KR810000355B1 - Preparation for pharmacologically active compounds - Google Patents

Abstract

Title compds. (I; R1 and R2 are same or not, H, lower alkyl, cycloalkyl, lower alkenyl, aralkyl; R3 = H, lower alkyl, lower alkenyl or alkoxyalkyl; X = -CH2, O or S; Y = =S, =O, =NR5 or CHR6; Alk = C1-6 alkylene; R5 = H, nitro, cyano, lower alkyl, aryl, alkylsulfonyl or arylsulfonyl; R6 = nitro, arylsulfonyl, alkylsulfonyl; m = 2-4; n = 1-2) were prepd. by the reaction of compd. II(A = H or IV(P = separating group; Q = =NR5 or -CHR6; or A and B are =CS) and III(Z = H, Z' = H or IV; or Z and Z' are =CO or =CS).

Description

Method for preparing amino alkylfuran derivative

The present invention relates to a process for the preparation of novel aminoalkylfuran derivatives which selectively act on histamine acceptors.

Ash, Shield, Black, etc. subdivided histamine receptors (H-receptors) into H ₁ -receptors and H ₂ -receptors.

, 427」을 참고로 하고, 블랙씨등에 의한 분류는 「Nature 1972,

, 385」를 참고로 할 것.)(Classification by Ash and the shield `` Brit. J. Pharmacol. Chemother, 1966,

427 '', and the classification by Mr. Black is `` Nature 1972,

, 385 ”.)

Stimulation of bronchial and gastrointestinal smooth muscle is regulated through the H ₁ -receptor and this effect could be prevented by conventional histamine antagonists such as mepyrazine. Stimulation of gastric acid secretion or heart rate is controlled through H ₂ -receptors, which are not alleviated by mepyrazine but are prevented or eliminated by H ₂ -antagonists such as metiamide. Histamine stimulates H ₁ -receptors and H ₂ -receptors.

The inventors have found that the aminoalkylfuran derivatives of the present invention interfere with the secretion of gastric acid when the histamine H ₂ -receptors stimulate the secretion of gastric acid because some new aminoalkylfuran derivatives act as selective H ₂ -antagonists. I found the facts.

54)을 후술하는 바와같이 수정해서 사용함으로써 관류(灌流, perfuse)된 쥐의 위장에서 증명되고, 블랙씨 등이 기술한 동일한 방법(Nature 1972 236,385)을 사용하여 하이덴하인 소위가 장치된 의식이 있는 개에서 증명될수 있다.Their ability to interfere with gastric acid secretion when histamine H ₂ -receptors stimulate gastric acid secretion is described by Gash and Shield (Brit. J. Pharmacol. 1958).

54, which is demonstrated in the perfused rat's stomach by using a modified version, as described below, and equipped with the so-called HEIDENHAIN using the same method described by Mr. Black et al. (Nature 1972 236,385). It can be proved in dogs.

The compounds according to the invention do not modulate histamine caused by contraction of isolated gastrointestinal smooth muscle.

Histamine H ₂ -blocking compounds can be used to treat conditions where gastric acid is secreted excessively, such as gastric ulcers or peptic ulcers, or when treating allergic conditions where histamine acts as a known regulator. These compounds may be used alone or in combination with other active ingredients to treat an allergic or inflammatory condition such as dense.

Accordingly, the present invention provides a method for preparing a compound of formula (I), physiologically acceptable salts thereof, N-oxides and hydrates, and the like.

기로 가로막힌 저급알킬을 나타낸다;R ₁ and R ₂ in formula (I) are the same or different and are hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or oxygen atom.

Lower alkyl blocked with groups;

중에서 선택된 다른 이종원자를 함유하는 헤테로고리를 형성할 수도 있다;(R ₄ is hydrogen or lower alkyl) or R ₁ and R ₂ are attached to the nitrogen atom to oxygen and

It is also possible to form a hetero ring containing another hetero atom selected from among;

R ₃ is hydrogen, lower alkyl, lower alkenyl, or alkoxy alkyl;

X is -CH _2- , O, S;

Y represents = S, = O, = NR ₅ or = CHR ₆ ;

Alk represents C ₁ -C ₆ alkylene which is straight or condensed;

R ₅ is H, nitro, cyano, lower alkyl, aryl, alkylsulfonyl, arylsulfonyl;

R ₆ represents nitro, arylsulfonyl, alkylsulfonyl;

m is an integer from 2-4;

n is 1 or 2, where n is 0.1 or 2 when X is = S or -CH _2- .

When used in an alkyl group, the term "lower" means an alkyl group having 1-8 carbon atoms, and when used in an alkenyl group, an alkenyl group having 3-6 carbon atoms is preferably used.

The term "aryl" denotes a phenyl group, preferably phenyl or substituted by alkyl, alkoxy, halogen, or represents part of such a group.

The compounds according to the invention have the advantage of being easily prepared from readily available starting materials.

All compounds of formula (I) exhibit autotomerism, which includes all the tautomers. When Alk represents a branched alkylene group, an optical isomer exists, and this structural formula encompasses diastereomers and optical enantiomers.

A better class of compounds according to the invention is those having the following groups:

R ₁ and R ₂ represent hydrogen, alkyl, phenylalkyl, dialkylaminoalkyl, or both R ₁ and R ₂ have nitrogen atoms and are 5- or hexagonal saturated heterocycles, ie morpholino, piperidino , Pyrrolidino, N-alkylpiperazino and the like.

Alk represents straight chain C ₁ -C ₄ alkylene,

Y is = O, = S, = CHNO 2 or or R ₅ is a NR ₅ = hydrogen, nitro, cyano, lower alkyl, alkylsulfonyl, benzenesulfonyl.

X, m, n and R ₃ are made as described above.

A particularly good class of compounds according to the invention is those having the following groups:

R ₁ and R ₂ represent hydrogen, C ₁ -C ₃ alkyl, phenethyl or R ₁ and R ₂ both have a nitrogen atom to form a pyrrolidine ring.

Alk represents a C ₁ -C ₃ alkylene chain,

Y is = S, = CHNO ₂ or = NR ₅ where R ₅ is nitro, cyano, methylsulfonyl, benzenesulfonyl,

R ₃ is hydrogen, C ₁ -C ₃ alkyl, propenyl or C ₃ alkoxyalkyl,

n + m is 3 or 4,

X is as defined above.

As another good compound according to the present invention,

R ₁ and R ₂ are H, C ₁ -C ₃ alkyl, phenethyl or both R ₁ and R ₂ have a nitrogen atom to form a pyrrolidine ring,

Alk represents a C ₁ -C ₃ alkylene group,

Y is = S, = CHNO ₃ or = NR ₅ where R ₅ is nitro, cyano methylsulfonyl, benzenesulfonyl,

X is S or -CH _2- ,

R ₃ is hydrogen, methyl, methoxyethyl,

n is 1 and m is 2 or 3.

In addition, as the compound according to the present invention, particularly good ones

R ₁ is hydrogen, methyl, ethyl,

R ₂ is methyl, ethyl,

Alk represents a methylene group,

Y is = NCN, = NNO ₂ , = CHNO ₂ ,

R ₃ is hydrogen, methyl,

X is S or -CH _2-

n is 1 and m is 2.

Examples of particularly good compounds are;

N- (2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] methyl] -N'-methylthiourea

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methyl guanidine.

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine.

N-cyano-N '-[2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methylguadadine.

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine.

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '-(2-methoxyethyl) -2-nitro-1,1-ethenediamine.

N- [2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine.

N- [3-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethenediamine.

N- [2-[[[5- (ethylmethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-2-nitro-1,1-ethenediamine.

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-nitroguanidine.

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methanesulfonyl-N'-methyl guanidine.

N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-thiourea.

N-benzenesulfonyl-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylguanidine.

N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methyl-2-nitro-1,1-ethenediamine.

N-cyano-N '-[5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylguanidine.

N- [4- [5- (dimethylamino) methyl-2-furanyl] -butyl] -N'-methyl-2-nitro-1,1-ethenediamine.

N-cyano-N '-[4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methylguanidine.

N- [2-[[[5- [3- (dimethylamino) propyl] -2-furanyl] methyl] thio] -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-ethene Diamine.

Compounds according to the invention readily form physiologically acceptable salts. Such salts are salts of inorganic or organic acids, such as hydrochloride, addition salts of hydrochloric acid, sulfates.

Particularly useful as salts of organic acids are salts of aliphatic mono-di-carboxylic acids such as acetates, maleates and fumarates. These compounds may form hydrates. As pointed out, the compounds according to the invention also comprise N-oxides in which both R ₁ and R ₂ are not hydrogen.

The compounds according to the invention can be administered orally or topically or parenterally or in the form of suppositories, but a better method of administration is oral administration. They may also be used in the form of bases or physiologically tolerated salts. Generally, these compounds are mixed with pharmaceutically acceptable mediators or diluents to provide pharmaceutical compositions.

The compounds according to the invention can be administered in admixture with other active ingredients such as conventional antihistamines if necessary. In oral administration, pharmaceutical compositions are usually conveniently administered in the form of capsules or tablets, and the tablets may be slow release tablets. The composition may be in the form of dragees or syrups and suitable topical agents include ointments, lotions, creams, powders or sprays. A suitable daily dosage for oral administration is about 100 mg-1.2 g per day in the form of a glazing unit containing 20-200 mg per dosage unit. In the case of a soluble tablet, a suitable curing method is two to three times a day.

Parenteral administration may be by regular intervals or by continuous infusion and the injection may contain 10-100 mg / ml of active ingredient.

Topical agents include sprays, ointments, creams or lotions, and these compositions contain an effective amount of the active ingredient, and the active ingredient comprises 1.5-2% of the total composition by weight.

기를 도입할수 있는 화합물을 반응시켜 구조식(Ⅰ)의 화합물을 제조할수 있다.According to the present invention, the primary amine of the formula (II)

The compound of formula (I) may be prepared by reacting a compound capable of introducing a group.

기에서 R₃와 Y도 전술한 바와같다.In formula (II) R ₁ and R ₂ , n, X, m are as described above,

R ₃ and Y in the group are as described above.

기를 도입할수 있는 화합물은 R₃NCO 이소시안산염, R₃NCS 이소티오시안산염이나 구조식

또는

의 화합물로서 P는 이탈기이다.This amine is used in the form of a salt of a weak acid such as free base or acetic acid. Also

Compounds capable of introducing groups include R ₃ NCO isocyanate, R ₃ NCS isothiocyanate,

or

P is a leaving group.

의 경우에 반응은, 반응물을 섭씨 100-120도의 고온에서 용융시킴으로 일어나게 된다. 또한 아민(Ⅱ)와

의 반응은 질산은 이 존재하는 가운데 고온에서 아세토니트릴 같은 용매중에서 일어날수도 있으며, 아민(Ⅱ)와

를 실온에서 수용액 중에 교반시킴으로 일어날수도 있다.In the case of isocyanates or isothiocyanates, the reaction occurs by leaving the amine and isocyanate or isothiocyanate in a solvent such as acetonitrile,

In the case of the reaction occurs by melting the reactants at a high temperature of 100-120 degrees Celsius. Also with amine (II)

The reaction can occur in solvents such as acetonitrile at high temperatures in the presence of silver nitrate.

