 2-chloroethylamine salt in dry dimethylformamide was added to a cold solution of 12.4 f of furan-methanol while stirring, and after 2 hours, the solvent was removed. The resulting residue was made basic and extracted with ethyl acetate.

The residue obtained by removing the solvent from the extract was treated with an ethanolic solution of oxalic acid in ethanol and recrystallized from the resulting solid ethanol to give 2-[
3.05 ft of bisoxalate of [5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine was obtained.

Similarly, a bisoxalate of 2-[[5-(methylamino)methyl-2-7rane]methoxy]ethanamine having a melting point of 162-164 DEG C. was obtained by method (11).

Reference Example H Dry dimethylene, 406 cm of 2-[1-(4-bromobutyl)]furan and 370 cm of potassium phthalimide were stirred in formamide overnight at room temperature.

Pour the produced solution into ice water, filter the produced white solid,
It was crystallized from chloroform and petroleum chiller with a boiling point of 60-80°C to obtain 2-C4-(2-furanyl)butyl]-111-isoindole-1,3 with a melting point of 61-63°C.
4309 (211)-diones were obtained.

Similarly, the following compound f was prepared as fc.

(bl 2- [5-(2-furanyl)pentyl]-
1ti-isoindo-/'-1,3(211)-dione.

Melting point 54-56°C Reference example I 2-C4-(2-7ranyl)butyl]-5H-isoin F-ru 1.3(2)1)-dione 5.38t, paraformaldehyde 1.2t and dimethylamine hydrochloric acid salt 3
．． 26r was heated under reflux in 100 tnl of absolute ethanol, and after 6 hours, an additional 0.6 f of paraformaldehyde and 1.6 t of dimethylamine hydrochloride were added.
was added and heating under reflux was continued for another 20 hours.
- the resulting residue was made strong base with 5N arsenic hydroxide, extracted with ethyl acetate, the organic layer was evaporated and the crude product obtained was column chromatographed to give an amber oil. -25f was obtained.

1'Lf (silica/methanol): 0.4 nuclear s gas resonance spectrum (oDo13) = 8-8.6 (poly ha% 4H
), 7.75 (y:y bullet, 611), 7.3(
Multiplet m2H) b6.55 (singlet, 2H), 6
．． 3 (multiplet, 2H), 4.0 (multiplet, 211), 1
．． 9-264 (multiN11M s 4n) The following compounds were all prepared under the same pressure.

(bl 2-[5-[5-(dimethylamino)methyl-2-7ranyl]henthyl]-1H-1indole 1.3(2)1)-dione thin layer chromatography (silica/methanol (Rf: 0 ．．
4 Nuclear magnetic resonance spectrum 28.0-B, 8 (polyMH, 6
H), 7.70 (multiplet, 6H), 7.37 (triplet,
2H), 6.52/7 Gretz, 2H), 6.
30 (3k1m, 2H), 4. o (multiple 4L 2H),
2.2 (Multiplet, 4H) Reference Example J Lonoamine ethanol 20-7 lampprobionitrile 1.2
1f, dimethylamine hydrochloride 1.62t and hynola formaldehyde)'o,ry were heated at reflux for 24 hours,
The residue from which all the solvent was removed was made monobasic to pH 12, extracted with ethyl acetate, and the residue from which all the solvent was removed from the extract was purified by column chromatography (silica/methanol) and Rf (silica/methanol) = 0. 0.6f of 5-(dimethylamino)-methyl-2-furanpropionitrile was added.

Lithium aluminum hydride in ether at 0°C 2.0
To this was added the above nitrile 6, Of in dry ether with stirring, the reaction mixture was washed with water, the solvent was removed, and the residue was purified by column chromatography to obtain 5-(dimethylamino). 3.33 f'i of a monochromatic oily liquid of methyl-2-7-lane propanamide was obtained.

Nuclear magnetic resonance spectrum (0DOh): 8.2 (
Multiple lines.

2H), 7.6 (wide width signal, 2H) s7.75
(Singlet, 6H), 7.30 (Multiplet, 4H)
.

6.60 (singlet, 2H), 4.0 (
Multiple lines.

2H) Reference example K N,N-dimethylfuranmethanamine 7.5 at -40°C
Add 1.9 t of sulfur in small batches to a solution of 2 t of lithium derivative, stir the entire mixture at 10°C for 20 minutes,
-(3-bromopropyl)-1H-isoindole-1
, 16tf of 3(2H)-dione was added, and the mixture was heated to IkO°C.
The solvent was removed in vacuo and the resulting residue was filtered with ethyl acetate added to it. Extract with 2N sulfuric acid, make aqueous layer 1 basic, re-extract with ethyl acetate, dry organic phase, remove dissolved S and dissolve in crystalline solid ketethanol, treat with activated carbon and re-extract. Crystallized, melting point 64-6
7.59f of 2-[3-[[[5-(dimethylamino)-methyl-2-furanyl]thio]propyl]]-1H-inindole-1,3(2H)-dione was obtained at 5°C.

Reference example L 2-[[4-(5-dimethylamino)methyl-2-furanyl]phthyl] -1H-inindole-1,3(2
1-1)-Geo 72.9f and hydrazine water, hydrate 0
．． 55- was heated under reflux in ethanol for 6 hours, and the solvent was completely removed. The resulting crystalline residue was dissolved in 5N sodium hydroxide solution, extracted with ethyl acetate, and the solvent was removed from the extract. Product low viscosity yellow oily liquid 1.68f
I got it. Thin layer chromatography: Single spot nuclear magnetic resonance spectrum (ODO+, ) at Rf=0.15:
8.0-8.8 (multiplet, 4tI), 7.7 (singlet, 6H), 7.6 (wide 7-signal, 2H)
), 7.3 (multiplet.

4tl), 6.58 (singlet, 2H),
4.0 (multiplet, 2H) All of the following compounds were prepared from the corresponding phthalimides in a similar manner.

fbl 5-[5-(dimethylamino)methyl-2
-furanyl]hentanamine nuclear magnetic resonance spectrum (ODOI3): 8.0-8
．． 8 (multi-N wire% 6H), 7.75 (singlet, 6
H), 7.0-7.6 (multiplet, 4H)% 6.59 (
Singlet% 2H), 4.0 (multiplet, 2H) fc)
s-[[:(a-aminopropyl)thio]ethyl]-N
, N-dimethylfuran-2-methanamine nuclear magnetic resonance spectrum (OD ('11s): 8-8
．． 5 (multiplet, 2H), 7.75 (singlet, 6
H).

7.42 (triplet, 2H), 7.25 (multiplet, 2H)
.

6.58 (singlet 7, 211), 6.3 (singlet, 2H), 3.88 (singlet, 2H)
”: Example 1 Methyl-2-furanyl]ethyl]thio]ethyl]2-
r 2- [[[5-(dimethylamino)methyl-2-
5.3 f of furanyl]ethyl]thio]ethyl]-IH-isoindole-1,3(2H)-dione and 0.85 f of hydrazine hydrate were heated under reflux in ethanol for 30 hours, the solvent was removed, and 2 -[[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethanamine 7
talhydrazi)-'@ was obtained.

This salt was suspended in 1 f't of acetonitrile, 0.21 f'ft of methyl inthiocyanate was added, the suspension was stirred in a chamber for 5 hours, and further stirred at 60°C for 2 hours, then filtered.
The oil obtained by evaporating the filtrate was purified by column chromatography (silica/methanol) to obtain N-[z
0.3 f of a pale oily liquid of -[[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-methylthiourea was obtained.

Elemental analysis: 0.49.68%, H, 7.52%, N11
4.22% (calculated value 20 from Ot*H*lN10J.

50.14%, H, 7,37%s Nb14-62%
) The following compounds were produced in the same manner.

(b) N-methyl-N'-[2-[[[5-(1-
pyrrolidinyl)methyl-2-furanyl]ethyl]thio]
Ethyl]thiourea Elemental analysis: 0.52.33%, H, 7.12%, N.

Ob 52-14 N, N17.5Q%, N, 13.0
3%) (c) N -C4-[[C5-(dimethylamino)methyl-2-furanyl]ethyl]thio]butyl]
-N'-Methylthiourea Elemental analysis: 0% 51.69%, H, 8.53%, N.

12.83% (calculated value from 01aH*sNB08g:
o.

51.82%, HlB, 08%, N, 12.95%) (
d) N-[3-[[5-(dimethylamino)methyl-2-furanyl]thio]solovyl]-N'-methylthiourea Elemental analysis: 0,49.71%, H, 7,33%, N.

14.35%(-,I(,IN,calculated value from 08.20.

50.10%, H17, 30%, N, 14.62%)
(el N-methyl-N'-[2-[[5-(4-morpholinyl)methyl]-2-furanyl]methyl]thio]
Ethyl]thiourea Elemental analysis: 0.51.26%, H, 7.08%, N.

