DK149812B - ANALOGY PROCEDURE FOR THE PREPARATION OF AMINOAL COOLING FERRANTS - Google Patents

Description

U9312

The present invention relates to an analogous process for the preparation of novel aminoalkylfuran derivatives having a selective effect on histamine receptors with which compounds can be prepared pharmaceutical compositions.

A subdivision of histamine receptors (H receptors) into two groups referred to as H 1 and I 2 receptors has been proposed by Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427) and Black et al. eel. (Nature 1972, 236, 385) Stimulation of the soft musculature of the bronchial and gastrointestinal tract is mediated by H 2 receptors, and its effect can be prevented by conventional histamine antagonists such as mepyramine. Stomach acid secretion and heart rate are mediated by I 1 receptors; these effects are not modified by mepyramine but are prevented or abrogated by H2 antagonists such as methiamide. Histamine stimulates H 1 and 2 receptors.

It has been found that certain novel aminoalkylfuran derivatives are selective β-antagonists, that is, they inhibit the secretion of gastric acid when stimulated via histamine H2 receptors (Ash and Schild loc. Cit.). Their ability to prevent gastric acid secretion when stimulated via histamine H2 receptors can be demonstrated in a perfused rat stomach using the method described by Ghosh and Schild (Brit. J. Pharmacol. 1958 13 54). in the manner described below, and on awake dogs equipped with Heidenhain pockets using the same method as described by Black et al. (Nature 1972 236 385). The compounds prepared by the method of the present invention do not modify histamine-induced contractions in isolated soft muscle from the gastrointestinal tract.

Prior art antagonists, particularly burimamide and methiamide, are described particularly in British Patent Specification No. 1,307,539 and British Patent Specification No. 1,338,169 as active histamine receptors different from the H 1 receptor. However, it is clear that an imidazole ring is required for the H2 antagonist effect. Thus, there is no suggestion that this ring could be replaced with a furan ring.

Thus, there are so significant structural differences between the compounds prepared by the process of the present invention and prior art compounds that claims for differences in biological data for said compound classes do not appear relevant.

Compounds with histamine H2-blocking effect can be used to treat conditions where there is a hypersecretion of gastric acid, e.g. in gastric and peptic ulceration, and in the treatment of allergic conditions in which histamine is a known mediator. The compounds can be used either alone or in combination with other active substances to treat allergic and inflammatory conditions, e.g. urticaria.

149312 3

The present invention is based on this disclosure and relates to an analogous process for the preparation of compounds of general formula I

r · ^ Y

\ _yT \ _ i 3

N-Alk-V V ^ - (CH2) X (CH2) mNHCNHR I

Wherein R 1 and R 2, which may have the same or different meaning, represent hydrogen, C 1-6 alkyl, optionally with C 1-6 alkyl, C 1-6 alkoxy or halogen substituted phenyl alkyl of 1-8 carbon atoms. in the alkyl portion or C2-6 alkyl which is interrupted by a group -N-: i.

wherein R f represents hydrogen or C 1-6 alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing -O- or -N (C -alkyl) -, R 3 represents hydrogen, C 1-6 alkyl, C 1-6 alkenyl or C 1-6 alkoxy-C 1-6 alkyl, X represents O or S; Y represents = S, = O, = NRS or = CHNC> 2, Alk represents a straight or branched alkylene chain of 1-6 carbon atoms, R5 represents hydrogen, nitro, cyano, g-alkyl, C 1-6 alkylsulfonyl or phenylsulfonyl, m represents an integer from 2 to 4, and n represents 1 or 2, or, when X represents S or -Ch 2 - / n may further denote O, with the proviso that Y cannot be = CHNO 2 when R1, R2 and R 3 is methyl, Alk is methylene, X is S, n is 1, and m is 2, or physiologically tolerable acid addition salts or hydrates thereof.

149812 4

The present compounds have the advantage that they can be readily prepared from readily available starting materials.

All the compounds of formula I may exhibit tautomerism, and the general formula must cover all the tautomers. When "Alk" denotes a branched alkylene group, optical isomers may exist and the formula should cover all diastereoisomers and optical enantiomers.

In a preferred class of compounds, the symbols indicated have the following meaning: 1 2 R and R independently represent hydrogen, C 1 -C 6 alkyl, phen-x 4 ° in 2 yl-C 1-6 alkyl or di (C 1-6 alkyl) ) amino or C1-6 alkyl, or R and R together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated heterocyclic ring of the kind set forth in claim 1, e.g. morpholino, piperidino, pyrrolidino and N-alkylpiperazine

Alk represents a straight alkylene chain of 1-4 carbon atoms.

Y represents -S, = O, = CHNC> 2 or = NR, where R represents hydrogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkylsulfonyl or phenylsulfonyl.

In a particularly preferred compound class, the symbols listed below have the following meaning: 1 n R and R independently represent hydrogen, alkyl of 1-3 1 2 carbon atoms or phenylethyl, or R and R together with the nitrogen atom to which they are attached; forming a pyrrolidine ring. Alk represents straight-chain alkylene having 1 to 3 carbon atoms. Y represents = S, = CHNO 5 or or NR where R represents nitro, cyano, methylsulfonyl or phenylsulfonyl. R represents hydrogen, alkyl of 1-3 carbon atoms, propylene or alkoxyalkyl of 3 carbon atoms, n + m being 3 or 4 and X having the meaning given above. In a further preferred connection sketch, the symbols set forth below have the following meaning.

R 2 and R 2 independently represent hydrogen, alkyl of 1-3 1 2 carbon atoms or phenylethyl, or R and R together with the nitrogen atom to which they are attached form a pyrrolidine ring. Alk represents alkylene having 1-3 carbon atoms. Y represents = S, = CHNO 4 or NR 5 = NR, where R represents nitro, cyano, methylsulfonyl or phenylsulfonyl. X represents S or -CH2 ~. R 3 represents hydrogen, methyl or methoxyethyl. n represents 1 and m represents 2 or 3.

In a further particularly preferred compound class, the symbols set forth below have the following meaning: in 2 R, hydrogen, methyl or ethyl. R is methyl or ethyl. Alk represents methylene. Y represents = NCN, = NNO 2 or = CHNO 2 · R 2 represents hydrogen or methyl. X represents S or -CH2 ~. n represents 1 and m represents 2.

Particularly preferred specific compounds are: N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- methylthiourea N-cyano-N' - [2 - [[[ 5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N "-methylguanidine N-cyano-N '- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio ] ethyl] - Ν '' - methylguanidine N- [2 - [[[5- (diethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -Ν'-methyl-2-nitro-1,1- ethylenediamine N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν '- (2-methoxyethyl) -2-nitro-1,1-ethenediamine N- [2 - [t [5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν'-methyl-2-nitro-1,1-ethylenediamine N- [3 - [[5- (dimethylamino) methyl 2-furanyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethylenediamine N- [2 - [[[5- (ethylmethylamino) methyl] -2-furanyl] methyl] thio] ethyl] - N * -methyl-2-nitro-1,1-ethenediamine N- [2- [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν '- nitroguanidine N- [ 2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- methanesulfonyl-N "-methylguanidine 6- [4- [5- (dimethylla) mi.no} methyl-2-furanyl] butyl] -N '-methylthiourea N-benzenesulfonyl-N' - [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N "-methylguanidine N-15- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N1-methyl-2-nitro - 1,1-ethenediamine N-cyano-N '- [5- [5- dimethylamino) methyl-2-furanyl] pentyl] -N'-methyl-guanidine 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 "-methyl-guanidine N- [2 - [[[5- [3- [dimethylamino] propyl] ] -2-furanylmethyl] thio] ethyl] -N '- methyl-2-nitro-1,1-ethylenediamine and N- [2- [[[5- [[2- (dimethylamino) ethyl] amino] methyl] 2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethenediamine.

Of these compounds, N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1/1-ethylenediamine is particularly preferred, and a preferred variant therefore, the process of the invention assumes that this compound is prepared.

The compounds of the invention form easily physiologically tolerable salts. Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulfates. Particularly valuable salts of organic acids are formed with aliphatic mono- or di-carboxylic acids. Examples of such salts are acetates, maleates and fuarates. The hydrochlorides are preferred. The compounds can also form hydrates.

The present compounds may be administered orally, topically or parenterally or as suppositories, and the preferred route of administration is the oral. They can be used in the form of the base or as physiologically tolerable salt. The compounds are usually mixed with a pharmaceutically tolerable carrier or diluent to form a pharmaceutical composition.

The compounds of this invention may be administered in combination with other active ingredients, if necessary e.g. usual antihistamines. For oral administration, the pharmaceutical preparation may be in the form of capsules or tablets which may be slow release tablets. The preparation may also be in the form of a dragee or may be in syrup form. Suitable topical preparations include ointments, lotions, creams, powders and sprays.

A convenient daily dose for oral administration is in the range of 100 mg to 1.2 g / day in the form of dosage units containing between 20 and 200 mg per day. dosage unit. A convenient cure in the case of slow release tablets may be administration two or three times daily.

Parenteral administration can be performed by intermittent injections or by continuous infusion. Injection solutions may contain 10 - 100 mg / ml of active substance.

For topical application a spray, ointment, cream or lotion can be used. These compositions may contain an effective amount of the active ingredient, e.g. in the range of 1 1/2 - 2% by weight of the total composition.

The process of the invention for the preparation of the compounds of formula I is characterized in that a primary amine of the general formula II

r1 \ [j i]

/ N-Alk II

R 2 wherein R 1, R 2, Alk, η, X and m are as defined above are reacted with an alkali metal cyanate or thiocyanate or an isocyanate of the general formula R3NCO or an isothiocyanate of the general formula R3NCS or with a compound of the general formula

R3NHC-U or R3NHC-E

II 5 ».

NR CHNCU

which formulas R3 and R5 have the meaning given above, and U represents a leaving group, or b) for the preparation of compounds wherein Y represents = NRS or = CHNC> 2, optionally substituting an amine of the general formula II with a compound of the general formula

U U

\ /

C

CHWO2 or by the general formula

U U

\ / NR5

wherein R 5 and U have the meaning given above, prepared compound of the general formula III

R1 U-- "N1-Alk-L (CH2) nX (CH2) xnNHi" "U111

R2 / II

Q

where Q represents = NR5 or = CHNO2 and U, R5, R1, R2, Alk, X, n and m have the meaning given above, reacted with ammonia or a primary amine of the general formula R3NH2, where R3 has the above meaning, or

c) for the preparation of compounds wherein X represents sulfur and n represents 1 and when R 1 and R 2 are both hydrogen, Y is different from = CHNO 2, a compound of the general formula V or VI

R1 -1

^ N-Alk- Ji— CH2OR7 V

y 0 * 0 QC ^ S- ^ O- ™ 2ci 0

wherein R 1 and R 2 are as defined above, and R 7 is hydrogen or acyl and wherein a primary or secondary amino group of the compound of general formula V is optionally protected is reacted with a thiol of general formula VII

HSiCHjJrøCNHR3 VII

Y 'where m and R3 have the meaning given above and Y' has the same meaning as Y except for ^ HNO 2 when R 1 and R 2 in the compound prepared are both hydrogen, if necessary followed by removal of the protecting groups, or d) for preparation. of compounds wherein Y represents a group of NCN, a compound of formula I wherein Y represents sulfur is reacted with a heavy metal cyanamide, or e) to produce compounds where Y is = NRS and Alk represents methylene or branched alkylene, a compound with the general formula VII! 10 149812

L J1- (CH2) nX (CH2) mNHCNHR3 VIII

HH5 where n, m, X, R3 and R5 have the meaning given above are subjected to Mannich reaction with an aldehyde R'CHO (where R'CH = corresponds to the 12 12 group Alk) and an amine R 'R' NH (where R 1 and R 'have the meaning given above for R, respectively, R **, except hydrogen) or 12 ° a salt of an amine R' R NH (wherein R 1 and R * have the meaning given above), or

f) for the preparation of compounds wherein Y represents sulfur, optionally prepared by reacting a compound II with carbon disulfide and then with a compound of the general formula IV prepared by a chloroic acid ester.