It can also occur by stirring in an aqueous solution at room temperature.

When R ₃ is hydrogen, cyanates and thiocyanates of alkali metals are used. The leaving group is halogen, thiomethyl, 3,5-dimethylpyrazoryl or alkoxy, preferably thiomethyl.

기의 도입은 먼저 아민(Ⅱ)와 다음 구조식의 화합물을 반응시킴으로 효과적일수도 있다.Also

The introduction of the group may be effective by first reacting the amine (II) with a compound of the structure

Where P is a leaving group as described above. This reaction is effective by refluxing in a solvent such as ether or acetonitrile at ambient temperature. The resulting compound of formula III is refluxed at ambient temperature and treated with primary amine R ₃ NH ₂ to afford the desired final product.

는 =NR₅나 =CHR₆를 나타낸다.In structural formula (III)

Represents = NR ₅ or = CHR ₆ .

Another method for preparing a product wherein Y is sulfur is isothiocyanate (IV) formed by heating an amine (II) with carbon disulfide and then reacting with a chloroformate ester such as ethyl chloroformate, preferably an alkanol solvent such as ethanol. In an amine R ₃ NH ₂ .

Alternatively, compounds wherein X is sulfur, n is 1, both R ₁ and R ₂ are hydrogen and Y is not = CHNO ₂ can be prepared from starting materials of formula (V) or formula (VI).

R ₇ in formula (V) is an acyl group such as hydrogen or acetyl or a P-nitrobenzoyl group.

If both R ₁ and R ₂ in the product are hydrogen, the product is protected as a phthalimido group in the compound of formula (V). Therefore, the compound is reacted with thiol of structural formula and then leaves the protecting group in a suitable step.

When the compound of formula (V) is used, the reaction is preferably carried out at 0 degrees Celsius with concentrated hydrochloric acid. When the compound of formula (VI) is used, the reaction is carried out in a holding solvent such as dimethylformamide at room temperature.

Chloromethyl compound (VI) can be prepared from similar alcohols using thionyl chloride or cyclohydrochloric acid.

Products in which Y is an NCN group may be prepared by heating the compound of formula (I) in which Y is sulfur, in an aqueous solution, preferably with an intermediate rate of cyanamide such as silver, lead, cadmium or mercury.

In addition, compounds in which Y is NR ₅ and Alk is a methylene group or a branched alkylene group may be formed by a Mannich reaction using a suitable aldehyde and a secondary amine or a salt of a primary amine or a secondary amine. It can be prepared from the compound of.

For example, (CH ₃ ) ₂ NCH ₂ -groups can be introduced using dimethylamine and formaldehyde. This reaction can be carried out by reacting the amine salt with the compound of formula with aqueous solution of formaldehyde or refluxing the amine salt with the compound of formula with paraformaldehyde.

In the course described above the effective methods for preparing the compounds according to the invention have been discussed the primary amines of formula (II). These compounds are novel and the present invention also includes a method for producing these compounds. These intermediates can be prepared by several methods, such as:

An amine of formula (II) wherein X is S and n is 1 may be prepared by reacting furfurylthiol of formula (VII) with ω-bromo alkyl phthalimide of formula (X).

기를 생성된 구조식(ⅩⅠ)의화합물 안으로 도입시킨다.By the Mannich reaction

Is introduced into the compound of formula (XI).

Reaction with hydrazine hydrate is then removed to form the amine of formula (II).

In another method for preparing amines of formula II wherein X is S and n is 1, 2-furfuryl chloride can be used as starting material.

Reaction of ω-aminoalkylthiol in which the amine group is protected as phthalimide (XII) with furfuryl chloride forms an intermediate of formula (XI). Treatment of this as described above gives an amine of formula (II).

In another method for preparing amine (II) wherein X is S and n is 1, the starting material of formula (XIII) is used.

This compound is treated with ω-aminoalkylthiol in an acidic state. If desired, the amine group may be protected.

Alternatively, the compound of formula (XIII) may be converted into a similar acetate salt in the basic state before reacting with ω-aminoalkylthiol.

The primary amine of formula (II) (except X = S and n = 0) reacts furan with lithium butyl to produce a thiothio derivative (IV), followed by α, ω-dihalo-compound Hal (CH ₂ ) NX (CH ₂ ) m Hal (Hal is reacted with chlorine, bromine, iodine) and treated with (i) potassium phthalimide to give (ii) the reaction product of formula (VV). Prepared by reacting with Mannich and reacting with hydrazine hydrate to remove the protecting group.

Intermediates in which X is S and n is 0 react with the furan of the structural formula (XVI) in which R ₁ and R ₂ are not hydrogen with lithium and sulfur atoms and with w-bromoalkylphthalimide (X) The compound of (iii) can be prepared by reacting with hydrazine hydrate to remove the protecting group.

In order to prepare an intermediate in which X is an oxygen atom and n is 1, a Hal (CH ₂ ) m NH ₂ compound in which Hal represents a halogen atom, preferably chlorine, in the presence of a base such as tertiary potassium butoxide in a solvent such as dimethylformamide What is necessary is just to react with alcohol of a structural formula (XIII).

Intermediates of formula (II) wherein m is 2 and X is sulfur or oxygen can be prepared by reacting ethyleneimine with a compound of formula (XIII) or an isotropic thiol.

In addition, the amine of the formula (II) can be prepared using the compound of the formula (n) in which n, m, and X have been described as starting materials.

기를 도입할수도 있으나 가급적 이 반응은 구조식(ⅩⅨ)이나 (ⅩⅩ)의 화합물을 가지고 행하는 것이 좋다.The nitrile compound was reacted with Mannich and reduced with LiAlH ₄ to prepare a compound of formula II. When using the Mannich reaction,

A group may be introduced, but preferably this reaction is carried out with a compound of formula (VII) or (VII).

The Mannich reaction using suitable aldehydes and amines is used to prepare compounds in which Alk represents methylene or branched alkylene groups, especially formaldehyde when Alk is methylene.

In another method for preparing compounds wherein Alk is methylene, furan-2-carboxylic acid is used as starting material. This compound is reacted with an amine of the formula R ₁ R ₂ NH to reduce the amide of the formula (XI) to LiAlH ₄ to prepare a compound of the formula (XI).

In order to convert the compound of formula (XII) into the compound of formula (XIII), hydroxymethyl group is introduced using formaldehyde and acetic acid.

If both R ₁ and R ₂ are hydrogen, the amino group is protected as a portalamide during hydroxymethylation.

Indeed the deprotection reaction is effective by using hydrazine hydrate.

In the case where both R ₁ and R ₂ are not hydrogen, hydroxymethylation is effective by using lithium butyl and by adding formaldehyde.

When Alk is a C ₂ or higher straight chain alkylene group, the following two methods are suitable.

One convenient method is used to prepare ethylene derivatives similar to the methylene derivatives above using carboxylic acids (XIII) instead of furan-2-carboxylic acids.

When the alkylene chain, i.e., Alk is C ₂ or more, the thiothio derivative of structure (XIV) is treated with dihaloalkane of the structure Hal Alk Hal wherein Hal is chlorine, bromine or iodine and (iii) amine R ₁ R ₂ NH (Ii) to prepare a compound of formula (XIV) wherein Alk is C ₃ -C ₆ .

When R ₁ and R ₂ are hydrogen, the amine R ₁ R ₂ NH is substituted with potassium phthalimide in both reactions. The product of both reactions is hydroxymethylated as described above, leaving the protecting group in a suitable step to prepare a compound of formula (XIII).

If R ₁ is intended to yield a compound in which R ₂ is not hydrogen, the dimethylamino compound is converted to an appropriate substituted amino group by the Eschweiler Clarke method using formaldehyde and phlomic acid. May be obtained but it is preferred to use substituted amines at appropriate stages of the reaction.

An amine of formula II wherein n is 2 can be prepared by using as a starting material a compound of formula IV wherein Z is a leaving group, i.e., tosioxy, mesoxyoxy or bromine.

The compound is reacted with the ω-phthalimido-alkylthiol of the structural formula (XIII) to react with the resulting compound and leaving the protecting group to produce an amine of the desired structural formula (II).

During the preparation of the compounds of the invention, compounds of formula (V) can be reacted with thiols of formula (VII) wherein Y is = CHNO2.

The compound of formula IV wherein Y = CHNO ₂ and m is 2 may be prepared by reacting the thiazolidine intermediate of formula IV with the amine R ₃ NH ₂ . Thiazolidine (XV) is prepared from cysteamine and bismethylthio compound (XVI).

Thiols of formula (VII) wherein Y is = CHNO ₂ and m is 2 are novel compounds and the present invention also includes methods for preparing these compounds.

In order to better understand the present invention, the following examples are described. Preparation Methods 1-4 describe methods for preparing starting materials, Example AL is an example of a method for preparing amines of formula (II) and related intermediates, and Examples 1-32 are compounds of formula (I). The preparation method of is described and Example 33 is an example of preparation of a pharmaceutical composition.

[Manufacturing Method 1]

(a) 5- (methylamino) methyl-2-furanmethanol

A mixture of 2-furanmethanol (49 g), methylamine hydrochloride (51.5 g) and 36% formaldehyde solution (50 mL) was stirred at 0-3 degrees Celsius for 3 hours and allowed to stand for 16 hours. Excess sodium carbonate was added thereto and the slurry was extracted with ethyl acetate.

After removing the solvent, the residue was distilled off to collect 5- (methylamino) methyl-2-furanmethanol (36.2 g).

Boiling point; 111-113 degrees Celsius (0.2 mmHg).

From the amine hydrochloride similar to 2-furanmethanol the following materials were prepared in the same manner.

(b) 5-[(2-phenylethyl) amino] methyl-2-furanmethanol. Oil.

Rf; 0.45 (silica / acetone)

NMR (CCl ₄ ) 7.29, br. S (4H); 6.8 s (2H); 6.40 s (2H); 5.62 s (2H); 4.0 br (2H); 2.87 s (5H).

(c) 5-[(1-methylethyl) amino] methyl-2-furanmethanol. Oil.

Rf; 0.55 (silica / methanol)

Analysis measured value; C, 63.55; H, 8/78; N, 8.09.

Calculated C ₉ H ₁₅ NO ₂ ; C, 63.88; H, 8.94; N, 8.28%.

(d) 5- (ethylmethylamino) methyl-2-furanmethanol.

Rf; 0.32 (silica / acetone)

NMR (CDCl ₃ ) 8.93t (3H); 7.80 s (2H); 7.55q (2H); 6.05 s (2H); 6.33br. s (1H); 5.47 s (2H); 3.80 (2 H).

(e) 5 [[(2-dimethylamino) ethyl] amino] methyl-2-furan-methanol bismaleate.

Melting point; 119-121 degrees celsius

[Manufacturing Method 2]

5- [2- (N, N-dimethylamino) ethyl] -2-furanmethanol

N, N-dimethyl-2-furanethanamine (9.8 g), 30% aqueous formaldehyde solution (17.5 g) and glacial acetic acid (18 ml) were heated at a temperature of 70 degrees Celsius for 5 hours. The reaction was cooled, basified by addition of sodium hydroxide and extracted with ether. The organic extract was distilled off to collect the oily material.