12.51% (Ol, H, 3N, 0. Calculated value from S figure: 0°51.03%, H, 7,04%, N, 12.75
%) (fl N-methyl-N'-[2-[[[s-[
4-Methyl-piperazinyl)methyl]-2-furanyl]
Methyl]thio]ethyl]thiourea Elemental analysis: 0% 50.93%, N17.74%%N
%15.82%@(0saHiaNn08* Calculation f direct: 0゜51.25%%I(,8,03%%N, 15
．． 94%) (gl N -[2-[C2-C5-(dimethylamino)methyl-2-furanyl]ethyl]thio]
Ethyl]-N'-methylthiourea Elemental analysis: 0.50.19%%jt, 7.20%, N.

13.18% (0,, H,3N, 0.S, T H,0
Calculated value from: 0.50.32%, H, 7,74%, N
, 13.54%) Example 2 (a) N -C5-r 5- (dimethylamino)
Methiurea 5-[5-(dimethylamino)methyl-2-7ranyl]
Stir 0.5f of pentanamine and 0.25r of methylisothiocyanate in acetonitrile at room temperature for 24 hours and remove the solvent [2. Column chromatography treatment of raw bottom material (
silica/methanol) and triturate the resulting oil with ether.

Gray-white crystals of N-C5-C3-(dimethylamino)methyl-2-furanyl]pentyl]-N'methylthiourea with a melting point of 66-69 DEG C. were obtained.

The following compound was similarly prepared from the corresponding amine and methyl thiophanate.

(b) N -[3-[[[s-(dimethylamino)methyl-2-furanyl]ethyl]thio]propyl]-
N'-methylthiourea elemental analysis: 0.51.38%, H, 7.93%, N11
3.41% (calculated value 20 from 01!HIIJNIO8s.

51.79%,) 1.7-69%, N, 13.94%)
(c) N-[4-C5-(dimethylamino)methyl-2-furanylcobutyl] + NI-methylthiourea nuclear magnetic resonance spectrum (0001,) τ: 8-8.6 (
Multiplet, 4H), 7.72 (singlet, 6H).

7.35 (double line, 2H)%6.98 (double line s 3
H) h6.2-6.8 (multiplet% 4) (), 4.0 (
Doublet, 2H), 3-3.8 (multiplet, 2H) (a) N -[2-[[s -(dimethylamino)
mef2-7ranyl] me)-1i-V]:c chill]-
N'-Methylthiourea Elemental analysis: 0,51.91%, t(, 8,1'4%, N
.

14.98% (01 TomiH@IN, (1-8 , , H
, Calculated value from 0: 0,51.40%, H,7,91%
, N, 14.99%) Example 3 1-C thiocyanato)-2-methquinethyl 1.1
7t and 2-[[[5-(dimethylamino)methyl-2-
The residual oil obtained after removal of the solvent was chromatographed (silica/methanol) with 2.14 f of furanyl]ethyl]thio]ethanamine in acetonitrile overnight. 2-[[[5-(
A light-colored oily liquid of dimethylamino)methyl-2-furanyl]ethyl]thio]]-N'-(2-methquinethyl)thiourea was obtained.

Elemental analysis 20% 50.64%, N17.51%, N%
12.58% (calculated value from 014H snow, N wealth 0 wet S3 20150.75%, H, 7,55%, N, 12.69
%) Similarly, the following compound was prepared by combining [6 isothiocyanate and 2-[[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]-ethanamine color.

(bl N -[2-[([5-(dimethylamino)
Methyl-2-7ranyl]methyl]thio]ethyl]-N'
-(2-propenyl)thiourea Elemental analysis 20, 52.68%, H, 7, 58%, N.

: 0.52.1 4X, H, 7, 50X, N
, 1 3.03%) (c) N -C2-C[[5-(dimethylamino)
Methyl-2-furanyl]ethyl]thio]ethyl]-N'
-(1-methylethyl)thiourea Elemental analysis: 0,51.
84%, H, 7,88%, N.

: 0,51.90X, H, 8,09%, N, 12.9
7%) Example 4 A solution of 1.5 f of z-CC[5-(methylamino)methyl-2-furanyl]ethyl]thio]ethanamine in 24 ml of methylurea acetonitrile is stirred.

To this, methyl isocyanate in acetonitrile 15-)
All of the 0.45 f solution was removed, and after 30 minutes, the Bath C solution was evaporated to dryness, and the resulting oily liquid was subjected to color chromatography. First, silica/methanol: 0.88 ammonia = 79:
1 and then treated with alumina/methanol to form hN-[
An oily substance consisting of 0.25 t of z-[[[s-(methylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-methylurea was obtained.

Elemental analysis' Os 51-00%, H, 7,38%,
N.

15.91% (calculated value 20 from 011N19NmOm8.

51.33%, H, 7,44X, N, 16.33
%) Example 5 0.33f' of methyl isocyanate is added to a suspension of the complex 2f of 2-[[[5-(dimethylamine)methyl-2-furanyl]ethyl]thio]ethanamine and phthalhydrazide in 50 of acetonitrile. was added, and after 2 hours, the resulting solution was completely filtered, and the filtrate was evaporated to obtain an oily substance (1□), which was purified by column chromatography (silica/methanol).
N-[2-'': [[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-methylurea was obtained.

Elemental analysis: 0.52.38%, H, 7.61%, N.

15.25% (01, H□N, 0,8・2 Calculated value from H2O: 0,52.24X, H% 7.76%, N,
15.32%) The following compound vlI was prepared in the same manner.

(bl N-methyl-N'-[2-[[[5-(1-
methyl-2-furanyl ethyl thio]
Ethyl]urea Elemental analysis: 0% 54.70%, H, 7.33%, N.

14.07% (014H Goose, N, (1!S @-!-
Calculated value from H,0: 0.54.87%, H,7,8
9%, N, 13.71%) Example 6 2-[11[:5-(dimethylamino)methyl-2furanyl]methyl]thio]-ethanamine (2.14t and isopropyliso7ane) in 0.89fk acetonitrile The residue obtained upon removal of the solvent was recrystallized from methanol and ether to give a melting point of 65.
N-[2-[[(5-(dimethylamino)methyl-2-furanyl"]methyl]thio]ethyl)-N' at ~67°C
-2.8ft of crystals of (1-methylethyl)urea were obtained.

The following compounds were produced in the same manner.

(b) N -C3-C[[5-(dimethylamino)
Methyl-2-furanyl]ethyl]thio]propyl]-N
'-Methylurea, melting point 69-69.5°C Example 7 2-[[(5-(dimethylamicamethyl-
A solution of 2.8 f of 2-furanyl[ethyl]thio]ethanamine dichloride and 3.75 t of potassium cyanate was heated on a steam path for 8 hours to remove excess carbonate from the reacted product. In addition, the organic matter was continuously extracted with diethyl ether, and the residual liquid obtained by total evaporation of the extract was subjected to column chromatography to obtain N-[:z-IIC[s-(
A waxy solid 1.28F of dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]urea was obtained.

Elemental analysis: 0% 48.22%, H, 7°50%, N1
15.61% (0IIHI・NsO,8*H,(,1
Calculated value from 20.48.00%, N17.63%, N
, 15.27%) Example 8 2-[[[5-(dimethylamine)methyl-2-furanyl]ethyl]thio]ethanamine 2.14 thxH5-yt-y-N in 10-ethanol - A solution of 1.5 t of nidrothiourea was heated to 40°C for 5 minutes, and the precipitate formed was filtered off to form ethyl acetate with a boiling point of 80-100.
Recrystallized from petroleum ether at °C, melting point 103-104
N at °C, -[2-1:[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl] -N'-
Nidotetraguanidine was obtained.

Example 9 A mixture of the methyl ester of 2-([(5-(methyla-den))methyl-2-7ranyl]methyl]thio]ethaneanne 2.OIi and N-cyano-N'-methylcarnonamidothionic acid 12551 is steamed. Chromatographic treatment (silica/methanol:ammonia 99:1.Rf=
0.65) L, N-cyano-N'- with a melting point of 81-85°C
(2-([(5-(methyla))methyl-2-7ranyl]methythio]ethyl]-N'-methylguanidine 1
．． 05g was obtained.

Similarly, the corresponding amino and N-cyano-N'-methylcarno? The following compound was prepared from methyl ester of ζ-compensated tothionic acid.

(b) N-cyano-N'-[2-4([5-(1
-Methylethyl)aminocomethyl-2-furanyl]methyl]thio]ethyl)-N"-Methylguanidine Elemental analysis 20.54.73%, N17.82%, N122.31
(calculated value from 0xaljaiNs08: 0.54.
34 parts%, H17.49%, N, 22.64%) (c) N-anor N'-[2-[[[5-(diethylamino)methyl-2-7ranyl]methyl]flythio]
Ethyl)-N"-methylguanidine Elemental analysis: 0.54
73%, H, 7,82%, N12065% (0,, H2
Calculated value from 6N, 08.47 H, O: 0,55.4
6%, H, 7, 70%, N120, 78%) (al N-n anor N'-[2-[[[5-(1
-hyrolysinyl)meF-ru2-7u-ru)methyl)
Thio]ethyl)-N"-methylguanidine Elemental analysis 20, 5397%, H, 7,37%, N121, 91% (U
, 61123N, 0867H, 0.
,N.