An N-Alk-C 3 -CH 2> nx (CH 2) mNCS IV

wherein R 1, R 2, Alk, X, m and n are as defined above, are reacted with an amine of the general formula R'N1 · / where R 3 is as defined above, and the final product, if desired, is converted to a physiologically tolerable salt by reaction with a physiologically tolerable, organic or inorganic acid, or a won salt is converted to another salt by reaction with a physiologically tolerable acid.

u 149812

The amine may be used as the free base or in the form of a salt with a weak acid, e.g. acetic acid.

The reaction with isocyanate or isothiocyanate (process variant a) can be carried out by leaving the amine and isocyanate or isothiocyanate in a solvent, e.g. acetonitrile. The reaction with R3NHC-U or R3NHC-U

IN! 5 I

NR CHNO 2 can be carried out by condensing the reactants at elevated temperature, e.g. 100-120 ° C. The reaction between the amine of formula II and

R3NHC-U

«5 NO

alternatively may be carried out in a solvent, e.g. acetonitrile, at elevated temperature in the presence of silver nitrate. Alternatively, the amine of formula II and the compound R NHC-U may be stirred in an aqueous 1 CHNO solution at room temperature. When R represents hydrogen, alkali metal cyanates and thiocyanates are used. Examples of leaving groups are halogen, methylthio, 3,5-dimethylpyrazolyl, and alkoxy, preferably methylthio.

The optional initial part of process variant b), namely the preparation of the compound of formula III, may be carried out in a solvent, e.g. ether or acetonitrile, at a temperature between room temperature and the reflux temperature of the solvent. Treatment of the compound of general formula III

R1

^ N-Alk-1Γ ji- (CH0) X (CH_} NHC- U III

/ 2 n 2 m fl

R2 Q

5 6 3 where Q represents = NR or = CHR, with a primary amine R NH 2 at a temperature between room temperature and reflux temperature leads to the desired final product.

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In process variant c), a starting material of the general formula V or VI is reacted

Q1 Q ^ N-AlltriLCH 2 Cl M-A1X-II J> -CB, OR f, / O 2 o ir v 'vi 7 where R may be hydrogen or acyl such as acetyl or p-nitrobenzoyl.

1 2

If R and R in the products are both hydrogen, the amino group may be protected in a compound of formula V such as e.g. phthalimido. The above compounds may be reacted with a thiol of the general formula VII as defined above, with, if necessary, subsequent removal of the protecting groups.

When the compound of formula V is used, the reaction is preferably carried out at 0 ° C in concentrated hydrochloric acid. When a compound of formula VI is used, the reaction can be carried out at room temperature in an organic solvent, e.g. dimethylformamide. The chloromethyl compound of formula VI may be prepared from the corresponding alcohol, e.g. using thionyl chloride or concentrated hydrochloric acid.

In process variant d), products in which Y is a group = NCN can be prepared from compounds of formula I wherein Y is sulfur by heating the latter compound with a heavy metal cyanamide, e.g. a cyanamide of silver, lead, cadmium or mercury, preferably in aqueous solution.

c

In process variant e), compounds in which Y is = NR and Alk is a methylene group or a branched alkylene chain can be prepared from compounds of the general formula VIII as defined above by a Mannich reaction. Eg. For example, the group (CH ^^ NCNC ^) may be introduced using dimethylamine and formaldehyde. The process may be carried out by reacting the amine salt with aqueous formaldehyde and the compound of formula VIII or by boiling the amine salt with para-formaldehyde and the compound of formula VIII under reflux. .

In the above-mentioned process variants for the preparation of the compounds of formula I, primary amines of formula II are referred to. These amines are novel compounds which can be prepared in various ways as illustrated below.

Amines of formula II wherein X is S and n is 1 can be prepared

from furfurylthiol of formula IX

by reaction with a ω-bromoalkylphthalimide of the general formula

JU

Br (CH2, m \ KJ | X

0 R1

The group N-Alk can be introduced into the resultant compound of general formula XI

0 l ^^ CH2MCH2) mN ^ S ^ X!

ISLAND

by e.g. a Mannich reaction.

Removal of the protecting group by reaction with e.g. hydrazine hydrate leads to an amine of formula II.

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In an alternative process for the preparation of amines of formula II wherein X is S and n is 1, 2-furfuryl chloride can be used as starting material. The reaction between furfuryl chloride and

a ω-aminoalkylthiol in which the amino group is protected, e.g. as a phthalimide of general formula XII

HS (CH2) »\ JcnJI XI1 o leads to an intermediate of formula XI. This is treated in the manner described above to form an amine of formula II.

In a further process for the preparation of amines of formula II wherein X is S and n is 1, a compound of general formula XIII is used as starting material.

R1 I-

'^ N-Alk-i! i-CH, -OH XIII

This compound can be treated under acidic conditions with a ω-aminoalkylthiol in which the amino group, if desired, can be protected. Alternatively, the compound of formula XIII can be converted to the corresponding acetate before the reaction under basic conditions with the ω-aminoalkylthiol.

Primary amines of formula II (except those where X is S and n is 0) can be prepared by reacting furan with butyllithium to form a lithium derivative of formula XIV

O- Li XIV

() which is then first reacted with an α, ω-dihalogen compound Hal (CH2) nX (CH2) mHal, where Hal represents chlorine, bromine or iodine, and then with

ii) potassium phthalimide. The reaction product of general formula XV

0

^^ (CH2) nX (CH2) m / N ^ jl XV

0 is then subjected to e.g. a Mannich reaction and the protecting group is removed with e.g. hydrazine hydrate.

Intermediates where X is S and n is 0 can be prepared from a furan of the general formula XVI

r1 \ _o

^ N-Alk-XVI

1 2

wherein neither R nor R is hydrogen, by reaction thereof with lithium and elemental sulfur followed by reaction with a ω-bromo-alkylphthalimide of formula X. The resulting product of general formula XVII

0

\ -AlkJ ^ -S (CH 2) ml / N ^ | XVII

o can then be reacted with hydrazine hydrate to remove the protecting group.

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The position of an intermediate where X is an oxygen atom and n is 1 consists of reacting an alcohol of formula XIII in a solvent such as dimethylformamide with a compound Hal where

Hal represents a halogen atom, preferably chlorine, in the presence of a base, especially potassium tert-butoxide.

Intermediates of formula II, where m is 2 and X is S or 0, can also be prepared using ethyleneimine. This compound is reacted with a compound of formula XIII or the isosteric thiol.

Amines of formula II may also be prepared by starting from a compound of general formula XVIII

- (CH2) nX (CH2) m-1CN XVIII

where n, m and X have the meaning given above. A Mannich reaction is carried out on this nitrile compound followed by reduction with lithium aluminum hydride to give a compound of formula II.

When a Mannich reaction is used, the group, β-Alk can be introduced ir

at any convenient step, but the reaction is preferably carried out on compounds of general formulas XIX and XX

_I i [lj-CH2 OH (CH2) nX (CH2) m \ ^^ (^ j] XIX XX o

The Mannich reaction using a suitable aldehyde and a suitable amine is used to prepare compounds wherein Alk represents a methylene group or a branched alkylene group. When Alk denotes methylene, formaldehyde is used.

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Another process for the preparation of compounds wherein Alk is methylene is based on furan-2-carboxylic acid as a starting material.

1 2

This is reacted with an amine of the general formula R R NB to give an amide of the general formula XXI which is then reduced by e.g. lithium aluminum hydride to form a compound of general formula XXII

R O R2

XXI XXII

To convert a compound of formula XXII into a compound of formula XIII, the hydroxymethyl group may be introduced using formaldehyde and acetic acid. If R and R are both hydrogen, the amino group during hydroxymethylation is protected as phthalimide. Removal of the protecting group is then carried out using hydrazine hydrate.

When neither R nor R is hydrogen, the hydroxymethylation can be carried out using butyllithium followed by formaldehyde.

When Alk represents a straight chain alkylene group containing two or more carbon atoms, the following two methods can be used.

A convenient method of use for ethylene derivatives analogous to that described above for methylene derivatives is based on the carboxylic acid of formula XXIII

hoocch2 -O XXIII

instead of furan-2-carboxylic acid.

When the alkylene chain, Alk, is more than 2 carbon atoms, the lithio derivative of formula XIV can be first treated with i) a dihaloalkane of the formula Hal-Alk-Hal, where Hal represents chlorine, bromine or iodine, and then with 1 2 il) an amine of formula RR NH to form a compound of formula XVI wherein Alk contains 3 to 6 carbon atoms.

1 2 When R and R are hydrogen, the potassium phthalimide replaces the amine 1 2 R R NH in both of the above reactions. Both reaction products are hydroxymethylated as described above, then the protecting group, if appropriate, is removed to form a compound of formula XIII.

1 2

If compounds are to be prepared wherein R and R are different from hydrogen, the free amino compounds can be converted into suitable substituted amino compounds, e.g. using formaldehyde and formic acid by an Eschweiler-Clarke technique to form dimethylamino compounds, but it is preferred to use the substituted amine at an appropriate stage in the reaction.

Amines of formula II where n is 2 can be prepared by using as a starting material a compound of general formula XXIV

{J-CH2CH2Z XXIV

wherein Z represents a leaving group, e.g. tosyloxy, mesyloxy or bromine. This compound is reacted with a ω-phthalimidoalkylthiol of formula XII. The resulting compound is then subjected to a Mannich reaction, after which the protecting group is removed to give the desired amine of formula II.

In the preparation of compounds of formula I, a compound of formula V can be reacted with a thiol of formula VII wherein: Among other things, are compounds of formula VII wherein Y is = CHNO 2 and m is 2 can be prepared from a thiazolidine intermediate of formula XXV

19 149812 / ”Λ

S NH

XXV

Ι! Ήνο2 3

by reaction with an amine R NH 2. The thiazolidine of formula XXV can be prepared from cysteamine and a bis-methylthio compound of formula XXVI

CH3S | SCH3 XXVI

CHNO 2

The thiols of formula VII wherein Y is = CHNO 2 and m is 2 are novel compounds'

The invention is further illustrated in the examples below. Preparation Examples 1-4 describe the preparation of starting materials, Examples A - L describe the preparation of amines of formula II and related intermediates, and Examples 1-27 illustrate the preparation of compounds of formula I.

Preparation Example 1.

a) 5- (Methylamino) methyl-2-furanmethanol.

A mixture of 49 g of 2-furan methanol, 51.5 g of methylamine hydrochloride and 50 ml of 36% formaldehyde solution is stirred at 0 - 3 ° C for 3 hours and then allowed to stand for 16 hours. An excess of sodium carbonate is added and the slurry is extracted with ethyl acetate. After removal of solvent, the residue is distilled to give 36.2 g of 5- (methylamino) methyl-2-furan methanol, bp 111 -113 ° C / 0.2 mm Hg.