Boiling point; 90-100 degrees centigrade

Analysis measured value; C, 64.C; H, 8.9; N, 8.0

Calculated C ₉ H ₁₅ NO ₂ ; C, 63.9; H, 8.9; N, 8.2%

[Manufacturing Method 3]

2 [1- (4-bromobutyl)] furan

N-lithium butyl (375 mL) dissolved 1.6 M in hexane was added to a dry tetrahydrofuran (375 mL) solution containing furan (40.8 g). The mixture was stirred at 40 degrees Celsius for 3 hours, then 1,4-dibromobutane (129.6 g) was added at -30 degrees Celsius and the reaction was stirred at room temperature for 4 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The obtained extract was distilled off to obtain a clear colorless liquid.

Boiling point; 60-62 degrees Celsius (0.5mmHg)

N, N-dimethyl-4- (2-furanyl) butanamine

Dimethylamine (56 g) was added to a toluene (500 mL) solution containing 2- [1- (4-bromobutyl)] furan (82 g). The solution was stirred at room temperature for 2 days and made acidic by addition of hydrochloric acid.

The acid layer was separated, washed with ether, made basic by addition of sodium hydroxide and extracted with ether. The ethereal extract was distilled off to obtain a colorless transparent oily substance.

Boiling point; 55-58 degrees Celsius (0.8mmHg)

Melting point of hydrochloride; 133-136 degrees celsius

Analysis observed; C, 59.01; H, 9.02; N, 6.87

Calcd for C ₁₀ H ₁₇ NO · HCl; C, 58.96; H, 8.91; N, 6.88%

5- [4- (dimethylamino) butyl] -2-furanmethanol

(a) Dry tetrahydrofuran (125 ml) containing 1.6 mol of n-lithium butyl (125 ml) dissolved in n-hexane containing N, N-dimethyl-4- (2furanyl) butanamine (33.4 g) Cold solution was added.

The mixture was stirred at room temperature for 4 hours, paraformaldehyde (6.0 g) was added thereto, and the mixture was further stirred for 1 hour. The reaction was cooled with water, extracted with chloroform, and the oil and fat extract was distilled to collect the colorless transparent oily compound.

Boiling point; 100-105 degrees Celsius (0.1 mmHg).

Melting point; 26-28.5 degrees Celsius

Analysis measured value; C, 67.09; H, 10.01; N, 7.06

Calcd for C ₁₁ H ₁₉ NO ₂ ; C, 66.97; H, 9.71; N, 7.10%

Prepared in the same manner;

(b) 5- [3- (dimethylamino) propyl] -2-furanmethanol

Boiling point; 160 degrees Celsius (0.08mmHg)

Melting point; 24 degrees celsius

Analysis observed; C, 64.66; H, 9. 36; N, 7.39

Calcd for C ₁₀ H ₁₇ NO ₂ , 1 / 5H ₂ O; C, 64.28; H, 9.39; N, 7.50%

[Manufacturing Method 4]

Acetic acid [5- [4-N, N-dimethylamino] butyl] -2-furanylmethyl

A mixture of 5- [4- (dimethylamino) butyl] -2-furanmethanol (4.9 g), acetic anhydride (25 g), molten powdered sodium acetate (10 g), and benzene (25 mL) was stirred at room temperature for 24 hours. It was.

The reaction was diluted with water (100 mL) and extracted with ethyl acetate. The extract was distilled off to collect the colorless transparent oily material.

Boiling point; 100 degrees Celsius (0.5mmHg)

Analysis observed; C, 65.72; H, 9.03; N, 5.95

Calcd for C ₁₃ H ₂ 1NO ₃ ; C, 65.24; H, 8.85; N, 5.85%

Example A

(a) 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine

It was stirred while dropping 5- (dimethylamino) -methyl-2-furan methanol (15.5 g) into concentrated hydrochloric acid (40 mL) ice-cooled solution containing cysteamine hydrochloride (11.36 g).

After standing for 18 hours at 0 degrees Celsius, excess anhydrous sodium carbonate was added thereto and the resulting solid was extracted with diethyl ether. The residue was distilled off to remove the solvent, and 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (11.6 g) was collected.

Boiling point; 104-106 degrees Celsius (0.1mmHg)

Melting point of pictrates; 142-144 degrees celsius

Identically prepared from similar furanmethanol and cysteamine hydrochloride;

(b) 2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] -ethanamine

Melting point of monofractate; 142-144 degrees celsius

(c) 2-[[[5- (1-methylethyl) amino] methyl-2-furanyl] methyl] thio] -ethanamine. Oil.

Rf; 0.4 (Silica / Methanol: 0.880 Ammonia 79: 1)

(d) 2-[[[5- (diethylaminomethyl) -2-furanyl] methyl] thio] -ethanamine.

Boiling point; 134-135 degrees Celsius (1mmHg)

(e) 2-[[[5- (1-piperidinyl) methyl-2-furanyl] methyl] thio] -ethanamine. Oil.

Rf; 0.37 (silica / methanol: 0.880 ammonia 79: 1)

(f) 2-[[[5- (aminomethyl) -2-furanyl] methyl] thio] -ethanamine.

Melting point of dihydrochloride; 222-224 degrees Celsius (decomposition).

(g) N [-5-[[[(2-aminoethyl) thio] methyl] -2-furanyl] methyl]-benzene ethanamine oil.

Rf; 0.33 (silica / methanol: 0.880 ammonia 79: 1)

(h) 2-[[[5- (2-dimethylamino) ethyl] -2-furanyl] methyl] thio] -ethanamine.

Boiling point; 150-155 degrees Celsius (0.44mmHg)

(i) 2-[[[5- (3-dimethylamino) propyl] -2-furanyl] methyl] thio] -ethanamine.

Boiling point; 150 degrees Celsius (0.05mmHg)

(j) 2-[[[5- (ethylmethylamino) methyl] -2-furanyl] methyl] thio] -ethanamine.

Rf; 0.34 (silica / methanol: 0.880 ammonia 79: 1)

(k) 2-[[[5- (2-dimethylaminoethyl) imino] methyl-2-furanyl] -methyl] thio] ethanamine.

Melting point of trimaleate; 132-135 degrees celsius

(l) 2-[[[5- (1-pyrrolidino] methyl-2-furanyl] methyl] thio] -ethanamine.

Melting point of bisoxalate; 136.5-138.5 degrees Celsius

Example B

2-[[[5- (4-dimethylamino) butyl-2-furanyl] methyl] thio] -ethanamine

Cysteamine hydrochloride (4.5 g) was added to a dry dimethylformamide (125 mL) cold solution containing potassium tert-butoxide (8.98 g). The mixture was stirred for 20 minutes and then acetic acid [5- [4- (dimethylamino) butyl] -2-furanyl] methyl (9.6 g) was added. The reaction was heated at 90 ° C. for 4 hours, poured into a mixture of ice and water, and extracted with chloroform to distill the organic extract to give yellow oil. Tube chromatography on silica using methanol / 0.880 ammonia (9: 1) as eluent was followed by further distillation to give a colorless oil.

Boiling point; 140 degrees Celsius (0.05mmHg)

Analysis observed; C, 60.81; H, 9. 86; N, 10.44

Calcd for C ₁₃ H ₂₄ N ₂ OS; C, 60.91; H, 9.94; N, 10.93%

Example C

2-[[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H) dione

To a dry dimethylformamide solution containing 2-phthalamido-ethanol (1.03 g), 80% sodium hydride (0.115 g) was added dropwise at 0 degrees Celsius. After 20 minutes, a dry dimethylformamide solution containing 2-furanethanol and 4-methylbenzenesulfonate (1.33 g) was added dropwise thereto and the solution was stirred overnight at room temperature. The mixture was poured into an ice-water solution to separate white solid 2-[[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H) -dione (1.3 g). .

Melting point; 53-55 degrees celsius

Example D

(a) 2- [2-[[(2-furanyl) methyl] thio] ethyl-1H-isoindole-1,3 (2H) -dione

80% sodium hydride (1.58 g) was added dropwise to a dry dimethylformamide (50 mL) solution containing furfuryl mercaptan (6 g). After 30 minutes, 2-bromoethyl phthalamide (16.71 g) solution was added to dry dimethylformamide (65 mL) and the solution was heated at 100 degrees Celsius for 2 days.

After removal of the solvent the residue was washed with water and extracted with ethyl acetate.

The solvent was removed from the obtained ethyl acetate extract and the residue was recrystallized from cyclohexane to give 2- [2-[[(2-furanyl) methyl] thio] ethyl-1H-isoindole-1,3 (2H) -dione ( 7.8 g) was obtained.

Melting point; 62-63 Celsius

those prepared identically from ω-bromoalkylphthalimide and frucrylmercaptan;

(b) 2- [3-[[(2-furanyl) methyl] thio] propyl] -1 H-isoindole-1,3 (2H) -dione

NMR (CDCl ₃ ) 7.7-8.3 m (2H); 7.2-7.7 m (2H); 6.29 s (2H); 6.23 t (2H); 3.7 m (2H); 2.7 m (1 H); 2.4 m (4 H).

(c) 2- [4-[[(2-furanyl) methyl] thio] butyl] -1 H-isoindole-1,3 (2H) -dione,

NMR (CDCl ₃ ) 8-8.5 m (4H); 7.49 t (2H); 6.33 m (4 H); 3.7n (2H); 2.7 m (1 H); 2.3 m (4H).

Example E

(a) 2- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio-ethyl-1H-isoindole-1,3 (2H) -dione. Acetic acid (50 mL) with 36% formaldehyde solution (3 mL) and 2- [2-[[(2-furanyl) methyl] thio] ethyl] -1 H-isoindole-1,3 (2H)- A mixture of dione (10 g), dimethyl ammonium chloride (3.1 g) was heated on a steam bath for 9 hours.

The solution was cooled and the solvent removed in vacuo. 5N sodium hydroxide was added to the residue to make basic and extracted with ethyl acetate. The organic phase was treated with activated charcoal, dried and evaporated to purify by column chromatography (silica / ethanol: ethyl acetate 1: 1) to collect oil (5.7 g).

Rf; 0.4

NMR (DCDL ₃ / DMSO) 7.71 s (6H); 7.22 t (2H); 6.52 s (2H); 6.2 s (2H); 6.1 t (2H); 3.8 m (2H); 2.2 m (4 H).

Amines similar to 2- [ω-[[[(2-furanyl) methyl] thio] -alkyl] -1H-isoindole-1,3-dione, which are prepared equivalently from formaldehyde;

(b) 2- [2-[[[5- (1-pyrrolidinyl) methyl] -2-furanyl] methyl] thio] -ethyl-1H-isoindole-1,3 (2H) -dione.

NMR (CDCl ₃ ) 8-8.4 m (4H); 7-7.6 m (6H) 6-6.5 m (6H); 3.7-4.0 m (2H); 2-2.4 m (4H).

(c) 2- [3-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] -propyl-1H-isoindole-1,3 (2H) -dione.