2α9196) (e) N-cyano-N'-[3-[[[5-(diethylamino)methyl-2-7ranyl]methyl]thio]furovir]-N''-methylguanidif Elemental analysis: 0.52
．． 86%* Hh 7569' b N b20, 64
qb (O port H2, N, O8・lH3O calculation value:
0% 52. s o S b H & Z 5996
h Na31, 20%) 2-[[[5-(dimethylamino)methyl-2-7ranyl]methyl]thio] dissolved in 107μ of acetonitrile
Ethanamine 10.7 Methyl ester of N- and N-cyano-N'-methyl rubamimidothionic acid 7, 1.9
A solution of 935 g of silver nitrate in 20 parts of acetonitrile was added to a suspension of 20.7 g of potassium carbonate dispersed in a solution of 70° C. over 1 hour, the mixture was stirred for 16 hours, the solid formed was filtered off, and the filtrate was filtered. Evaporate and dissolve the resulting residue in 250 ml of ethyl acetate, add a portion of the solution lα5
The condensate was washed with 6 ml of water, the ethyl acetate layer was evaporated, and the resulting residual solid was crystallized from 1.75 ml of isopropyl acetate to give N"-cyano-N-[2
-(C[5-,(dimethylaminomethyl)-2-7ranyl]methyl]thio]ethyl)-N'-methylguanidine 0.35 was obtained.

A solution of 9.09.9% of nananosic acid in 30a of ethanol was added to a portion of the above solution, and from the filtrate 13.74 g of nananosinate with a melting point of 92.5-94°C was obtained. Obtained.

Elemental analysis 20% 54.91 section, H, 7,94%, N11
4.02% (013H21N508 ・(116-J1
Calculated value from 04: 0.55.51%, il, 7.90
%,N.

1407%) Cyanamide powder 4.2II was added to a stirring solution of 2.3 g of Natrium in absolute ethanol,
After 30 minutes, a solution of methoxyethylthiocyanate 11.71 in absolute ethanol was added to the cold solution, and after 1 hour at room temperature dimethyl sulfate 12.66.9 was added over 30 minutes and the mixture was allowed to stand overnight. Stir, then remove the solvent, flush the remaining solid thoroughly with water, and dissolve the methyl N-Schiff/-N'-2(methoxyethyl) carnotomimidothionate with a melting point of 94.5-95.5°C. A white crystalline solid of the ester was obtained.

Similarly, N-cyano-N' with a melting point of 109 to 110°C
The methyl ester of -(2-zorobenyl)carnomitothionic acid was prepared.

2.14 g of guanidine 2-[[[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethanamine and N-
A 1.7:1 mixture of the methyl ester of Schiffnor N'-,(2-methoxyethyl)carpamimidobonic acid was heated on a steam path for 6.5 hours, with occasional vacuum applied to remove the methanethiol, and the resulting crude product Chromatographic processing (
silica gel/methanol) and N-cyano-N'-[2-([[5(dimethylamino)methyl-2
-7ranyl]methyl]thio]ethyl]-N''-(2-methogynethyl)guanidine], 4.9 was obtained.

Elemental analysis: 0.50.51%, f(, 7.20 yen, N.

1941 Section (() 1d(2,0, N5028 @ H
i1'F from 20: (+14: (],
5 0. 4 2 % % kl, 7.
50%, N.

1960%) Similarly, the following compound was prepared from 2-(([5-(dimethylamino)-methyl-2-furanyl]methyl]thio]ethanamine and the corresponding N-alkyl-N'-cyanocarpamimidothionic acid methyl ester. was manufactured.

(bl 'N-CyanoN'-[,2-([(5-(
Dimethylamino)methyl-2-7ranyl]methyl]thio]ethyl]-N'-(z-;;ropenyl)guanidine Elemental analysis: [], 5333φ, H, 7, 01 section, N.

2070% (08, H,, N, 08.) (, Calculated value from O: 0% 53.09 section, N17.37 qb,
N, 20.6'4%) (c) N-cyano-N"-(2-(((5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl)-N"-(1- Methyl ethyl) guanidine elemental analysis: 0, FML971, H, '1.'lO%, N
%2α57%(0,,)I,,N, 08 @H,0
Calculated values from: 0, 52.78 coefficient, H, 7, 91 coefficient, N
.

Example 12 2.14 g of 2-[((5-(dimethylamino)methyl-2-7ranyl]methyl]thio]ethanamine and N,
8-Dimethylisothiouronium iodide was heated on a steam path for 3 hours, the solvent removed and the residue dissolved in methanol and added to Ambarlyst.
) A 26 N-[2-(([5
-(dimethylamino)methyl-2-7ranyl]methyl)
1.5 g of an amber oily liquid of ethyl]-N'-methylguanidine was obtained.

Elemental analysis: 0.5α92H, H, 8.23%, N.

Calculated value: 0.5076%, H, 8, 34 yen, N.

19, 74’4) The following compounds were produced in the same manner.

(b) N -[2-([[5-(dimethylamino)
Methyl-2-7ranyl]methyl]thio]ethyl], -N
l, Ng-dimethylguanidine nuclear magnetic resonance spectrum (0 DOIs) near, 75 (singlet, 6
H), 6. s~7.3 (multiplet b8H>565 (multiplet, 4H), 6.22 (singlet, 2H), 3.8
0 (multiplet, 2o), 2. o~35 (broad signal, 2H) Example 13 N-1f - 1-methylfi-2-nitroethanazine 1.5% of ethylene dichloride in 1.1-bismethylthio-
2-nitroethene99. To a stirring solution of oIi (α6 mol) was added 112.5 ml of an ethanolic solution of 33-thimethylamine in 0.8/ml of ethylene dichloride.
d (0.94 mol was added at 70° C. over 5.5 hours, the solution was heated to boiling and the solvent of 0.7) was distilled off,
Cool the solution and add 2N hydrochloric acid 0.25%, then saline α25
The residue obtained by removing the solvent was dissolved in isopropyl acetate α51, and the heated solution was heated with activated carbon lα09.
After treatment with and recrystallization, 35.0 # of yellow columnar crystals of the target compound with a melting point of 114° C. were obtained.

-2-7 ranyl]methyl]thio]ethyl]-N' hydrochloride 2-[[[5-(methylamino)methyl-2-7rael]methyl]thio]ethanamine 1011 in 25 liters of water
(0.05 mol) and N-methyl-1-methylthio-2-
A solution of ditroethenamine 7.4 II was prepared at 50°C for 2
Stir for a while, acetone 35Qm! Add V, distillate 2
Remove the solvent by atmospheric distillation until 75 rnl is collected, and add 27.5 rnl of an ethanolic solution of hydrogen chloride to the residual liquid.
t (2 mol) and the resulting solution was stirred overnight at room temperature to collect the resulting product 11.0.9 with a melting point of 1611 and recrystallized from ethanol to obtain a colorless fine solid 10.1 with a melting point of 162°C. I got .9.

Elemental analysis: 0.42.6%, H% 6.3, N, 16.
4% (0,, H,.N, Calculated value from Os8 @ H01: 0% 428 coefficient, H, 6, 2 coefficient %N, 16.696
) Example 14 Tyl-2-furanyl]ethyl]thio]ethyl]-N'-
Methyl-2-nitro-1,1-ethenediamine 2-([(5-(methylamino)methyl-2-furanyl]ethyl]thio]ethanamine 0.9N and N-methyl-1-methylthio-2-nitro The edenamine mixture was heated at 100 to 120°C for 30 minutes while suctioning with an aspirator, and the resulting residue was subjected to column chromatography (silica/methanol: O, S S ammonia).
and crystallized from acetonitrile, it has a melting point of 10
N-(2-(((5-(methylamino)
Methyl-2-7Ciel]methyl]thio]ethyl)-N'
-Methyl-2-nitro-1,1-ethenediamine 0,6
I got 519.

The following compounds were produced in the same manner.

(b) N-[2-[[(5-(1-methylethyl)acinocomethyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine element Analysis: 0.49.7591+, n, 7.2196.
N.

16.36% (014th maNaOm S @1H20
Calculated value from: 0.49.83, ■, 7.47%, N
.

16,60%) (c) N-methyl-2-nitro-N'-["2-[
([5-((2-phenylethyl)aminocomethyl-2
-Furanyl]methyl]thio]ethyl]-1,1-ethenodiamine Elemental analysis: 0.5719, H, 6,53%, N113
83% (OuHzsNnoxs 11-> Total from HaO: 0, 5 7. 1 2
Taro, 1(,6,81% ThN.