Similarly, from 2-furan methanol and the corresponding amine hydrochloride is prepared: b) 5 - [(2-Phenylethyl) amino] methyl-2-furan methanol, oil having R ^ value 0.45 (silica / acetone), NMR Spectrum (CCl4): 7.29, broad s (4H); 6.8 S (2H); 6.40 s (2H); 5.62 s (2H); 4.0 wide (2H); 2.87 s (5H).

C) 5- [(1-Methylethyl) amino] methyl-2-furan methanol, oil having Rf value 0.55 (silica) methanol).

Analysis:

Calculated for C 9 H 15 NO 2: C 63.88 H 8.94 N 8.28 Found: C 63.35 H 8.78 N 8.09.

d) 5- (Ethylmethylamino) methyl-2-furanmethanol, R ^ value 0.32 (silica / acetone), NMR spectrum (CDCl ^): 8.93 t (3H); 7.80 s (3H); 7.55 q (2H); 6.50 s (2H); 6.33 wide s (1H); 5.47 s (2H); 3.80 m (2H).

e) 5 - [[2- (Dimethylamino) ethyl] amino] methyl-2-furanmethanol-bis-salt salt, mp 119 - 121 ° C.

Preparation Example 2.

5- [2- (Ν, Ν-Dimethylamino) ethyl] -2-furanmethanol.

9.8 g of N, N-dimethyl-2-furanethanamine, 17.5 g of 30% aqueous formaldehyde and 18 ml of glacial acetic acid are heated to 70 ° C for 5 hours. The reaction mixture is cooled, adjusted to basic reaction with sodium hydroxide and extracted with ether. The organic extracts are distilled to give an oil of boiling point 90 - 100 ° C / 0.5 mm Hg.

Analysis:

Calcd. For C ^ HH ^ NCNC ^: C, 63.9; H, 8.9; N, 8.2 Found:

Preparation Example 3.

2- [1- (4-bromobutyl)] furan.

375 ml of 1.6M n-butyllithium in hexane are added to a solution of 40.8 g of furan in 375 ml of dry tetrahydrofuran and the mixture is stirred at 40 ° C for 3 hours. 129.6 g of 1,4-dibromobutane is then added at -30 ° C, 21149812 and the reaction mixture is stirred at room temperature for 4 hours. Water is added and the mixture is extracted with ethyl acetate. Distillation of the extract gives a clear colorless liquid, boiling point 60 - 62 ° C / 0.5 mm Hg.

N, N-Dimethyl-4- (2-furanyl) butaneamine.

56 g of dimethylamine are added to a solution of 82 g of 2- [1- (4-bromobutyl) 3 furan in 500 ml of toluene. The resulting solution is stirred at room temperature for 2 days, then acidified with hydrochloric acid. The acidic phase is separated, washed with ether, adjusted to basic reaction with sodium hydroxide and extracted with ether. The ethereal extract is distilled to give a clear colorless oil, boiling point 55 - 58 ° C / 0.8 mm Hg. The hydrochloride salt melts at 133 -136 ° C.

Analysis:

Calculated for C C HH NO NON.HCl: C 58.96 H 8.91 N 6.88 Found: C 59.01 H 9.02 N 6.87.

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

a) 125 ml of 1.6M n-butyllithium in n-hexane are added to an ice-cooled solution of 33.4 g of N, N-dimethyl-4- (2-furanyl) butanamine in 125 ml of dry tetrahydrofuran. The mixture is stirred at room temperature for 4 hours. 6.0 g of paraformaldehyde are then added and the mixture is stirred for an additional 1 hour. The reaction is quenched with water and extracted with chloroform. The organic extracts are distilled to give a clear colorless oil, boiling point 100 - 105 ° C / 0.1 mm Hg, mp 26 - 28.5 ° C.

v

Analysis:

Calculated for CnH19NO2: C 66.97 H 9.71 N 7.10 Found: C 67.09 H 10.01 N 7.06.

Similarly prepared: b) 5- [3- (Dimethylamino) propyl] - 2-furan methanol, boiling point 160 ° C / 0.08 mm Hg, m.p. 24 ° C.

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Analysis:

Calculated for C 10 H 17 NO 2 .1 / 5H 2 O: C 64.28 H 9.39 N 7.50 Found: C 64.66 H 9.36 N 7.39.

Preparation Example 4.

[5- [4- [N, N-Dimethylamino] butyl] -2-furanylmethylethanoate.

A mixture of 4.9 g of 5- [4- (dimethylamino) butyl] -2-furan methanol, 25 g of acetic anhydride and 10 g of molten and powdered sodium acetate in 25 ml of benzene is stirred at room temperature for 24 hours. The reaction mixture is diluted with 100 ml of water and extracted with ethyl acetate.

The combined extracts are distilled to give a clear colorless oil, boiling point 100 ° C / 0.5 mm Hg.

Analysis:

Calculated for C C ^H ^NO ^: C 65.24 H 8.85 N 5.85 Found: C 65.62 H 9.03 N 5.95.

Example A.

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

15.5 g of 5- (dimethylamino) methyl-2-furan methanol are added dropwise to a stirred, ice-cold solution of 11.36 g of cysteamine hydrochloride in 40 ml of concentrated hydrochloric acid. After standing at 0 ° C for 18 hours, an excess amount of anhydrous sodium carbonate is added and the resulting solid is extracted with diethyl ether. Removal of the solvent followed by distillation of the residue leads to 11.6 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine, bp 104 - 106 ° C / 0.1 mm Hg. The picrate salt melts at 142 - 144 ° C.

Similarly, from the corresponding furan methanols and cysteamine hydrochloride are prepared: b) 2 - [[[5- (Methylamino) methyl-2-furanyl] methyl] thio] ethanamine, whose monopyrate salt melts at 116 - 118 ° C.

C) 2 - [[[5 - [(1-Methylethyl) amino] methyl-2-furanyl] methyl] thio] ethanamine, oil, R R value 0.4 (silica / methanol: 0.880 ammonia) in the ratio 79: 1).

d) 2 - [[5- (Diethylaminomethyl) -2-furanyl] methyl] thio] ethanamine, bp 134-135 ° C / 1 mm Hg.

e) 2 - [[t5 “(1-Piperidinyl) methyl-2-furanyl] methyl] thio] ethanarain, oil, R ^ value 0.37 (silica / methanol, 880 ammonia in a 79: 1 ratio).

g) N- [5- [[[(2-Aminoethyl) thio] methyl] -2-furanyl] methyl] benzenethanamine, oil, R, value 0.33 (silica / methanol: 0.880 ammonia in the ratio 79: 1).

h) 2- [[[5-t2- (Dimethylamino) ethyl] -2-furanyl] methyl] thio] ethanamine, bp 150 - 155 ° C / 0.04 mm Hg.

i) 2- [[[5- [3- (Dimethylamino) propyl] -2-furanyl] methyl] thio] ethanamine, boiling point 150 ° C / 0.05 mm Hg.

j) 2 - [[[5- (Ethylmethylamino) methyl-2-furanyl] methyl] thio] ethanamine, R 2 value 0.34 (silica / methanol: 0.880 ammonia in a 79: 1 ratio).

k) 2 - [[[5 - [(2-Dimethylaminoethyl) amino] methyl-2-furanyl] methyl] thio] -ethanamine, the tris.-maleate salt melts at 132-135 ° C.

l) 2 - [[[5- (1-Pyrrolidino) methyl-2-furanyl] methyl] thio] ethanamine, the bis-oxalate salt melts at 136.5 - 138.5 ° C.

Example B.

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

4.5 g of cysteamine hydrochloride are added to a cooled solution of 8.98 g of potassium tert-butoxide in 125 ml of dry dimethylformamide. The mixture is stirred for 20 minutes and 9.6 g of [5- [4- (dimethylamino) butyl] -2-furanyl] methylethanoate is added. The reaction mixture is heated to 90 ° C for 4 hours, poured onto an ice / water mixture and extracted with chloroform. Distillation of the organic extract gives a yellow oil which after column chromatography on silica using methanol: 0.880 9: 1 ammonia as eluent and further distillation gives a colorless oil with boiling point 140 ° C / 0.05 mm Hg .

Analysis:

Calculated for C 13 H 24 N 2 OS: C 60.91 H 9.44 N 10.93 Found: C 60.81 H 9.86 N 10.44.

Example C.

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

0.155 g of 80% sodium hydride is added portionwise to a solution of 1.03 g of 2-phthalimido-ethanethiol in dry dimethylformamide at 0 ° C. After 20 minutes, a solution of 1.33 g of 2-furanethanol-4-methylbenzenesulfonate in dry dimethylformamide is added dropwise and the solution is stirred overnight at room temperature. The mixture is poured into ice water and 1.3 g of 2 - [[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H) dione is isolated as a white solid, m.p. 53-55 ° C.

Example D.

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

1.58 g of 80% sodium hydride is saturated portionwise to a solution of 6 g of furfury imercaptan in 50 ml of dry dimethylformamide. After 30 minutes, a solution of 16.71 g of 2-bromethylphthalimide in 65 ml of dry dimethylformamide is added and the solution is heated to 110 ° C for 2 days. After removal of solvents, the residue is washed with water and extracted with ethyl acetate. The ethyl acetate extracts are combined, the solvent removed and the residue recrystallized from cyclohexane to give 7.8 g of 2- [2--[(2-furanyl) methyl] thio] ethyl] -1H-isoindole-1,3 (2H) dione , mp 62 - 63 ° C.

Similarly prepared from the ω-bromoalkylphthalimide and fururylmercaptan: b) 2- [3- [[(2-Furanyl) methyl] thio] propyl] -1β-isoindole-1,3 (2H) dione, NMR Spectrum (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 (1H) ·, 2.4 m (4H).

c) 2- [4 - [[(2-Furanyl) methyl] thio] butyl] -1H-isoindole-1,3 (2H) dione, NMR spectrum (CDCl3) δ 8 - 8.5 m (4H) ; 7.49 t (2H); 6.33 m (4H); 3.7 η - (2H); 2.7 m (1H); 2.3 m (4H).

Example E.

a) 2- [2- [I [5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -1H-isoindole-1,3 (2H) dione.

A mixture of 10 g of 2- [2 - [[(2-furanyl) methyl] thio] ethyl] -ΙΗ-isoindole-1,3 (2H) dione, 3.1 g of dimethylammonium chloride and 3 ml of 36% formaldehyde solution in 50 ml of acetic acid is heated on a steam bath for 9 hours. The solution is cooled and the solvent removed in vacuo. The residue is adjusted to basic reaction with 5N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is treated with activated charcoal, dried and evaporated to give 5.7 g of an oil which is purified by column chromatography (silica / ethanol: ethyl acetate in a 1: 1 ratio), R ^ value 0.4. NMR Spectrum (CDCl3 / dimethylsulfoxide): 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 (4H).