Rf; 0.45 (silica / methanol)

(d) 2- [4-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] -butyl] -1 H-isoindole-1,3 (2H) -dione

Rf; 0.26 (silica / methanol)

(e) 2- [2-[[[5- (4-methyl-1-piperazinyl] methyl] -2-furanyl] -methyl] thio] ethyl] -1 H-isoindole-1,3 (2H ) -Dion.

NMR (CDCl ₃ ) 7.75 s (3H); 7.52 s (8H); 7-7.5 m (2H); 6.5 s (2H) 6-6.3 m (4H); 3.85 m (2 H); 2-2.4 m (4H).

(f) 2- [2-[[[5- (4-morpholinyl) methyl] -2-furanyl] methyl] thio] -ethyl] -1H-isoindole-1,3 (2H) -dione

NMR (CDCl ₃ ) 7.54 m (4H); 7.24 m (2 H); 6.50 s (2H); 6.22 m (6 H); 3.8 m (2H); 2.0-2.4 m (4H).

Example F

2- [2-[[2- [5- (dimethylamino) methyl-2-furanyl] ethyl] thio] ethyl] -1 H-isoindole-1,3 (2H) -dione

2-[[2- (2-furanyl) ethyl] thio-1H-isoindole-1,3 (2H) -dione (0.5 g), dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) Heated under reflux in ethanol.

After 5 hours, dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were added thereto and heating continued for 16 hours. The solvent was removed and the residue was made basic and extracted with ethyl acetate to give an oil. This was subjected to tube chromatography (silica / methanol) to give 2- [2- [5- (dimethylamino) methyl-2-furanyl] ethyl] thio-ethyl] -1H-isoindole-1,3 (2H) as a pale oil. Dione (0.43 g) was collected.

Analysis observed; C, 61.48; H, 6. 13; N, 7.63

Calcd. For C ₁₉ H ₂₂ N ₂ O ₃ S.3 / 4H ₂ O; C, 61.35; H, 6. 37; N, 7.53%

Example G

2-[[5- (dimethylamino) methyl-2-furanyl] methoxy] ethanamine

Method

Tetrahydrofuran (40 ml) containing methanesulfonic acid (11.6 g) was added to a dry tetrahydrofuran solution containing 5- (dimethylamino) methyl-2-furanmethanol (6.2 g) and ethyleneamine (2.82 g). It was. The solution was evaporated and the oily residue was heated at 98-100 degrees Celsius for 10 minutes.

After 18 hours, 5N sodium hydroxide (60 mL) was added and after 2 hours the suspension was filtered, treated with decolorized activated carbon and evaporated.

The resulting oil was chromatographed first with methanol-ammonia 0.88 at 79: 1 and the eluate was discarded. Next, the eluate chromatographed with methanol-ammonia 0.88 at 19: 1 was evaporated to obtain an oil. 0.2 g of bis-oxalate (obtained from ethanol) of [5- (dimethylamino) methyl-2-furanyl] methoxy] -ethanamine was obtained.

Melting point; 125-128 degrees celsius

Method (ii)

2-chloroethylamine hydrochloride while stirring dry dimethylformamide cold solution containing potassium tert-butoxide (8.96 g) and 5- (dimethyl-amino) methyl-2-furanmethanol (12.4 g) (6.25 g) was added dropwise a dry dimethyl formamide solution.

After 2 hours the solvent was removed and the residue was made basic and extracted with ethyl acetate. After removal of the solvent the residue was treated with ethanol oxalic acid in ethanol.

The resulting crystalline salt was recrystallized in ethanol to give 2-[[5- (dimethylamino) methyl-2-furan) methoxy ethanamine (3.05 g).

Melting point of bisoxalate; 130-133 degrees celsius

Prepared identically by method (ii);

(b) 2-[[5- (methylamino) methyl-2-furan] methoxy] ethanamine,

Melting point of bisoxalate; 162-164 degrees Celsius

Example H

(a) 2- [4- (2-furanyl) butyl] -1 H-isoindole-1,3 (2H) -dione

2 [1- (4-bromobutyl)] furan (406 mg) and potassium phthalimide (370 mg) were stirred in dry dimethylformamide overnight at room temperature.

The solution was poured into ice-water, the resulting white solid was filtered and dried, and then recrystallized in chloroform / petroleum ether (60-80 degrees C. boiling point) to give a white microcrystalline 2- [4- (2- Furanyl) butyl] -1H-isoindole-1,3 (2H) -dione (430 mg) was obtained.

Melting point; 61-63 Celsius

Prepared in the same manner;

(b) 2- [5- (2-furanyl) pentyl] -1 H-phosphoindole-1,3 (2H) -dione

Melting point; 54-56 degrees celsius

Example I

(a) 2- [4- (5- (dimethylamino) methyl-2-furanyl-butyl] -1 H-isoindole-1,3 (2H) -dione

2- [4- (2-furanyl) butyl] -1H-isoindole-1,3 (2H) -dione (5.38 g), paraformaldehyde (1.2 g) and dimethylamine hydrochloride (3.26 g) It was refluxed in (100 mL). After 6 hours, paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and heating continued for 20 hours.

The solvent was evaporated and 5N sodium hydroxide was added to the residue to make it highly basic, extracted with ethyl acetate, and the organic layer was evaporated. The crude product was purified by tube chromatography to give amber oil (3.25 g).

Rf; 0.4 (silica / methanol)

NMR (CDCl ₃ ) 8-8.6 m (4H); 7.75 s (6 H); 7.3 m (2H); 6.55 S (2 H); 6.3 m (2H); 1.9-2.4 m (4H).

As prepared in the same manner;

(b) 2- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl-1H-isoindole-1,3 (2H) -dione

TLC Rf; 0.4 (silica / methanol)

NMR 8.0-8.8 m (6H); 7.70 m (6 H); 7.37 t (2 H); 6.52 s (2H); 6.30 t (2 h); 4.0 m (2H); 2.2 m (4 H).

Example J

5- (dimethylamino) methyl-2-furanpropanamine

Furanpropionitrile (1.21 g), dimethylamine hydrochloride (1.62 g), paraformaldehyde (0.7 g) and ethanol (20 mL) were heated to reflux for 24 hours.

The solvent was removed and the residue was brought to pH 12 and extracted with ethyl acetate. After the solvent was removed, the remaining oil was purified by column chromatography (silica / methanol) to separate 5- (dimethylamino) -methyl-2-furanpropionitrile (0.6 g).

Rf; 0.55 (silica / methanol).

Dry ether (40 ml) containing nitrile (6.0 g) was added dropwise to ether containing lithium aluminum hydride (2.0 g) and stirred at 0 degrees Celsius. Water was added, the solvent was removed, and the residue was subjected to column chromatography to give 5- (dimethylamino) -methyl-2-furanpropanamine (3.33 g) as a pale oil.

NMR (CDCl ₃ ) 8.2 m (2H); 7.6 br (2H); 7.75 s (6 H); 7.30 m (4 H); 6.60 s (2 H); 4.0 m (2 H).

Example K

2- [3-[[[5- (dimethylamino) methyl-2-furanyl] thio] propyl]]-1H-isoindole-1,3 (2H) -dione

Sulfur (1.9 g) was added dropwise at -40 degrees Celsius to a solution of a thio derivative of N, N-dimethylfuran methaneamine (75 g). The mixture was stirred at -10 degrees Celsius for 20 minutes and 2- (3-bromopropyl) -1H-isoindole-1,3 (2H) -dione (16 g) was added. The mixture was left overnight at 0 degrees Celsius, the solvent was removed in vacuo and the residue in ethyl acetate was filtered off and extracted with 2N sulfuric acid. The aqueous layer was basified, reextracted with ethyl acetate and the organic layer was dried. The crystalline solid obtained by removing the solvent was recrystallized from ethanol (activated carbon) to give 2- [3-[[5- (dimethylamino) -methyl-2-furanyl] thio] propyl]]-1H-isoindole-1,3 (2H) -dione (7.59 g) was obtained.

Melting point; 64-65 degrees celsius

Example L

(a) 4- [5- (dimethylamino) methyl-2-furanyl] butanamine

2-[[4- (5-dimethylamino) methyl-2-furanyl] butyl-1H-isoindole-1,3 (2H) -dione (2.9 g) and hydrazine hydrate (0.5 mL) in ethanol for 6 hours At reflux. The crystalline residue obtained by removing the solvent was dissolved in 5N sodium hydroxide solution, which was extracted with ethyl acetate, and then the solvent was removed to give a yellow mobile oil (1.68 g). A single point appeared at the position where the R _f value was 0.15. (TLC Silica / Methanol)

NMR (CDCl ₃ ) 8.0-8.8 m (4H); 7.7 s (6H); 7.6 br (2H); 7.3 m (4H); 6.548 s (2H); 4.0 m (2 H).

Identically prepared from similar phthalimides;

(b) 5- [5- (dimethylamino) methyl-2-furanyl] pentanamine

NMR (CDCl ₃ ) 8.0-8.8 m (6H); 7.75 s (6 H); 7.0-7.6 m (2H); 4.0 m (2 H).

(c) 5-[[[(3-aminopropyl) thio] methyl] -N, N-dimethylfuran-2-methanamine

MNR (CDCl ₃ ) 8-8.5 m (2H); 7.57 s (6H); 7.42 t (2H); 7.25 m (2 H); 6.58 s (2H); 6.3 s (2H); 3.88 s (2H).

Example 1

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methylthiourea

2- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl-1H-isoindole-1,3 (2H) -dione (5.3 g) with hydrazine hydrate (0.85 g) was refluxed in ethanol for 30 minutes. The solvent was evaporated to give the phthalhydrazide salt of 2 [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine.

This salt (1 g) was suspended in acetonitrile and methyl isothiocyanate (0.21 g) was added. The suspension was stirred for 5 hours at room temperature, stirred for 2 hours at 60 degrees Celsius, filtered and evaporated, and the oil obtained by purification was purified by tube chromatography (silica / methanol) to give a pale oil, N-2-[[[5- Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methylthiourea (0.3 g) was isolated.