1402%) (dl N-methyl-2-nitroN'-[2-[[
[5-((1-piperidinyl)methyl2-furanyl]methyl]thio]ethyl)-1,1-ethenodiamine Elemental analysis: 0.53.3 (i%Th)i, 7.5'1
%, N1 calculated value: 0.53.33%, H, 7.44%, N
.

Section 15, 61) (e) N -[2-C[[5-[2-(dimethylamino)ethyl-2-furanyl]ethyl]thio]ethyl]
-N'-Methyl-2-nitro-1,1-ethenodiamine Melting point: 955-96°C.

(f) N -r 2- [[[5-[3-(dimethylamino)propyl]-2-2ranyl]methyl]thio]
Ethyl]-N'-methyl-2-nitro-1,1-ethenediamine nuclear magnetic resonance spectrum A/r (ODo 11):
s, l -7,1 (multiplet, 6H)% 7.65 (singlet, 6H), 7.1 (singlet b3H) b
6.5 (multiplet, 2H), 6.28 (singlet, 2
H).

4.0 (multiplet, 2B), 3.38 (singlet, I
H) (g) N-[2-([(5-(4-(dimethylamino)butyl]-2-furanyl]methyl]thio]ethyl]-N-methyl-2-nitro-1,1-ethenodiamine) Waxy solid elemental analysis: 0.53.90%, H, 7.95% N11
5.64% (calculated value from 01 H1sN4038: 0
゜53, 91st Section, H% 7.92%, N, 15.72%
)(h) N -(2-[((5-(ethylmethylamino)methyl-2-7ranyl]methyl]thio]ethyl]
-N'-Methyl-2-nitro-1,1-ethenediazene nuclear magnetic resonance spectrum t (0DOj3): 8.9
0 (triple line, 38), 776 (singlet, 3H)
.

68-7.5 (multiplet% 7H), 65 (wide signal, 28), 6.42<singlet, 2H), 6.2
5 (singlet, 2H), 3,85 (multiplet, 2B
), 3.77 (singlet, 211), 3.35
(singlet, IH), (1) N -(2-[(
[5-[(2-(dimethylamino)ethyl]aono]methyl-2-7ranyl]methyl]thio]ethyl)-N'-
Methyl-2-nitro-1,1-ethenodiamine nuclear magnetic resonance spectrum τ (ODO/s) near, 79
(Singlet, 6H), 7-7.6 (Multiplet, 1°H), 66 (Multiplet, 2H), 6.26 (Singlet, 2H), 622 (Singlet, 20), 3
83 (multiplet, 2H), 3.37 (singlet, 11
1), 2-3.2 (wide signal, 11 yam), 0.
8~0.2 (wide signal, IH) (j) 2-
(2-[5-(dimethylamino)methyl-2-furanylmethoxy]ethyl)-N'-methyl-2-nitro-1
, 1-etheno 17, melting point 110-112°C Example 15 N-methyl-2-nitro-N'-[2-[[[5-((
1-pyrrolidinyl)methyl]-2-7ranyl]methyl]
thio]ethyl]-1,1-ethenodiamine 2-(([5-(1-pyrrolidino)methyl-
Bisoxalate of 2-7ranyl]methyl]thio]ethanamine 2.1,9. A mixture of 1.12 g of potassium hydroxide and 0.9.9 g of N-methyl-(l-methylthio)-2-nitroethanamine was stirred at room temperature for 18 hours, the water was removed by vacuum evaporation, and the residue was drained of the excess. Extraction with ethyl acetate in the presence of anhydrous sodium carbonate and evaporation of the extract gave a residue which was crystallized from isonorovir acetate to give the white crystalline isomer 0.9.9, mp 79-82°C.

Elemental analysis: [I, 52.78%, H, 7.05%, N1
16,57 To (OtsHznN40s Calculated value from S: 0°5292%, H, 7,11%%Nm16.
46) Example 16 N-(2-([[5-(Methylamino)methoxy-methylurea) A solution of 2.0 g of N-[2-mercaptoethyl)-N'-methylurea in concentrated hydrochloric acid at 00°C. While stirring, a solution of 2011 5-(methylamino)methyl-2-7 ranemethanol in 3 ml of water was added dropwise to this.

After 24 hours, 100 nl of ethyl acetate and an excess of anhydrous sodium carbonate were added, the suspension was filtered, the filtrate was evaporated to dryness, and the resulting oily residue was subjected to column chromatography (silica/methanol: O, S S ammonia 79:1.
) L, the corresponding eluent was evaporated to dryness to give an oil 0.42.9% identical to the product of Example 4.

Example 17 A solution of 1 g of N-cyano-N'-(2-mercaptoethyl)-N''-methylguanidine in concentrated hydrochloric acid at 0° C. was dissolved in 5-(dimethylamino) over 10 minutes with stirring.
-2-Furan methanol 0.98.9 was added dropwise and kept at room temperature for 3 hours, then the solution was neutralized with excess anhydrous sodium carbonate, the resulting solid was extracted with ethyl acetate, and the solvent was removed from the extract. The resulting oil was chromatographed to give a product identical to the compound of Example 10.

Example 18 Ranylethyl[thio]ethyl)-N"-cyano-N'-
Methylguanidine-2-(5-hydroxymethyl-2-7-ranylmethyl)
-1) 1-isoindole-1,3(2H)-dione 1
0,17 was dissolved in 15 mA of thionyl chloride with gentle heating, and the solution was evaporated to dryness. The residue was reevaporated with a mixture of cyclohexine and benzene = 1:1, and the residue was suspended in ether. The filtered mass was washed with ether and dried to give 2-(5-chloromethyl-2-furanylmethyl) with a melting point of 1' 19-122°C (decomposition).
-1H-isoindole-1,3(21()-dione was obtained.

Elemental analysis: 0.61.32%, H%3.71%sN
b2.00chi (014th 1o0I! Calculated value from NO4: 0.6099, Hl 3.66 excellent, N, 5.08%
) methyl]-2-furanylmethyl]thio]ethyl]4 mb of dry dimethylformamide N"-cyano-N-(
2-Mercaptoethyl)-N'-methylguanidine 1.
0.9 and 0.152 g of sodium hydride was added with stirring at room temperature to a mixture of 2-(5-chloromethyl-2-7
ranylmethyl)-1) 1-isoindole-1,3(2
A solution of 1.74.9 of H)-dione was slowly added, the solution was stirred for 2 hours and then evaporated to dryness, and the resulting oily residue was suspended in a mixture of 25 tNF of ethyl acetate and 2 Qml of water to give a solid. The residue was filtered and crystallized from methanol to give 1.4 g of the title compound, melting point 179-182°C.

-Methylguanidine N''-cyano-N-[2-([
5-[(1,3-dioxo-2H-isoindole-2
A suspension of 4,45 II and 0.61 l of hydrazine hydrate was heated under reflux for 4 hours, and m
The residue obtained by evaporating the suspension to dryness was dissolved in 15 ml of water at 0°C, neutralized with 5N hydrochloric acid, the resulting suspension was filtered, excess anhydrous sodium carbonate was added to the filtrate, and the solution was evaporated. Dry and harden.
The resulting residue is mixed with anhydrous 61 [sodium], the mixed solid is extracted with ethanol, the extract is evaporated, the resulting triangular face is mixed with anhydrous sodium sulfate, and the mixture is extracted with ethyl acetate to obtain an oily liquid. Column chromatography treatment of 12.9 (Nrica/methanol:α88 ammonia 79:1
) L, the oil obtained by evaporation of the eluate gradually solidified to give 1.88 g of the title compound with a melting point of 80-82°C.

Elemental analysis: 0.49.57, H, 6,66%, N12
593% (011HI? Calculated value from 1,08: 0.
49.41%, 11.641%%N, 26.20%) Example 19 N-cyanoimide-lupamoditeone in ruamino)methyl-2-7ranyl]methyl]thio]ethyl)-N"-metelquanidine ether 2-[CC3-(
Add 1.07.9 g of dimethylamino)methyl-2-furanyl]ethyl]thio]ethanamine and stir overnight.
The resulting crystalline silica solid was filtered, washed with ether, and dried to give N-cyano-N'-[2-[[
14 g of [5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl-carnotomimidothionic acid methyl ester L was obtained.

N-cyano-N'-[2-[[[s-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N
"-Methylguanidine 33 qbN'-anor N-[2-[[(5-(dimethylamino)methyl-2-7ranyl]methyl]thio]ethyl] in an ethanol solution containing methylamine)
A solution of carnotomimidothionic acid methyl ester 1.06.9 was stirred at room temperature for 4 hours, and the solution was evaporated to dryness. The resulting oily residue was crystallized from ethyl acetate and light petroleum with a boiling point of 80-100°C. : The title compound was obtained at 17-80°C.