Similarly, from 2- [ω - [[(2-furanyl) methyl] thio] alkyl] -1H-isoindole-1,3 (2H) dione, the corresponding amine and formaldehyde are prepared; b) 2- [2- [[[5- [(1-Pyrrolidinyl) methyl] -2-furanyl] methyl] thio] ethyl] -1H-isoindole-1,3 (2H) dione. NMR Spectrum (CDCl 3): 8 - 8.4 m (4H); 7 - 7.6 m (6H); 6 - 6.5 m (6H); 3.7 - 4.0 m (2H) j 2 - 2.4 m (4H).

c) 2- [3- [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -1H-isoindole-1,3 (2H) dione, R ^ value 0.45 (silica / methanol).

d) 2- [4 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] butyl] -1H-isoindole-1,3 (2H) dione, R 2 value 0.26 (silica / methanol). NMR Spectrum (CDCl3): 8.85 m (4H)? 7.7 s (6H); 7.42 t (2H); 6.52 s (2H); 6.29 m (4H); 3.9 m (2H); 2 - 2.4 m (4H).

(E) 2 - 12 - [[5- [(4-Methyl-1-piperazinyl) methyl] -2-furanyl] methyl] thiol-ethyl] -1H-SiSOin-1/3 (2H) dione . NMR Spectrum (CDCl3): 7.75 s (3H); 7.52 s (8H); 7 - 7.5 m (2H); v.6.5 s (2H); 6 - 6.3 m (4H); 3.85 m (2H); 2 - 2.4 m (4H).

f) 2- [2- [[[5- [(4-Morpholinyl) methyl] -2-furanyl] methyl] thio] ethyl] -1H-isoindole-1,3 (2H) dione. NMR Spectrum (CDCl3): 7.54 m (4H); 7.24 m (2H); 6.50 s (2H) j 6.22 m (8H); 3.8 m (2H); 2.0 - 2.4 m (4H).

Example F.

2- [2 - [[2- [5- (dimethylamino) methyl-2-furanyl] -ethyl] thio] ethyl] -LH-iso-indole-1,3 (2H) dione.

0.5 g of 2 - [[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H) dione, 0.27 g of dimethylamine hydrochloride and 0.102 g of paraformaldehyde are heated together under reflux in ethanol . After 5 hours, an additional 0.27 g of dimethylamine hydrochloride and 0.102 g of paraformaldehyde are added and heating is continued for an additional 16 hours. The solvent is removed and the residue is adjusted to basic reaction and extracted with ethyl acetate to give an oil which, after column chromatography (silica / methanol), gives 0.43 g of 2- [2 - [[2- [5- (dimethylamino)] methyl 2-furanyl] ethyl] thio] ethyl] -1H-isoindole-1,3 (2H) dione in the form of a light oil.

Analysis:

Calcd for CigH22N2O3S.3 / 4H2O: C, 61.35; H, 6.37; N, 7.53. Found: C, 61.48;

NMR Spectrum (CDCl3): 2.15, AA BB, (4H); 3.90, AB, (2H); 6.08, t, (2H) ·, 6.50, s, (2H); 7.08, s, 7.15, t, (6H); 7.69, s, (6H).

Example G.

2 - [[5- (Dimethylamino) methyl-2-furanyl] methoxy] ethanamine, reaction pathway i).

To a solution of 6.2 g of 5- (dimethylamino) methyl-2-furanmethanol and 2.82 g of ethyleneimine in dry tetrahydrofuran is added a solution of 11.6 g of methanesulfonic acid in 40 ml of tetrahydrofuran. The solution is evaporated and the oily residue is heated to 98-100 ° C for 10 minutes. After 18 hours, 60 ml of 5N sodium hydroxide solution is added and the solution is evaporated to dryness. Anhydrous sodium sulfate and 150 ml of ethyl acetate are added and after 2 hours the suspension is filtered, decolorized with activated charcoal and evaporated. The resulting oil is chromatographed on silica, first with methanol / ammonia 0.88 in the ratio of 79: 1, then the eluate is discarded, and then with methanol / ammonia 0.88 in the ratio 19: 1. This eluate is evaporated to give an oil from which (of ethanol) 0.2 g of bis-oxalate salt is obtained. of 2 - [(5- (dimethylamino) methyl-2-furanyl] methoxy] ethanamine, m.p. 125 - 128 ° C.

Reaction pathway ii).

A solution of 6.25 g of 2-chloroethylamine hydrochloride in dry dimethylformamide is added dropwise to a stirred, cooled solution of 8.96 g of potassium tert-butoxide and 12.4 g of 5- (dimethylamino) methyl-2 furan-methanol in the same solvent. After 2 hours, the solvent is removed and the residue is adjusted to basic reaction and extracted with ethyl acetate. After removal of the solvent, the residue in ethanol is treated with ethanolic oxalic acid. The crystalline salt is recrystallized from ethanol to give 3.05 g of 2 - [[5- (dimethylamino) methyl-2-furanyl] methoxy] ethanamine, bis-oxalate, m.p. 130 - 133 ° C.

Similarly, reaction pathway ii) is prepared: b) 2- [[5- (Methylamino) methyl) -2-furan] methoxy] ethanamine, bis-oxalate, m.p. 162 - 164 ° C.

Example H.

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

406 mg of 2- [1- (4-bromobutyl)] furan and 370 mg of potassium phthalimide are stirred at room temperature overnight in dry dimethylformamide. The solution is poured onto ice water and the resulting white solid is filtered, dried and recrystallized from chloroform / petroleum ether (boiling range 60 - 80 ° C) to give 430 mg of 2- (4- (2-furanyl) butyl] -1H-isoindole-1,3 (2H) dione in the form of white microcrystals, mp 61-63 ° C.

Similarly, b) 2- [5- (2-Furanyl) pentyl] -1H-isoindole-1,3 (2H) dione, m.p. 54-56 ° C.

Example I.

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

5.38 g of 2- [4- (2-Furanyl) butyl] -1H-isoindole-1,3 (2H) dione, 1.2 g of para-formaldehyde and 3.26 g of dimethylamine hydrochloride are refluxed in 100 ml absolute ethanol. After 6 hours, an additional 0.6 g of paraformaldehyde and 1.6 g of dimethylamine hydrochloride are added and heating is continued for an additional 20 hours. The solvent is removed, the residue is made strongly basic with 5N sodium hydroxide solution and extracted with ethyl acetate and the organic phase is evaporated. The crude product is purified by column chromatography to give 3.25 g of amber oil with R ^ value 0.4 (silica / methanol). NMR Spectrum (CDCl3): 8 - 8.6 m (4H); 7.75 s (6H); 7.3 m (2H); 6.55 s (2H); 6.3 m (2H); 4.0 m (2H); 1.9 - 2.4 m (4H).

Similarly: b) 2- [5- [5- (Dimethylamino) methyl-2-furanyl] pentyl] -1H-isoindole-1,3- (2H) dione. R ^ value by thin layer chromatography: 0.4 (silica / methanol). NMR Spectrum: 8.0 - 8.8 m (6H); 7.70 (6H); 7.37 t (2H); 6.52 s (2H) j 6.3a t (2H); 4.0 m (2H) ·, 2.2 m (4H).

Example J.

5- (Dimethylamino) methyl-2-furanpropanamin.

1.21 g of furan propionitrile, 1.62 g of dimethylamine hydrochloride and 0.7 g of paraformaldehyde in 20 ml of ethanol are heated at reflux for 24 hours. The solvents are removed and the residue is adjusted to basic reaction, pH 12, and extracted with ethyl acetate. After removal of solvents, the oil recovered as the residue is purified by column chromatography (silica / methanol) and isolated 0/6 g of 5- (dimethylamino) methyl-2-furanopropionitrile, R .

6.0 g of the nitrile in 40 ml of dry ether are added dropwise with stirring to 2.0 g of lithium aluminum hydride in ether at 0 ° C. Water is added, the solvents removed and, after column chromatography, 3.33 g of 5- (dimethylamino) methyl-2-furan propanamine is obtained as a light oil. NMR Spectrum (CDCl3): 8.2 m (2H); 7.6 wide (2H); 7.75 s (6H); 7.30 m (4H) j 6.60 s (2H) j 4.0 m (2H).

Example K.

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

1.9 g of sulfur are added portionwise to a solution of 7.5 g of the lithio derivative of Ν, Ν-dimethylfuran methanamine at -40 ° C. The mixture is stirred at -10 ° C for 20 minutes and 16 g of 2- (3-bromopropyl) 1H-isoindole-1,3 (2H) dione is added. The mixture is allowed to stand at 0 ° C overnight, the solvent is removed in vacuo and the residue in ethyl acetate is filtered and extracted with 2N sulfuric acid solution. The aqueous phase is adjusted to basic reaction and back extracted with ethyl acetate and the organic phase is dried. Upon removal of the solvent, a crystalline solid is obtained which upon recrystallization from ethanol (activated carbon) gives 7.59 g of 2- [3 - [[[5- (dimethylamino) methyl] -2-furanyl] thio] propyl]] - 1H -isoindole-1,3 (2H) dione, m.p. 64 - 65WC.

Example L.

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

2.9 g of 2- [[4- (5-dimethylamino) methyl-2-furanyl] butyl] -1H-isoindole-1,3- (2H) dione and 0.55 ml of hydrazine hydrate are refluxed in ethanol for 6 hours. The solvent is removed and the crystalline residue is dissolved in 5N sodium hydroxide solution. This solution is extracted with ethyl acetate and, by removing the solvent, the product is obtained in the form of 1.68 g of volatile yellow oil. Thin layer chromatography (silica / methanol) gives a single spot, Rf value 0.15.

14 149812 NMR Spectrum (CDCl 8): 8.0 - 8.8 m (4H); 7.7 s (6H); 7.6 wide (2H) j 7.3 m (4H); 6.58 s (2H); 4.0 m (2H).

Similarly, from the corresponding phthalimide is prepared: b) 5- [5- (Dimethylamino) methyl-2-furanyl] pentanamine. NMR Spectrum (CDCl3): 8.0 - 8.8 m (6H); 7.75 s (6H) \ 7.0 - 7.6 m (4H); 6.60 s (2H)} 4.0 m (2H).

c) 5- [C (3-Aminopropyl) thio] methyl] -N, N-dimethylfuran-2-methanamine. NMR Spectrum (CDCl3): 8 - 8.5 m (2H); 7.75 s (6H); 7.42 t (2H)} 7.25 m (2H); 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] -Ν '- methylthiourea.

5.3 g of 2- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -1Η-isoindole-1,3 (2H) dione and 0.85 g of hydrazine hydrate are refluxed ethanol for 30 hours. Evaporation of the solvent gives the phthalhydrazide salt of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine.

1 g of this salt is suspended in acetonitrile and 0.21 g of methyl isothiocyanate is added. The suspension is stirred at room temperature for 5 hours and at 60 ° C for 2 hours, filtered and evaporated to give an oil which is purified by column chromatography (silica / methanol). N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea is isolated in the form of 0.3 g of light oil.

Analysis:

Calculated for C 12 H 21 N 3 OS 2: C 50.14 H 7.37 N 14.62 Pound: C 49.68 H 7.52 N 14.22.

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

Analysis:

Calcd. For C 14 H 23 N 3 O 2 2.1 / 2H 2 O: C 52.14 H 7.50 N 13.03 Found: C 52.33 H 7.12 N 13.17.

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

Analysis:

Calcd for c14 H25 N3 OS2: c 51.82 H 8.08 N 12.95

Found: C, 51.69; H, 8.53; N, 12.83.

d) N- [3 - [[5- (Dimethylamino) methyl-2-furanyl] thio] propyl] -N'-methyl-thiourea.

Analysis:

Calcd for C12 H21 N3 OS2: C 50.10 H 7.30 N 14.62

Found: C, 49.71; H, 7.33; N, 14.35.