Analysis observed; C, 49.68; H, 7.52; N, 14.22

Calcd for C ₁₂ H ₂₁ N ₃ OS ₂ ; C, 50.14; H, 7.37; N, 14.62%

To be prepared in the same way;

(b) N-methyl-N '-[2-[[[5- (1-pyrrolidinyl) methyl-2-furanyl] methyl] thio] ethyl] thiourea

Analysis observed; C, 52.33; H, 7. 12; N, 13.17

Calcd for C ₁₄ H ₂₃ N ₃ OS ₂ 1 / 2H ₂ O; C, 52.14; H, 7. 50; H, 13.03%

(c) N- [4-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] butyl] -N'-methylthiourea

Analysis observed; C, 51.69; H, 8.53; N, 12.83

Calcd for C ₁₄ H ₂₅ N ₃ OS ₂ ; C, 51.82; H, 8.08; N, 12.95%

(d) N- [3-[[5- (dimethylamino) methyl-2-furanyl] thiopropyl] -N'-methylthiourea

Analysis observed; C, 49.71; H, 7.33; N, 14.35

Calcd for C ₁₂ H ₂₁ N ₃ OS ₂ ; C, 50.10; H, 7. 30; N, 14.62%

(e) N-methyl-N '-[2-[[[5- (4-morpholinyl) methyl] -2-furanyl] methyl] thio] ethyl] thiourea

Analysis observed; C, 51.26; H, 7.08; N, 12.51

Calcd for C ₁₄ H ₂₃ N ₃ O ₂ S ₂ ; C, 51.03; H, 7.04; N, 12.75%

(f) N-methyl-N '-[2-[[[5-[(4-morpholinyl) methyl] -2-furanyl] methyl] thio] ethyl] thiourea

Analysis observed; C, 50.93; H, 7. 74; N, 15.82

Calcd for C ₁₅ H ₂₆ N ₄ OS ₂ ; C, 51.25; H, 8.03; N, 15.94%

(g) N- [2-[[2- [5- (dimethylamino) methyl-2-furanyl] ethyl] thio] ethyl] -N'-methylthiourea

Analysis observed; C, 50.19; H, 7. 20; N, 13.18

Calcd for _{C 13 H 23 N 3 O 2} O · 1 / 2H 2 O; C, 50.32; H, 7. 74; N, 13.54%

Example 2

(a) N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylthiourea

5- [5- (dimethylamino) methyl-2-furanyl] pentanamine (0.5 g) and methyl isothiocyanate (0.25 g) were stirred in acetonitrile at room temperature for 24 hours. The solvent was removed and the product was purified by column chromatography (silica / methanol) and triturated with ether to give the off-white crystals N-5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N '. -Methylthiourea was obtained.

Melting point; 66-69 degrees Celsius

Identically prepared from similar amines and methyl isothiocyanate;

(b) N- [3-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -propyl] -N'-methylthiourea

Analysis observed; C, 51.38; H, 7.93; N, 13.41

Calcd for C ₁₃ H ₂₃ N ₂ OS ₂ ; C, 51.79; H, 7.69; N, 13.94%

(c) N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methylthiourea

NMR (CDCl ₃ ) 8-8.6 m (4H) 7.22 S (6H); 7.35 t (2 H); 6.98 d (3 H); 6.2-6.8 m (4H); 4.0d (2H); 3-3.8 m (2 H).

(d) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methoxy] ethyl] -N'-methylthiourea

Analysis observed; C, 51.91; H, 8.14; N, 14.98

Calcd for C ₁₂ H ₂₁ N ₃ O ₂ S.1 / 2H ₂ O; C, 51.40; H, 7.91; N, 14.99%

Example 3

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N '-(2-methoxyethyl) thiourea)

1- (isothiocyanato) -2-methoxyethane (1.17 g) and 2-[[[(5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine (2.14 g) The solvent was removed and the residual oil was chromatographed (silica / methanol) to give N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] as a pale oil. Ethyl-N '-(2-methoxyethyl) thiourea was obtained.

Rf: 0.45

Analysis observed; C, 50.64; H, 7.51; N, 12.69

Calcd for C ₁₄ H ₂₅ N ₃ O ₂ S ₂ ; C, 50.75; H, 7.55; N, 12.68%

Prepared identically from similar isothiocyanates and 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine;

(b) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '-(2-propenyl) thiourea

Analysis observed; C, 52.68; H, 7. 58; N, 13.16

Calcd for C ₁₄ H ₂₃ N ₃ OS ₂ 1 / 2H ₂ O; C, 52.14; H, 7. 50; H, 13.03%

(c) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N- (1-methylethyl) thiourea

Analysis observed; C, 51.84; H, 7.88; N, 13.00

Calcd for C ₁₄ H ₂₅ N ₃ OS ₂ 1 / 2H ₂ O; C, 51.90; H, 8.09; N, 12.97%

Example 4

N- [2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methylurea

Acetonitrile (24 mL) solution containing 2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine (1.5 g) was added thereto while stirring with methyl isocyanate (0.45 g). Acetonitrile (15 mL) solution containing d) was added dropwise. After 30 minutes, the solution was evaporated to dryness. The oil obtained was first chromatographed on silica / methanol: 0.88 ammonia 79: 1 phase and then tube chromatography on alumina / methanol to give N- [2-[[[5- ( An oil consisting of methylamino) methyl-2-furanyl] -methyl] thio] ethyl] -N'-methylurea (0.25 g) was obtained.

Analysis observed; C, 51.00; H, 7.38; N, 15.91

Calcd for C ₁₁ H ₁₉ N ₃ O ₂ S; C, 51.33; H, 7.44; N, 16.33%

Example 5

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methylurea

Methyl isocyanate in the suspension of acetonitrile (50 mL) containing 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethaneamine and phthalhydrazide complex (2 g) (0.33 g) was added. After 2 hours, the solution was filtered and the filtrate was evaporated. The oil obtained was purified by tube chromatography (silica / methanol) and purified by N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl]. Thio] ethyl] -N'-methylurea was obtained.

Analysis observed; C, 52.38; H, 77.61; N, 15.25

Calcd for _{C 12 H 21 N 3 O 2} S · 1 / 4H 2 O; C, 52.24; H, 7.76; N, 15.32%

To be prepared in the same way;

(b) N-methyl-N '-[2-[[[5- (1-pyrrolidinyl) methyl-2-furanyl] -methyl] thio] ethyl] urea

Analysis observed; C, 54.70; H, 7.33; N, 14.07

Calcd for _{C 14 H 23 N 3 O 2} S · 1 / 2H 2 O; C, 54.87; H, 7.89; N, 13.71%

Example 6

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N '-(1-methylethyl) urea

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine (2.14 g) and isopropyl isocyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. The solvent was removed and the residue was recrystallized from methanol: ether to give the crystals N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '-(1-methyl Ethyl) urea (2.8 g) was obtained.

Melting point; 65-67 degrees Celsius

To be prepared in the same way;

(b) N- [3-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N'-methylurea

Melting point; 69-69.5 degrees Celsius

Example 7

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] urea

Dihydrochloric acid 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (2.8 g), potassium cyanate (3.75 g) and water (50 mL) for 8 hours on a steam bath Heated. Excess sodium carbonate solid was added and the organics were extracted successively with diethyl ether. The extract was evaporated and the residue was chromatographed to give a lead-like solid N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] urea (1.28 g). Got.

Analysis observed; C, 48.22; H, 7.50; N, 15.61

Calcd for C ₁₁ N ₁₉ N ₃ O ₂ SH ₂ O; C, 48.00; H, 7.63; N, 15.27%

Example 8

N- [2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-nitroguanidine

2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethanamine (2.14 g), S-methyl-N-nitroisothiourea (1.5 g), ethanol (10 mL) Heated at 40 degrees Celsius for 5 minutes. The resulting precipitate was filtered and recrystallized from ethyl acetate and petroleum ether (boiling point; 80-100 degrees Celsius) to give N- [2-[[[5-dimethylamino) methyl-2-furanyl] methyl] -thio]. Ethyl-N'-nitroguanidine was obtained.

Melting point; 103-104 degrees celsius

Example 9

(a) N-cyano-N '-[2-[[[5- (methylamino) methyl-2-furanyl] methyl] -thio] ethyl-N'-methylguanidine

2-[[[5- (methylamino) methyl-2-furanyl] -methyl] -thio] ethanamine (2.0 g), N-cyano-N'-methylcarbamimido-thio acid, methyl ester (1.25 g) was heated on a steam bath for 6.5 hours. Vacuum was removed at regular intervals to remove methanethiol and the crude product was purified by column chromatography to obtain N-cyano-N '-[2-[[[5- (methylamino) methyl-2-furanyl] methyl]. Thio] ethyl] -N'-methylguanidine (1.05 g) was obtained.

Rf; 0.65 (silica / methanol: ammonia 79: 1)

Melting point; 81-85 degrees Celsius

Similarly prepared from similar amines and N-cyano-N'-methylcarbamimidiothioic acid, methyl ester

(b) N-cyano-N '-[2-[[[5- (1-methylethyl) amino] methyl-2-furanyl] methyl] thio] ethyl] -N'-methylguanidine

Analysis observed; C, 54.73; H, 7. 82; N, 22.31

Calcd for C ₁₄ H ₂₃ N ₅ OS; C, 54.34; H, 7. 49; N, 22.64%

(c) N-cyano-N '-[2-[[[5- (diethylamino) methyl-2-furanyl] -methyl] thio] ethyl] -N'-methylguanidine

Analysis observed; C, 53.54; H, 7. 82; N, 20.65

Calcd for C ₁₅ H ₂₅ N ₅ OS · 3 / 4H ₂ O; C, 53.46; H, 7. 70; N, 20.78%

(d) N-cyano-N '-[2-[[[5- (1-pyrrolidinyl) methyl-2-furanyl] -methyl] thio] ethyl] -N'-methylguanidine

Analysis observed; C, 53.97; H, 6.87; N, 21.06

Calcd for C ₁₅ H ₂₃ N ₅ OS · 3 / 4H ₂ O; C, 53.79; H, 7. 37; N, 20.91%

(e) N-cyano-N '-[3-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] propyl-N'-methylguanidine

Analysis observed; C, 52.86; H, 7. 49; N, 20.64

Calcd for C ₁₄ H ₂₃ N ₅ OS · 3 / 4H ₂ O; C, 52.80; H, 7.59; N, 21.20%

Example 10

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methylguanidine

Suspension in which potassium carbonate (20.7 g) is suspended in a 2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethanamine (10.7 g) solution, and N-cyano-N While stirring acetonitrile (107 ml) containing '-methylcarbam-imidothioic acid methyl ester (7.1 g), acetonitrile (20 ml) solution containing silver nitrate (9.35 g) was added at 70 degrees Celsius. Added for hours. The mixture was stirred for 16 h, the solids were filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (250 mL), a portion of this (10.5 mL) was washed with water (6 mL), and the solid obtained by evaporation of the ethyl acetate layer was crystallized in isopropyl acetate (1.75 mL) to give N ＂-. Cyano-N- [2-[[[5- (dimethylaminomethyl) -2-furanyl] -methyl] thio] ethyl] -N'-methylguanidine (0.35 g) was obtained.

Melting point; 79-81.5 degrees Celsius

Above, the residue was dissolved in ethyl acetate and ethanol (30 mL) containing sebacic acid (9.09 g) was added to the remaining solution (225 mL) and filtered to give sebacate (13.74 g).

Melting point; 92.5-94 degrees Celsius

Analysis measured value; C, 54.91; H, 7.94; N, 14.02.

Calcd for C ₁₃ H ₂₁ N ₅ OS · C ₁₀ H ₈ O ₄ ; C, 55.51; H, 7.90; N, 14.07%

Example 11

N-cyano-N '-(2-methoxyethyl) carbamimidothioic acid, methyl ester

Powdered cyanamide (4.2 g) was added to this, stirring the anhydrous ethanol solution containing sodium (2.3 g). After 30 minutes, anhydrous ethanol solution containing methoxyethyl isothiocyanate (11.7 g) was added to the cold solution, and after 1 hour, dimethyl sulfate (12.66 g) was added at room temperature for 30 minutes, and the mixture was overnight. Stirred. The solvent was removed and the residue was washed well with water to give N-cyano-N'-2 (methoxyethyl) carbamimido-thio acid, methyl ester (12.37 g) as a white crystalline solid.