Example 20 115 g of hezotylamine and N-cyano-N'-[2
-[((5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-rupamimidothione!3.
Heat 12 & over oil gas at 100℃ for 12 hours,
The reaction product was chromatographed (silica/methanol) to give N-cyano-N/-42-(((5-(dimethylamino)methyl-2-77yl]methyl]thio]ethyl)-N"- Hebutylguanidine hydrate 2.31 II was obtained.

at:o49 Elemental analysis: (J, 56.99%, H, 8,32%,
N11753% (0,, Hs, calculated value from N508@H, O: 0h57.43, H, 8, 81, Nb17
．． 63%) Example 21 (a) N -C2-CCC5-(dimethylamino)
Methyl-2-furanyl]ethyl]thio]ethyl]2-[
2.141 N of [[5-(dimethylamino)methyl-2-7ranyl]methyl]thio]ethanamine and 1.65 N of 1.1-bis(methylthio)-2-nitroethene were heated under reflux in acetonitrile for 8 hours. , remove the solvent,
An ethanol solution of 0.75.9% of 2-methoxyethylamine was added to the residue, and the mixture was further heated under reflux for 8 hours, and the solvent was removed. The resulting oily residue was purified by column chromatography to obtain N-[2- (([5-(dimethylamino)methyl-2-7ranyl]methyl)thio]ethyl)-N'-(2-methoxyethyl)-2-nitro1.
1-ethenediamine1. Obtained Og.

Nuclear magnetic resonance spectrum r (ODOZi) near, 7
3 (singlet, 6H), 7-7.5 (multiplet,
6.2 to 7 with 2H (multiple line, 111+), 6.23 (singlet, 2H), 3.81 (singlet, 2H)
, 3.42 (singlet, IH).

(b) Similarly, N-( with melting point ioo~101°C
2-[((5-(dimethylamino)methyl-2-7ranyl]methyl]thio]ethyl]-2-nitro-1,1-ethenediamine was produced.

Example 22 Ru-2-7ranyl]butyl]-N'-methyl-24-[
5-(dimethylamino)methyl-2-7ranyl]butanamine 0.719 and 1.1-bis(thiomethyl)-
0.6.9 of 2-nitroethane was heated under reflux in 12μ of acetonitrile for 22 hours, the residue from which the solvent was removed was heated under reflux for 2 hours in a 33% methylamine ethanol solution, and the residue from which the solvent was removed was subjected to column chromatography. Purified by graph processing (silica/methanol) to give N-(4-(5-(
dimethylamino)methyl-2-7ranyl)methyl]-N
/-methyl-2-nitro 1,1-ethenediamine 3
10 m9 was obtained.

Elemental analysis: Os 55.54'16% N18.
23%, N.

1775 excellent (0, aHxaNaOs・1H,0 empty calculation value: 0k55.26%, H, 8,229”b N%1
Section 842) Similarly, the following compound was produced H,,IC.

(b) N-[5-[s-(dimethyla])methyl-2-7ranyl]hentyl)-N'-, Ifk-
2-nitro-1,1-ethenediamine elemental analysis: 0.56.769J, H, a36%, N.

17, 37% (01iHzsNnOi 11N Hz
Calculated value from O: 0.56.43, H, 13,469
6,N.

Section 1755) (c) N -(3-[(5-(dimethylai))methyl-2-7ranyl]thio]propyl)-N'-methyl-2-nitro-1,1-edendiai elemental analysis :0.
49.36%, H, 7, 19'16. N.

17, 45% (0, sH!lN40s Calculated value from 8 20149.66%, H%7.0596.N, 17
．． 84%) (d) N-[3-(5-(dimethyla-den))methyl-2-7ranyl]propyl]-N'-methyl-2-nitro-1,1-ethenediamine Elemental analysis: 0,55 .69%, I(, 7,84 excellent(0
1s) Its N4 Calculated value from os: N, 55.3
1 section, H% 7.72 section) (e) N-(2ri, (((5-(diethylamino))f
2-7ranyl]methyl[thio]ethyl]-N'-methyl-2-dimethyl-1,1-ethenediaZn Elemental analysis: 0m5L38H, H, 7,44, N115
．． 66% (OssHxiN4018e; Calculated value from yH20: 0%51.26, H% 774, N115
94%) (r) N -(3-[[(5-(dimethylamino)
Methyl-2-furanyl]ethyl]thio]propyl]-N
'-Methyl-2-nitro-1,1-ethenediamine Elemental analysis 20% 49.57%, H, 7, 20, N11
5.59% (014H14N4018” 7HzO
Total value from: 0.49.86chi, H, 7.47th, N
116.61) Example 23 4-(5-(dimethylamino)methyl-2-7ranyl)
04 g of butanamine and 0.3 N of N-cyanoimidocarnomodithionic acid dimethyl ester were stirred in ethanol for 3 hours at room temperature, then a solution of 331 methylamine in ethanol was added, the mixture was heated to reflux for 2 hours, and the solvent was removed under reduced pressure. The removed residue is subjected to column chromatography (
The desired product was obtained as a pale yellow oil.

Nuclear magnetic resonance spectrum τ (ODO/3): 8-8.5
(wide signal, 4H), 7.77 (singlet, 6l-1), 6.61-75 (multiplet, 9H), 4
．． 0 (multiplet, 2B), 2.8-3,7 (multiplet, 2H
) (b) Similarly, N-cyano-N'-[5-, (5
-(dimethylaζ])methyl-2-7ranyl]pentyl]-N'-methylguanidine was produced.

Nuclear magnetic resonance spectrum τ(0DO1!s):8. O~
8.7 (wide signal, 6) 1), 7.68 (singlet, 6H), 7.32 (triple line, 211), 7
, 10 (double line, 3) 1), 6.7 (quadruple line, 2H)
, 6.48 (singlet b2H), 3.8-4.3 (
Multiplet % 4) 1) Example 24 Dimethyl ester of dimethanesulfonyliminodithiolunozonic acid 1.9.9 and 2-[[(5-(dimethylaz])methyl-2-furanyl]ethyl] Thio]-ethanamine 2.14.9 was stirred in ethanol at room temperature for 3 hours to form a solution of 334 methylamine in ethanol 20 rLe
was added, the whole was heated under reflux for 16 hours, and the product was purified by column chromatography (Nlica/methanol) to yf
'Ii6, N-[2-(((5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl)-N
27 g of a pale oily liquid of '-methanesulfonyl-N"-methylguanidine was obtained. 1. Elemental analysis - 〇, Section 43.54, H, Section 7, Section 05, N11
5,・48廑（Ots Hz4NnOasz・IHlo
Calculated value from: n, 43.70%, H, 7,00 excellent, N
115.69 Excellent) The following compound was prepared using the same pressure.

(b) N-benzenesulfonyl-N'-C2-(
((5-(dimethylamino)methyl-2-72yl]methyl]thio]ethyl)-N'-methylguanidine Elemental analysis: 0.50.30*, Hb 6.25'fks
Nb22, 93 fight (Cs brutal HssNaOsB, H 0
Calculated value: Ob 50.47%, H% & 54*, N
, 13.08 hours) Example 25 N-cyano-N'-methylcarnomine imidothionate methyl ester 6, IJiF in methanol 159Ij
,) dimethylamino 4.8J' and 2-[([2-7
A solution of ranyl]methyl]thio]ethanamine 78I in dimethylformand 50JIJ
A solution of get things,
From this, N-cyano-N'-[2-
([((2-7ranyl]methyl]thio]ethyl]-N'
-Crystal 3911 of methylguanidine was obtained.

3.1 g of this amine 4511 dimethylanne hydrochloride and 3.161 g of a 36% aqueous solution of formaldehyde were heated in 20 tnl of ethanol at 50° C. for 60 hours, the solvent was removed and the residue was partitioned between ethyl acetate and a basic aqueous solution. The combined organic extracts were dried and the oily residue obtained by evaporation was treated with nananocinic acid in isopronozenol.
2 g of the title compound, nananosinate salt having a melting point of 93-94°C was obtained.

Example 26 To a cold solution of sodium hydroxide α81 in 1.7 IR1 of monomethylthiourea was added 1.52 Jil of carbon disulfide with stirring, firstly to 2-([(5-(dimethylamino)methy). −
2-75nyl]methyl]thio]ethane(n) 4.28j
' was added gradually, and when the addition was complete, the mixture was heated to 100°C for 2 minutes.
After heating for an hour and then cooling to below 40°C, 1.94 trIj of ethyl chloroformate was added, stirring was continued for an additional 30 minutes, the highly viscous yellow oil at the bottom was extracted with chloroform, and the extract was dried.

Evaporation gave an oily N,N-dimethyl-5-([[2-(thiocyanato)ethyl]thio]ethyl]furanmethanamine) of nt=o, 43c silica/methanol).

3396 of this crude intiocyanate 0.46 II
Dissolve in 25 mg of ethanol solution of methylamine.