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

Analysis:

Calculated for C 14 H 23 N 3 O 2 S 2: C 51'03 H 7'04 N 12> 75

Found: C, 51.26; H, 7.08; N, 12.51.

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

Analysis:

Calcd for C 15 H 2 N 4 OS 2: C 51.25 H 8.03 N 15.94

Found: C, 50.93; H, 7.74; N, 15.82.

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

Analysis:

Calcd for C 13 H 23 N 3 O 3 · 0.1 / 2H 2 O: C 50.32 H 7.74 N 13.54

Found: C 50.19 H 7.20 N 13.18.

32 149812

Example 2.

a) N- [5- [5- (Dimethylamino) methyl-2-furanyl] pentyl] -Ν'-methylthiourea.

0.5 g of 5- [5- (dimethylamino) methyl-2-furanyl] pentanamine and 0.25 g of methyl isothiocyanate are stirred in acetonitrile at room temperature for 24 hours. The solvent is removed and the product purified by column chromatography (silica / methanol) to give, after trituration with ether, N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] - N'-methylthiourea as off-white crystals, m.p. 66-69 ° C.

Similarly prepared from the corresponding amine and methyl isothiocyanate: b) N- [3 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] propyl] - N'-methylthiourea.

Analysis:

Calculated for C 13 H 23 N 2 OS 2: C 51.79 H 7.69 N 13.94 Found: C 51.38 H 7.93 N 13.41.

c) N- [4- [5- (Dimethylamino) methyl-2-furanyl] butyl] -N1-methylthiourea. NMR Spectrum (CDCl3) τ = 8 - 8.6 m (4H); 7.72 s (6H); 7.35 t (2H); 6.98 d (3H); 6.2 - 6.8 m (4H); 4.0 d (2H); 3 - 3.8 m (2H).

d) N- [2 - [[5- (Dimethylamino) methyl-2-furanyl] methoxy] ethyl] -N'-methyl-thiourea.

Analysis:

Calculated for C 12 H 21 N 3 O 2 S.1 / 2H 2 O: C 51.40 H 7.91 N 14.99 Found: C 51.91 H 8.14 N 14.98.

Example 3

a) N- [2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N · - (2-methoxyethyl) thiourea.

1.17 g of 1- (isothiocyanato) -2-methoxyethane and 2.14 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine in acetonitrile are allowed to stand overnight. The solvent is removed and the residue oil chromatographed (silica / methanol) to give N - [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N '- ( 2-methoxyethyl) thiourea in the form of a light oil, R 2 value 0.45.

Analysis:

Calcd for C₂jH₂NN3 ° 2S2; c 50.75 H 7.55 N 12.69 Found: C 50.64 H 7.51 N 12.58.

Similarly prepared from the corresponding isothiocyanate 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:

Calcd for C 14 H 23 N 3 O 2 2.1 / 2H 2 O: C 52.14 H 7.50 N 13.03

Found: C, 52.68; H, 7.58; N, 13.16.

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

Analysis:

Calcd for C 14 H 25 N 3 O 2 2.1 / 2H 2 O: C 51.90 H 8.09 N 12.97

Found: C 51.84 H 7.88 N 13.00.

Example 4

N- [2- [[[5- (Methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-urea.

To a stirred solution of 1.5 g of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine in 24 ml of acetonitrile is added dropwise a solution of 0.45 g of methyl isocyanate in 15 ml. ml of acetonitrile. After 30 minutes, the solution is evaporated to dryness to give an oil which is column chromatographed first on silica / methanol: 79: 1 ammonia at 79: 1, then on alumina / methanol to give 0.25 g of an oil consisting of N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν'-methylurea.

Analysis:

Calcd. For c11 H19 N3 O2 S: c 51.33 H 7.44 N 16.33 Found: C 51.00 H 7.38 N 15.91.

Example 5

a) N- [2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N * methylurea.

0.33 g of methyl isocyanate is added to a suspension of 2 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine-phthalhydrazide complex in 50 ml of acetonitrile. After 2 hours, the solution is filtered and the filtrate is evaporated to give an oil which is purified by column chromatography (silica / methanol) to give N- [2 - [[5- (dimethylamino) methyl-2-furanyl] methyl ] thio] ethyl] -N'-methylurea.

Analysis:

Calc'd for 1/41 O: C 52.24 H 7.76 N 15.32

Found: C, 52.38; H, 7.61; N, 15.25.

Similarly prepared: b) N-Methyl-N '- [2 - [[[5- (1-pyrrolidinyl) methyl-2-furanyl] methyl] thio] ethyl] urea.

Analysis:

Calculated for C ^ H ^ N ^ S 1/25 ° C: C, 54.87; H, 7.89; N, 13.71

Found: C, 54.70; H, 7.33; N, 14.07.

Example 6

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

2.14 g of 2- [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and 0.89 g of isopropyl isocyanate are dissolved in acetonitrile and left to stand overnight. The solvents are removed and the residue is recrystallized from methanol: ether to give 2.8 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν '- ( 1-methylethyl) urea in the form of crystals, mp 65-67 ° C.

Similarly prepared: b) N- [3- [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N, - methylurea melting point 69-69.5 ° C.

Example 7

N-12 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] urea.

A solution of 2.8 g of 2 - [[15- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine dihydrochloride and 3.75 g of potassium cyanate in 50 ml of water is heated in a steam bath for 8 hours. An excess amount of solid sodium carbonate is added and organic matter is continuously extracted with diethyl ether. The extracts are evaporated and the residue after column chromatography gives 1.28 g of N-12- [[(5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] urea as a waxy solid.

Analysis:

Calculated for CuH19N3O2SH2O: C 48.00 H 7.63 N 15.27 Found: C 48.22 H 7.50 N 15.61.

Example 8.

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

A solution of 2.14 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and 1.5 g of S-methyl-N-nitroisothiourea in 10 ml of ethanol is heated to 40 ° C 5 minutes. The resulting precipitate is filtered off and recrystallized from ethyl acetate and petroleum ether (boiling range 80-100 ° C) to give N- [2 - [[[5- (di-3δ 149812 methylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N1-nitroguanidine, mp 103 - 104 ° C.

Example 9

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

A mixture of 2.0 g of 2 - [[[5- (methylamino) methyl] -2-furanyl] methyl] thio] ethanamine and 1.25 g of N-cyano-N'-methylcarbamimidothioic acid methyl ester is heated on a steam bath. for 6 1/2 hours. Vacuum is applied at regular intervals to remove methane thiol. The crude product is purified by column chromatography, R ^ value 0.65 (silica / methanol: 79: 1 ratio) to give 1.05 g of N-cyano-N '- (2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "-methyl-guanidine, mp 81-85 ° C.

Similarly prepared from the corresponding amine and N-cyano-N'-methylcarbamimidothioic acid methyl ester: b) N-Cyano-N '- [2-Γ [(5- (1-methylethyl) amino] methyl-2-furanyl ] methyl] thio] ethyl] -N "methylguanidine.

Analysis:

Calculated for C 14 H 23 N 5 OS: C 54.34 H 7.49 N 22.64 Found: C 54.73 H 7.82 N 22.31.

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

Analysis:

Calcd for C 15 H 25 N 5 S 3 / 4H 2 O: C, 53.46; H, 7.70; N, 20.78

Found: C, 53.54; H, 7.82; N, 20.65.

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

Analysis:

Calcd for C 15 H 23 N 5 S * 3 / 4H 2 O: C 53.79 H 7.37 N 20.91

Found: C, 53.97; H, 6.87; N, 21.06.

E) N-Cyano-N '- [3 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N "-methylguanidine.

Analysis:

Calculated for C 14 H 23 N 5 S 1 / 2H 2 O: C 52.80 H 7.59 N 21.20 Found: C 52.86 H 7.49 N 20.64.

Example 10.

N-Cyano-N '- [2 - [[[5- (dimethylamino) methy1-2-furanyl] methyl] thio] ethyl] -N "methylguanidine.

To a stirred suspension of 20.7 g of potassium carbonate in a solution of 10.7 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and 7.1 g of N-cyano N'-methylcarbamimidothioic acid methyl ester in 107 ml of acetonitrile at 70 ° C is added a solution of 9.35 g of silver nitrate in 20 ml of acetonitrile over 1 hour. The mixture is stirred for 16 hours, the solid is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 250 ml of ethyl acetate. Wash 10.5 ml of it with 6 ml of water and evaporate the ethyl acetate phase to give a solid which is crystallized from 1.75 ml of isopropyl acetate to give 0.35 g of N "-cyano-N- [2 - [[ [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylguanidine, m.p. 79 - 81.5 ° C.

To a further portion of 225 ml of the ethyl acetate phase is added a solution of 9.09 g of sebacic acid in 30 ml of ethanol and of the filtered solution 13.74 g of the sebacate salt, mp 92.5 - 94 ° C is obtained.

Analysis:

Calcd for C 13 H 21 N 5 OS * C 10 H 8 ° 4: C 55'51 H 7'90 N 14'07 Found: C 54.91 H 7.94 N 14.02.

Example 11.

N-Cyano-N'- (2-methoxyethyl) carbamimidothioic acid methyl ester.

4.2 g of powdered cyanamide is added to a stirred solution of 2.3 g of sodium in absolute ethanol. After 30 minutes, a solution of methoxyethylisothiocyanate (11.7 g) in absolute ethanol was added to the cooled solution. After a further 1 hour at room temperature, 12.66 g of dimethyl sulfate is added over 30 minutes and the mixture is stirred overnight. The solvent is removed and the solid obtained as the residue is thoroughly washed with water to give 12.37 g of N-cyano-N'-2 (methoxyethyl) carbamimidothioic acid methyl ester as a white crystalline solid, m.p. 94.5 - 95.5 ° C.

Similarly prepared: N-Cyano-N '- (2-propenyl) carbamimidothioic acid methyl ester, mp 109-110 ° C.

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

A mixture of 2.14 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine · and 1.73 g of N-cyano-N '- (2-methoxyethyl) carbimimidothioic acid methyl ester is heated on a steam bath for 6 1/2 hours. Occasional vacuum is applied to remove methane thiol. The crude product is purified by chromatography (silica gel / methanol) to give 1.4 g of N-cyano-N1- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N - (2-methoxyethyl) guanidine.

Analysis:

Calc'd for C 15 H 25 N 5 O 2 S.H 2 O: C 50.42 H 7.50 N 19.60 Found: C 50.51 H 7.20 N 19.41.

Similarly, from 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and the corresponding N-alkyl or N-alkenyl-N1-cyanocarbamimidothioic acid methyl ester are prepared: b) N-cyano-N 1- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- (2-propenyl) guanidine.

NMR Spectrum (CDCl3): τ = 3.83, s, 3.7-4.4, m, (5H); 4.5-4.9, tn, (2H); 6.13, brt, 6.27, s, (4H); 6.55, s, 6.65, q, (4H); 7.29, t, (2H); 7.72, s, (6H).

39 149812

Analysis:

Calc'd for C 15 H 23 N 5 OS * H 2 O: C 53.09 H 7.37 N 20.64

Found: C, 53.33; H, 7.01; N, 20.70.

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

Analysis:

Calc'd for c15 H25 N5 OS * H2®: C 52.78 H 7.91 N 20.52

Found: C, 52.97; H, 7.70; N, 20.57.

Example 12.