Melting point; 94.5-95.5 degrees Celsius

To be prepared in the same way;

N-cyano-N '-(2-propenyl) carbamimidothioic acid, methyl ester

Melting point; 109-110 degrees celsius

(a) N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-(2-methoxyethyl) guanidine

2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethanamine (2.14 g) with N-cyano-N '-(2-methoxyethyl) -carbamididoti A mixture of OH, methyl ester (1.73 g) and the like were heated on a steam bath for 6.5 hours. Occasionally, vacuum was removed to remove methanethiol, and the crude product was purified by chromatography (silica gel / methanol) to give N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl]. Methyl] thio] ethyl] -N '-(2-methoxyethyl) guanidine (1.4 g) was collected.

Analysis measured value; C, 50.51; H, 7. 20; N, 19.41

Calcd. For C ₁₅ H ₂₅ N ₅ O ₂ S.H ₂ O; C, 50.42; H, 7.50; N, 19.60%

Similarly prepared from N-alkyl-N'-cyanocarbamimidiothioic acid, methyl ester, similar to 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine ;

(b) N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethyl] -N'-(2-propenyl) guanidine

Analysis observed; C, 53.33; H, 7.0 1; N, 20.70

Calculated values of C ₁₅ H ₂₃ N ₅ OS · H ₂ O; C, 53.09; H, 7. 37; N, 20.64%

(c) N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethyl] -N'-(1-methylethyl) guanidine

Analysis observed; C, 52.97; H, 7. 70; N, 20.57

Calcd for C ₁₅ H ₂₅ H ₅ OS · H ₂ O; C, 52.78; H, 7.91; N, 20.52%

Example 12

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methylguanidine

A mixture of 2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethanamine (2.14 g) and iodide N, S-dimethylisothiouronium was heated over a steam bath for 3 hours It was. The residue present in methanol is eluted from Amberlyst A26 ion exchange resin to give amber oil N- [2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethyl] -N '-Methylguanidine (1.5 g) was obtained.

Analysis observed; C, 50.92; H, 8.23; N, 19.90

C ₁₂ H ₂₂ N ₄ OS, 3 / 4H ₂ O

Calculated value; C, 50.76; H, 8.34; N, 19.74%

To be prepared in the same way;

(b) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N ', N'-dimethylguanidine

NMR (CDCl ₃ ) 7.75 s (6H); 6.8-7.3 m (8H); 6.5 m (4H); 6.22 s (2 H); 3.80 m (2 H); 2.0-3.5 br (2H)

Example 13

N-methyl-1-methylthio-2-nitroethanamine

Ethylene dichloride (1.51) solution containing 1,1-bismethylthio-2-nitro-edene (99.0 g, 0.6 mole) while stirring, ethanol / ethylene dichloride (33% ethanol) containing methylamine Ethylene dichloride 0.8 L: 0.94 mol) containing 112.5 ml of methyl methylamine was added at 70 degrees Celsius for 5 hours 30 minutes.

The solution was heated until it was stopped, 0.7 L of the solvent was distilled off, and the cooled solution was washed with 2N hydrochloric acid (0.25 L) and brine (0.25 L). The solvent was removed and the residue was crystallized in isopropacetic acid (0.5 L) and the hot solution was treated with activated charcoal (10.0 g) to give a yellow template product (35.0 g).

Melting point; 114 degrees celsius

Hydrochloric acid N- [2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1, 1-edendiamine

2-[[[5- (methylamino) -methyl-2-furanyl] methyl] thio] ethanamine (10 g, 0.05 mole) solution and N-methyl-1-methylthio-2-nitroeramine (7.4 Water (g) containing g) was stirred at 50 degrees Celsius for 2 hours. Acetone (350 mL) was added thereto, and the solvent was distilled off at atmospheric pressure until the effluent became 275 mL, and then ethanol hydrogen chloride (2 mol; 275 mL) was added to the residue, and the solution was stirred overnight at room temperature. . The product having a melting point of 161 degrees Celsius (11.0 g) was collected and recrystallized from ethanol to give a colorless microcrystalline solid (10.1 g).

Melting point; 162 degrees celsius

Analysis measured value; C, 42.6; H, 6.3; N16.4

_{C 12 H 2 0N 4 O 3} S · HCl Calcd of; C, 42.8; H, 6.2; N, 16.6%

Example 14

(a) N- [2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] -N'-methyl-2-nitro-1,1-ethenediamine

A mixture of 2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine (0.9 g) and N-methyl-1-methylthio-2-nitro-ethenamine was mixed with positive pressure ( heated at 100-120 degrees Celsius for 30 minutes under water pump pressure. The residue was purified by column chromatography (silica / methanol: 0.88 ammonia) and crystallized in acetonitrile to give N- [2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methyl] -2-nitro1,1-ethenediamine (0.65 g) was obtained.

Melting point; 106-108 degrees Celsius

Prepared in the same manner;

(b) N- [2-[[[5-[(1-methylethyl) amino] methyl-2-furanyl] -methyl] thio] ethyl-N'-methyl-2-nitro-1,1-ethene Diamine

Analysis measured value; C, 49.75; H, 7. 21; N, 16.36

Calcd for _{C 14 H 24 N 4 O 3} S · 1 / 2H 2 O; C, 49.83; H, 7.47; N, 16.06%

(c) N-methyl-2-nitro-N '-[2-[[[5-[(2-phenylethyl) amino] methyl-2-furanyl] -methyl] thio] ethyl-1,1-ethene Diamine

Analysis measured value; C, 57.19; H, 6.53; N, 13.83

Calcd for C ₁₉ H ₂₆ N ₄ O ₃ S · 1 / 2H ₂ O; C, 57.12; H, 6.81; N, 14.02%

(d) N-methyl-2-nitro-N '-[2-[[[5-[(1-piperidinyl) methyl] -2-furanyl] -methyl] thio] ethyl] -1,1- Ethendiamine

Analysis measured value; C, 53.36; H, 7.51; N, 14.23

Calcd for C ₁₆ H ₂₆ N ₄ O ₃ S. 1 / 4H ₂ O; C, 53.33; H, 7. 44; N, 15.61%

(e) N- [2-[[[5-[(2-dimethylamino) ethyl] -2-furanyl] methyl] thio] -ethyl] -N'-methyl-2-nitro-1,1-ethene Diamine

Melting point; 95.5-96 degrees Celsius

(f) N- [2-[[[5- [3- (dimethylamino) propyl] -2-furanyl] methyl] -thio] ethyl] -N'-methyl-2-nitro-1,1-ethene Diamine

NMR τ (CDCl ₃ ) 7.1-8.1 m (6H); 7.65 s (6 H); 7.1 s (3H); 6.5 m (2H); 6.28 s (2 H); 4.0 m (2H); 3.38 s (1 H)

(g) N- [2-[[[5- [4- (dimethylamino) butyl] -2-furanyl] -methyl] -thio] ethyl] -N-methyl-2-nitro-1,1-ethene Diamine

Analysis of solids such as lead; C, 53.90; H, 7.95; N, 15.64

Calcd for C ₁₆ H ₂₈ N ₄ O ₃ O ₃ S; C, 53.91; H, 7.92; N, 15.72%

(h) N- [2-[[[5-[(ethylmethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

NMR τ (CDCl ₃ ) 8.90t (3H); 7.76 s (3 H); 6.8-7.5 m (7 H); 6.5 br (2H); 6.25 s (2 H); 3.77 s (2H); 3.35 s (1 H)

(i) N- [2-[[[5-[[2- (dimethylamino) ethyl] amino] methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1, 1-ethenediamine

NMR τ (CDCl ₃ ) 7.79 s (6H); 7-7.76 m (10 H); 6.6 m (2H); 6.26 (2H); 6.22 s (2H); 3.85 m (2H); 3.37 s (1 H); 2-3.2 br (1H); 0.8-0.2 br (1 H);

(j) N- [2-[[[5-[[2- (dimethylamino) methyl-2-furanylmethoxy] ethyl-N'-2-nitro-1,1-ethenediamine

Melting point; 110-112 degrees celsius

Example 15

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

Water (400 mL) containing N-methyl-1- (methylthio) -2-nitroethenamine (230 g) was heated at 45-50 degrees Celsius with stirring. 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (321 g) was added dropwise thereto for 4 hours, and the resulting solution was further stirred for 3 hours and 30 minutes. The solution was then heated to reflux for 30 minutes, cooled to 70 degrees Celsius and 4-methyl-pentan-2-one (2 L) was added. Water was removed by azeotropic distillation under reduced pressure (260 atm) and the resulting solution was treated with activated carbon (10 g) at 50 degrees Celsius. The solution was filtered, cooled to 10 degrees Celsius, filtered again and dried to form N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methyl- 2-nitro-1,1-ethenediamine (380 g) was obtained.

Melting point; 69-70 degrees Celsius

Example 16

N-methyl-2-nitro-N '-[2-[[[5-[(1-pyrrolidinyl) methyl] -2-furanyl] methyl] ting] ethyl-1,1-ethenediamine

2-[[[5- (1-pyrrolidino) methyl-2-furanyl] -methyl] thio] ethanamine bisoxalate (2.1 g) and potassium hydroxide (1.12 g), and N-methyl- (1 A mixture such as water (9 ml) containing -methylthio) -2-nitro-ethenamine (0.9 g) was stirred at room temperature for 18 hours.

Water was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate in the presence of excess anhydrous sodium carbonate. The residue obtained by evaporating the solvent was crystallized in isopropyl acetate to give a white crystalline solid (0.9 g).

Melting point; 79-82 degrees Celsius

Analysis measured value; C, 52.78; H, 7.05; N, 16.57

Calcd for C ₁₅ H ₂₄ N ₄ O ₃ S; C, 52.92; H, 7. 11; N, 16.46%

Example 17

N- [2-[[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylurea

Concentrate the concentrated hydrochloric acid solution containing N- [2- (mercaptomethyl] -N'-methylurea (2.0 g), while containing 5- (methylamino) methyl-2-furan-methanol (2.0 g) A solution of water (3 ml) was added dropwise at 0 ° C. After 24 hours, ethyl acetate (100 ml) and excess sodium anhydride were added, and the filtrate obtained by filtration was evaporated to dryness and the oily residue remained. Water was subjected to tube chromatography (silica / methanol: 0.88 ammonia 79: 1).

The eluate was evaporated to dryness to afford the same oil (0.42 g) as the product of Example 4.