After standing overnight, N-[2-[[(5-( dimethylamino)methyl-2-
0.16.9 of a pale oil of furanyl]ethyl]thio]ethyl)-N'-methylthiourea was isolated.

Example 27 N-cyano-N'-[2-[: CC5-(dimethethyl)-N'-methylguanidine N-C2-4CC5-(dimethylamino)methyl-2-
A solution of 1.3 g of furanyl]ethyl]thio]ethyl)-N'-methylthiourea was heated to reflux with lead cyanamide 1,5.9, the solution was filtered, and the filtrate was evaporated and the residue was dissolved in isozolo A alcohol. When treated with a solution of heptanosinic acid, the melting point was 9.
Monocenosinate of the title compound at 0-92°C 0.79
I got it.

Example 28 N-C2-CC3-C(2-propenylamino)amine 5-[(2-propenylamino)methyl]-2-furanmethanol oxalate (1:1) Formaldehyde (3
An aqueous solution of 64:4.9 ml) was prepared with amine hydrochloride (5 g) and 2-7 methanol (4,4, Ii?).
) was gradually added to the water-cooled mixture. After standing for 48 hours at room temperature, the solution was extracted with ethyl acetate, the aqueous portion was made alkaline with 5N sodium hydroxide, and the suspension was extracted with ethyl acetate. The extract was dried and evaporated and the oily residue was dissolved in ethanol (lOaz) to which a solution of ethanol in oxalic acid (5.7 g) was added. Crystallize with liberated solid ethanol to obtain 5-1
2-Zolobenylamino)methyl]-2-7 ranemethanol oxalate (s, 42.p) was obtained.

T, 3. C, silica; methanol, RfQ, 555-(
C(2-aminoethyl)thiocomethyl]-N-(2-f
(lopenyl)-2-furanmethanamine oxalic acid (1:2
), IH,'0 Water (15th edition) 5-((2-propenylamino)methyl]-2-furanmethanol oxalate (3,3,9)(
7) The aqueous solution was gradually added to a solution of concentrated hydrochloric acid (20 ml) cQ 2-aminoethanethiol hydrochloride (1,6,9). After 18 hours, an additional amount of sodium carbonate was added and the solid material was extracted with ethyl acetate (100%). The suspension was filtered and evaporated to remove an oily residue (2,5
1Ji') was obtained. This residual material is evaporated into ethanol (8IRE
) and added to a solution of oxalic acid (2,4,9) in ethanol (20 my, ). The liberated solid was crystallized from ethanol to give 5-r ((2-achinoethyl)thiocomethyl]-N-(2-zorobenyl)-2-7ranmethanamine oxalate (1:2), IHtO (3, 9g)
I got it. m, p.

163-164.5°C T, 1. c Silica; Methanol: O, Sa Ammonia (79:1), Rf O, 38 N-[2-r(5-((2-Zolobenylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'- Methyl-2-nitro-1,1-ethenediamine 5-C((2-aminoethyl)thiocomethyl]-N-(
2-propenyl)-2-7ranmethanamine oxalic acid (1:2)HzO(1,5,9), sodium hydroxide (0,69) and N-methyl-1-(methylthio)-
2-nitroethinamine (0,6,9) and water (5rni
) was stirred at room temperature for 3 days. The suspension was extracted with ethyl acetate, the suspension was filtered and evaporated to give an oily residue. This residue is removed by chromatography (
N-[2-[(
5-[(2-propenylamino)methyl]-2-furanylmethyl]thio]ethyl)-N'-methyl-2-nitro-1,1-ethenediamine (O,SN) was obtained. N
, m-r-(ODO11/DM80; 1:2
) -0,2-br, to, (IH); 2.86
br, m, (IH); 3.42 S.

(1B); 3.81, m, (2H); 4.00 5
．． 00-m, (3I(); 6.19, *, (2
H); 6.23-s.

(2H); 6.30-6.90. m, (58)-;6.
90-7.40. m, (5B.) To l-Cm a
ilica; methanol: 0.88 (79:
1) Rfo, 56 Example 29 A mixture of amine 5-((cyclohexylamino)methyl]-2-furan methanol formaldehyde (36%; 2.6 mt, ) solution and cyclohexylamine hydrochloride (3,83N) Water-cooled 2-furanmethanol (1,96,9)
added to. After standing at room temperature for 24 hours, the solution was washed with ethyl acetate and basified to pH 12 with 5N sodium hydroxide. The solution was extracted with ethyl acetate, the extracts treated with decolorizing charcoal, dried, filtered, and evaporated as a semisolid to 5-[(cyclohexylamino)methyl]-2-furanmethanol (2,2N). I got it.

T, 1. c, silica; methanol RfO, 475-
[((2-aminoethyl)thiocomethyl]-N-cipo
hexyl-2-furanmethanamine”1Nf) hydrochloric acid (1
5ag) 5-[(cyclohexylamino)methyl]-
A solution of 2-propylene methanol (269) was slowly added to a water-cooled solution of 2-aminoethanethiol (1,5211) in concentrated hydrochloric acid. After standing for 12 hours at a temperature of 0-4°C, an additional amount of anhydrous sodium carbonate was added and the solids were extracted with ethyl acetate (loogo). The extract was treated with decolorizing charcoal, the suspension was filtered and the filtrate was evaporated in vacuo to give 5-([(2-aminoethyl)thiocomethyl)-N-cyclohexyl- as an amber oil. 2-
7 methanamine ((2,989) was obtained.T, 1
．． c, silica: methanol; 088 ammonia (79
:1)l'LfO,33N,m,r,(ODOLB)3
．． 91. a, (2H); 6.22. i, (2B);6.
31. a, (2) 1); 6, 90-7.80, m
, (5f(); 7.80-9.30.

Bra me (13H).

5-[[ (2-Aj/:cfl) f:1o]ethyl], N-cyclohexyl-2-7ranemethaneamine (0,5N) and N-methyl-1-(methylo)-2 - The mixed solution with ditroethenamine (0,3,9) was stirred at room temperature for 3 days. The solution was evaporated in vacuo and the oily residue was chromatographed (silica/methanol - 0, 88 ammonia, 79 :1) to give N-(2-[[5-(cyclohexylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenecyamine as an oily substance. I got it.

T, 1. c, silica; methanol: 0.88
Ammonia (79:1) lLfO, 6°N, m, r, (ODOI!3) 0.50-0.0
0, br, s.

(1B);2.00-4.00. br, s, (IH);
3.40. s, (IH); 3.84. a, (2B)e
6.17-s = (2f(); 6.28
, s - (2H); 670. Turtle, (2)1
); 7.10, s, (3H); 7
．． 25, t, (2H); 7.00-7.80
, br.

s, (IH); 7.80 9.10. m, (IOH)
.

Example 30 pharmaceutical composition To dispense 10,000 tablets.

Active Ingredients 500g US Pharmacopoeia Anhydrous Lactose 2.17 to t* 81a-Rx 1500 Dessert Flour 30011 British Pharmacopoeia Magnesium Stearate 30.9 is weighed and the active ingredient is passed through a 250 μm sieve and then blended with 4M in a blender. The powder is mixed well and compressed between 8.5M diameter punches in a tablet machine.

Note: A, B% Stag-e of Orpington, Que.
y Starch active ingredient in direct compressible form supplied by Mfg 0o (London) Ltd. lα0 factor w/w British Pharmacopoeia Water for Injection plus 100.0 ow/w.

British Pharmacopoeia dilute salt & adjust pH to 5.0.

The active ingredient is mixed with water for injection to dissolve it, and then the pharmacopoeia hydrochloric acid is gradually added until the pH reaches 5, which is OK. Pass nitrogen through the solution 5
It is then clarified by filtration through a membrane filter with a pore size of 1.35 μm, filled into 2M glass ampoules with 2.2 ml each, each ampoule sealed in a nitrogen atmosphere, and sterilized at 121°C for 30 minutes. .

(C) Extended release oral tablet containing 150 mg of active ingredient Active ingredient for 10,000 tablets 1.504) ftHR** α40 2 US Pharmacopoeia Anhydrous Lactose 2.060 British Pharmacopoeia Magnesium Stearate 409 do.

The active ingredients, anhydrous lactose and most of Cutina Ii R are mixed well and the mixture is then kneaded by mixing with the remaining industrial methanol denatured alcohol 74°0, 10% solution of Cutina HR in Pl. , pass the kneaded mass through a sieve with an opening of 1.2M to form granules,
Dry at 50° C. in a fluidized bed dryer. Granule opening 0.8
Passed through a 5 U sieve, mixed with magnesium stearate and tested in a Schleuniger tester on a tablet making machine with a 12.5 U diameter punch.
It is compression molded until it has a hardness of 10 kg (as measured with a tester).

Note: Outina HR is from 8ipon Products L in London.
It is a variety of finely hydrogenated castor oil supplied by id).