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

A mixture of 2.14 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and N, S-dimethylisothiuronium iodide is heated on a steam bath for 3 hours. The residue in methanol is eluted from an "Amberlyst A26" ® ion exchange resin to give 1.5 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -''- methyl guanidine in the form of an amber oil.

Analysis:

Calcd for C12 H22 N4 O3.3 / 4H2 O: C, 50.76; H, 8.34; N, 19.74. Found: C, 50.92; H, 8.23, N, 19.90.

Similarly prepared: b) N- [2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N ', N "-dimethylguanidine. NMR Spectrum (CDCl3): 7 , 75 s (6H) j 6.8 - 7.3 m (8H); 6.5 m (4H), 6.22 s (2H) j 3.80 m (2H); 2.0 - 2.5 broad (2H).

Example 13

N-Methyl-1-methylthio-2-nitroethenamine.

A solution of methylamine in ethanol / ethylene dichloride (112.5 ml of 33% ethanolic methylamine in 0.8 liters of ethylene dichloride; 0.94 mol) is added over 5 1/2 hours at 70 ° C to a stirred solution. of 99.0 g (0.6 mol) of 1,1-bis-methylthio-2-nitroethene in 1.5 liters of ethylene dichloride. The solution is heated to boiling and 0.7 liters of solvent are distilled off. The cooled solution is washed with 0.25 liters of 2N hydrochloric acid solution and then with 0.25 liters of brine. The solvent is removed and the residue is crystallized from 1/2 liter of isopropyl acetate while the hot solution is treated with 10.0 g of activated charcoal. The product, 35.0 g, forms yellow prisms, mp 114 ° C.

N- [2 - [[[5- (Methylamino) methyl-2-furanyl] methyl] thio] ethyl] -''-methyl-2-nitro-1,1-ethylenediamine hydrochloride.

A solution of 10 g (0.05 mol) of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine and 7.4 g of N-methyl-1-methylthio-2-nitroethenamine in 25 ml of water is stirred at 50 ° C for 2 hours. 350 ml of acetone are added and the solvent is removed by distillation at atmospheric pressure until 275 ml of distillate is collected. 27.5 ml of 2M ethanolic hydrogen chloride are added to the residue and the solution is stirred overnight at room temperature. 11.0 g of product of melting point 161 ° C is isolated and this is recrystallized from ethanol to give 10.1 g of a colorless microcrystalline solid, mp 162 ° C.

Analysis:

Calcd for C 12 H 20 N 4 O 3 S.HCl: C 42.8 H 6.2 N 16.6 Found: C 42.6 H6.3 N 16.4.

Example 14.

a) N- [2 - [[[5- (Methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- methyl-2-nitro-1,1-ethylenediamine.

A mixture of 0.9 g of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] -ethanamine and 0.6 g of N-methyl-1-methylthio-2-nitroethhenamine is heated to 100 - 120 ° C for 30 minutes under water pump pressure. The residue is purified by column chromatography (silica / methanol: 0.88 ammonia) to give N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl 2-nitro-1,1-ethylenediamine, of which 0.65 g of m.p. 106 -108 ° C is obtained by recrystallization from acetonitrile.

Similarly, b) N- [2- [[[5- (1-Methylethyl) amino] methyl-2-furanyl] methyl] thio] -ethyl] -N'-methyl-2-nitro-1 , 1-ethenediamine.

Analysis:

Calcd for C 14 H 24 N 4 O 3 S.1 / 2H 2 O: C 49.83 H 7.47 N 16.60 Found: C 49.75 H 7.21 N 16.36.

NMR Spectrum (CDCl3): T = -0.3, brs, (1H) ·, 3.0, brs, (1H); 3.38, s, (1H); 3.85, AB, (2H); 6.25, s, (4H); 6.60, m, (2H); 6.90-7.40, m, (6H) j 8.00 brs, (1H); 8.92, d, (6H).

c) N-Methyl-2-nitro-N '- [2- [i [5 - [(2-phenylethyl) amino] methyl] -2-furanyl] methyl] thio] ethyl] -1,1-ethylenediamine .

Analysis:

Calcd for CigH26N403S.1 / 2H2O: C 57.12 H 6.81 N 14.02

Found: C, 57.19. H, 6.53; N, 13.83.

NMR Spectrum (CDCl3): T = 2.50-3.00, m, (5H); 3.43, ε, (1H); 3.90, m, (2H); 6.28, s, 6.31, s, (4H); 6.50-7.00, m, (2H); 7.00-7.50, m, (9H); 7.90, m, (2H).

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

Analysis:

Calculated for C C ^H₂gN40O3S.1 / 4H₂O: C, 53.33; H, 7.44; N, 15.61

Found: C, 53.36; H, 7.51; N, 14.23.

NMR Spectrum (CDCl3): T = 0-0.5, brm (1H); 3.35, s, (1H); 3.80, s, (2H); 6.28, s, (2H); 6.50, s, 6.30-6.80, m, (5H); 6.80-7.40, m, (5H); 7.40-7.80, m, (4H); 8.00-8.80, m, (6H); E) N- [2- [[[5- [2- [Dimethylamino] ethyl] -2-furanyl] methyl] thio] ethyl] - N, -methyl-2-nitro-1,1-ethylenediamine, mp 95.5 - 96 ° C.

f) N- [2 - [[[5- [3- [Dimethylamino] propyl] -2-furanyl] methyl] thio] ethyl] - N'-methyl-2-nitro-1,1-ethylenediamine. NMR Spectrum (CDCl3): τ = 8.1 - 7.1 m (6H); 7.65 s (6H)} 7.1 s (3H) f 6.5 m (2H); 6.28 s (2H) · 4.0m (2H); 3.38 s (1H).

g) N- [2 - [[[5- [4- [Dimethylamino] butyl] -2-furanyl] methyl] thio] ethyl] - N-methyl-2-nitro-1,1-ethylenediamine. Waxy solid.

Analysis:

Calcd for C 18 H 28 N 4 O 3 S: C 53.91 H 7.92 N 15.72 Found: C 53.90 H 7.95 N 15.64.

NMR Spectrum (CDCl3): δ = 3.38, s, (1H); 3.83, 4.03, AB, (2H); 6.30, s, (2H); 6.30-7.50, m, (11H); 7.80, s, (6H); 8.00-8.70, m, (4H).

h) N- [2 - [[[5- (Ethylmethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N'-methyl-2-nitro-1,1-ethylenediamine. NMR Spectrum (CDCl3): τ = 8.90 t (3H); 7.76 s (3H) j 6.8 - 7.5 m (7H); 6.5 wide (2H); 6.42 s (2H); 6.25 s (2H); 3.77 s (2H); 3.35 s (1H).

i) N- [2 - [[[5 - [[2- (Dimethylamino) ethyl] amino] methyl-2-furanyl] methyl] -thio] ethyl] -Ν'-methyl-2-nitro-1,1- ethenediamine. NMR Spectrum (CDCl3): τ = 7.79 s (6H); 7 - 7.6 m (10H); 6.6 m (2H); 6.26 s (2H); 6.22 s (2H); 3.85 m (2H); 3.37 s (1H) ·, 2 - 3.2 wide (1H) j 0.8 - 0.2 wide (1H).

j) N- [2- [5- (Dimethylamino) methyl-2-furanylmethoxy] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine, m.p. 110-112 ° C.

Example 15

N-Methyl-2-nitro-N'- [2- [[[5- [(1-pyrrolidinyl): methyl] -2-furanyl] methyl] thio] ethyl] -1,1-ethylenediamine.

A mixture of 2.1 g of 2 - [[[5- (1-pyrrolidino) methyl-2-furanyl] methyl] thio] ethanamine bis-oxalate salt, 1.12 g of potassium hydroxide and 0.9 g of N-methane. Thyl- (1-methylthio) -2-nitroethenamine 1 9 ml of water is stirred at room temperature for 18 hours. The water is removed by evaporation under reduced pressure and the residue is extracted with ethyl acetate in the presence of an excess amount of anhydrous sodium carbonate. Evaporation of the solvent gives a residue which is crystallized by isopropyl acetate to give 0.9 g of white crystalline solid, mp 79 - 82 ° C.

Analysis:

Calculated for C 52.92 H 7.11 N 16.46

Pound: C 52.78 H 7.05 N 16.57.

Example 16.

N- [2 - [[[5- (methylamino) methy1-2-furanyl] methyl] thio] ethyl] -Ν'-Me-thylurinstof.

To a stirred solution of 2.0 g of N- [2-mercaptoethyl] -N'-methylurine substance in concentrated hydrochloric acid at 0 ° C is added dropwise a solution of 2.0 g of 5- (methylamino) methyl-2-furan methanol in 3 ml of water. After 24 hours, add 100 ml of ethyl acetate and an excess of anhydrous sodium carbonate. The suspension is filtered, the filtrate is evaporated to dryness and the oily residue is subjected to column chromatography (silica / methanol: 0.88 ammonia in a 79: 1 ratio). The relevant eluate is evaporated to dryness to give 0.42 g of an oil identical to the product of Example 4.

NMR Spectrum (CDCl 3): τ = 3.85, s, (2H); 4.3-4.8, m, (2H); 6.27, s, (4H); 6.64, q, (2H); 7.22, d, 7.32, t, 7.54, s, (8H); 8.05, brs, (1H).

Example 17

N-Cyano-N '- [2 - [[[5- (dimethylamino) methy1-2-furanyl] methyl] thio] ethyl] -N "methylguanidine.

To a stirred solution of 1 g of N-cyano-N '- (2-mercaptoethyl) -N' - methylguanidine in concentrated hydrochloric acid at 0 ° C is added dropwise over 10 minutes 0.98 g of 5- (dimethylamino) -2 -furanmethanol.

After 3 hours at room temperature, the solution is neutralized with an excess amount of anhydrous sodium carbonate and the resulting ice cream is extracted with ethyl acetate. Evaporation of the solution gives an oil from which, after column chromatography, a product identical to the compound of Example 10 is obtained.

NMR Spectrum (CDCl 3): τ = 3.82, s, 3.6-4.4, brm, (4H); 6.28, s, (2H); 6.57, s, 6.63, q, (4H); 7.15, d, 7.30, t, (5H); 7.65, s, (1H).

Example 18 - [2- [[5- (Aminomethyl) -2-furanylmethyl] thio] ethyl] -N "-cyano-N'-methyl-1-guanidine.

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

10 g of 2- (5-hydroxymethyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) dione is dissolved in 15 ml of thionyl chloride with gentle heating. The solution is evaporated to dryness and the solid residue is evaporated again with 1: 1 cyclohexane benzene. The residue is suspended in ether and the suspension is filtered, washed with ether and dried to give 10.1 g of 2- (5-chloromethyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) dione, m.p. 122 ° C (dec.).

Analysis:

Calc'd for C 14 H 10 ClNO45 C 60.99 H 3.66 N 5.08 Found: C 61.32 H 3.71 N 5.00.

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

To a stirred solution of 1.0 g of N-cyano-N- (2-mercaptoethyl) -N * -methylguanidine and 0.152 g of sodium hydride in 4 ml of dry dimethylformamide at room temperature is slowly added a solution of 1.74 g of 2- ( 5-Chloro-methyl-2-furanylmethyl) -1H-isoindole-1,3 (2H) dione in 8 ml of dry dimethylformamide After stirring for 2 hours the solution is evaporated to dryness and the oily residue is suspended in a mixture of 25 Ethyl acetate (20 ml) and water (20 ml) The solid residue is filtered and crystallized by methanol to give 1.4 g of the title compound, mp 179 - 182 ° C.