NMR (CDCl ₃ ) τ 3.85 s (2H); 4.3-4.8 m (2H); 6.27 s (4H); 6.49q (2H); 7.22d 7.32t 7.54s (8H); 8.50 brs (1H)

Example 18

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methylguanidine

5- (dimethylamine) -2-furanmethanol (0.98 g) while stirring a concentrated hydrochloric acid solution containing N-cyano-N '-(2-mercaptoethyl) -N'-methylguanidine (1 g) Was added dropwise at 0 degrees Celsius for 10 minutes. After 3 hours excess sodium carbonate was added at room temperature to neutralize the solution and the resulting solid was extracted with ethyl acetate. The oil obtained by removing the solvent was subjected to tube chromatography to obtain the same product as the compound of Example 10. (0.42g)

NMR (CDCl ₃ ) τ 3.82 s 3.6-4.4 brm, (4H); 6.28 s (2 H); 6.57s 6.63q (4H); 7.15d. 7.30 t (5H); 7.65 s (6 H)

Example 19

N- [2-[[5- (aminomethyl) -2-furanylmethyl] thio] ethyl] -N'-cyano-N'-methylguanidine

2- (5-chloromethyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) -dione

2- (5-hydroxymethyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) -dione (10 g) was dissolved in thionyl chloride (15 mL) but dissolved slowly with heating. The solution was evaporated to dryness and the solid residue was evaporated again with cyclohexane-benzene (1: 1), and then the suspension obtained by floating the residue in ether was filtered, washed with ether and dried to give 2- ( 5-Chloromethyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) -dione (10.1 g) was obtained.

Melting point; 119-122 degrees Celsius (decomposition)

Analysis measured value; C, 61.32; H, 3.71; N, 5.00

Calcd for C ₁₄ H ₁₀ ClHO ₄ ; C, 60.99; H, 3. 66; N, 5.08%

N-cyano-N- [2-[[5- [1,3-dioxo-2H-isoindol-2-yl) methyl] -2-furanylmethyl] thio] ethyl-N'-methylguanidine

Dry diketylformamide (4 ml) solution containing N'cyano-N- (2-mercaptoethyl) -N'-methylguanidine (1.0 g) and sodium hydride (0.152 g) A dry dimethylformamide (8 mL) solution containing 2- (5-chloromethyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) -dione (1.74 g) was added slowly at room temperature. After stirring for 2 hours the solution was evaporated to dryness and the oily residue was suspended in an ethyl acetate (25 mL) -water (20 mL) mixture. The solid residue was filtered and then crystallized in methanol to give the title compound (1.4 g).

Melting point; 179-182 degrees celsius

N- [2-[[5- (aminomethyl) -2-furanylmethyl] thio] ethyl] -N'-cyano-N'-methylguanidine

N'-cyano-N- [2-[[5- [1,3-dioxo-2H-isoindol-2-yl) methyl] -2-furanylmethyl] dispersed in methanol (35 mL) Suspension of thio] ethyl] -N'-methyl-guanidine (4.45 g) and hydrazine hydrate (0.6 g) is evaporated to dryness and the residue is dissolved in water (15 mL) at 0 degrees Celsius and then neutralized with 5N hydrochloric acid. It was. This suspension was filtered, excess anhydrous sodium carbonate was added and the solution was evaporated to dryness. The residue was mixed with anhydrous sodium sulfate and the extract obtained by extracting the solids with ethanol was evaporated to give a semi-solid. This was mixed with anhydrous sodium sulfate, extracted with ethyl acetate (2.12 g), was subjected to tube chromatography (silica / methanol: 0,88 ammonia 79.1), and the eluate was evaporated to slowly solidify the resulting oil (1.88 g). ) Was obtained.

Melting point; 80-82 degrees celsius

Analysis measured value; C, 49.57; H, 6. 66; N, 25.93

Calculated by C ₁₁ H ₁₇ N ₅ OS; C, 49.41; H, 6. 41; N, 26.20%

Example 20

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

2-nitromethylene thiazolidine

Of water (30 mL) and ethanol (100 mL) containing cysteamine hydrochloride (11.36 g), potassium hydroxide (5.61 g), 1,1-bis (methylthio) -2-nitroethene (16.52 g) The mixture was heated at reflux for 1 h. The suspension was evaporated to dryness and the residue was suspended in water and the residue obtained by filtration was crystallized in methanol to give 2-nitroethylene thiazolidine (9.2 g).

Melting point; 141-142 degrees Celsius

Analysis measured value; C, 32.91; H, 4.13; N, 19.10

Calcd for C ₄ H ₆ N ₂ 0 ₂ S; C, 32.87; H, 4.14; N, 19.17%

N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethenediamine

A 33% solution of methyleneamine and a 2-nitroethylene thiazolidine (5 g) solution in ethanol (40 mL) were allowed to stand at room temperature for 65 hours. The separated solid was filtered, washed with ethanol and dried to give N- (2-mercapto-ethyl) -N'-methyl-2-nitro-1,1-ethenediamine (4.98 g).

Melting point; 174-175 degrees Celsius, decomposition: 209-211 degrees Celsius

Analysis measured value; C, 34.05; H, 5.87; N, 23.85

Calcd for C ₅ H ₁₁ N ₃ 0 ₂ S; C, 33.88; H, 6. 26; N, 23.71%

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

Concentrated hydrochloric acid (2 mL) containing N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethenediamine (345 mg) was dissolved in 5- (dimethylamino) methyl at 0 degrees Celsius. It was dripped at 2-furanmethanol (428 mg). The solution was left at 0 ° C. for 7 days, after which the reaction was diluted with water (3 mL), excess potassium carbonate was added and the solid component was extracted with ethyl acetate (50 mL). The solvent was evaporated and the residue was purified by preparative layer chromatography to give the title compound (10 mg) as in Example 15.

Example 21

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

N, N-dimethyl-2-furanmethane amine (125 mg) was dissolved in glacial acetic acid (1 mL) and paraformaldehyde (30 mg) was added. Dilute with concentrated hydrochloric acid (1 ml) and water (30 ml) containing N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethenediamine (354 mg), and add potassium carbonate. Saturated and extracted with ethyl acetate. The extract was purified by prepared layer chromatography to give the title compound (89 mg) as in Example 15.

Example 22

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl-N'-methylguanidine

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl-thio] ethyl] carbamimidothioic acid, methyl ester

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine (1.07 g) was replaced with N-cyanoimido-carbamodithioic acid and dimentyl ester (0.73 g). It was added to the containing ether solution and stirred overnight. The crystalline solid formed was filtered off, washed with ether and dried to give N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -carbamimi Dothioic acid and methyl ester (1.14 g) were obtained.

Melting point; 78-79 degrees Celsius

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methylguanidine

N'-cyano-N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] carbamimidothio acid, ethanol containing methyl ester (1.06 g) A 33% solution of methylamine (10 mL) was stirred at rt for 4 h.

The solution was evaporated to dryness and the oily residue was crystallized in ethyl acetate (boiling point; 80-100 degrees Celsius) to afford the title compound.

Melting point; 77-80 degrees celsius

Example 23

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-heptylguanidine

Heptylamine (1.15 g) and N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -carbamimidothioic acid (3.12 g) The mixture of was heated at 100 degrees Celsius for 12 hours on an oil bath. The product was chromatographed (silica / methanol) to give N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-heptylguanidine hydrate ( 2.31 g) was obtained.

Rf; 0.49

Analysis measured value; C, 56.99; H, 8.32; N, 17.53

Calcd for C ₁₉ H ₃₃ N ₅ OS.H ₂ O; C, 57.43; H, 8.81; N, 17.63%

Example 24

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methyl-2-nitro-1,1-ethedamine

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine (4.25 g) and 1,1-bis (methylthio) -2-nitroethene (3.3 g) Reflux in acetonitrile (50 mL) for 14 h. The solvent was removed and the residue was dissolved in 35% petanol methaneamine (50 mL) and the solution was refluxed for 8 hours.

The solvent was removed, the residue contained in methanol was treated with activated charcoal, filtered and the solvent was evaporated to give the title compound (5.0 g) as in Example 15.

Example 25

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N '-(2-methoxyethyl) -2-nitro-1,1 Ethendiamine

2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine (2.14 g) and 1,1-bis (methylthio) -2-nitroethene (1.65 g) Reflux in acetonitrile for 8 hours. The solvent was removed and an ethanol solution of 2-methoxyethylamine (0.75 g) was added, followed by further reflux for 8 hours, and the solvent was removed to obtain an oil. This was purified by column chromatography to obtain N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '-(2-methoxyethyl) -2-nitro- 1,1-ethenediamine (1.0 g) was obtained.

NMRτ (CDCl ₃ ) 7.73 s (6H); 7-7.5 m (2H); 6.2-7 m (11 H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1 H)

To be prepared in the same way;

(b) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] 2-nitro-1,1-ethenediamine

Melting point; 100-101 degrees celsius

Example 26

(a) N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro-1,1-ethenediamine

Acetonitrile (12 ml) containing 4- [5- (dimethylamino) methyl-2-furanyl] butanamine (0.7 g) and 1,1-bis (thiomethyl) -2-nitroethene (0.6 g) ) Was refluxed for 22 hours. The solvent was removed and the residue was refluxed for 2 h in 33% ethanol methylamine. The solvent was removed and the residue was purified by column chromatography (silica / methanol) to give N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro-1, 1-ethenediamine (310 mg) was obtained.

Analysis measured value; C, 55.54; H, 8.23; N, 17.75

Calcd for C ₁₄ H ₂₄ N ₄ O ₃ 1 / 2H ₂ O; C, 55.26; H, 8.22; N, 18.42%

(b) N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methyl-2-nitro-1,1-ethenediamine

Analytical observations; C, 56.76; H, 8. 36; N, 17.37

Calcd for C ₁₅ H ₂₆ N ₄ O ₃ H ₂ O; C, 56.43; H, 8. 46; N, 17.55%

(c) N- [3-[[5- (dimethylamino) methyl-2-furanyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethenediamine

Analytical observations; C, 49.36; H, 7. 19; N, 17.45

Calcd for C ₁₃ H ₂₂ N ₄ O ₃ ; C, 49.66; H, 7.05; N, 17.84%

(d) N- [3- [5- (dimethylamino) methyl-2-furanyl] propyl] -N'-methyl-2-nitro-1,1-ethenediamine

Analytical observations; C, 55.09; H, 7.84

Calcd for C ₁₃ H ₂₂ N ₄ O ₃ ; C, 55.31; H, 7.72%

(e) N- [2-[[[5- (diethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

Analytical observations; C, 51.38; H, 7. 44; N, 15.66

Calcd for C ₁₅ H ₂₆ N ₄ O ₃ S. 1 / 2H ₂ O; C, 51.26; H, 7. 74; N, 15.94%

(f) N- [3-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethenediamine

Analytical observations; C, 49.57; H, 7. 20; N, 15.59

Calcd for _{C 14 H 24 N 4 O 3} S · 1 / 2H 2 O; C, 49.86; H, 7.47; N, 16.61%

Example 27

(a) N-cyano-N '-[4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methylguanidine

4- [5- (dimethylamino) methyl-2-furanyl] butanamine (0.4 g), N-cyanoimidocarbamodithioic acid and dimethyl ester (0.3 g) were stirred in ethanol for 3 hours at room temperature. An ethanol solution containing 33% methaneimine was then added and the mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the product was purified by column chromatography (silica / methanol) to give the product as a pale yellow oil.