Active ingredient 2.0 tw/v British Pharmacopoeia dilute hydrochloric acid appropriate amount BPO sorbitol solution 6 Qv/v flavoring
Add an appropriate amount of distilled water to make 100 volumes.

The active ingredient is stirred and dissolved with a quantity of water by gradually adding hydrochloric acid until the pH of the solution of the active ingredient falls to 5.0, the sorbitol solution, flavoring and residual water are added and the pH of the solution is adjusted. Readjust to 5.0. The syrup is clarified by filtering through a suitable cellulose filter.

(e) Active ingredient 50m? Contains capsules for oral administration Active ingredient 500#Sta-Rx
Use 1500 1700 & British Pharmacopoeia Magnesium Stearate 201°Cg. The active ingredient is passed through a 250 μm mesh sieve, blended with other powders, and the mixed powder is filled into suitable filling material M a M size hard gelatin capsules.

(f) Ointment active ingredient 20M amount % British Pharmacopoeia white soft nosorafuin Remaining active ingredient opening width 50 μm
Pass it through a sieve and mix it with a high speed shear mixer (8hear m).
Mix evenly with white soft paraffin in a 1xer).

(g) Cream active ingredient 20 weight English Pharmacopoeia Setomacro ♂ emulsifying ointment 30.0 (Oetomacrog)
ol Emulsifying Oimtmeut B
P) Chlorocresol 0.1 distilled water
Open the remaining active ingredients to 150 μm.
Pass it through a sieve and mix well with the emulsified ointment at 65℃. The chlorocresol is dissolved in water at 65° C. and then added to the oily active ingredient mixture and creamed by stirring continuously while the resulting emulsion cools.

The active ingredient here is one of the compounds of the present invention. Although the compound of Example 10 is preferred, other compounds may be used.

The compounds of formula (I) are inhibitors of gastric acid secretion induced by hymethane, and this has been demonstrated by the method of Ghosh and Schild (M, N% Ghosh and H,0,
S-ch d, Br1t, J %of Phar
ma cology.

This was proven in a test on rats using a modified method of 1958.13.54).

A female rat weighing approximately 150 g was made to fast for one meal.

Give an 8% sucrose solution in saline instead of drinking water.

Rats are anesthetized with a single intraperitoneal injection of a 25% w/v urethane solution at a rate of 0.5 μ/100.9 body weight, and the trachea and jugular vein are cannulated.

The stomach is exposed through a midline incision in the abdominal wall, communicating with the stomach and lungs by cutting the connecting tissue, making a small hole in the medial fundus, and irrigating the stomach with 5% dextrose. Connect the Jum tube to the esophagus, then cut the esophagus and communicating nerve above the cannula.

Next, a small hole is made in the pylorus of the stomach, and a large organic glass cannula is inserted through the small hole in the pylorus so that the proximal end of the cannula exits the stomach through the small hole in the pylorus. The cannula is shaped in such a way that it reduces the effective volume of the stomach and creates a turbulent flow of irrigation fluid over the mucosal surface. The drainage cannula is then inserted into the stoma of the gastric pylorus, and both cannulas are properly tied with a converging system around the stomach in a position that avoids the main blood vessels. A puncture is made in the body wall and the cannula is passed through. 1.5 each through the esophageal cannula and the pyloric cannula.
The stomach was emptied with 5-glucose solution at 39°C at a flow rate of 1 min, and the effluent was passed through a microflo pH electrode.The pH value was recorded on a pH meter and a stationary recorder.

The baseline output of acid secretion from the stomach was monitored by PT-I measurements of blood infusions, and then an increase in acid secretion was induced by continuous intravenous infusion of histamine in doses close to the maximal dose. A stable plateau is created and the pH of the irrigation effluent is measured when these conditions are achieved.

The test compound is administered to rats by intravenous injection, and changes in gastric acid secretion are monitored by measuring changes in pH of the injected fluid.

From the pH change in the buoyant effluent, the difference in acid secretion between baseline output and histamine-induced plateau levels was calculated as hydrogen ion concentration molar 1/2, and the decrease in acid secretion caused by administration of the test compound was also calculated in the irrigated effluent. It is calculated as a change in hydrogen ion concentration in moles per liter from the pH change in . The rate of decrease in acid secretion caused by administration of the test compound can then be calculated from the above two numbers.

ED5 for inhibition of acid secretion. administer a given dose of the test compound to one rat, repeat this procedure with three or more doses in each of four rats, and use the results obtained to ED5o is determined by the standard least squares method used when determining the dose response line.

The following EI)5G values were obtained by applying the above method to a solid phase.

Example 2 (cl 1.58
0659 (a)
2.30 10 1, 39 14 (1) 0.2314(f)
0.8 14 (h) 0.4821 (al
1.8222 (a)
0.55 Examples io and 14(a) of 400
in mice at doses up to ~/Kp and 200 m
1? No signs of significant changes in the behavior of these 7 animals, nor any death of the driven animals, occurred when administered orally separately at doses up to 1 hour.

Agent Patent Attorney Masaaki Aki Sawa 1 person MitsugaiContinued from page 1Priority claim G:>December 6, 1976 [Area] United Kingdom (GB) ■50685 05413, 1977 [Alias] United Kingdom (GB) ■20
187 (Inventor: John Bradshaw) 22 Whiteley Close, Wear Zone End, Hertfordshire, United Kingdom

Claims (1)