U9812 N- [2- [[5- (Aminomethyl) -2-furanylmethyl] thio] ethyl] -KT-cyano-N'-methyl-guanidine.

A suspension of 4.45 g of N "-cyano-N- [2 - [[5 - [(1,3-dioxo-2H-isoindol-2-yl) methyl] -2-furanylmethyl] thio] ethyl] The N'-methylguanidine and 0.6 g of hydrazine hydrate in 35 ml of methanol are heated at reflux for 4 hours, the suspension is evaporated to dryness and the residue is dissolved in 15 ml of water at 0 ° C and neutralized with 5N hydrochloric acid solution. The residue is mixed with anhydrous sodium sulfate and the solid is extracted with ethanol, and by evaporation of the extract a semi-solid is mixed with anhydrous sodium sulfate and extracted with ethyl acetate to give 2 12 g of an oil which is subjected to column chromatography (silica / methanol, 88 ammonia in a 79: 1 ratio).

Evaporation of the relevant eluate gives a slowly solidifying oil, which constitutes 1.88 g of the title compound, mp 80 - 82 ° C.

Analysis:

Calculated for C C-H ^NgOS: C 49.41 H 6.41 N 26.20 Found: C 49.57 H 6.66 N 25.93.

Example 19.

N-Cyano-N 1 T 2 [f [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N "methylguanidine.

N-Cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -carbamimidothiosyre acid methyl ester.

1.07 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine are added to a solution of 0.73 g of N-cyanoimidocarbamodithioic acid-dimethyl ester in ether and stirred overnight. The crystalline substance formed is filtered off, washed with ether and dried to give 1.14 g of N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl ] carbamimidothioic acid methyl ester, m.p. 78-79 ° C.

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

A solution of 1.06 g of N'-cyano-N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] carbamimidothioic acid methyl ester in 10 ml of 33% ethanolic methylamine Stir at room temperature for 4 hours.

. The solution is evaporated to dryness, and the oily residue is crystallized by ethyl acetate / petroleum ether (boiling range 80 - 100 ° C) to give the title compound, mp 77 - 80 ° C.

Example 20

N-Cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N "-heptylguanidin.

A mixture of 1.15 g of heptylamine and 3.12 g of N-cyano-N * - [2 - [[(5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] carbamimidothioic acid is heated on an oil bath to 100 ° The product is chromatographed (silica / methanol) to give 2.31 g of N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl ] -N "-heptyl-guanidine hydrate, R ^ value 0.49.

Analysis:

Calcd. For ^ - ^ Η ^ βΝ ^ Οε.ί ^ Ο: C 57.43 H 8.81 N 17.63 Found: C 56.99 H 8.32 N 17.53.

Example 21.

a) N- (2- [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- (2-methoxyethyl) -2-nitro-1,1-ethylenediamine.

2.14 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and 1.65 g of 1,1-bis (methylthio) -2-nitroethene are refluxed in acetonitrile for 8 hours . The solvents are removed and an ethanolic solution of 0.75 g of 2-methoxyethylamine is added. After refluxing for an additional 8 hours, the solvents are removed to give an oil. This is purified by column chromatography to give 1.0 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν '- (2-methoxyethyl) -2 -nitro-l, l - ethenediamine.

NMR Spectrum (CDCl3): τ = 7.73 s (6H); 7 - 7.5 m (2H) j 6.2 - 7 m (1H); 6.23 s (2H); 3.81 s (2H); 3.42 s (1H).

Similarly prepared: b) N- [2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -2-nitro-1,1-ethylenediamine, m.p. 100-101 ° C.

Example 22.

a) N- [4- [5- (Dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro - 1,1-ethylenediamine.

0.7 g of 4- [5- (dimethylamino) methyl-2-furanyl] butanamine and 0.6 g of 1,1-bis (thiomethyl) -2-nitroethene in 12 ml of acetonitrile are refluxed for 22 hours. The solvent is removed and the residue is refluxed for 2 hours in 33% ethanolic methylamine solution. The solvents are removed and the residue is purified by column chromatography (silica / methanol) to give 310 mg of N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -Ν'-methyl-2-nitro-1 , 1-ethenediamine.

Analysis:

Calcd for C 14 H 24 N 4 O 3.1 / 2H 2 O: C 55.26 H 8.22 N 18.42 Found: C 55.54 H 8.23 N 17.75.

NMR Spectrum (CDCl3): Γ = 0.15, brm, (1H); 2.80-3.70, brm, 3.33, s, (2H); 3.85, 4.02, AB, (2H); 6.61, s, 6.40-7.50, m, (9H); 7.77, s, (6H) j 8.0-8.50, brm, (4H).

Similarly,: b) N- [5- [5- (Dimethylamino) methyl-2-furanyl] pentyl] -Ν'-methyl-2-nitro-1,1-ethylenediamine.

Analysis:

Calcd for C 15 H 2 N 4 O 3 · 1 / 2H 2 O: C 56.43 H 8.46 N 17.55 Found: C 56.76 H 8.36 N 17.37.

NMR Spectrum (CDCl3): T = 0.00, brs, (1H); 3.20 brs, (1H); 3.38, s, (1H); 3.8, 4.07, AB, (2H); 6.28, s, 6.60-7.50, m, (9H); 7.73, s, (6H); 8.00-8.80, brm, (6H).

c) N- [3 - [[5- (Dimethylamino) methyl-2-furanyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethylenediamine.

Analysis:

Calculated for C 13 H 22 N 4 O 3 S: C 49.66 H 7.05 N 17.84 Found: C 49.36 H 7.19 N 17.45.

NMR Spectrum (CDCl3): Γ = -0.50-0.00, brs, (1H); 3.20-3.60, brs, (1H); 3.37, s, (1H); 3.50, d, (1H); 3.79, d, (1H); 6.54, s, 6.60, 1, (4H); 7.08, brs, 7.17, t, (5H); 7.74, s, (6H); 8.10, m, (2H).

d) N- [3- [5- (Dimethylamino) methyl-2-furanyl] propyl] -N'-methyl-2-nitro-1,1-ethylenediamine.

Analysis:

Calcd for c13H22N4 ° 3i c 55.33. H, 7.72. Found: C, 55.09; H, 7.84.

NMR Spectrum (CDCl3): 3.38, s, (1H); 3.38, 4.02, AB (2H); 3.00-4.00, brm, (1H); 6.40-7.50, m, 6.59, s, 7.08, brm, (10H); 7.25, s, 8.00, m, (8H).

E) N- [2 - [[[5- (Diethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- methyl-2-nitro-1,1-ethylenediamine.

Analysis:

Calcd for C 15 H 2 N 4 O 3 S.1 / 2H 2 O: C 51.26 H 7.74 N 15.94

Found: C, 51.38; H, 7.44; N, 15.66.

NMR Spectrum (CDCl 3): Γ = 3.40, s, (1H); 3.75-4.00, m, (2H); 6.25, s, 6.36, s, 6.50, vbr - t in D 2 O, 7.1 brs -> s in D 2 O, 7.26, t, 7.48, 1 »(17H); 8.96, t, (6H).

f) N-13 - [[15- (Dimethylamino) methyl-2-furanyl] methyl] thio] propyl] - N'-methyl-2-nitro-1,1-ethylenediamine.

Analysis:

Calculated for C24H24N4O3S.1 / 2H2O: C 49.86 H 7.47 N 16.61

Found: C 49.57 H 7.20 N 15.59.

NMR Spectrum (CDCl 3): T-3.33, s, (1H); 3.88, s, (2H); 6.30, s, (2H); 6.55, s, (2H); 6.70, m, (2H); 7.20, br, (4H) f 7.42, t, (2H); 7.75, s, (6H); 8.20, m, (2H).

Example 23

a) N-Cyano-N '- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N' -methyl-guanidine.

0.4 g of 4- [5- (dimethylamino) methyl-2-furanyl] butanamine and 0.3 g of N-cyanoamidocarbamodithioic acid dimethyl ester are stirred in ethanol at room temperature for 3 hours. A solution of 33% methylamine in ethanol is added and the mixture is heated under reflux for 2 hours. The solvent is removed under reduced pressure and the product is purified by column chromatography (silica / methanol) to give the product in the form of a pale yellow oil.

NMR Spectrum (CDCl3): τ = 8 - 8f5 wide (4H); 7.77 s (6H) f 6.61 - 7.5 η (9H) f 4.0 m (2H); 2.8 - 3.7 m (2H).

Similarly prepared: b) N-Cyano-N '- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylguanidine.

NMR Spectrum (CDCL3): τ = 8.0 - 8.7 broad (6H) ·, 7.68 s (6H); 7.32 t (2H); 7.10 d (3H); 6.7 q (2H) ·, 6.48 s (2H); 3.8 - 4.3 m (4H).

Example 23 a) N- [2- [[in 5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N'-methanesulfonyl-N "-methylguanidine.

1.9 g of methanesulfonylimidodithiocarbamic acid dimethyl ester and 2.14 g of 2- [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine are stirred in ethanol at room temperature for 3 hours. 20 ml of 33% ethanolic methylamine are added and the mixture is refluxed for 16 hours. The product is purified by column chromatography (silica / methanol) to give 2.7 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N * methanesulfonyl -N "-methyl-guanidine in the form of a light oil.

NMR Spectrum (CDCl 3): t = 3.2, brs, (1H); 3.7, brs, 3.8, AB, (3H); 6.22, s, (2H); 6.52, s + q (4H), 7.05, s, 7.12, d, 7.25, t, (8H); 7.70, s, (6H).

Analysis:

Calcd for C 13 H 24 N 4 C> 3S2.1 / 2H2O: C 43.70 H 7.00 N 15.69 Found: C 43.54 H 7.05 N 15.48.

Similarly: b) N-benzenesulfonyl-N * - C 2 - [C C 5 - (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "-methylguanidine.

NMR Spectrum (CDCl 3): τ = 2.1, m, (2H); 2.4-2.7, m, (3H); 2.8-3.7, 2brs, (2H); 3.90, s, (2H); 6.39, s, (2H); 6.6, s, 6.7, m, (5H); 7.25, d, 7.43, m, (5H); 7.78, s, (6H).

51 149812

Analysis:

Calcd for C 18 H 26 N 4 O 3 S, H 2 O: c 50.47 H 6.54 N 13.08 Pound · C 50.30 H 6.25 N 12.93.

Example 25

N-Cyano-N '- [2 - [[i5 (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "methylguanidine.

A solution of 8.25 g of silver nitrate in 50 ml of dimethylformamide is added dropwise to a solution of 6.1 g of N-cyano-N'-methylcarbamimido-thioic acid methyl ester, 4.8 g of triethylamine and 7.8 g of 2 - [[[ 2-furanyl] methyl] thio] ethanamine in 150 ml of methanol. After 42 hours at 50 ° C, the mixture is filtered and the filtrate is evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is dried and evaporated to give an oil to give 3.9 g of crystalline N-cyano-N '- [2 - [[[2-furanyl] methyl] thio] ethyl] -Ν' ' -methylguanidine, mp 78 - 82 ° C.