NMRτ (CDCl ₃ ) 8-8.5 br (4H); 7.77 s (6 H); 6.61-7.5 m (9H); 4.0 m (2H); 2.8-3.7m (2H)

Manufactured in the same way

(b) N-cyano-N '-[5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylguanidine

NMRτ (CDCl ₃ ) 8.0-8.7 br (6H); 7.68 s (6 H); 7.32 t (2H); 7.10d (3H); 6.7q (2H); 6.48 s (2H); 3.8-4.3 m (4H)

Example 28

(a) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methanesulfonyl-N'-methylguanidine

Methanesulfonyliminodithiocarbamic acid, dimethyl ester (1.9 g) and 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio-ethanamine (2.14 g) in ethanol for 3 hours Stir at room temperature. To this was added 33% ethanol methylamine (20 mL) and heated to reflux for 16 h. The product was purified by column chromatography (silica / methanol) to obtain a pale oil, N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methanesulfonyl- N'-methylguanidine (2.7 g) was obtained.

Analysis measured value; C, 43.54; H, 7.05; N, 15.48

Calcd. For C ₁₃ H ₂₄ N ₄ O ₃ S ₂ .1 / 2H ₂ O; C, 43.70; H, 7.00; N, 15.69%

To be prepared in the same way;

(b) N-benzenesulfonyl-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl [thio] ethyl] -N'-methylguanidine

Analysis measured value; C, 50.30; H, 6. 25; N, 12.93

C ₁₈ H ₂₆ N ₄ O ₃ S. Calculated value of H ₂ O; C, 50.47; H, 6. 54; N, 13.08%

Example 29

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methylguanidine

N-cyano-N'-methylcarbamimidiothioic acid, methyl ester (6.1 g), triethylamine (4.8 g) and 2-[[[2-furanyl] methyl] thio] ethanamine (7.8 g) To a methanol (150 mL) solution containing dimethyl formamide (50 mL) solution containing silver nitrate (8.25 g) was added dropwise. After 42 hours, the mixture was filtered at 50 degrees Celsius and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. Drying and evaporation of the organic layer yielded crystalline N-cyano-N '-[2-[[[2- (furanyl] methyl] thio] ethyl] -N'-methylguanidine (3.9 g) in oil obtained by drying. I did it.

Melting point; 78-82 degrees Celsius

A solution of this amine (4.5 g), dimethylamine hydrochloride (3.1 g), and 36% aqueous formaldehyde solution (3.16 g) was heated in ethanol (20 mL) at 50 degrees Celsius for 60 hours. The residue was partitioned between ethyl acetate and aqueous base solution. The combined organic extracts were dried and evaporated and the oil was treated with sebacic acid in isopropanol to give sebacate (2 g) of the title compound.

Melting point; 93-94 Celsius

Example 30

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N-methylthiourea

Carbon disulfide (1.52 g) was added thereto while stirring cold water (1.7 mL) containing sodium hydroxide (0.8 g). To this was slowly added 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (4.28 g) and then the mixture was heated at 100 degrees Celsius for 2 hours.

After cooling the mixture to 40 degrees Celsius or less, ethyl chloroformate (ClCOOCH ₂ CH ₃ ) (1.94 mL) was added and stirring continued for 30 minutes. The slightly yellow oil was extracted with chloroform, dried and evaporated to give N, N-dimethyl-5-[[[[2- (isothiocyanato) ethyl] thio] methyl] furanmethanamine as an oil.

Rf; 0.43 (silica / methanol)

Prepared isothiocyanate (0.46 g) was dissolved in 33% ethanol methylamine (25 mL) and allowed to stand overnight to afford 2-[[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio]. N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylou, the same pale oil as the material produced from ethanamine and methyl isothiocyanate Lea (0.16 g) was isolated.

Example 31

N-cyano-N '-[2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N'-methylguanidine

N- [2-[[[5- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethyl] -N'-methylthiourea (1.3 g) was refluxed with lead cyanamide (1.5 g) While heating. The solution was filtered and the filtrate was evaporated and the residue was treated with a sebacic acid solution in isopropanol to give the mono sebacate of the title compound (0.7 g).

Melting point; 90-92 Celsius

Example 32

Hydrochloric acid N-2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methyl-2-nitro-1,1-ethenediamine

Methylated industrial spirit containing 0.16 g equivalents of hydrogen chloride at 74 degrees P. (200 mL) to N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N '-Methyl-2-nitro-1,1-ethenediamine (50 g, 0.16 mol) was dissolved. Ethyl acetate (200 mL) was slowly added to this solution, and the crystallized hydrochloric acid was filtered to methylate industrial alcohol 74 degrees. Washed with a mixture of P. (50 mL) and ethyl acetate (50 mL) and dried at 50 degrees Celsius. The product thus obtained was a whitish solid (50 g).

Melting point; 133-134 degrees celsius

Example 33

Pharmaceutical Composition

* A.E. starch that can be directly compressed. Staley Mfg. Co. (London) Limited, Orpington, Kent.

The drug was filtered through a 250 μm sieve and then the four powders were immediately mixed in a mill and compressed between punches with a diameter of 8.5 mm in a tabetting amchine.

The active ingredient was dissolved well while mixing with distilled water for injection, and then hydrochloric acid was added slowly until the solution had a pH of 5. Nitrogen was sparged in this solution, filtered through a membrane filter with a pore size of 1.35 μm, and then purified. Then, 2 mL of glass ampoules (2.2 mL each) were charged. The ampoules were sealed in a nitrogen atmosphere and then sterilized in an autoclave for 30 minutes at 121 degrees Celsius.

Cutina H.R is a fine product of cured castor oil, manufactured by London Chiffon Products Limited.

The active ingredient, anhydrous lactose, and most of the cutie and HL were mixed with each other and then the mixture was wetted by mixing in a methylated industrial spirit 74 ° C. with 10% solution of the remaining cutie or HL. The wetted material was granulated by passing through a sieve having a pore size of 1.2 mm and dried in a fluid bed dryer at 50 degrees Celsius. The granules were then filtered through a sieve of 0.85 mm pore size and blended with magnesium stearate and then compressed to a hardness of at least 10 kg (Schelewinge tester) on a tablet machine with a punch of 12.5 mm diameter.

The active ingredient was dissolved while stirring with some distilled water, and hydrochloric acid was added stepwise until the pH of the solution reached 5.0. Sorbitol solution, flavor and remaining distilled water were added to this solution and the pH was adjusted back to 5. This syrup was purified by filtration through a suitable cellulose filter plate.

The active ingredient was filtered through the object of 250 μm and combined with other powders. This powder was filled into a hard gelatin capsule of particle number 3 on a suitable charger.

The active ingredient was filtered through a sieve having a pore size of 150 μm and then uniformly combined with white soft paraffin in the high-short run.

The active ingredient was filtered through a sieve having a pore size of 150 μm and well blended with cetomacrogol emulsified ointment at 65 degrees Celsius.

Chlorocresol was dissolved in water at 65 degrees Celsius and the solution was mixed with the oil-based drug mixture. The resulting dough emulsion was cooled with continued stirring to prepare a cream. The active ingredient may be used as the compound of the present invention, in particular the compounds of Examples 10 and 15, but the following compounds according to the present invention.

It was found that the compounds of formula (I) act as inhibitors of gastric acid secretion induced by histamine. This is described in the British Journal of Pharmacy, Volume 13, page 54, published in 1958. yen. Gauche and H. Five. This was demonstrated by modifying the shield's method and testing it on rats. Rats weighing about 150 g were starved overnight and given saline containing 8% sugar instead of drinking water. Then, anesthesia was injected once intraperitoneally with 25% W / V urethane solution (0,5ml / 100g), and cannulas were installed in the trachea and jugular vein. The abdominal wall was cut open to expose the stomach and the connective tissue was cut to separate the stomach from the liver and spleen. A small hole was made in the bottom of the stomach and the stomach was washed with 5% glucose solution. Then, a rubber tube was inserted into the esophagus and the esophagus and the vagus nerve were cut on the rubber tube. After making a pore in the upper pyloric region, a large Perspex canopy was placed on top of the lower pores above, with the inlet end of the canyon wool passing through the pores of the pyloric section. This type of canewool reduces the effective volume of the stomach and allows turbulent flow of the perfusion fluid on the mucosa. In the next step, drainage canes were inserted through the pores of the upper base. Two canine wool ligatures were tied and fixed around the gastric vessels. It made a stab on the wall and passed through Canueul. A 5% glucose solution was charged over the esophagus and pylori at the rate of 1.5 ml / min at 39 degrees Celsius. The effluent was allowed to flow over a micro-flow pH electrode (electrode for measuring the pH of the liquid when the flow rate of the liquid was fine) and recorded below the pH and with a flat bed recorder. The basal release of acid secreted from the stomach was examined by measuring the pH of the perfusion eluate, and the lowest dose of histamine was continuously injected intravenously to increase acid secretion. This operation results in a stable plateau of gastric acid secretion and the pH of the perfusion extract is determined when this condition is obtained. Now, the test compound was injected intravenously into rats, and the change in gastric acid secretion was measured by measuring the pH change value of the perfusion eluate. From the pH change value of the perfusion eluate, the acid content difference between the base ejection amount and the high plateau value stimulated by histamine was calculated as hydrogen ion concentration water / 1. In addition, the decrease in acid secretion caused by administration of the test compound from the perfusion eluate pH difference was calculated as the change in hydrogen ion concentration water / 1. From the two coefficients thus obtained, the percent reduction in acid release caused by administration of the test compound can be calculated.

The test compound was administered to one rat at a dose of three or more ED ₅₀ values for inhibiting acid secretion, and at least four rats were repeated for each measurement. As a result, the ED ₅₀ value was calculated by the standard method which is the least square method. The value of ED ₅₀ obtained is as follows.

Claims (1)

As detailed herein, the compound of formula (II) below may be reacted with a compound of formula (III) to separate the final product into a pharmaceutically acceptable salt as Process for preparing aminoalkylfuran derivatives of general formula (I) which can be converted.

Wherein R ₁ and R ₂ are the same or different and are hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or oxygen atom

(R ₄ represents hydrogen or lower alkyl) in which intermediate alkyl is bonded. Or R ₁ and R ₂ together with the nitrogen atom to which they are attached,

It is also possible to form heterocycles containing these double atoms selected from among them. R ₃ is hydrogen, lower alkyl, lower alkenyl, or alkoxy alkyl, X is -CH _2- , oxygen or sulfur Y is = S, = O, = NR ₅ or = CHR ₆ , Alk is a C ₁ -C ₆ alkylene which forms a straight or branched chain, R ₅ is hydrogen, nitro, cyano, lower alkyl, aryl, alkylsulfonyl, or arylsulfonyl, R ₆ is nitro, arylsulfonyl or alkylsulfonyl, m is an integer from 2-4, n is 0, 1 or 2 when n is 1 or 2 or X or S or -CH _2- .

Where A is hydrogen and B is hydrogen or

P is a separator,

Is = NR ₅ or -CHR ₆ ] or both A and B are = CS.

Where Z is hydrogen and Z 'is hydrogen or

Or Z and Z 'are both = CO and = CS.