[Scope of Claims] (1) A compound represented by the general formula (1) [wherein R and R2 are the same or different groups, hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl, or Group -N(R
4) represents lower alkyl interrupted by - (in the formula, it 4 represents hydrogen or lower alkyl);
and R1 together with the nitrogen atom to which they are attached form a heterocyclic ring which may contain other heteroatoms selected from 0 and -N(R4)-, and aa is hydrogen, lower alkyl, lower alkenyl ti is alkoxyalkyl, -x is -OH snow-10 or S, Y is =8, =0
, =NR, or =OHRs (where R is H, nitro,
cyano, lower alkyl, alkylsulfonyl or arylsulfonyl, B is nitro), Alk is a linear or branched alkylene chain of 1 to 6 carbon atoms, m is 2 is an integer of ~4,
” is 1 or 2, or X is 8 or 10H,
-, n is 0°1 or 2. however%
Rl+ Rm and R3 are all methyl groups, R9, h
When tk is a methylene group, X is 8, and n is 1 and m is 2, Y is not a group =OHNOx] and medically acceptable salts thereof. (2) R1 and R2 each independently represent hydrogen, alkyl, phenylalkyl, dialkylaminoalkyl, or together with a nitrogen atom, form a 5- or 6-membered saturated heterocyclic ring, AJk ii: 1~
Covering a linear alkylene chain of 4 carbon atoms, Y=S,
=O1=OHNO2 or =NR. (In the formula, R5 is hydrogen, nitro, cyano, lower alkyl, alkylsulfonyl-**Hachensensulfonyl)
A compound according to claim 1, wherein X, m, n and R3 have the meanings defined in claim 1. (3) A compound according to claim 1 or 2, in which the alkyl group has 1 to 8 carbon atoms. <4+ Compounds according to claim 1 or 2 in which the alkenyl group has 3 to 6 carbon atoms. (5) Claims 1 to 4 in which the aryl group as part of the group is phenyl or substituted phenyl.
Compounds described in any of the sections. (a) Claim 1 in which n0m is 3 or 4
A compound according to any of Items 5 to 5. (7) Claim 111:1: The compound according to any one of items 1 to 6, wherein λ1k represents a methylene group. (81R+ is H- or 0-04 alkyl, R2
8. A compound according to any one of claims 1 to 7, wherein is O, -c4 alkyl. (9) A compound according to any one of claims 1 to 8, wherein a and/or R2 are methyl or ethyl. α[I Compound according to any one of claims 1 to 9, wherein X is a sulfur atom・αη
Claims 1 to 1 in which 10H2- group is
Compound 0 described in any term among the θ terms (2) IL! and R, are each independently hydrogen, 1
represents an alkyl or phenethyl of ~3 carbon atoms, or forms a pyrrolidine ring together with a nitrogen atom,
Alk represents an alkylene chain having 1 to 3 carbon atoms,
Y is =8, -0HN02 or =NR5 (in the formula, fL= is nitro, cyano, methylsulfonyl or fc is benzenesulfonyl), Rs tj: hydrogen, alkyl of 1 to 3 carbon atoms, propenyl or 3 2. A compound according to claim 1, which represents alkoxyalkyl on the backing atom, n -1-m is 3 or 4, and X has the meaning defined in claim 1. (2) FL', i- and R8 each independently)1
．． represents an alkyl or phenethyl group having 1 to 3 carbon atoms, or forms a pyrrolidine ring together with the t1 elementary atom, and Alk represents an alkylene group having 1 to 3 carbon atoms;
Y is =8, -=CHN02, or =NILs (in the formula R
6 is nitro, cyano, methylsulfonylmatahbenzenesulfonyl), X is 8, -0H2-, and "8
is hydrogen, methyl or methoxyethyl -0, n is 1
The compound according to claim 1, wherein m is 2 or 3. α4) ■ is hydrogen, methyl or ethyl, FLZ
is methyl or ethyl, Alk represents a methylene group, and Y is =NON, =NNOj or =OHN (h
and %R3 is hydrogen or methyl, X is st or =CH,-, n is 1 and m is 2. 0119 N-(2 -(((5-(dimethylamino)
Methyl-2-furanyl]ethyl]thio]ethyl]-N'
- The compound according to claim 1, which is methylthiourea. N-cyano-N'-(2-[:((:5-<dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl) -Nll-methylguanidine according to claim 1 (171N-cyano-N'-(2-(:((5-(methylamine)methyl-2-7ranyl)methyl]thio]ethyl) -Nll-methylguanidine, Compound according to item 1. (to) N -C2-[[[s-(diethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-
A compound according to claim 1 which is methyl-2-nitro-1,1-ethenecyamine. α(e N-(2-([(5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-
The compound according to claim 1, which is (2-methoxyether)-2-nitro-1-1-ethenediamine. (a) N-C2-C[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-(2
-methoxyethyl)thiourea. elF) N-C2-CCC3-(methylamino)methyl-2-furanyl]ethyl]thio]ethyl) + N
The compound according to claim 1, which is /-methyl-2-nitro-1,1-ethenediamine. (4) N-[3-([5-(tumethylamine)methyl-2-furanyl]thio]propyl)-N/-, t-thyl-2-ditro-1,1-ethenediamine, Compound 3 described in Section 1, cl, N-'[
: 2- [([: 5- (ethylmethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-N'-
Methyl-2-nitro-1,1-ethenediamine is special, + of juice request! l:j l phase ratio fl described in IJI81
c'+'IIJ. Mountain 9, C' N-(2-(((:5- ・Methylamino)
Mef-2-75'nyl]methyl-1thio]ethyl)-N
/-'Nidrog I Herring Time 1, 1hr of demand
The compound described in Section 1ifV1. (c) N-('2-(((5-'(dimethylamino)
The compound according to claim 1, which is 71 f Ru2-75nyl]methyl]1o]ethyl]-N/-methanesulfonyl-N//-methylguanidine. Kan N-(4-(5-(dimethylamino)methyl-2-
Furanyl]phther)-N'-methylthiourea T. A compound according to claim 1. stem) N-benzenesulfonyl-N'-(2-([(5
-(dimethylamino)methyl-2-furanyl]ethyl]
The compound according to claim 1, which is (thio]ethyl) -N//-methylguanidine. (c) N-[5-(5-(dimethylamino)methyl-
2-furanyl]hentyl) -N/-methyl-2-=)
Claim 1 which is 0-1.1-ethenediamine
Compounds described in Section. 6! The compound according to claim 1, which is IN-cyano-N'-[5-(5-(dimethylamine)methyl-2-furanyl]pentyl)N'-'□methylguanidine. (1) N-(4-(5-(dimethylamino)methyl-
2-7ranyl]zotel]-N'-methyl-2-nitro-
A compound according to claim 1 which is 1,1-ethenediamine. 00 N-cyano-N'-(4-(5-(-,7methylamine)-methyl-2-furanyl)butyl-N//-menalguanidine. 0 N -C2-[[5-((dimethylamino]propyl]-2-furanyl]methyl]thio]ethyl-N'-
A compound according to claim 1 which is methyl-2-nitro-1,1-ethenediamine. (g) N -(2-[(:(5-([2-(dimethylamino)ethyl]amine]methyl-2-furanyl]methyl)f)-r-f]'-N'-mef 2-Nitro-1,1-ethenediamine. (b) A compound according to any one of claims 15 to 33, which is 2-nitro-1,1-ethenediamine. A salt according to claim 1 which is an acid addition salt that can be used for medical purposes.B) A patent which is a hydrochloride of the compound according to any one of claims 15 to 33. Salt according to claim 1. (to) Compounds according to claim 1 described in Examples 1 to 30 of the present specification other than the compounds described in claims 15 to 33. (b) Compound represented by formula (1)j LL+ [wherein R1 and tt2 are the same or different groups, hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl, or group -N(
EL4)-(wherein R4 represents hydrogen or a lower alkyl group), or R
1 and Ru, together with the nitrogen atom to which they are bonded, form a heterocyclic ring which may contain other heteroatoms selected from 0 and -N(R4)-, and R, is hydrogen, lower alkyl , lower alkenyl or alkoxyalkyl, X is -OH, -10mak is S, and Y is =S. = 0, = N Its 'J = Okl Ra (
In the formula, a is H, nitro, cyano, lower alkyl, alkylsulfonyl or arylsulfonyl, and R, i
j), Alk means a linear or branched alkylene chain of 1 to 6 back atoms,
m is an integer from 2 to 4, n is an integer from 1 to 2, or when X is 8 or -OH,-, n is (),
1 or 2. Tatami, Itl + R* and R
When all 3 are methyl groups, Alk is a methylene group, Q, X is 8, and n is 1 and m is 2, Y does not become a group =OHNOn. ] and a medically acceptable salt thereof, □ a compound represented by formula (11) (wherein Rl + Rm t X eA
lk, m and n have the abovementioned meanings), alkali metal cyanates or thiocyanates, isocyanates of the formula axNoo or NF of the formula axNoo
L. or a compound represented by R, NHO-P (in the formula, FL3
1 HRa R6 and R6 have the above-mentioned meanings, P is a leaving group) to collect the compound of general formula (1) or a salt thereof, or further convert this salt into another salt. A method for producing a compound of general formula (1) and a medically usable salt thereof, which is characterized by the following. A compound represented by formula (■)゛ [wherein R and R8 are the same or different groups, hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl, tfc is M'=-
N (R4) - (in the formula R4 represents a lower alkyl group), or R1 and R2 together with the nitrogen atom bonded to them represent 0 and - A heterocycle of the form JRL, which may contain other heteroatoms selected from N(R4)-, where R is hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl, and X is -C1(□-10 or S and Y is =NRs or =OH[R6 (wherein 5 is 1, nitro, cyano, lower alkyl, alkylsulfonyl or arylsulfonyl, and R6 represents nitro), means an is-like or branched alkylene chain of 1 to 6 carbon atoms, m is an integer of 2 to 4, n is an integer of 1 to 2, or
or -0)12-, then n is 0.1 or 2. However, when RltRl and FL3 are all methyl groups, Alk is a methylene group, X is S, and n is 1 and m is 2, Y is a group =
It will not become OHN02. ] and a method for producing a medically usable salt thereof, a compound represented by formula (If) 1 (in which R1, R1, X, Alk, m' and n have the above-mentioned meanings); A compound represented by the formula % or formula 11 [where It and R6 have the above-mentioned meanings and P is a leaving group]. ) is then reacted with a compound represented by the formula θ11)kL+ [wherein (=NR, or =OH
FL. (in the formula) R6 and R- have the above-mentioned meanings),
P is a leaving group9, tt, , n, , Alk,
X. n and In have the above meanings] and the formula 3NH2 (
(in the formula) Ls has the above-mentioned meaning), and the resulting compound or its salt is collected, or this salt is further converted into another salt. A method for producing a compound of general formula (1) and a medically usable salt thereof. OI A method as claimed in claim 37 or 38 substantially according to embodiments 30 to 30 herein. (7) A compound represented by formula (1) (wherein R1 and [Lz are the same or different groups, hydrogen, lower alkyl, cycloalkyl, lower alknyl, aralkyl, or group -N(
144)-(wherein R4 represents hydrogen or lower alkyl,
or R5 and YL2, together with the nitrogen atoms bonded to them, may contain other heteroatoms selected from 0 and -N(R4)-; form a cyclic ring, 'EL3 is hydrogen, lower alkyl, lower alkenyl or alkotoxydialkyl, X is -OH, -10 or 8, Y is =8, =0, =NR, or =0 Summer (R6 (in the formula, FLS is H, nitro, cyano, lower alkyl, alkylsulfony) R4 is arylsulfonyl, and R represents nitro), and Alk is a straight chain of 1 to 6 carbon atoms or means a branched alkylene chain, m is 2
-4, n is a number of 1 to 2, or when X is 8 or -OH, -, n is 0. l't or 2. However, when a, , a, and R3 are all methyl groups, Alk is a methylene group, X is 8, and n is 1 and m is 2, Y is a group = 0)INOx It won't be. ] or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent;
and optionally other active ingredients. fr CI) A composition according to claim 4 in a form suitable for oral, topical or parenteral administration or administration by suppository. 42. The composition for oral administration according to claim 41, which is in the form of a tablet. 43. A composition according to claim 42 in the form of a slow release tablet. The composition according to claim 45, containing 20 to 200 Hi of active ingredient in @41 tablets. (c) The composition according to claim 45 described in Example 30 of the present specification.