A solution of 4.5 g of this amine, 3.1 g of dimethylamine hydrochloride and 3.16 g of 36% aqueous formaldehyde in 20 ml of ethanol is heated to 50 ° C for 60 hours. The residue is partitioned between ethyl acetate and aqueous base. The organic extracts are combined, dried and evaporated to give an oil, which by treatment with sebacic acid in isopropanol gives 2 g of the sebacic acid salt of the title compound, mp 93 - 94 ° C.

Example 26

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl3methyl] thio] ethyl] -N '- methylthiourea.

1.52 g of carbon disulfide is added with stirring to a cooled solution of 0.8 g of sodium hydroxide in 1.7 ml of water. 4.28 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine are slowly added and after the addition is complete the mixture is heated to 100 ° C for 2 hours.

After cooling to below 40 ° C, 1.94 ml of chloroformic acid ethyl ester is added and stirring is continued for a further 30 minutes. The lower 52- 1-49812 thick yellow oil is extracted with chloroform, dried and evaporated to give N, N-dimethyl-5 - [[[2- (isothiocyanateb) ethyl] thiojmethyl] furan methanamine as an oil, R ^ value 0.43 (silica / methanol).

Dissolve 0.46 g of the crude isothiocyanate in 25 ml of 33% ethanolic methylamine and allow to stand overnight, and N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylurea is isolated in the form of 0.16 g of light oil which is identical to the substance prepared from 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] - ethanamine and methyl isothiocyanate.

Example 27

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

A solution of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -Ν'-methylthiourea is heated under reflux with 1.5 g of lead cyanamide. The solution is filtered and the filtrate is evaporated. Treatment of the residue with a solution of sebacic acid in isopropanol gives 0.7 g of the title compound as monosebacate salt, m.p. 90 - 92 ° C.

PHARMACOLOGICAL RESULTS

The compounds of general formula I have been shown to inhibit gastric acid secretion induced by histamine. This has been demonstrated in rats using a modification of the method described by M.N. Ghosh and H.O. Schild in British Journal of Pharmacology 1958, Volume 13, page 54.

Female rats weighing approx. 150 g of suites overnight and then 8% sucrose in normal saline instead of drinking water.

The rats are anesthetized by a single intraperitoneal injection of a 25 w / v% urethane solution (0.5 ml / 100 g), and cannulae are inserted into the trachea and throat veins.

A midline incision is made in the abdominal wall to expose the abdomen which is separated from the liver and spleen by cutting the connective tissue. A small opening is made in the fundus region of the abdomen and the abdomen is washed with a 5% dextrose solution .; The esophagus is drained with a rubber tube and the oesophagus and vagi are then cut over the cannula.

A small opening is then made in the pyloric region of the abdomen.

A large perspex cannula is placed in the abdomen via the opening in the fundus region in such a way that the entrance end of the cannula exits the stomach through the opening in the pylorus region. The cannula is of such a shape that it reduces the effective volume in the stomach and that a turbulent flow is produced in the perfusion fluid over the mucosal surface. A drain cannula is then inserted through the opening in the fundus region of the abdomen. Both needles are held in place by ligatures around the abdomen so as to avoid the head blood vessels. Holes are inserted into the wall and the needles are pierced. The stomach is perfused through the oesophagus and pylorus cannula with 5% dextrose solution at 39 ° C at a rate of 1.5 ml / minute in each cannula. The effluent is passed through a microflow pH electrode and measured via a pH meter and a flat-bed recorder.

The basal amount of gastric acid secretion is determined by measuring the pH of the perfusion effector, and then increased acid secretion is induced by a continued intravenous infusion of a submaximal histamine dose; this produces a stable high level of acid secretion and the pH of the perfusion effluent is determined when this state is reached.

The test compound is then administered to the rat by intravenous injection and the change in "gastric acid" secretion is determined by measuring the change in pH in the perfusion effluent.

Based on the change in the pH of the perfusion effluent, the difference in acid secretion between the basal amount and the histamine-stimulated level is calculated as hydrogen ion concentration in mol / L. The reduction in acid secretion induced by administration of the test compound is also calculated as the change in hydrogen ion concentration in mol / L based on the difference in the pH of the perfusion effluent. The percentage reduction in acid secretion induced by administration of the test compound can then be calculated from the two values obtained.

ED 50 values for inhibition of acid secretion are determined by administering one dose of the test compound to one rat and repeating this in at least 4 rats for each of three or more dose levels. The results obtained are then used to calculate the ED ^ value by the least squares method used for any dose-response line.

Using the above-described technique, the ED ^ values listed below have been obtained:

Compound prepared according to Example No. ED 2 value, mg / kg 2 (c) 1.5 2 (d) 6.2 6 (b) 6.6 8 0.65 9 (a) 2.30 10 1.39 H (b) 3.3 14 (a) 0.23 14 (b) 3.4 14 (f) 0.8 14 (h) 0.48 14 (1) 0.59 15 2.8 2Ka) 1, 82 22 (a) 0.55 22 (c) 2.3 22 (e) 1.46 23 (b) 2.6 24 (a) 3.8 24 (b) 3.4

Claims (9)

149812 An analogous process for the preparation of aminoalkylfuran derivatives of the general formula IR \ Ϊ N-Alk- / \ - (CH2) nX (CH2) mNHCNHR3 In R2 / X ° wherein R1 and R2, which may have the same or different meaning, represents hydrogen, C1-6 alkyl, optionally with C1-6 alkyl, C1-6 alkoxy or halogen substituted phenylalkyl of 1-8 carbon atoms in the alkyl moiety or C2-6 alkyl which is interrupted by a group -Nf: L ΈΓ where R 'represents hydrogen or C ^gg alkyl, or R og and R₂ together with the nitrogen atom to which they are attached form a 5- or 10-membered saturated ring optionally containing -O- or -N (C ^ggalkyl) -, R3 represents hydrogen, C ^gg alkyl, Cg g g alkenyl or Cj_g alkoxy-C ^ g alkyl, X represents -CH₂ ~, O or S; Y represents = S, = O, = NR 5 or = CHNO 2, Alk represents a straight or branched alkylene chain of 1-6 carbon atoms, R 5 represents hydrogen, nitro, cyano, C 1-6 alkyl, g-alkylsulfonyl or phenylsulfonyl, m represents an integer from 2 to 4, and n represents 1 or 2, or when X represents S or -CH 2 -, n may further denote 0, with the proviso that Y cannot be = CHNC> 2 when R1, R2 and R 3 is methyl, Alk is methylene, X is S, n is 1, and m is 2, or physiologically tolerable acid addition salts or hydrates thereof, characterized in that a) a compound of the general formula II R N-Slk-1 O (CH2) nX (CH2) mNH2 XI R2 / wherein R1, R2, Alk, η, X and m are as defined above, react with an alkali metal cyanate or thiocyanate or an isocyanate with the general formula R3NC0 or an isothiocyanate of the general formula R3NCS or with a compound of the general formula R3NHC-U or R3NHC-U II 5 II NR CHNO 'in which formulas R3 and R5 g, and U represents a leaving group, or b) for the preparation of compounds wherein Y represents = NRS or = CHNO 2, optionally reacting an amine of general formula II with a compound of general formula UU \ / C CHNO2 or of the general formula 149812 U u \ / NR5 wherein R5 and U have the meaning given above, prepared compound of the general formula III E \ f ~ 1 XN-Alk-kn> (CH2) nX (CH2> .n, H = - 0 111 S where Q is = NR5 or = CHNO2 and U, RB, R1, R2, Alk, X, n and m have the meaning given above, react with ammonia or a primary amine with the general formula R3NH2, where R3 is as defined above, or c) to prepare compounds wherein X represents sulfur and n represents 1 and when R1 and R2 are both hydrogen, Y is different from = CHNO2, a compound of the general Formula V or VI is 1-I N-Alkyl oi 1 - cH 2 OR 7 v O o jL vi 0 where R 1 and R 2 are as defined above and R 7 is hydrogen or acyl, and wherein a primary or secondary amino group of the compound of the general formula V is optionally protected is reacted with a thiol of the general formula VII HS (CH2) NHCNHR3 VII II Y '5 wherein m and R3 are as defined above and Y * has the same meaning as Y except = CHNO 2 when R 1 and R 2 in the compound prepared are both hydrogen, if necessary followed by removal of the protecting groups, or d) for the preparation of compounds wherein Y represents a group NCN, a compound having the formula I wherein Y represents sulfur is reacted with a heavy metal cyanamide, or e) to prepare compounds where Y is = NR 5 and Alk represents methylene or branched alkylene, a compound of the general formula VIII o CH2) mHHC1 IHR3 VIII 2 '5 3 NIT 149812 where n, m, X, R3 and R5 are as defined above are subjected to Mannich reaction with an aldehyde R'CHO (where R'CH = corresponds to the group Alk) and an amine r ^ 'r ^' nh (where R1 'and R ^' have the above an- 1 o (R, except hydrogen) or a salt of an amine R 'R NH (wherein R' and R have the meaning given above), or f) for the preparation of compounds wherein Y represents sulfur , optionally prepared by reacting a compound II with carbon disulfide and then with a chloroformic acid ester compound of the general formula IV R 1 -1 N-Alk-v. IV / 0 R1 / 10 wherein R1, R1, Alk, X, m and n have the meaning given above, are reacted with an amine of the general formula R3NH2, where R3 has the meaning given above and the final product, if desired, is converted to a physiologically tolerable salt upon reaction with a physiologically tolerable, organic or inorganic acid, or a won salt is converted to another salt by reaction with a physiologically tolerable acid. Process according to claim 1, characterized in that compounds are prepared wherein R 1 and R 2 independently represent hydrogen, C 1-6 alkyl, phenyl-20 alkyl of 1-8 carbon atoms in the alkyl moiety or di- (C alkyl) amine C 1-6 alkyl, e1 is R1 ° 9 R1 together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocyclic ring of the kind set forth in claim 1, and Alk represents a straight alkyl chain with 1-4 carbon atoms. 149812 Method according to claim 1 or 2, characterized in that n + m is 3 or 4. Process according to any one of claims 1-3, characterized in that Alk represents methylene. Process according to any one of claims 1-4, characterized in that R1 is hydrogen or alkyl of 1-4 carbon atoms and R2 is alkyl of 1-4 carbon atoms. Process according to any one of claims 1-5, characterized in that R 1 and / or R 2 are methyl or ethyl. Process according to claim 1, characterized in that R 1 and R 2 independently of each other represent hydrogen, alkyl of 1-3 carbon atoms or phenylethyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidine ring, Alk represents a alkyl represents a chain of 1-3 carbon atoms, Y represents = S, = CHNO 2 or = NR 5, where R 5 represents nitro, cyano, methylsulfonyl or phenylsulfonyl, R , n + m denotes 3 or 4. Process according to claim 1, characterized in that R 1 and R 2 independently represent hydrogen, alkyl of 1-3 carbon atoms, phenylethyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidine ring, Alk represents alkylene having 1-3 carbon atoms, Y represents = S, = CHNO 2 or = NR 5, where R 5 represents nitro, cyano, methylsulfonyl or phenylsulfonyl, X represents S or -CF 2 -, R 3 represents hydrogen, methyl or methoxyethyl, n denotes 1, and m denotes 2 or 3. Process according to claim 1, characterized in that R 1 represents hydrogen, methyl or ethyl, R 2 represents methyl or ethyl, Alk represents methylene, Y represents = NCN, = NNO 2 or = CHNO 2, R 3 represents hydrogen or methyl, X represents S or -Cl ·, n represents 1, and m represents 2.